[The use of narcotic analgesics in primary care in Spain (1988-1991). An evaluation of the impact of new technologies in the pharmaceutical sector]. To analyse the results of the policy of encouraging rational use of analgesics in Spain. Longitudinal retrospective and observational study, on the exhaustive information deriving from the filling out of Analgesic Extra-therapeutic Dose notebooks. SITE. Primary Care treatment of terminal oncological patients carried out basically in the Province of Barcelona. All treatments carried out under the extra-therapeutic dose notebook during the last quarter of 1988 and the first quarters of 1989, 1990, and 1991. Revision of initial treatment, change of medication and posology and returns on the basis of the extensive documentation generated. Consumption has risen from 157 authorized cases in 1989 to 404 in 1991. Consumption has increased sharply, although the opinion that such analgesics are under-used still predominates. Along with the quantitative increase there has been a corresponding deterioration in the rationale informing use and control, both medically (patterns of treatment, excesses) and socially (cost effectiveness, fair allocation). The evaluation in force before the advent of new technology and policies should be reinstated if we wish to achieve the desired level of effectiveness, adapting national health care by coordinating social and health care and bringing up to standard the training and supply of information to health workers. It is suggested that a "Consensus" Conference should be organised to bring up to date the basis on which analgesics are used and regulated.


The effect of H2-blockade on plasma gastrin concentration in patients with an achlorhydric stomach. The mechanisms of hypergastrinaemia during H2-receptor antagonist therapy remain unclear. In addition, the effect of food stimulation in conditions of hypergastrinaemia is poorly understood. These effects may be important when considering long-term therapy with potent acid inhibitory agents. To investigate this we studied the effect of H2-receptor antagonist therapy on basal and meal-stimulated plasma gastrin concentrations in 9 patients with pentagastrin fast gastric achlorhydria associated with pernicious anaemia. The subjects received in double-blind randomized fashion 28-day courses of 300 mg ranitidine q.d.s. and placebo, with one-month wash-out between. The fasting and peptone meal-stimulated gastrin concentrations were studied on the final day of each course of treatment. The median fasting gastrin concentrations (ng/L) were similar following placebo (1100, range 25-2100), and 300 mg ranitidine q.d.s. (1075, range 15-2600) and both markedly elevated when compared with our laboratory's normal range of 0-100. Despite the elevated basal levels the pernicious anaemia patients still showed a further increase in response to the peptone meal. Their median peak percentage rise over basal in response to the meal was similar following placebo (96%, range 0-375) and 300 mg ranitidine q.d.s. (100%, range 25-425) (both P less than 0.02 c.f. basal). This study shows that: (a) in hypergastrinaemia in pernicious anaemia subjects, meal stimulation leads to a marked and prolonged increase in plasma gastrin concentrations; (b) H2-receptor antagonists have no effect on plasma gastrin in the neutral stomach and this is consistent with their gastrin effect being entirely secondary to acid inhibition.


Cyclic GMP modulators on vascular adrenergic neurotransmission. The presence of the endothelium reduced the sensitivity of isolated rabbit carotid artery to endogenous norepinephrine released by electrical stimulation of adrenergic nerves or displaced by tyramine and to exogenously applied norepinephrine, phenylephrine and UK 14304. The maximal contractions induced by the selective alpha 2-agonist UK 14304 were much more profoundly depressed in arteries with endothelium than those induced by the nonselective alpha-adrenoceptor agonist norepinephrine or by the selective alpha 1-agonist. LY 83583, a cyclic-guanosine-monophosphate (GMP)-lowering agent, abolished the endothelium-dependent depression of tone induced by the agonists and converted the sensitivity of arteries with endothelium to that of endothelium-denuded preparations. M & B 22948, a selective cyclic GMP phosphodiesterase inhibitor, significantly inhibited contractions caused by electrical stimulation of adrenergic nerves, tyramine, norepinephrine and UK 14304 in rings with, but not in those without, endothelium. Yohimbine, an alpha 2-adrenoceptor antagonist, increased contractions caused by UK 14304 in rings with endothelium only, but had no significant effect on the contractions caused by exogenously applied norepinephrine or phenylephrine. In the presence of prazosin, an alpha 1-blocker, UK 14304 caused minimal relaxation (about 20%) in rings with endothelium only which were inhibited by yohimbine, suggesting a minor role of direct endothelial cell alpha 2-mediated release of relaxing factors. The over-flow of endogenous norepinephrine caused by electrical stimulation was not affected by treatment with LY 83583 or M & B 22948, suggesting that altering cyclic GMP levels has no major role in prejunctional modulation of norepinephrine release. These findings support the notion that intrinsic levels of cyclic GMP may act as a regulator of adrenergic neurotransmission due primarily to endothelium-derived relaxing factor which is released basally, and to a lesser extent by an activation of endothelial cell alpha 2-adrenoceptors.


Protein kinase C as a mediator of TSH and thyroid autoantibody action. Although it is well-established that TSH activates a cAMP-dependent pathway in the thyroid follicular cell leading to thyroid hormone synthesis and release, the present review provides new evidence that TSH also activates a non-cAMP-dependent signal transduction system. This cascade involves phosphoinositide (PI) turnover, diacylglycerol accumulation and protein kinase C (PKC) activation. Activation of this pathway leads to an inhibition of differentiated thyroid function in vitro. Recent evidence suggests that TSH can activate both pathways via a single transcription unit. Unlike TSH, TSH-receptor antibodies may selectively activate cAMP with no effects on PI turnover. In contrast, preliminary studies suggest TSH-blocking antibodies may activate PKC. PKC may be an important mediator of TSH and, possibly, thyroid autoantibody action.


Micromanipulation of adhesion of phorbol 12-myristate-13-acetate-stimulated T lymphocytes to planar membranes containing intercellular adhesion molecule-1. This paper presents an analytical and experimental methodology to determine the physical strength of cell adhesion to a planar membrane containing one set of adhesion molecules. In particular, the T lymphocyte adhesion due to the interaction of the lymphocyte function associated molecule 1 on the surface of the cell, with its counter-receptor, intercellular adhesion molecule-1 (ICAM-1), on the planar membrane, was investigated. A micromanipulation method and mathematical analysis of cell deformation were used to determine (a) the area of conjugation between the cell and the substrate and (b) the energy that must be supplied to detach a unit area of the cell membrane from its substrate. T lymphocytes stimulated with phorbol 12-myristate-13-acetate (PMA) conjugated strongly with the planar membrane containing purified ICAM-1. The T lymphocytes attached to the planar membrane deviated occasionally from their round configuration by extending pseudopods but without changing the size of the contact area. These adherent cells were dramatically deformed and then detached when pulled away from the planar membrane by a micropipette. Detachment occurred by a gradual decrease in the radius of the contact area. The physical strength of adhesion between a PMA-stimulated T lymphocyte and a planar membrane containing 1,000 ICAM-1 molecules/micron 2 was comparable to the strength of adhesion between a cytotoxic T cell and its target cell. The comparison of the adhesive energy density, measured at constant cell shape, with the model predictions suggests that the physical strength of cell adhesion may increase significantly when the adhesion bonds in the contact area are immobilized by the actin cytoskeleton.


The effect of second-line antirheumatic drugs on interleukin-8 mRNA synthesis and protein secretion in human endothelial cells. Interactions between interleukin 8 (IL-8) and endothelial cells play an important role in the emigration of mononuclear cells from the blood into areas of inflammation. We examined the ability of specific second-line antirheumatic drugs to regulate (IL-8) gene expression and protein secretion in interleukin 1 (IL-1) stimulated human umbilical vein endothelial cells and peripheral blood mononuclear cells. The drugs sodium aurothiomalate, D-penicillamine and sulphasalazine were all able to modulate IL-8 mRNA synthesis in and protein secretion from endothelial cells. A bimodal effect was observed: at low concentrations IL-8 was suppressed, whereas higher concentrations resulted in an increased IL-8 production. In endothelial cells, treatment with hydrocortisone led to a linear suppression of IL-8 production in concentrations ranging from 0.5 micrograms/ml up to 500 micrograms/ml. Sulphapyridine, auranofin, hydroxychloroquine and methotrexate, had no effect on IL-8 secretion in endothelial cells. By contrast, 5-aminosalicylic acid induced a threefold increase in the IL-8 release. In peripheral blood mononuclear cells it was only possible to suppress the IL-8 production by hydrocortisone treatment. These results indicate that suppression of IL-8 production in endothelial cells could be an important factor in the mode of action for a number of second-line antirheumatic drugs.


Systemic hyperthermia in the treatment of HIV-related Kaposi's sarcoma. A phase I study. Ten Caucasian males with HIV-related Kaposi's sarcoma, a disseminated disease which is refractory to usual therapies, underwent a single session of systemic hyperthermia with maintenance of core temperatures at 42 degrees C for 1 h. One complete remission and 7 partial remissions were identified when assessed 30 days post-treatment. Two mixed responses were noted in patients whose tumors showed autocrine growth. At 60 days 2 of the 7 partial responders began to show tumor progression. The complete remission persisted at 120 days. Surrogate markers of HIV activity fell in all responding patients. In no patient was there evidence of HIV activation. No adverse effects of heating were noted on CMV retinitis. Hairy leukoplakia resolved with heating in all patients. CD4 counts showed no appreciable change in any of the 8 patients with a presenting CD4 count below 60. In the 2 patients who presented with a CD4 count above 400, CD4 counts rose dramatically following treatment. No deaths were noted in this phase I study. The use of systemic hyperthermia in treatment of HIV-related illness warrants further study.


Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses. The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg.


The metabolism of CGS 15873 in man using stable isotope pattern recognition techniques. CGS 15873 is a relatively specific dopamine agonist with preferential activity at the presynaptic autoreceptor and therefore may represent a novel agent for the treatment of schizophrenia and/or Parkinson's disease. Several metabolites have been identified in the rat and monkey using an isotopically enriched dosing solution and pattern recognition techniques coupled with GC/MS and LC/MS. In this study, the metabolism of CGS 15873 was investigated in man using these same techniques. In urine, specific isotope clusters were found that matched the dosing solution pattern. Three metabolites were identified: an O-glucuronide conjugate of the parent drug, N-despropyl CGS 15873, and a keto metabolite of CGS 15873. Thermospray LC/MS allowed for the direct confirmation of the conjugated metabolite. GC/MS required derivatization but afforded greater sensitivity compared to LC/MS.


Immunoprecipitation of a pertussis toxin substrate of the G(o) family from rat islets of Langerhans. Rat islets express a pertussis toxin sensitive G-protein involved in receptor-mediated inhibition of insulin secretion. This has been assumed previously to represent "G(i)" which couples inhibitory receptors to adenylate cyclase. Incubation of islet G-proteins with 32P-NAD and pertussis toxin resulted in the labelling of a band of molecular weight 40,000. This band was very broad and did not allow resolution of individual components. Incubation of the radiolabelled proteins with an anti-G(o) antiserum resulted in specific immunoprecipitation of a 32P-labelled band. These results demonstrate that the complement of pertussis toxin sensitive G-proteins in rat islets includes G(o).


Upregulation of HLA class II, but not intercellular adhesion molecule 1 (ICAM-1) by granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin-3 (IL-3) in synergy with dexamethasone. In this study we have compared the effects of granulocyte macrophage colony stimulating factor (GM-CSF) on purified normal blood monocytes, with two other haemopoietic growth factors, Interleukin (IL-) 3 and Macrophage (M-)CSF on HLA class I, class II and intercellular adhesion molecule 1 (ICAM-1) expression in the presence and absence of dexamethasone (Dex). IL-3 alone, like GM-CSF, was a weak inducer of HLA class II expression but in combination with Dex markedly enhanced HLA-DR, DP and DQ expression. Similar changes were observed for HLA class I expression. The response to both IL-3 and GM-CSF was not additive in the presence of an optimal concentration of one cytokine and titrating concentrations of the other indicating that they may use common receptors and signal transduction mechanisms. Although IL-3 or GM-CSF alone also enhanced ICAM-1 expression, Dex inhibited both constitutive and the cytokine induced expression of this antigen. In contrast M-CSF, in the presence or absence of Dex, failed to enhance ICAM-1, HLA class I or II expression. These observations further highlight differences between the effects of the haemopoietic growth factors GM-CSF and IL-3 versus M-CSF in the regulation of monocyte function. Finally, the distinct effect of a combination of glucocorticoids with GM-CSF or IL-3 to induce high levels of HLA expression on human monocytes suggests they may have an important role during inflammatory conditions in vivo.


Prolonged infusion of varied doses of dopexamine hydrochloride for low cardiac output after cardiac surgery. Circulatory failure after cardiac surgery often calls for active hemodynamic management with fluids, inotropes, and vasodilators. Dopexamine hydrochloride is a new combined beta 2-adrenergic and DA1-dopaminergic receptor agonist and an inhibitor of the uptake-1 mechanism of endogenous catecholamines. As a result, it exerts inotropic and vasodilator effects on the heart and systemic vasculature. The effects were examined over a mean of 22 hours, using 1 to 4 micrograms/kg/min of dopexamine to treat low cardiac output states following coronary bypass and valvular/ventricular repair surgery. In 8 out of 14 patients, low cardiac output was readily reversed by 1 microgram/kg/min of dopexamine. Six patients required higher doses (2 to 4 micrograms/kg/min) to achieve a satisfactory cardiac index. Significant changes from control values were observed throughout the infusion for heart rate (67 to 102 beats/min), cardiac index (2.0 to 3.4 L/min/m2), and systemic vascular resistance (1,545 to 914 dyne.s.cm-5). Pulmonary vascular resistance, pulmonary artery wedge pressure, and right atrial pressure were also significantly reduced during the infusion. Most of these changes reversed when dopexamine was discontinued, suggesting a drug-specific effect and a lack of tolerance. Nausea was a frequent complaint, but was no more frequent than in a random sample of similar patients. Titration of dopexamine, 1 to 4 micrograms/kg/min, was efficacious in producing circulatory improvement in patients with a low cardiac output after cardiac surgery.


Retinal on-bipolar cells contain a nitric oxide-sensitive guanylate cyclase. Retinal on-bipolar cells possess specialized glutamate receptors which are coupled via a G-protein to the control of a cyclic GMP (cGMP) cascade. Whole-cell voltage clamp recordings were obtained from light-responsive on-bipolar cells in retinal slices of the dogfish. Inclusion of nitroprusside in the patch-pipette solution induced effects in on-bipolar cells which were consistent with a rise in intracellular cGMP and thus stimulation of guanylate cyclase (GC) activity. Conversely, the soluble GC inhibitors, methylene blue and ferricyanide, induced effects consistent with a fall in intracellular cGMP. Activators of particulate GC had no effect. We conclude that cGMP synthesis in on-bipolar cells is catalysed by a NO-sensitive cyclase.


Enrichment of glutamate in zinc-containing terminals of the cat visual cortex. The presence of glutamate and GABA was examined in zinc-containing terminals of the cat visual cortex using a post-embedding immunogold method. The surface density of immunogold-labelling was also evaluated in morphologically defined ultrastructural elements, namely terminals having round synaptic vesicles and making asymmetrical synapses (RA boutons), terminals with flat vesicles and symmetrical synapses (FS) and glial cell processes. Glutamate immunoreactivity was highest in RA terminals and in zinc-containing boutons. It was lower in FS terminals and lowest in glial cell processes. GABA immunoreactivity was highest in FS terminals and low in all other ultrastructural elements analysed, including zinc-containing terminals. Therefore, zinc-containing terminals show an enrichment of glutamate and they are likely to use this amino acid as their neurotransmitter. Moreover, the fact that many RA terminals that are negative for zinc show an enrichment of immunoreactive glutamate suggests that zinc-containing fibres represent a subpopulation of the glutamate axonal network.


Cholecystokinin is released from a crossed corticostriatal pathway. The release of striatal cholecystokinin, glutamate, aspartate and dopamine was studied in vivo with microdialysis in decorticated rats, with or without callosotomy. Unlesioned rats were also analysed. Unilateral decortication produced a unilateral decrease in K(+)-stimulated extracellular striatal glutamate and aspartate levels, without decreasing cholecystokinin or dopamine levels. However, following decortication plus callosotomy, basal and K(+)-stimulated extracellular cholecystokinin and glutamate levels were significantly decreased in the striatum ipsilateral to side of decortication. Aspartate levels were bilaterally decreased. These results give evidence for the existence of crossed corticostriatal projections containing releasable cholecystokinin and glutamate.


Antianxiety properties of the angiotensin II antagonist, DUP 753, in the rat using the elevated plus-maze. The angiotensin II receptor antagonist, DUP 753 (Losartan), was compared with diazepam for antianxiety properties in the rat using the elevated plus-maze. Oral diazepam (5 mg kg-1) resulted in a significantly greater number of entries of rats into the open arms of the maze, an increase in time spent in the open arms and a decreased time spent in the closed arms. Oral doses of DUP 753 likewise resulted in significantly greater numbers of entries into the open arms (active at 0.0001, 0.001, 0.01 and 0.1 mg kg-1), increased time spent on the open arms (active at 0.0001-0.01 mg kg-1) and a decreased time spent in the closed arms (active at 0.0001, 0.01 and 0.1 mg kg-1). Larger (1.0 mg kg-1) or smaller (0.00001 mg kg-1) doses of DUP 753 were not active.


Differential distribution of gamma-glutamyl cycle molecules in the vomeronasal organ of rats. Molecules related to the gamma-glutamyl cycle, including thiols, glutathione (GSH) and gamma-glutamyl transpeptidase (gamma-GT) were identified histochemically and immunohistochemically in the vomeronasal organ of neonatal and adult rats. Thiols and GSH were distributed in the mucomicrovillar complex (MMC), vomeronasal receptor neurons and acinar cells of vomeronasal glands (VNG). gamma-GT was localized in the MMC and in the VNG, where it was associated mainly with the luminal surface of the acinar cells and ducts. The VNO of the neonates exhibited higher staining intensities for all compounds than that of the adults. The data indicate that components of the gamma-glutamyl cycle are present in the VNO and that they are secreted into mucus, where they may be associated with perireceptor events including clearance of pheromones and detoxification of xenobiotics.


Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons. We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.


Calcium dynamics in neurons treated with toxic and non-toxic concentrations of glutamate. Intracellular calcium concentration ([Ca2+]i) dynamics were simultaneously monitored in multiple cultured rat neurons loaded with Fluo-3 and continuously stimulated with glutamate (GLU). Three response types were observed: 10 microM GLU caused an initial transient increase in [Ca2+]i; 20 microM a biphasic response characterized by a 150-350 s 'calcium trough' between peaks; and 40 microM an initial sustained increase in [Ca2+]i. Neurons in calcium-free medium treated with 40 microM GLU showed only an initial transient increase in [Ca2+]i, demonstrating the dependence of sustained secondary increases in [Ca2+]i on extracellular calcium sources. We observed synchronized responses of multiple neurons within a given culture well, after GLU treatment, supporting the hypothesis that sustained influx of extracellular calcium may be stimulated by depletion of intracellular calcium and/or the release of endogenous excitatory amino acids.


[Somatostatin as a modulator of vagal effects on heart rhythm]. In 11 experiments on anesthetised cats burst stimulation of peripheral cut end of right vagus nerve leads to synchronization of cardiac and vagus rhythms. Alterations of burst sequence frequency within definite limits has been synchronously reproduced by heart thus creating managed bradycardia possibility. Somatostatin (10(-8)-10(-9) M intravenously) decreases heart rate and inhibits total vagus chronotropic effect. Vagolytic effect of somatostatin caused a decrease of tonic component of the vagus chronotropic effect. On the other hand, somatostatin augmented the extent of the vagal synchronizing influences and caused enlargement of the ranges of managed bradycardia. The observed results testify to participation of the peptidergic mechanisms in genesis of vagal managed bradycardia.


[Different effects of typical and atypical neuroleptics on K+-stimulated dopamine release from isolated rat striatum]. Effects of haloperidol (10(-7)-alpha 10(-5) M), trifluoperazine, metoclopramide, tiapride, sulpiride, thioridazine, clozapine remoxipride, raclopride, cis- and trans-isomers of carbidine, SCH 23390 (all at the 10(-6) M) on the K(+)-stimulated (28 mM) dopamine (DA) release from isolated rat striatum were studied. Haloperidol at the concentration of 10(-7) and 10(-6) M failed to affect, while at 10(-5) M the drug decreased the stimulated striatal DA release. Trifluoperazine, metoclopramide and tiapride were shown not to modify this process. Sulpiride, thioridazine, clozapine, remoxipride, raclopride, isomers of carbidine were found to increase significantly the stimulated striatal DA release. SCH 23390 failed to affect K(+)-stimulated release of DA in the striatum and also did not change K(+)-stimulated release enhancement produced by raclopride. It is suggested that the mechanism underlying observed effects of the drugs may contribute to pharmacological profile of atypical neuroleptics.


Antilymphocytic antibodies and marrow transplantation. XII. Suppression of graft-versus-host disease by T-cell-modulating and depleting antimouse CD3 antibody is most effective when preinjected in the marrow recipient. A hamster antimouse CD3 monoclonal antibody (MoAb) opened the way to experimental studies on the suppression of allograft rejection and cytokine-related morbidity after treatment with antibodies modulating the CD3/T-cell receptor complex (CD3/TCR). Because earlier attempts to suppress graft-versus-host disease (GVHD) in patients by in vitro treatment of donor marrow with anti-CD3 MoAb had remained inconclusive, we used a rat IgG2b antimouse CD3 MoAb (17A2) with fewer side effects to analyze suppression of GVHD in the mouse model. Detailed phenotyping of blood, spleen, and lymphnode T cells after the injection of 400 micrograms 17A2 in C57BL/6 mice showed 60% CD3 downmodulation and 50% T-cell depletion for spleen cells. Injection of these spleen cells, together with bone marrow cells, in fully mismatched preirradiated CBA mice delayed GVHD by only 6 days. Ex vivo treatment of donor cells with 17A2 was not effective. In contrast, conditioning of marrow recipients with a single injection of 17A2 delayed 50% GVHD mortality by 100 days and prevented GVHD altogether after prolonged treatment, with survivors showing complete chimerism and specific transplantation tolerance. This difference in antibody effect contrasts with earlier experiences with nonmodulating but more strongly T-cell-depleting MoAbs of the same isotype, which prevent GVHD no matter whether applied in vitro or injected into donor or recipient mice. Our data indicate that CD3/TCR reexpression in marrow recipients with no circulating 17A2 is the reason why ex vivo donor cell treatment with anti-CD3 MoAb is comparatively ineffective. Our data, which allow separate evaluation of cell-depleting and cell-modulating antibody activity, help to explain previous clinical failure to suppress GVHD and provide evidence in favor of conditioning the marrow recipient with anti-CD3 MoAb as a therapeutic alternative.


A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia. Twenty-six patients with hairy cell leukemia (HCL) were treated with 2-chlorodeoxyadenosine (2-CdA), a purine analogue resistant to adenosine deaminase, at 0.1 mg/kg/d for 7 days by continuous intravenous infusion. Fifteen patients were previously untreated, while 11 patients had received prior treatment with splenectomy alone (three patients), interferon alpha alone (four), splenectomy, then interferon alpha (two), or splenectomy, interferon alpha, then 2-deoxycoformycin (2-DCF) (two). Sixteen (80%) of 20 patients evaluable at 3 months achieved complete remission (CR), and four (20%) achieved partial remission (PR) following a single cycle of therapy. All four patients in PR had complete recovery of their peripheral blood counts (except one patient whose platelet count remained 84,000/microL), but had residual HCL in the bone marrow (three patients) or residual splenomegaly (one). Patients with bulky adenopathy, massive splenomegaly, and severe pancytopenia responded as well as those with only modest marrow involvement. The three patients with residual marrow disease received a second cycle of 2-CdA, and two have attained CR. Therefore, 18 of 20 (90%) achieved CR with either one or two cycles of therapy. No patient achieving CR has relapsed at a median follow-up of 12 (+/- 2.1) months. Toxicities included myelosuppression and culture-negative fever. A community-acquired pneumonia was the only infectious complication. Since a single cycle of 2-CdA induces sustained CR in the vast majority of patients with minimal toxicity, this agent is emerging as the treatment of choice for all patients with HCL.


Taxol: a review of its preclinical in vivo antitumor activity. Taxol has been demonstrated in numerous laboratories worldwide to have broad-spectrum antitumor activity against many tumor models. The susceptible tumors include murine leukemias and solid tumors, and human solid tumor xenografts. The initial findings of taxol's ineffectiveness against most distal site tumor models was probably a consequence of the insolubility of taxol in nearly all the vehicles used in those early studies. On the occasions when an ethanol-based vehicle was used to dissolve taxol, substantial distal site antitumor activity was observed. Although no definitive schedule dependency data have evolved, once-a-day or every-other-day i.v. injections for several treatments have proved to be reproducibly effective in stringent s.c. tumor models. Attempts to discern a therapeutically synergistic cytotoxic drug combination was made on two occasions without success. In the manner evaluated, taxol plus either adriamycin, cisplatin, cyclophosphamide or etoposide (VP-16) were not meaningfully more efficacious than the more effective drug in each of those combination settings.


Seasonality, biting cycle and parity of the yellow fever vector mosquito Haemagogus janthinomys in Trinidad. 1. Age composition, seasonal abundance and diel patterns of landing activity of the sylvan vector of yellow fever Haemagogus janthinomys Dyar were monitored weekly during 1981-82 by human collectors on the ground at Point Gourde in Chaguaramas Forest, 16 km west of Port of Spain, Trinidad. 2. Landing collections of Hg. janthinomys showed only diurnal activity, from 06.00 to 18.00 (sunrise to sunset, universal time), with a single peak of activity between 10.00 and 16.00 hours. 3. Densities of Hg. janthinomys were about 6 times greater during the wet season (May-November) than during the dry season (December-April); the annual Williams' mean landing rate on two collectors was 9.3 per day. 4. Monthly parous rates averaged 59% (range 0-86%) and some females were up to seven-pars. Retained eggs (range 1-21, mean 7.7/female) were found in the ovaries of 1.3% of landing females, all of which had stage I ovarian follicles for the next gonotrophic cycle. Hence blood-feeding is not inhibited by egg retention, which might promote transovarial transmission of virus. Implications of these findings are discussed in relation to yellow fever epidemiology.


The susceptibility of the mosquitoes Aedes notoscriptus and Culex annulirostris to infection with dog heartworm Dirofilaria immitis and their vector efficiency. The mosquitoes Aedes notoscriptus (Skuse) and Culex annulirostris Skuse were fed on a dog infected with Dirofilaria immitis (Leidy) and a blood parasite count of approximately 5000 microfilaria per ml. Cx annulirostris ingested almost 4 times as much blood and almost 4 times as many microfilariae as Ae.notoscriptus (mean 26.0 compared to 6.6). Attrition of the filarial numbers occurred primarily within the midgut during the first 24 h following ingestion and was greater in Cx annulirostris than Ae.notoscriptus. Aedes notoscriptus sustained development of almost 8 times as many third-stage infective larvae as Cx annulirostris (mean of 3.8 compared to 0.5), and thus had a vector efficiency index of 57.6 compared to 1.9 for Cx annulirostris. In a series of investigations Ae.notoscriptus has now been shown to be an important vector for dog heartworm in southern Australia and may be a significant factor in the apparent burgeoning of the disease.


Effects of Toxorhynchites moctezuma larval predation on Aedes aegypti populations: experimental evaluation. Predatory larvae of the mosquito Toxorhynchites moctezuma were used experimentally to control a standing crop of larvae of the dengue vector mosquito Ae.aegypti. Each week, fifty Ae.aegypti first instar larvae were introduced to each of five water-filled drums (220 litres) of the type commonly used for domestic water storage in Caribbean dwellings. At the beginning of the fourth week, a certain number (0, 1, 2, 5 or 10) of first instar Tx.moctezuma larvae were introduced to each drum and the daily yield of Ae.aegypti adults from each drum was monitored thereafter. The experiment was repeated three times. With only one or two Tx.moctezuma larvae, predation on Ae.aegypti larvae stopped the output of Ae.aegypti adults for 1 week. Five or ten Tx.moctezuma prevented any Ae.aegypti emergence for up to 16 weeks. Cannibalism among Tx.moctezuma larvae was seldom observed and appeared not to be a hindrance in using this species against Ae.aegypti. Thus Tx.moctezuma is regarded as a good candidate for the biological control of Ae.aegypti by augmentative releases.


Suppression of Aedes aegypti by predatory Toxorhynchites moctezuma in an island habitat. Larval populations of the mosquito Aedes aegypti were suppressed by predatory Toxorhynchites moctezuma mosquito larvae released systematically in a village on Union Island (Saint Vincent and the Grenadines) during March-December 1988. Eggs and larvae of Tx.moctezuma were transported from Trinidad and introduced into all semi-permanent and permanent water-holding containers in the experimental village at Clifton. The semi-isolated village of Ashton served as control. Base-line Ae.aegypti indices (house, ovitrap, Breteau, cistern/tank, drum/barrel, small containers) were obtained for the two villages over a 4-month period prior to the introduction of the predatory Tx.moctezuma mosquito larvae. After sustained releases of predators for 5 months, all indices of Ae.aegypti were lower in the treated village than in the untreated village during the last 3 months of the year.


Laboratory evaluation of Toxorhynchites splendens (Diptera: Culicidae) for predation of Aedes albopictus mosquito larvae. Biology of the mosquito Toxorhynchites splendens (Wiedemann) was studied in the laboratory to provide baseline data for using the predatory larvae of this species against those of Aedes albopictus (Skuse) in a biological control programme. The mean incubation time of Tx.splendens eggs was 43.8 h and the time required for newly-hatched larvae to initiate predation was 2.5 h. Mean numbers of prey larvae consumed and killed by each Tx.splendens larva totalled 389 and 345 respectively. The larval period of Tx.splendens was not significantly different for rearing individually or in groups of nine, with equal prey density, and duration of larval development was proportional to prey density. In mass rearing, larval cannibalism was usually observed during days 1-3 post-eclosion. The incidence of cannibalism decreased sharply on the fourth day after hatching when some larvae became fourth-instar. Adult female Tx.splendens usually commenced oviposition on day 4 after emergence. The number of eggs laid daily increased on day 7 and the peak oviposition of 6.3 eggs/female/day occurred on day 11. When oviposition containers were provided only intermittently, gravid females of Tx.splendens scattered most of their eggs on the dry floor of the cage. Viability of eggs laid by females aged 4-14 days was high (60-90%) but decreased to less than 40% as the females aged.


Biological control of container-breeding mosquitoes, Aedes albopictus and Culex quinquefasciatus, in a Japanese island by release of Toxorhynchites splendens adults. To control container-breeding mosquitoes in the small island of Minnajima (0.56 km2), northern Okinawa, Japan, laboratory-reared adults (aged 7-10 days) of Toxorhynchites splendens (Palawan strain), a mosquito with predatory larvae, were released repeatedly during 1984, 1986 and 1987. Thirteen species of mosquitoes (Diptera: Culicidae) occurred in artificial containers, ground pools or crab-holes on the island, the predominant species being Aedes (Stegomyia) albopictus and Culex (Culex) quinquefasciatus. Predatory mosquito larvae of Culex (Lutzia) fuscanus and Cx (Lt.) halifaxii were found commonly in wet containers. In the first year of study, during a period of 54 days from 13 May to 5 July 1984, totals of 879 female and 806 male adults of Tx.splendens were released on six occasions. Similarly, between 29 April and 30 August 1986, totals of 2920 female and 2878 male adult Tx.splendens were released. In the third study year, totals of 2041 female and 1783 male Tx.splendens were released on eight occasions during 199 days from 23 April to 7 November 1987. After adult releases at two sites, the immature stages of Tx.splendens were found in 164 out of 502 traps in 1984, 421 out of 933 traps in 1986, and 151 out of 502 traps in 1987. The number of immatures of Tx.splendens present in each trap varied from 1 to 40 in 1984, 1 to 29 in 1986 and 1 to 9 in 1987. Numbers of immatures of the target species found in the traps during August-September averaged 71.9/trap/month in 1984, 114.7/trap/month in 1986 and 36.0/trap/month in 1987, significantly less in the traps with Tx.splendens than in those without them. The present field studies indicated that, in this small island, approximately 250 adult female and 200 male Tx.splendens per month should be released from April to November, and the releases should be carried out every year, in order to control effectively the target mosquitoes Ae.albopictus and Cx quinquefasciatus breeding in artificial containers in Minnajima.


Talpid2 limb bud mesoderm does not express GHox-8 and has an altered expression pattern of GHox-7. We have studied the expression patterns of the chick homeobox-containing genes, GHox-7 and GHox-8, in the talpid2 (ta2) chick mutant whose limbs have abnormal pattern. These studies provide new insight into how homeobox gene expression and limb patterning may be related. This is the first study demonstrating a natural change in GHox-7 and GHox-8 along the anteroposterior axis. While GHox-7 is expressed asymmetrically in normal limb buds, it is expressed at a uniform level across the anteroposterior axis of ta2 limb buds. GHox-8 is expressed in anterior mesoderm of normal limb buds, but is undetectable in ta2 limb bud mesoderm. These data are consistent with the subtle anteroposterior polarity in ta2 limbs, and allow us to propose that ta2 limb buds lack anterior positional information, but have a narrow range of posterior positional values. We suggest that in normal limb buds GHox-8 may establish the anterior limb bud boundary. Furthermore, we point out that coexpression of GHox-7 and GHox-8 in normal anterior limb bud mesoderm can be correlated with the reduced apical ridge maintenance activity of this tissue, while the lack of coexpression in ta2 limb buds is correlated with the strong ridge maintenance activity in the mutant's anterior limb bud mesoderm. Last, ta2 limbs contain no dying cells in their anterior and posterior border mesoderm; nevertheless, they express GHox-7 in these regions. These data challenge the proposal that this gene determines cell death.


Laparoscopic orchiectomy for cryptorchidism. A 28-year-old man was admitted for removal of an undescented testis. The operation was performed via the laparoscopic approach. Laparoscopy has for years been recommended for locating the intraabdominal testis. Therapeutic laparoscopy is gaining increased popularity and this brief report shows that an intraabdominal testis can be easily removed via the laparoscope.


Balloon tamponade and vasoactive drugs in the control of acute variceal haemorrhage. Successful pharmacological arrest of haemorrhage might avoid the risk of aspiration associated with tamponade and early studies have suggested that the vasoactive agent somatostatin may be as effective and perhaps safer than tamponade in controlling variceal haemorrhage. In our view, vasopressin has not established a role in management but we retain an open mind regarding the potential use of terlipressin in combination with nitroglycerin. It is unlikely that any of these agents can improve significantly our ability to control variceal haemorrhage when compared to balloon tamponade but they may reduce the incidence of pulmonary complications and thereby reduce subsequent mortality. Tamponade has proved successful in controlling acute haemorrhage from oesophageal varices in our hands. Late complications continue to give cause for concern but until effective safe alternatives to tamponade are developed, we continue to advocate its use for emergency control of acute variceal haemorrhage. Our own studies have shown that the high mortality seen in this patient population may reflect the severity of the underlying liver disease rather than failure of a management policy employing oesophageal tamponade for the initial control of acute variceal haemorrhage.


Prophylaxis of first variceal bleeding.

Prophylaxis of first variceal bleeding. Surgical, endoscopic and pharmacological treatment options are available for prophylaxis of first upper intestinal haemorrhage in cirrhotic patients. Randomized controlled trials have revealed that a prophylactic portocaval shunt operation should not be performed because its beneficial effect on the bleeding rate is outweighed by a slightly increased mortality. Prophylactic portal non-decompressive surgery (mainly gastro-oesophageal vascular disconnection) has been shown to reduce the bleeding rate and mortality in Japanese cirrhotic patients. However, further trials in different populations must confirm this positive effect. beta-blockers have fewer side-effects and are probably more effective for prophylaxis of the first bleed than sclerotherapy, but survival is only marginally influenced. Nadolol is preferable to propranolol. The effect of sclerotherapy is in part related to the technical experience of the physician. Although sclerotherapy has only minor effects on the bleeding rate, it is associated with a trend towards a prolonged survival. This may be caused by non-specific effects. On the basis of the published trials, only preliminary recommendations can be given. Prophylactic treatment may be useful in cirrhotic patients who are at high risk of bleeding. Life quality may be improved with continuous beta-blocker treatment. Some studies suggest that alcoholics with large varices may also profit from regular prophylactic sclerotherapy performed by experienced physicians.


Recent developments in the pathophysiology and treatment of hepatic encephalopathy. The pathophysiology of HE has not yet been clarified. At present the main mechanisms under discussion are the combined effects of different toxins, such as ammonia, mercaptans, phenols and short- and medium-chain fatty acids, as well as a change particularly in GABAergic and glutamatergic neurotransmission. In this chapter the current views on the importance of these individual factors in the pathophysiology of HE are discussed; possible connections between changes in neurotransmission and the effect of different neurotoxins are presented. In addition, possible therapies resulting from recent knowledge of the pathophysiology of this disease are discussed, such as the use of Bz receptor antagonists.


Effect of histamine H2-receptor antagonists on vitamin B12 absorption. To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin). Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources. Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed. H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs. H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.


Remarkable increase in CD26-positive T cells in patients with human T lymphotropic virus type I (HTLV-I) associated myelopathy. We used two-color flow cytometric analysis to investigate CD26+ (Ta1+) cells in peripheral blood T lymphocytes from patients with human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy (HAM). The percentage of CD26+ cells among CD3+ cells was markedly increased in patients with HAM, compared with anti-HTLV-I seropositive carriers (p < 0.001) and seronegative controls (p < 0.01). Within the subpopulation of T cells, a significantly high percentage of CD26+ cells was detected in both CD4+ and CD8+ cell populations. Furthermore, analysis of HLA-DR+ T cells revealed similar results. In contrast CD4+CD45RA+ cells were significantly decreased in comparison with controls. These results suggest that immunologically activated or memory T cells found in peripheral blood may be etiologically relevant to HAM.


Postoperative complications and survival after pancreatoduodenectomy in patients aged over 70 years. An analysis of postoperative complications and survival was conducted in 31 patients undergoing pancreatoduodenectomy (PD) for carcinoma of the pancreas or periampullary carcinoma. Of them, 11 were over 70 years of age and 20 were under 70. Anastomotic leakage was the most common complication after PD. Definite pancreatic leakage was found in one patient in the over 70 group, and one case each of pancreatic, biliary, and gastric leakage were found in the under 70 group. All complications were treated conservatively without any further operative intervention. The overall morbidity rate was 41.9% (13/31), being 45.5% (5/11) in the over 70 group and 40.0% (8/20) in the under 70 group, and no operative deaths occurred within 30 days after surgery. The cumulative survival rate of the patients aged over 70 years with carcinoma of the pancreas or periampullary carcinoma did not differ significantly from the rate of those under 70. It was thus concluded that PD achieves an adequate prognosis and survival in patients over 70 years of age.


Gastric emptying after pancreatoduodenectomy with total stomach preservation and selective proximal vagotomy. This study evaluates postoperative gastric emptying following a new method of pancreatoduodenectomy with total stomach preservation and selective proximal vagotomy performed on 10 patients with diseases affecting the head of the pancreas, 7 being malignant and 3 benign. Reconstruction was carried out using the Billroth I and Billroth II techniques in 5 patients each, respectively. Early postoperative gastric emptying was evaluated by the time before intragastric tube removal and the resumption of oral intake, as well as by barium gastric radiography, while late postoperative gastric emptying was evaluated by the acetaminophen method. No difference was seen in early postoperative gastric emptying between the two surgical techniques, the mean time which elapsed before intragastric tube removal being 4.4 days for the Billroth I and 4.5 days for the Billroth II patients, and the mean time until the resumption of oral intake being 6.8 days for the Billroth I and 7.0 days for the Billroth II patients. A significant delay in gastric emptying was seen in the Billroth II patients compared to a normal control group, 30 and 45 min after acetaminophen administration, but the difference in gastric emptying between the Billroth I and II patients was not significant. Moreover, both techniques impaired gastric emptying much less than Traverso's pylorus-preserving pancreatoduodenectomy.


Medium-chain triglycerides and long-term parenteral nutrition in children. There are no data concerning long-term utilization of medium-chain triglycerides (MCTs) in parenteral nutrition (PN) in children. Our study included 12 children, aged 1.5-17 yr, on total PN at home, supplying a daily intake of 214 +/- 92 mg/kg nitrogen and 47 +/- 17 kcal/kg nonprotein energy (NPE). NPE included 10-32% long-chain triglycerides (LCTs) (Intralipid 20%). After switching to emulsion containing 50% MCT and 50% LCT (Medialipide) at the same dosage regimen and infusion rate as before, the subjects were monitored at 1, 3, and 6 mo. No signs of clinical intolerance were observed. Among the laboratory parameters evaluated, the only significant (p < 0.05) changes were 1) an increase in apolipoproteins A-I and A-II at 1, 3, and 6 mo and 2) a decrease in gamma-glutamyltransferase (gamma-GT) at 6 mo. There were no changes in the status of essential fatty acids in plasma or in phospholipids (in erythrocyte membranes). Moderate urinary excretion of dicarboxylic acids (adipic, suberic, and sebacic) was evidence of peroxysomal omega-oxidation. The results support the proposal for use of MCT-rich emulsion in long-term PN, given its metabolic advantages relative to LCT.


Chronic ethanol feeding and microvillus membrane glycosylation in normal and protein-malnourished rat intestine. Ethanol feeding to rats for 40 days enhanced (p < 0.001) the activities of alkaline phosphatase, sucrase, gamma-glutamyltransferase (GTP), and p-nitrophenyl (PNP)-beta-D-galactosidase (p < 0.05) with no change in leucine amino peptidase (LAP) and PNP-beta-D-glucosidase activities in intestine compared with control rats. The activities of alkaline phosphatase, sucrase, and GTP were diminished (p < 0.01) in ethanol-fed malnourished rats. There was no change in LAP activity, but the levels of glucosidase and galactosidase were elevated under these conditions. Brush-border sialic acid, fucose, hexose, and hexosamine contents were elevated in ethanol-fed protein-deficient animals. Ethanol administration to normally fed rats elevated the membrane sialic acid and hexose contents, reduced fucose content, and had no effect on brush-border hexosamine content compared with the control group. These results are in agreement with data on lectin binding to brush borders under these conditions. Alcohol ingestion reduced the incorporation of [14C]-glucosamine into brush borders in rats maintained on an 18% protein diet but augmented the incorporation of [14C]-glucosamine and [14C]-mannose in protein-malnourished membranes. These observations suggest that nutrition status influences the sensitivity of microvillus membrane glycosylation to ethanol feeding in rat intestine.


The transport of neurotransmitters into synaptic vesicles. As investigations identify additional plasma membrane neurotransmitter transporters, attention has focused on the molecular basis of neurotransmitter transport into synaptic vesicles. The transport of biogenic amines into chromaffin granules has served as the paradigm for understanding vesicular transport. Recent work now describes the vesicular transport of other classical neurotransmitters, which occur by distinct but related mechanisms. To determine their biochemical basis, several of the transporters have been functionally reconstituted in liposomes. The ability of vesicular amine transport to protect against the neurotoxin MPP+ has permitted the isolation of the first cDNA clone for a member of this family, and the sequence establishes a relationship with drug-resistance transporters in bacteria.


Retroviruses and nervous system disease. During the past decade retroviruses have been recognized as causes of human neurological disease. A wide clinical spectrum of neurological and neuromuscular diseases have been reported with HIV infections, and studies of these diseases have raised novel and exciting hypotheses of pathogenesis. As yet the full clinical spectrum of diseases associated with HTLV-1 has yet to be defined, and the pathogenesis of the chronic spastic paraparesis remains a mystery. Chronic neurological diseases in animals caused by both oncoviruses and lentiviruses can provide some clues to the pathogenesis of these newly recognized human neurological illnesses.


N-glycosylation of membrane glycoproteins in retinol-deficient rat liver. The effect of vitamin A deficiency on N-linked oligosaccharides of membrane glycoproteins was studied in rat liver in order to evaluate the suggested role of retinol in protein N-glycosylation. First, oligosaccharides of newly synthesized glycoproteins from rough endoplasmic reticulum of vitamin A deficient liver were compared with that of pair-fed controls. Oligosaccharides were metabolically labelled with D-[2-3H]mannose, released from the glycoproteins with endoglycosidase H, purified by reversed phase HPLC and ion exchange chromatography, and were reduced with sodium borohydride. HPLC fractionation of the oligosaccharide alditols showed that the glycoproteins carried mainly four oligosaccharide species, Glc1Man9GlcNAc2, Man9GlcNAc2, Man8GlcNAc2 and Man7GlcNAc2, in identical relative amounts in the vitamin A deficient and the control tissue. In particular, no increase in the proportion of short chain oligosaccharides was noted in vitamin A deficient liver. Second, the number of N-linked oligosaccharides was estimated in dipeptidylpeptidase IV (DPP IV), a major glycoprotein constituent of the hepatic plasma membrane, comparing the newly synthesized glycoprotein from rough endoplasmic reticulum and the mature form of DPP IV from the plasma membrane. No evidence was obtained that retinol deficiency caused incomplete glycosylation of this membrane glycoprotein. From these data, the suggested role of retinol as a cofactor involved in the synthesis of N-linked oligosaccharides of glycoproteins must be questioned.


Neuropsychological performance in asymptomatic HIV infection. This study compared 74 human immunodeficiency virus (HIV)-negative and 131 HIV-positive asymptomatic homosexual or bisexual men on an extensive neuropsychological test battery. HIV-positive subjects' performance was significantly worse on verbal memory and psychomotor skills. The prevalence of mild but persistent neurobehavioral impairment in the HIV-positive group was approximately twice that in HIV-negative patients, consistently across several criteria for impairment. There was evidence that degree of neuropsychological impairment was related to patients' perceptions of dysfunction in daily life. Findings were not related to degree of depression or to medication effects. These data suggest that approximately 10% to 20% of HIV-positive asymptomatic men suffer mild neuropsychological impairment that influences their daily lives.


Purification of Rhodotorula gracilis D-amino acid oxidase. A protocol is presented for preparing Rhodotorula gracilis D-amino acid oxidase in homogeneous form and in high yield in 3 to 4 days. The method takes advantage of (a) cell rupture by alternate freeze-thawing, (b) use of DEAE-Sepharose to bind contaminants, and (c) enzyme binding to a Mono S column. The D-amino acid oxidase isolated by this means has the same spectral and catalytic properties as the enzyme previously obtained, and possesses improved long-term stability.


P-glycoprotein-mediated multidrug resistance and cytotoxic effector cells. Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. MDR is a complex and multifactorial phenomenon. One important and common mechanism used by cancer cells as a defense against cytotoxic drugs is a 170-kD plasma membrane glycoprotein, P-glycoprotein (P-gp). P-gp confers resistance by actively pumping cytotoxic drugs out of cancer cells. Paradoxically, P-gp overexpression on tumor cells is frequently associated with enhanced susceptibility to lymphokine-activated killer cell activity. This enhanced susceptibility is not observed with P-gp- MDR cells, nor is susceptibility to natural killer cells increased. The physiologic, evolutionary and immunologic concepts with regard to the P-gp and the possible intervention of the function of the P-gp in cancer therapy are reviewed.


High-level expression of human asparagine synthetase and production of monoclonal antibodies for enzyme purification. In order to obtain large quantities of extremely pure human asparagine synthetase for detailed kinetic and structural studies, its gene was cloned into a 2mu plasmid (pBS24.1GAS) suitable for replication in a Saccharomyces cerevisiae cir0 strain (AB116). In this construct, the transcription of the asparagine synthetase gene is regulated by the alcohol dehydrogenase II/glyceraldehyde-3-phosphate dehydrogenase promoter, which is subject to glucose repression. The expression of the enzyme was allowed to take place in yeast minimal medium containing D-galactose as the only sugar nutrient. Eleven monoclonal antibodies to recombinant human asparagine synthetase were produced and one of them was selected to make immunoaffinity resins. After single-step immunoaffinity chromatography, more than 1.2 mg of homogeneous enzyme was obtained from the total cell extract from a 100-ml yeast culture. The yield of pure enzyme was over 100-fold higher than that of a previously reported yeast expression system. SDS-PAGE analysis showed the enzyme to be extremely pure and isoelectric focusing gel electrophoresis showed that the enzyme has an isoelectric point of 7.5. Immunoaffinity-purified recombinant human asparagine synthetase demonstrated both glutamine-dependent and ammonia-dependent asparagine synthetase activities, as well as glutaminase activity.


Analysis of the TSH receptor gene structure in various thyroid disorders: DNA from thyroid adenomas can have large insertions or deletions. We examined the structure of the TSH receptor gene in various thyroid disorders by a restriction fragment length polymorphism (RFLP) study with a cloned human TSH receptor cDNA as a probe. Southern blot analysis of DNAs in peripheral white blood cells obtained from normal individuals revealed a single band in each of several restriction enzyme digestions, indicating that the TSH receptor gene is a single copy gene in the human genome. Although RFLPs were not detected in peripheral blood cells and thyroid tissues in patients with Graves' disease, thyroid carcinomas, or subacute thyroiditis, significant RFLPs were found in 2 of 6 patients with adenoma in all restriction enzyme digestions examined. Moreover, these RFLPs were heterozygous and adenoma specific, and these additional bands in adenoma were amplified in both cases. We conclude that there are no major abnormalities in the structure of the TSH receptor gene in patients with Graves' disease, thyroid carcinoma, or subacute thyroiditis, although there may be a possibility of point mutations, small insertions, or deletions that cannot be detected by RFLP studies, and that there are large insertions or deletions in the region, including the TSH receptor gene, in some patients with thyroid adenoma.


Long-term observation of pediatric aplastic anemia. Fifty-nine verified cases of acquired aplastic anemia (AA), diagnosed at the Pediatric Department of the National Taiwan University Hospital from 1977 to 1987, were reviewed and analyzed. The demographic features showed a high relative incidence (acute myelogenous leukemia/AA ratio, 2.2/1), a high percentage of non-severe AA (39%) and a high association with hepatitis (20.8%). No evidence of hepatitis A, B or C virus infection was found in five cases of hepatitis-associated AA. No sex preponderance was noted in this pediatric series. The 10-year projected survival rate of the total series approached 55%. The crude two-year-survival and two-year-transfusion-free-survival rates were 59% and 44%, respectively, in the conservative therapy group treated with androgens and steroids; 36% and 32%, respectively, in patients with severe AA in the conservative therapy group; and 73% and 64%, respectively, in the aggressive therapy group treated with cyclosporin, anti-lymphocyte globulin or bone marrow transplant. The major causes of death were hemorrhage (44%) and infection (56%) in the conservative therapy group; but in the aggressive therapy group, two out of three deaths were related to therapeutic complications. Multivariate analysis of prognostic factors revealed that severity and treatment modality were independent risk factors. Only two out of 31 patients who survived more than two years (long-term survivors) experienced late mortalities. At two, five, seven and 10 years after diagnosis, 61%, 55%, 41% and 40% of the long-term survivors had inadequate hematopoietic recovery.


Comparison of umbilical blood gas and acid-base status of small-for-date and normal Chinese newborns. A prospective study of umbilical arterial blood gas in appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) babies was performed at our hospital from August 1989 to July 1990. A total of of 512 cases were included, 432 cases in the AGA group and 80 cases in the SGA group, with gestational ages ranging from 26 to 42 weeks. Umbilical arterial blood was collected immediately after delivery of the newborns. Comparisons of maternal age, gestational age, birth body weight and body length of infants. Apgar scores at one minute and five minutes, cord arterial blood pH, pO2, pCO2, base excess, bicarbonate, total CO2, O2 saturation and O2 content between the AGA and SGA groups were taken into account. Our results demonstrated significant differences in birth body weight, birth body length, Apgar scores at one minute and five minutes and gestational age in the SGA group compared with those in the AGA group. The parameters of cord arterial blood gas were not correlated with gestational age in either group. The mean pH value in the AGA group (7.30 +/- 0.05) was higher than that in the SGA group (7.28 +/- 0.08). The same trend of difference was also noted between the AGA (7.30 +/- 0.04) and SGA (7.27 +/- 0.07) babies who were delivered by Cesarean section (p < 0.05). The latter results imply a more academic state in SGA babies which is independent of labor. Prepartum asphyxia plays an important role in determining the prognosis of SGA babies. We suggest routine umbilical cord blood gas and acid-base analysis at delivery to assess fetal asphyxia.


Surgical repair of ventricular septal defect without ventriculotomy in the first 12 months of life. Sixty-eight infants with clinical evidence of a large ventricular septal defect (VSD), refractory to conventional medical treatment, underwent surgical closure within the first 12 months of life from August 1987 to June 1991. There were 43 males and 25 females. The ages of the patients ranged from two to 12 months, with a mean age of 6.6 months. The mean body weight of the patients was 5.4 kg (range, 2.3-10 kg). Surgery was performed because of intractable heart failure in 27 infants (39.7%), failure to thrive in 40 (58.8%), repeated pneumonia in 43 (63.2%) and prolonged endotracheal intubation in nine (13.2%). There were 21 patients with a supracristal VSD (30.9%) and 47 patients with perimembranous VSD (69.1%). Nine patients (13.2%) had preoperative cardiac catheterization. Transatrial repair of perimembranous VSDs and transpulmonary repair of supracristal VSDs was used exclusively without ventriculotomy. Surgically induced heart blocks did not occur in any of the patients. Only two patients (2.9%) died during the early postoperative period. Diagnosis in most cases was confirmed by the present advanced integrated color Doppler echocardiographic technology which is widely used by pediatric cardiologists. There was no need to perform cardiac catheterization in most patients with VSDs. The morbidity and mortality were very low. We strongly suggest that for infants with a large VSD, primary repair should be the procedure of choice.


Clinical analysis of 206 cases of kidney transplantation. From July 1981 to May 1991, 206 kidney transplantations were performed at the Chang Gung Memorial Hospital. There were 762 patients on our waiting list for transplantation at that time. Patient follow-up care was undertaken, alternately, by urologists and nephrologists. The average follow-up period was 4.0 +/- 2.8 years. Patient data were registered in the UCLA (University of California at Los Angeles) International Kidney Transplant Registry. Eighty patients received living-related transplants, 126 received cadaveric transplants. Twenty-four per cent of transplant recipients were carriers of HBsAg. Their survival rates were equal to those of non-carriers up to five years postoperatively, although they were prone to episodes of hepatitis. Nineteen kidneys were from HBsAg carriers with recipient survival rates, five years postoperatively, not significantly different from those who received kidneys from non-carriers. However, there was one case of seroconversion from HBsAg negative to HBsAg positive status. There were 19 deaths among the recipients, the major cause of death being infection (57.9%). Eight grafts were lost due to medical noncompliance. Malignant lymphomas were noted in three cases who are now alive and well. Three cases of hepatomas were noted, but unfortunately none of them survived. The transplant recipients were found to enjoy a better quality of life after undergoing psychiatric evaluation. The one-year patient survival rate was 97.4% and 96.2% for living-related and cadaveric transplants, respectively. The one-year graft survival rate was 96.0% and 88.5% for living-related and cadaveric transplants, respectively. Kidney transplantation is a well-accepted method of treatment for end-stage renal disease.


Electroejaculation in spinal cord injured males. Electroejaculation is a newly developed method to retrieve sperm in anejaculatory spinal cord injured (SCI) males. We studied 25 completely traumatic SCI males from August 1990 to May 1991. The patients' ages ranged from 18.7 to 43.3 years, and the interval since injury ranged from four months to 14.1 years. The level of injury varied from C5 to T12. Bi-directional emission was found in 12 patients, antegrade in nine, retrograde in one and failure in three. Electroejaculatory stimulation parameters were 434 +/- 54 mA for mean maximum current, 21.7 +/- 2.7 volts for mean maximum voltage and 35.9 +/- 3.1 degrees C for mean maximum probe temperature. The antegrade semen obtained showed wide variations in sperm quality and quantity between subjects. The total sperm count was 478 +/- 809 x 10(6) in the antegrade portion, and the sperm motility was below 5% in most cases. The retrograde portion was usually worse. There was no correlation between sperm quality and quantity with patient age, injury level or injury period. Bladder management had no effect on the results of electrical stimulation. Epididymitis had a negative impact on the success of retrieval. Low-level injury victims needed analgesia or anesthesia to complete the stimulation. The major side effects were minimal autonomic dysreflexia and mild rectal mucosal change. Repeated stimulation may improve sperm counts, but semen quality deteriorates if the procedure is performed once a week. As a whole, electroejaculation is a safe, effective and simple procedure to retrieve sperm in anejaculatory persons, especially SCI patients.


Measurement of viscosity of human semen with a rotational viscometer. The viscosity of 130 human seminal plasma samples was studied with a rotational viscometer instead of by the traditional subjective rating method. The average seminal viscosity one hour after ejaculation was 9.35 +/- 0.99 centipoise (cps), which was statistically identical to that in the third hour (8.63 +/- 0.77 cps). Seminal viscosity showed a significant negative correlation with the percentage of motile sperm (p < 0.05); however, no significant correlation between seminal viscosity and sperm concentration could be found (r = -0.15, p = 0.098). The seminal viscosity of the oligoasthenospermic group was significantly higher than that of the normospermic group (p < 0.01); there was also a trend towards higher viscosity in the semen of asthenospermia and oligospermia when compared with the normospermic group. It is concluded that seminal viscosity may be higher in cases of poor-quality semen; however, sperm motility and concentration are not the sole determinants of viscosity. Determining the seminal viscosity with this rapid, objective and quantitative method is valuable in identifying and treating the subgroup of infertile men with viscid semen.


Surgical treatment for Perthes disease at risk. The treatment of Perthes disease has remained controversial ever since the disorder was first described in 1910. It is generally accepted that surgical treatment is favorable if the patients are at risk clinically or radiologically. From March 1983 to March 1988, 13 patients suffering from severe Perthes disease were treated surgically at the National Taiwan University Hospital. There were 12 boys and one girl with an average age of eight years and eight months (ranging from five years and 10 months to 12 years and one month). They were all at risk either clinically or radiologically. All patients suffered from hip pain, limping and limited range of motion, except one who was pain-free. All femoral heads were classified as Catterall group III or IV, and had at least two radiologic risk signs. After nonsurgical treatment for an average duration of 13 months, including bed rest, traction and bracing as inpatients or outpatients, operations, including varus derotational osteotomy of the femur in three, Salter innominate osteotomy in one, combined surgery in three and triple innominate osteotomy in six patients, were performed. After following up for 36 months, we determined that surgical containment for Perthes disease can achieve satisfactory results. In our preliminary report, triple innominate osteotomy was one of the relatively simple and effective procedures.


A dynamic study of the ankle-foot complex. A kinematic study of the ankle-foot complex in 19 healthy volunteers was performed using computerized radiocinematography. We found that the instant centers of rotation of the ankle joint fell closely within the talus in the sagittal plane. When the ankle joint moved, the talus, the calcaneus and the navicular bone performed different excursions. Except for the movement in the sagittal plane, the calcaneus assumed eversion in dorsiflexion and inversion in plantar flexion when the ankle moved in an open kinematic chain (under non-weight-bearing conditions). In a closed kinetic chain movement (under weight-bearing conditions), the lower leg exhibited internal rotation, and the talus moved plantarward when the ankle was dorsiflexed. The internal rotation of the lower leg did not cause a slippery rotation of the foot on the surface, but rather it was converted into eversion of the calcaneus in the frontal plane.


Immunohistochemical study of dystrophin in neuromuscular disorders. Dystrophin, a protein product of the gene that is affected in Duchenne/Becker muscular dystrophy (DMD/BMD), is localized on the sarcolemma of muscle fibers. We tried to study various neuromuscular disorders, including DMD/BMD and their carriers, by the immunohistochemical method with two types of anti-dystrophin antibodies. No dystrophin stain was found on the muscles of cases of DMD. In cases of BMD, partial deficiency or a mosaic appearance of dystrophin was found. In members of DMD/BMD families, polyclonal antibody stains did not show definite membrane abnormality. However, partial deficiency or a mosaic appearance of dystrophin on muscle membranes was found in the carriers by a monoclonal anti C-terminal antibody stain. The explanation may be: 1) more non-specific antigen-antibody cross reactions occurred in the polyclonal antibody stain; and 2) a partial defect exists, such as a segmental deletion of the C-terminal portion of dystrophin. Dystrophin study in muscle diseases is a helpful tool for the following reasons: 1) it improves diagnostic accuracy and helps to differentiate variant types of muscle disorders; 2) it makes an early diagnosis possible before the onset of the symptoms of DMD/BMD; and 3) it detects nonsymptomatic carriers of DMD/BMD. However, without the aid of a genetic study, dystrophin antibody stains cannot absolutely rule out the diagnosis of carriers.


Tubal embryo transfer for the treatment of infertility. The outcome of treatment for male factor infertility with either gamete intrafallopian transfer (GIFT) or in vitro fertilization and embryo transfer (IVF/ET) has been unsatisfactory. A better approach may be tubal embryo transfer (TET). In our medical center, from November 1989 to December 1990, 80 couples (male factor, n = 35, non-male factor, n = 45) entered our program for TET. Superovulation was conducted with either human menopausal gonadotropins (hMG) or gonadotropin-releasing hormone agonist (GnRH-a, buserelin)/hMG. Ovum retrieval (OR) was possible in 73 patients and successful fertilization after insemination occurred in 64 of them. TET was performed only when there was at least one grade III-V embryo. The mean number of embryos transferred was 3.92 +/- 0.13 (range 1-5). There were 35 pregnancies out of 55 TET (64% per TET, 48% per OR). In the group with male factor infertility, OR occurred in 32, and 24 achieved fertilization. Ten pregnancies were achieved after 19 TET (53% per TET, 31% per OR). In comparison, the group with non-male factor infertility had a higher pregnancy rate (69% per TET and 61% per OR). There have been 15 live births, 14 ongoing pregnancies (eight sets of twins and 21 singletons), five abortions and one ectopic pregnancy. Our results indicate that: 1) TET is a valuable treatment for non-tubal factor infertility; and 2) in the group with male factor infertility, it has the advantages of demonstrating fertilization in vitro and preventing unrewarding laparoscopies.


Experience with treatment of gastroschisis and omphalocele. From 1982 to 1990, 31 neonates with omphalocele and 54 with gastroschisis were treated at Mackay Memorial Hospital. The overall survival rate for omphalocele was 71%, while it was 85% for gastroschisis. The rate of primary fascial closure for omphalocele (85%) and gastroschisis (87%) was similar. The mortality from omphalocele was almost exclusively due to the presence of serious associated congenital anomalies. Two cases of Cantrell's pentalogy and two of cloacal exstrophy were found. The incidence of major malformation with gastroschisis was 6%. Sepsis, inadequate perioperative resuscitation and prolonged gastrointestinal dysfunction were the major causes of death in gastroschisis. Among survivors, the hospital stay was significantly longer in the silon pouch group than in the primary fascial closure group (71.5 vs 31.3 days for gastroschisis, 41 vs 14 days for omphalocele). Advances in surgical technique, neonatal intensive care and ventilatory support have made primary fascial closure a superior approach without jeopardizing the babies' chance for survival. An improved survival rate and increased primary closure rate are the main features in the treatment of abdominal wall defects in the last decade.


Effects of age and posture on plasma active renin and plasma inactive renin in normal subjects. To investigate the effects of age and posture on plasma active and inactive renin, we measured the plasma active renin concentration (ARC) and inactive renin concentration (IRC) in 81 healthy subjects. The subjects were divided into five groups according to age and body position at the time the blood was taken. Group I included 15 five-day-old newborns in a supine position. Group H included 18 adults, aged from 20 to 50 years, who were in a supine position. Group III included 21 adults, over 50 years old, who were in a supine position. Group IV included 20 adults, aged from 20 to 50 years, who were in an upright position. Group V included 19 adults, over 50 years old, who were in an upright position. Twelve subjects were included in Groups II and IV. Plasma active renin was measured by the amount of angiotensin I general when an exogenous renin substrate was added. Plasma inactive renin was activated by trypsin. The results showed that, in a supine position, both ARC and IRC were significantly higher in newborns (Group I) than in the two adult groups (Groups II and III). The mean of the ARC/TPRC (total plasma renin concentration) ratio was lower in adults over 50 years old (Group III) than in those from 20 to 50 years old (Group II), but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)


Metastasis of hepatocellular carcinoma to the heart: unusual patterns in three cases with antemortem diagnosis. Unusual patterns of cardiac metastasis were noted in three cases of hepatocellular carcinoma (HCC): one patient was noted to have a large right ventricular (RV) tumor mass with intracavitary growth and myocardial invasion; the second had massive pulmonary and left atrial (LA) metastasis; and the third patient had a right atrial tumor mass with concomitant RV and LA involvement. Tumor implantation to the RV without right atrial involvement and extensive myocardial invasion is unusual in HCC. The LA involvement is probably related to tumor growth from the pulmonary veins following massive metastasis to the lung, direct invasion of the atrial septum or tumor implantation via a subclinical right-to-left shunt through the patent foramen ovale. To the best of our knowledge, such unusual intracavitary metastases in HCC have not been reported previously. Cardiac metastasis, without local gross recurrence, may be one of the presentations after lobectomy in patients with HCC.


Cutaneous alternariosis in association with scabies or iatrogenic Cushing's syndrome. Cutaneous alternariosis is rare. Most infections occur in immunocompromised hosts. We report the first three cases in Taiwan. The patients were elderly farmers residing in Tainan. They developed indolent, erythematous, ulcerated or crusted papules, plaques or pustules over the extensor aspect of the forearms or hands. Pure colonies of Alternaria sp were isolated from biopsy specimens in each case. The diagnosis was confirmed by detecting pleomorphic fungal elements in the dermis within suppurative, granulomatous infiltrates. All three patients were immunocompromised. They showed a negative reaction to an intradermal test of seven common antigens. Cases 2 and 3 had iatrogenic Cushing's syndrome. Cases 1 and 3 had extensive scabies, which in Case 1 was of the Norwegian type. To the best of our knowledge, scabies associated with alternariosis has not been reported previously. The infection showed spontaneous regression in Case 1; in Case 2, it resolved after seven weeks of intralesional amphotericin B at a dose of 1 mg/mL twice a week.


Computed tomographic finding in adenomyomatosis of the gallbladder. We report on an uncommon case of symptomatic generalized adenomyomatosis of the gallbladder. It was initially suspected by ultrasonography and further confirmed by computed tomography (CT). A postcontrast CT scan at the level of the gallbladder body demonstrated the characteristic rosary sign. The rosary sign is formed by the enhanced proliferative mucosal epithelium with the intramural diverticula surrounded by the unenhanced hypertrophied muscle coat of the gallbladder. Similar CT scans were obtained sequentially in the caudal direction. These CT scan findings indicated generalized adenomyomatosis of the gallbladder. The patient received a cholecystectomy. The pathologic report showed specific changes of adenomyomatosis corresponding to the findings on the CT scan. Generalized adenomyomatosis of the gallbladder, therefore, can be accurately diagnosed by CT.


Congenital short bowel syndrome: report of a case treated with home central parenteral nutrition. Congenital short bowel is a rare anomaly. Among the 21 cases reviewed in the literature, only four (19%) survived beyond infancy. We present a female infant with short small bowel, malrotation and floating colon, who was successfully treated with home central parenteral nutrition. Improved long-term survival in this group of patients is expected with prolonged parenteral nutritional support.


Pericentric inversions of chromosome 9 in Taiwanese fetuses. Using trypsin-Giemsa banding, a total of 1,350 unrelated Chinese fetuses were studied for pericentric inversion of chromosome 9 [inv(9) (p11; q13)]. Sixteen cases (1.2%) were found to have this variant. The prevalence was higher than that in a previous report on Asians. All the fetuses with inv(9) were born with a normal phenotype.


Acute renal failure and severe thrombocytopenia induced by rifampicin: report of a case. We report on a patient who developed life-threatening thrombocytopenia and acute renal failure after the reinstitution of rifampicin therapy for pulmonary tuberculosis. This combined reaction is rarely reported. Supportive treatment and withdrawal of rifampicin led to complete recovery. The increased incidence of drug-resistant tuberculosis and the need for the reintroduction of rifampicin therapy may lead to more such reactions being observed.


PCR amplified HLA DQ alpha and DQ beta DNA typed by dot-blot hybridization and direct sequence for suspect. For more effective screening of suspects, we combined two methods to individualize the biologic evidence from a crime scene: polymerase chain reaction (PCR) dot-blot hybridization for DNA typing of HLA Dq alpha; and PCR direct sequencing for DNA typing of HLA DQ beta. PCR-DQ alpha was typed by an AmpliType HLA DQ alpha kit from Cetus. PCR-DQ beta was typed by direct sequence using the dideoxy chain termination method. In 20 DNA samples, complete separation was demonstrated by these two polymorphic DNAs. This will be of considerable use in screening suspects in crime investigation work. The sensitivity of PCR is useful for trace evidence, and the rapid results of dot-blot hybridization and the precise results of direct sequencing have significant advantages.


Effects of splenectomy on portal pressure in short- and long-term portal hypertensive rats. Different hemodynamic patterns were noted in short- and long-term portal hypertensive rats, induced by partial portal vein ligation (PVL) performed two weeks and six months earlier. In order to investigate the effect of splenectomy on the portal pressure of portal hypertensive rats with different hemodynamics, an operation was performed on these two groups of animals and the portal pressure measured thereafter at different time points. Splenectomy in the short-term group produced an immediate, but transient, drop in portal pressure from 14.1 +/- 2.7 to 11.0 +/- 3.0 mmHg, which bounced back to pre-splenectomy values in 20 seconds. Two weeks later, the portal pressure in these splenectomized rats was 15.2 +/- 4.2 mmHg, which was indistinguishable from that of the pre-splenectomy condition of the short-term group. However, after an additional two weeks, portal pressure in the splenectomized rats rose to 16.4 +/- 2.1 mmHg, which was significantly higher than that of the pre-splenectomy condition of the short-term group. This difference in portal pressure became even more pronounced at six months. Sustained portal hypertension was observed in the long-term group, but the pressure was significantly lower than that in the short-term group. Splenectomy in the long-term group produced neither an immediate drop nor a delayed rebound in portal pressure. We conclude that splenectomies in portal hypertensive rats at different stages of disease produce different effects.


C-peptide response to glucagon in patients with non-insulin-dependent diabetes mellitus. To understand pancreatic beta cell function in patients with non-insulin-dependent diabetes, we analyzed C-peptide response to glucagon in 101 nonketotic patients with onset of diabetes at over 25 years of age and duration of diabetes of more than one year. The fasting serum C-peptide values (FCP), maximal incremental (delta CP) and 6-minute (6'CP) serum C-peptide values after 1 mg of intravenous glucagon administration were not related to age at diagnosis (r = 0.12, 0.06 and 0.10, respectively), duration of diabetes (r = 0.15, 0.05 and 0.10, respectively), fasting plasma glucose concentrations (r = 0.01, 0.18 and 0.12, respectively) or glycohemoglobin (HbA1c, r = 0.13, 0.22 and 0.16, respectively). In contrast, they showed a clear positive correlation with body mass index (BMI, r = 0.36, 0.52 and 0.41, p < 0.001). In order to evaluate the beta cell function in patients with different responses to treatment modalities, a subgroup of 45 patients was divided into three groups: diet successes (DS, n = 14), oral hypoglycemic agent (OHA) successes (OS, n = 19) and OHA failure (OF, n = 12). Among the three groups, patients in the OF group had the longest duration of diabetes (9.4 +/- 1.9 years) and the lowest BMI (19.3 +/- 1.0 kg/m2). Serum C-peptide responses to glucagon were different in the three study groups. Patients in the DS group had the highest response and patients in the OF group had the lowest response. However, the differences in mean FCP, delta CP and 6'CP among the three groups were not statistically significant, and there was a wide overlap of individual C-peptide values.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment and outcome of unexplained recurrent spontaneous abortions in subclinical autoimmune disorders. Patients with a history of three or more fetal losses before a gestational age of 20 weeks were examined. Only patients with normal chromosomal, hormonal and anatomic findings were included in this study. These patients were tested for the antinuclear antibody, the C3 and C4 levels, anti-ENA [Ro(SSA), La(SSB), SM, RNP, scl-70], anti-single-stranded DNA and anti-double-stranded DNA, lupus anticoagulant, anticardiolipin and antiphosphotidylserine. All of these patients were free of any symptoms, except for the repeated abortions. The results showed that 10 out of 213 (4.7%) patients with unexplained recurrent spontaneous abortions had abnormal serologic tests, and 28% of the abortions (nine out of 32 abortions) occurred during the second trimester. With treatment of low-dose aspirin alone, or in combination with prednisolone, two out of 11 pregnancies in these 10 patients resulted in repeated abortions (18%), which was significantly lower than their previous abortion rate where 32 out of 33 pregnancies resulted in abortions (97%). Four babies (three term and one premature) were delivered without any abnormalities and the other five pregnancies are beyond the 28th week of gestation and are progressing smoothly. This study revealed that subclinical autoimmune disorders may play a role in recurrent spontaneous abortions and adequate treatment can improve the pregnancy outcome.


Wilson's disease: clinical analysis of 71 cases and comparison with previous Chinese series. We analyzed 71 patients (45 males and 26 females) with Wilson's disease (WD) who were seen at our hospital from 1979 through 1990. The mean age at onset was 18.1 +/- 6.5 years, with 17.0 +/- 6.6 years for males and 20.2 +/- 5.7 years for females. The mean age at the time of diagnosis was 21.0 +/- 6.3 years. Hepatic WD was the most frequent mode of presentation in childhood with a mean age of 15.5 +/- 6.0 years, while neurologic WD tended to occur in adolescence with a mean age of 21.0 +/- 8.9 years. The ages of onset were 12.5 +/- 0.5 years for renal WD and 25.3 +/- 2.4 years for psychiatric WD. The common initial symptoms were neurologic and hepatobiliary. In addition, hematologic and renal disorders were also common during evaluation. The neurologic findings at the time of diagnosis were tremors (66.2%), dysarthria (56.3%), gait disturbances (46.5%), dystonia (42.3%) and decreased facial expressions (40.8%). Less frequent but notable neurologic presentations were psychosis (11.3%), epileptic seizures (5.6%) and hypokalemic periodic paralysis (1.4%). When compared with two previous large Chinese series, the present data show a male preponderance, an earlier age of onset for males and higher incidences of hepatic, hematologic and renal involvement. The possible reasons for the discrepancies between the present study and previous Chinese series are discussed.


Dorsal root entry zone lesions in the treatment of pain following brachial plexus avulsion and herpes zoster. Fifteen patients with brachial plexus avulsion injury and four patients with postherpetic pain submitted to dorsal root entry zone surgery. Nashold's method was used in all cases. The initial results in the group with brachial plexus avulsion injury were satisfactory. Twelve patients experienced pain relief. Only one patient had a poor result. Ten patients (66%) continued to have good pain relief in the follow-up period of 15-48 months. Three patients with postherpetic pain had good pain relief in the initial stage after surgery. Two of these four cases were found to have a recurrence of some pain, which could be relieved more or less by oral analgesics. No mortality or major complications were found in this series, although eight patients complained postoperatively of mild sensory weakness which disappeared within two weeks.


Can cancer pain attenuate the physical dependence on chronic long-term morphine treatment? This prospective and comparative study was designed to determine the role of cancer pain and attitudes towards morphine in attenuating the intensity and duration of physical dependence following chronic morphine treatment. Morphine was administered via a stepwise ladder approach in order of oral, spinal and intravenous routes depending on the adequacy of analgesia. On-demand titration of a dose, either upward or downward, was liberal and unlimited. Withdrawal strategy was evaluated and initiated either by patients (PI group) or their families (FI group). The manifestation of physical dependence on morphine was compared between patients who successfully withdrew (total withdrawal), and patients who failed to withdraw (episodic withdrawal), from morphine for a period of more than two weeks. Eighty-eight out of 627 patients (14.1%) were excluded from our protocol; 75% of these exclusions were due to objections toward morphine as the major form of analgesic. Drop-out due to poorly tolerated side effects was relatively rare (18.2%). Fifty-four (10.0%) achieved total withdrawal and 212 (39.3%) experienced episodic withdrawal. Non-pain-related abstinence symptoms were highly prevalent but were tolerable for both groups. Pain-related symptoms were more exaggerated during episodic withdrawal. Intolerable pain, rather than physical dependence, contributed to the failure to withdraw from morphine. Among a total of 539, addiction was found in only one patient (0.18%) who began drug use long before entering our protocol. Attitudes towards morphine affect the acceptance of treatment and hasten the withdrawal strategy. Families were more anxious about morphine than the patients themselves which led to more aggressive, but less tolerable, withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)


Conization with a carbon dioxide laser as a uterine-preservation operation for patients with preinvasive cervical carcinoma. Preinvasive cervical carcinoma (PCC) is a disease entity of the uterine cervix resulting from carcinoma in situ and various degrees of dysplasia. These cases are conventionally treated by a total abdominal hysterectomy. Effective management that can preserve the uterus is more desirable than hysterectomy. In this report, we present the results and complications of laser conization as a uterine-preservation treatment. At our dysplasia clinic, cases of reproductive age diagnosed with PCC can voluntarily undergo laser conization. From June 1985 to May 1988, there were 26 cases who received this treatment. After treatment, they were regularly followed up for more than three years. Before and after surgery, these cases were evaluated by a Pap smear for cytology, colposcopy, a cervical punch biopsy and endocervical curettage for histopathology. Eighteen cases with a satisfactory colposcopy were treated by laser vaporizing conization. Eight cases with an unsatisfactory colposcopy were treated by laser excisional conization. Their mean age was 35.8 (SD 7.7) years, and parity was 1.5 (SD 0.9). The instrument used was a Sharplan CO2 laser model 720. The power density was around 1,000 W/cm2 for vaporization, and 1,500 W/cm2 for excisional conization. During the operations, there was little bleeding. No case required a blood transfusion. The vaginal discharge decreased within four days after treatment. The cervical epithelium on the operated wound began growing after the second week, and the cervix healed well in four to six weeks. After healing, the squamocolumnar junction in each case was visible on colposcopy. No case suffered from cervical stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Secondary ovarian malignancy of extragenital origin: clinical analysis of 42 cases. Forty-two patients with secondary ovarian cancer from extragenital sites encountered in the past 14 years at the National Taiwan University Hospital were retrospectively analyzed. They accounted for 11.6% (42/362) of all ovarian cancers. The mean age was 43.7 years, and 32 patients were premenopausal. Gastric cancer was the most frequent primary malignancy (50.0%); other sites of extragenital primaries were colon (23.8%), breast (11.9%), rectum (4.8%), and indeterminate (9.5%). Bilateral ovarian involvement was found in 78.6% of patients. The most common presenting symptom was abdominal distension (52%). All patients received surgical intervention as the primary treatment; 30 patients had subsequent chemotherapy and four patients had postoperative radiotherapy. However, the outcome was poor; more than half of the patients died within one year, with a two-year survival rate of 22.5%.


Management of infected tibial plate osteosynthesis using a staging system for infected fractures. Osteomyelitis following plate osteosynthesis of a tibial shaft fracture was managed in 23 patients through a staging system and prospective treatment protocol. The staging system, which is arranged in an upstaging disease progression and downstaging treatment protocol, is composed of the status of osseous continuity (Type I to II) and the dead space created by the debridement surgery (Classes A to D). The follow-up period ranged from 20 to 48 months (average, 31.5 months). Staphylococcus aureus (35.5%) and Pseudomonas aeruginosa (29%) were the most commonly involved organisms. Twenty-two infections were initially arrested by one debridement, and one infection was arrested by three sequential debridements. There were seven Stage IA, one Stage IB, seven Stage IIA, two Stage IIB, three Stage IIC, and three Stage IID fractures in this study. The average number of surgical procedures were 1, 2, 2.1, 4, 4.7 and 6, respectively. The difficulty of treatment increased with the severity of the disease. The average time to bone union for Stage IIA, IIB, IIC and IID fractures were 11, 9, 20.3 and 21.5 months, respectively. A tibial osseous defect longer than 4 cm is a major prognostic factor for prolonged disability time. Important complications were nonunion one, bone graft stress fractures (two), and recurrence (three).


Computed tomography in diagnosis of septic sacroiliitis: report of three cases. Disorders of the sacroiliac joint are often overlooked during an initial physical examination because the patient is usually in a supine position and the posteriorly located joint is not accessible. Local pain and tenderness at the sacroiliac joint on lateral compression of the pelvis, together with Gaenslen and Fabere maneuvers, may direct the physician's attention to the joint. However, these symptoms are not specific or pathognomonic. Unusual presentation of septic sacroiliitis, which does not show radiologic changes during the early stages, may mimic gluteal, lumbar disc or intra-abdominal syndromes, leading to unnecessary abdominal exploration or lumbar discectomy. Computed tomography (CT), with its superb delineation of osseous, synovial and peri-articular structures, was applied to diagnose septic sacroiliitis in three patients. In Patient 1, septic arthritis and juxta-articular osteomyelitis with sequestrum formation were demonstrated by CT four weeks before abnormalities were shown on a roentgenogram. In Patients 2 and 3, inflammatory processes affected the synovium and peri-articular muscles; thus, abnormalities were shown by CT but not by a roentgenogram. We consider CT to be helpful and superior to conventional radiography in the diagnosis of septic sacroiliitis.


Non-mosaic trisomy 20 in cultures of amniotic fluid from a fetus with serious congenital malformation. We present a case of non-mosaic trisomy 20 in amniotic fluid associated with major congenital anomalies. A detailed prenatal ultrasonic examination was performed, and revealed dilatation of the cisterna magna and the fourth ventricle with hypoplasia of the vermis of the cerebellum. Fetal echocardiography showed overriding aorta and ventricular septal defects with pulmonary atresia. However, the karyotype of the lymphocyte in the cord blood was normal female 46, XX. The occurrence of the Dandy-Walker malformation in non-mosaic trisomy 20 has not been reported before, and the clinical significance of this major defect for prenatal diagnosis is discussed.