Shear stress-facilitated calcium ion transport across lipid bilayers. Small unilamellar liposomes were used in this study of shear stress effects on the trans-bilayer flux of calcium ions (Ca2+). Liposome suspensions were prepared from 99% egg phosphatidylcholine by a microporous filter extrusion technique. The inner aqueous phase of the unilamellar liposomes contained indo-1(5-), a fluorescent indicator of free Ca2+. The external aqueous phase was composed of Hepes-buffered saline containing normal physiological levels of common ionic species. Calcium ion levels were set at 100 nM and 1 mM in the inner and outer aqueous phases, respectively. Liposome suspensions were exposed to graded levels of uniform shear stress in an optically modified rotational viscometer. Intraliposome Ca2+ concentration was estimated from continuous measurement of indo-1(5-) fluorescence. Electronically measured particle size distribution was used to determine liposome surface area for estimation of trans-bilayer Ca2+ flux. Trans-bilayer Ca2+ flux increased linearly with applied shear rate from 27 s-1 to 2700 s-1. Diffusional resistance of the lipid bilayer, not the convective resistance of the surrounding fluid, was the limiting step in the transport of Ca2+. Liposome permeability to Ca2+ increased by nearly two orders of magnitude over the physiologically relevant shear rate range studied. Solute transport in injectable liposome preparations may be dramatically influenced by cardiovascular fluid stress. Solute delivery rates determined in liposomes exposed to static conditions may not accurately predict in vivo, cardiovascular solute transport.


Natural history and predictors of obesity after orthotopic heart transplantation. Excessive weight gain resulting in obesity is commonly seen after orthotopic heart transplantation. Obesity increases the risk for the development of many significant health problems and the associated morbidity and mortality. The purpose of this study was to define the occurrence, magnitude, and predictors of overweight/obesity in this group. We followed 47 consecutive patients for 1 year after orthotopic heart transplantation for changes in weight. Weight gain from baseline was significant at months 2, 4, 6, 8, and 10, with significant weight increments between each measurement interval (p < 0.05). The mean weight gain was 10.1 kg +/- 1.6 (standard error [SE]) at 12 months. Based on entry body mass index patients were divided into two groups: group I, overweight/obese, body mass index more than 27 kg/m2 (n = 11); group II, not overweight/obese, body mass index 27 kg/m2 or less (n = 36). No significant difference was found in the amount of weight gained between the two groups (group I, 10.3 kg +/- 1.2 [SE]; group II, 10.1 kg +/- 1.4 [SE]). Only age predicted weight gain, with younger patients gaining more than older patients after transplantation (14.2 +/- 13.2 kg versus 8.8 +/- 7.9 kg; p < 0.05). We found no relationship between the observed weight gain and any of the other measured predictors, that is, history of overweight, age, diabetes, family history of overweight, sex, patient's participation in cardiac rehabilitation. The universal nature of this weight gain and the lack of markers predicting patients at greatest risk for obesity underscores the seriousness of this problem.


Isolation of the plasma membrane and organelles from Chinese hamster ovary cells. Two methods are described enabling the plasma membrane from Chinese hamster ovary (CHO) cells to be obtained rapidly, relatively pure and with a good yield. In both cases, cells were disrupted by nitrogen cavitation in an isoosmotic buffer either at pH 5.4 or at pH 7.4. In the first approach, cells were lysed at pH 7.4 and the plasma membrane and cell organelles were isolated on a self-generated gradient of Percoll, at neutral pH. Mitochondria and endoplasmic reticulum were recovered in the denser fractions, plasma membrane fragments were found in the lighter fractions, but always contaminated by lysosomes. Because lysosomes were found to sediment in acidic conditions, cells were lysed at pH 5.4 and presedimentation (1500 x g) of the cell homogenate at the same pH enabled more than 80% of the lysosomes to be removed. Then, ultracentrifugation of the supernatant over a Percoll gradient at neutral pH yielded plasma membrane fractions practically free of lysosomes with an enrichment ratio of 3 and fractions of mitochondria and endoplasmic reticulum with enrichment ratios of 17 and 6, respectively. A major problem was encountered in the final step of elimination of Percoll from the purified plasma membrane fractions. Whatever the technique used for eliminating Percoll, plasma membranes were observed to be contaminated by a Percoll constituent which prevented further purification and biochemical identification of the lipids extracted from these membrane fractions to be carried out. A second method of plasma membrane preparation was tested consisting first in the coating of the cell surface with positive colloidal silica which was stabilized by an anionic polymer. Then, and through differential centrifugations, plasma membrane fractions were easily obtained within less than 1 h, with a yield of 65% and an enrichment ratio of 7. The coating pellicle was quantitatively removed thus enabling any biochemical manipulation of the plasma membrane to be carried out. The lipids present in the plasma membrane of CHO cells were analyzed and are described, both in terms of headgroup and acyl chain composition.


Effect of calcium channel antagonists on renal function in hypertensive heart transplant recipients. Orthotopic heart transplant recipients treated with immunosuppressive regimens based on cyclosporine have a high incidence of hypertension. Cyclosporine-induced nephrotoxicity characterized by afferent glomerular arteriolar vasoconstriction also develops in these patients. Calcium channel antagonists produce afferent glomerular arteriolar vasodilation. Angiotensin-converting enzyme inhibitors (ACEI) dilate the efferent arteriole and have been suggested to decrease glomerular filtration rate in subjects taking cyclosporine. To test the hypothesis that calcium channel antagonists would improve glomerular filtration rate in heart transplant patients receiving ACEI treatment, we reviewed the charts of our patients whose treatment for hypertension had been changed from an ACEI to a calcium channel antagonist. A change in renal function was assessed by the average of serum creatinine level, blood urea nitrogen, and creatinine clearance within 3 months before and after the change from ACEI to calcium channel antagonist. Blood pressure was assessed on two different occasions before and after conversion to calcium channel antagonist. The data were analyzed by a paired Student t test. Serum blood urea nitrogen and creatinine levels decreased significantly when patients were treated with calcium channel antagonists (p < 0.05). Creatinine clearance increased in all patients when the treatment was converted to a calcium channel antagonist (CCA) (ACEI = 56.4 +/- 19.3 ml/min versus CCA = 71.06 +/- 23.77, N = 9; p < 0.005). A 5-mm Hg decrease occurred in mean arterial pressure when treatment was changed from ACEI to calcium channel antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of retinoids on phosphatidylethanolamine lipid polymorphism. The interaction of all-trans-retinoic acid and all-trans-retinol with dielaidoylphosphatidylethanolamine has been studied by differential scanning calorimetry and 31P-NMR spectroscopy. Increasing concentrations of all-trans-retinoic acid up to a mol fraction of 0.09 were found to induce shifts to lower temperatures of both the L beta to L alpha and L alpha to hexagonal-HII phase transitions, with a slight decrease in the enthalpy change of the transitions. At higher concentrations no further effects on the transitions were observed, and this is interpreted as indicative of a limited miscibility of retinoic acid with the phospholipid. 31P-NMR spectroscopy confirmed that the L alpha to hexagonal-HII phase transition was shifted to lower temperatures in the presence of retinoic acid. On the other hand increasing concentrations of all-trans-retinol up to a mol fraction of 0.166, induced a progressive shift of the L beta to L alpha and the L alpha to hexagonal-HII phase transitions to lower temperatures. At higher concentrations the main gel to liquid-crystalline phase transition was further displaced to lower temperatures and the lamellar to hexagonal-HII phase transition was not observed in the thermograms. 31P-NMR spectroscopy indicated that retinol was able of inducing the phospholipid to adopt the hexagonal-HII phase at temperatures even below the main gel to liquid-crystalline phase transition temperature of the pure phospholipid.


Structure and activity studies of pardaxin and analogues using model membranes of phosphatidylcholine. Thirteen synthetic pardaxin analogues were assayed for their ability to interact with model membranes of phosphatidylcholine. The results suggested the following: An amphipathic alpha-helix from isoleucine-14 to leucine-26 is responsible for most of the membrane perturbing properties of pardaxin. A hydrophobic N-terminal region enhances the activity of the isoleucine-14 to leucine-26 alpha-helix by binding the pardaxin molecule to the lipid bilayer. A bend centered around 12Ser-13Pro appears to create overall amphipathicity for the two different helical regions of pardaxin, but this contributes only slightly to potency. The C-terminal amino acids are unimportant for membrane perturbing activity and may be present only to enhance transportation in an aqueous environment prior to membrane binding in the native system.


Evidence for antibody and immune-complex deposition in heart transplantation: a report of three cases. Immunofluorescence microscopy of endomyocardial biopsy specimens from heart allograft recipients identified immunopathologic changes in three of 17 patients. These changes included immunoglobulin G and complement C3 deposition in tissue structures such as capillary endothelium and basal membranes, cardiomyocyte sarcolemma, and interstitial tissue. Moreover, the immunopathologic changes could be correlated with acute cellular rejection episodes evidenced by endomyocardial biopsy criteria.


Interaction of synthetic glycophospholipids with phospholipid bilayer membranes. A series of glycophospholipids synthesized by coupling mono-, di-, or tri-saccharides to dioleoylphosphatidylethanolamine (DOPE) by reductive amination was used to investigate the interaction of glycophospholipids with phospholipid bilayer membranes. These synthetic glycophospholipids functioned as a stabilizer for the formation of DOPE bilayer vesicles. The minimal mol% of glycophospholipid needed to stabilize the DOPE vesicles were as follows: 8% N-neuraminlactosyl-DOPE (NANL-DOPE), 20% N-maltotriosyl-DOPE (MAT-DOPE), 30% N-lactosyl-DOPE (Lac-DOPE), and 42% N-galactosyl-DOPE (Gal-DOPE). The estimated hydration number of glycophospholipid in reverse micelles was 87, 73, 46, and 14 for NANL-DOPE, MAT-DOPE, Lac-DOPE, and Gal-DOPE, respectively. Thus, the hydration intensity of the glycophospholipid was directly related to the ability to stabilize the DOPE bilayer phase for vesicle formation. Glycophospholipids also reduced the transition temperature from gel to liquid-crystalline phase (Tm) of dipalmitoylphosphatidylcholine (DPPC) bilayers. Interestingly, incorporation of NANL-DOPE induced a decrease of membrane fluidity of DPPC bilayers in the gel phase while other glycophospholipids had no effect. Also, low level of NANL-DOPE but not other glycophospholipids increased the transition temperature (TH) from liquid-crystalline to hexagonal phase of dielaidoylphosphatidylethanolamine bilayers. These results showed that NANL-DOPE with a highly hydratable headgroup which provides a strong stabilization activity for the L alpha phase of phospholipid membranes, may also be involved in specific interactions with neighboring phospholipids via its saccharide moiety.


Effect of bovine prothrombin fragment 1 on the translational diffusion of phospholipids in Langmuir-Blodgett monolayers. Previous work has shown that bovine prothrombin fragment 1 binds to supported planar membranes composed of phosphatidylcholine and phosphatidylserine in a Ca(2+)-specific manner (Tendian et al. (1991) Biochemistry 30, 10991; Pearce et al. (1992) Biochemistry 31, 5983-5995). In the present work, fluorescence pattern photobleaching recovery has been used to examine the effect of membrane-bound fragment 1 on the translational diffusion coefficients of two fluorescent phospholipids in fluid-like phosphatidylserine/phosphatidylcholine Langmuir-Blodgett monolayers. The results show that saturating concentrations of fragment 1, in the presence of Ca2+, reduce the diffusion coefficient of nitrobenzoxadiazolyl-conjugated phosphatidylserine (NBD-PS) and nitrobenzoxadiazolyl-conjugated phosphatidylcholine (NBD-PC) by factors of approximately four and two, respectively. Ca2+ or fragment 1 alone do not have a statistically significant effect on NBD-PS or NBD-PC diffusion. In addition, a nonspecific protein (ovalbumin) does not change the diffusion coefficients of the fluorescent phospholipids either in the absence or presence of Ca2+. The fractions of the fluorescent phospholipids that are laterally mobile are approximately 0.9 for all samples. These results are interpreted with several models for possible mechanisms by which extrinsically bound proteins might retard phospholipid diffusion in membranes.


Comparative theoretical study of the conformations of amphotericin methyl ester and amphotericin B polar heads in the presence of water. Amphotericin methyl ester (AmE) is an interesting derivative of amphotericin B (AmB) because of its enhancement of selectivity against the fungicells. Both AmB and AmE molecules differ by the structure of their polar heads. This work deals with a theoretical study of conformations of the polar head of AmE in the presence of hydration water molecules. The results will be compared with our previous work concerning AmB.


Ethanol effects on the stratum corneum lipid phase behavior. The stratum corneum is considered to be the diffusional barrier of mammalian skin for water and most solutes. The intercellular lipid multilayer domains of the stratum corneum are believed to be the diffusional pathway for most lipophilic solutes. Fluidization of the lipid multilayers in the presence of ethanol is frequently conceived to result in enhanced permeation. Current investigations address the effect of ethanol on the phase behavior in terms of stratum corneum lipid alkyl chain packing, mobility and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy. Phospholipid multilamellar vesicles were also studied as model systems. There appeared to be no effect of ethanol on either the solid-solid phase transition or the gel phase interchain coupling of the stratum corneum lipids. However, there was a reduction in the mobility of the alkyl chains in the presence of ethanol. Possible mechanistic relationships between the current FTIR spectroscopic results with available literature data of ethanol induced lipophilic solute penetration enhancement through the skin are discussed.


The stratum corneum lipid thermotropic phase behavior. The stratum corneum, the outermost layer of mammalian skin, is considered the least permeable skin layer to the diffusion of water and other solutes. It is generally accepted that the intercellular lipid multilayer domain is the diffusional pathway for most lipophilic solutes. Fluidization of the lipid multilayers is believed to result in the loss of barrier properties of the stratum corneum. Current investigations address the lipid thermotropic phase behavior in terms of lipid alkyl chain packing, mobility and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy. A solid-solid phase transition is observed with increased alkyl chain mobility followed by a gel to liquid-crystalline phase transition near 65 degrees C. These results further elucidate the role of lipid fluidity that may contribute to the transport properties of the stratum corneum.


The functions of Myc proteins.

The functions of Myc proteins. The functions of Myc proteins have remained a mystery for a number of years. Recent data have now provided us with a clear working hypothesis of how myc may act. What appears to be still missing is a link between the biochemical properties of this oncoprotein and its observed biological effects. Further research will be necessary to fill this void.


Determination of (22R,S)budesonide in human plasma by automated liquid chromatography/thermospray mass spectrometry. (22R,S)Budesonide was isolated from human plasma by solid-phase extraction. Switching from reversed-phase conditions during sample application and washing to normal-phase conditions during elution afforded a very clean extract. Budesonide was derivatized with acetic anhydride to form the 21-acetyl derivative before analysis by reversed-phase liquid chromatography combined with thermospray mass spectrometry. Deuterium-labelled budesonide was used as internal standard. Standard samples prepared in human albumin solution were used for the calibration curve. An automated liquid chromatography/mass spectrometry system, allowing unattended overnight operation, was used for routine analysis. The recovery of budesonide from plasma was 88.9 +/- 5.9% (mean +/- SD) and the method was linear over the range 0.30-30 pmol (amount analysed), corresponding to plasma concentrations of 0.10-10 nmol l-1. Budesonide could be measured down to 0.10 nmol l-1 with a within-day variation of 10-18% (CV). The error was less than +/- 15% at 0.10 nmol l-1 and less than +/- 7% at concentrations of 0.20 nmol l-1 or higher. The total imprecision between days was 9% (CV) at a concentration of 0.30 nmol l-1.


Identification and quantitation of an oxidative metabolite of labetalol in sheep: pharmacokinetic and metabolic implications. A sensitive and selective assay has been developed for the identification and quantitation of 3-amino-1-phenyl butane (3-APB), a metabolite of labetalol, in biological fluids using electron impact gas chromatography/mass-selective detection. Samples were extracted with n-hexane, derivatized with heptafluorobutyric anhydride and chromatographed on a cross-linked fused-silica capillary column. A positive EI spectrum was obtained using a mass-selective detector. Identification of the metabolite was accomplished using an authentic standard; quantitation was performed in the selected ion monitoring mode using ions m/z 345 (M+) and 132. The assay was linear over the calibration range of 0.5-1000 ng of the analyte and the intra-sample coefficients of variation were less than 12% in all cases. The absolute recovery of 3-APB following extraction from urine and bile was found to be 102.9 +/- 4.9% and 98.3 +/- 1.45% (mean +/- SEM) respectively. The minimum quantitation limit of the assay was 0.5 ng ml-1 (approximately 2 pg injected). Application of the assay in a pharmacokinetic-pharmacodynamic study of labetalol in sheep is demonstrated. The metabolite was detected in urine and bile samples obtained from adult non-pregnant sheep following labetalol administration. The cumulative amount of 3-APB excreted in urine over 24 h was found to be 71.55 micrograms in one animal following a 100 mg dose of labetalol. Evidence for biliary excretion, glucuronidation and sulfation of 3-APB was also found.


Gas chromatographic/mass spectrometric analysis of stable isotopes of 3-methylhistidine in biological fluids: application to plasma kinetics in vivo. A simple and rapid method for measuring 3-methylhistidine (3MH) in plasma and urine is described. Internal standard, 1-methylhistidine (1MH), was added to plasma, acidified and absorbed onto cation-exchange columns. It was then eluted from columns, dried, and derivatized for gas chromatography/mass spectrometry. A major fragment of 3MH was monitored at 238 u and 3-methyl-(methyl-2H3)histidine (d3-3MH) (used for in vivo kinetics) at 241 u, whereas 1MH was monitored at 340 u and eluted 0.5 min later than 3MH. Standard curves for plasma analysis were linear and nanamole amounts of 3MH in plasma were determined with a precision of 3.5%. 3MH was also quantitated in urine; however, because of substantial amounts of 1MH, (18O2)1MH was used as the internal standard. Nanamole amounts of 3MH were determined in urine with a precision of 2.7%. Application of the 3MH analytical method was used to develop a kinetic compartmental model by using the stable isotope of 3MH, d3-3MH. Cattle, like humans, quantitatively excrete 3MH in the urine. A young bovine was injected with d3-3MH and the enrichment curve in plasma was evaluated in order to obtain a steady-state production rate of 3MH. The decay curve was modeled through the use of NIH-SAAM modeling program. The kinetics of d3-3MH from plasma were adequately described by a three-pool compartmental model. The de novo production rate of 3MH estimated in the calf was 665 mumol per day. This corresponded to an estimated fractional turnover rate of 1.56% per day, which was similar to estimates obtained from urine collections.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of peptides of human seminal plasma by mass spectrometry. A procedure is described to isolate peptides from complex biological fluids (e.g. seminal plasma) in pure form within a short time. The sequence of the isolated peptides was determined by liquid secondary ion mass spectrometry in combination with enzymatic cleavage reactions. The method was used for the structure elucidation of a peptide of molecular weight 2766 u with an N-terminal pyroglutamine residue.


Fragmentations of dipeptides in plasma desorption mass spectrometry: new rules for the sequence elucidation of oligopeptides. 252Cf plasma desorption mass spectrometry is well suited for determining both composition and sequence of unknown small oligopeptides. A systematic study of a large number of dipeptides first leads to establishing common rules of fragmentation from positive ion mass spectra. These rules are then applied to the sequence elucidation of larger peptides.


Laser microprobe mass spectrometric identification of cyclosporin-induced intrarenal microliths in rat. Using laser microprobe mass analysis (LAMMA), the composition of 'micro-calcifications (dystrophic type)' or 'metastatic calcifications', previously described in rats given high doses of cyclosporin, have been identified. Female Wistar rats given 12.5, 25 or 50 mg kg-1 per day of cyclosporin in olive oil by gastric gavage developed intrarenal calcifications detected by silver nitrate staining (von Kossa) in the outer medulla after two weeks. The calcifications stained red with periodic acid-Schiff reagent and appeared to be intraluminal microliths with concentric laminations. They could be identified by LAMMA as calcium phosphate (hydroxyapatite), indistinguishable from undecalcified bone. These studies indicate that intraluminal obstruction by calcium phosphate microliths, similar to that seen with magnesium depletion or high phosphate diets, may contribute to renal damage in rats given high-dose cyclosporin. LAMMA appears to be an appropriate technique for identifying both the elemental and organic moieities of intrarenal calcium deposits.


[Space-occupying lesions of the orbit: modern imaging diagnosis]. The paper summarises imaging of orbital diseases by CT and MRI. As localisation is an important clue to differential diagnosis in orbital tumours, the different pathologies are described according to sites of prevalent occurrence. Morphological criteria of orbital pathology are described, and the more frequent entities are illustrated.


[Quality control of laser imagers].

[Quality control of laser imagers]. Multiformat imagers based on laser systems are used for documentation in an increasing number of investigations. The specific problems of quality control are explained and the persistence of film processing in these imager systems of different configuration with (Machine 1: 3M-Laser-Imager-Plus M952 with connected 3M Film-Processor, 3M-Film IRB, X-Rax Chemical Mixer 3M-XPM, 3M-Developer and Fixer) or without (Machine 2: 3M-Laser-Imager-Plus M952 with separate DuPont-Cronex Film-processor, Kodak IR-Film, Kodak Automixer, Kodak-Developer and Fixer) connected film processing unit are investigated. In our checking based on DIN 6868 and ONORM S 5240 we found persistence of film processing in the equipment with directly adapted film processing unit according to DIN and ONORM. The checking of film persistence as demanded by DIN 6868 in these equipment could therefore be performed in longer periods. Systems with conventional darkroom processing comparatively show plain increased fluctuation, and hence the demanded daily control is essential to guarantee appropriate reaction and constant quality of documentation.


[The influence of the spectrum and the type of exposure on the contrast of double-sided coated x-ray film]. The present article describes the circumstances concerning the use of testing aids such as sensitometers with one-sided exposure. It is shown which phenomena must be considered if radiographic films coated on both sides are exposed with a) standard pocket sensitometers (one-sided exposure), b) lab sensitometers (double-sided exposure to ANSI Ph 2.9 [1964]), c) x-radiation in the cassette, intensifying screen and film system (to DIN 6867 T 1). The effect of the emission spectrum on the resulting contrast factor is described. The importance of different emulsion technologies (e.g. orthochromatic anticross-over films) for the contrast factor with one-sided exposure is described. The cross-over factor (c.o.), the apparent variation in sensitivity of the front and back emulsion with one-sided exposure, is the cause of the reduction in the contrast factor (G average) as against double-sided exposure: delta G(%) = c.o.2 x 10(3)/8.4


[The place of computed tomography and magnetic resonance tomography in the diagnosis of bone sequestra]. Conventional radiographs of 45 patients with chronic osteomyelitis, mostly of posttraumatic origin, were compared with computed tomography (CT) and operative findings. In addition, magnetic resonance imaging (MRI) was performed in 6 of these patients. In 28 patients (65%) bony sequestra were identified and in most cases histologically confirmed by surgical exploration. CT proved to be the method of choice for the preoperative diagnosis of sequestra in patients with chronic osteomyelitis. MRI provided no significant additional diagnostic information, its advantage appears to be a more detailed and accurate imaging of the extent of the intra- or extraosseous inflammation, thereby facilitating surgical planning.


[Potentialities and limitations of MR angiography in the imaging of intracranial aneurysms]. The potential value of MR angiography in imaging of intracranial aneurysms was analyzed in seven patients. Six cases were confirmed by angiography or computed tomography. In one patient MR angiography was not useful in distinguishing bleeding from an aneurysm. Five aneurysms were imaged by 3D angiography, one was diagnosed by 2D angiography. The extent of thrombosis was evaluated by selective presaturation. MR angiography was a useful non-invasive method in imaging of intracranial aneurysms. However, for complete work-up angiography is mandatory.


[Differential diagnosis of angiodysplasias using angiography and CT with special reference to the MR tomographic aspects]. The basic prerequisite for a rational therapy of angiodysplasia is differentiated diagnostics, especially the differentiation between arteriovenous malformations, haemangiomas, and venous malformations. Angiography reveals the arterialisation, arteriovenous fistulas, CT infiltrations of bone and soft-tissue. MRT demonstrates completely the extent of haemangiomas because of its bright signal intensity in the T2-weighted images. Hence, differentiation of malignant vessel tumours and malformations with rapid blood flow is possible, because the signal intensity is much lower in MRT. The three supplementary methods allow a correct diagnosis of angiodysplasia.


[Roentgeno-morphologic changes in the bones of battered children]. The demonstrated characteristic bone lesions should raise the suspicion of "battered child syndrome". The important role of the radiologist is stressed.


[The problem of diffuse cranial hyperostosis following cerebral trauma in early childhood--a case report]. This is a report on an uncommon case of cranial hyperostosis with generalised considerable thickening of the calvarium. As a consequence of a cerebral trauma in early childhood the patient developed an intracerebral haematoma. Subsequently a disturbance of brain growth with posttraumatic, symptomatic epilepsy was noted. The anticonvulsant long-term treatment was mainly based on dilantin (diphenylhydantoin). Two different reasons for the distinct skull changes in the present case must be taken into consideration. Firstly, a widening of the dipole induced by dilantin, and secondly, a compensatory thickening of the vault with alterations of the skull base as seen in cerebral atrophy or after relieved hydrocephalus. These mechanisms are discussed with regard to the relevant literature.


[Pachymeningeosis(-itis) haemorrhagica chronica interna]. A case of chronic internal haemorrhagic pachymeningeosis, a rare disease with uncharacteristic clinical appearance is presented. Derived from pathomorphological and histological findings, the typical CT appearance is described and main differential diagnoses are marked off by their characteristic criteria.


[Lymphangioleiomyomatosis].

[Lymphangioleiomyomatosis]. A female patient is presented with a history of asthma, recurrent pneumothoraces and chylothoraces. A CT of the chest revealed typical thin-walled cysts of lymphangioleiomyomatosis. The suggested diagnosis was confirmed histologically. CT is exceptionally suited to narrow down the scope of differential diagnosis of interstitial lung diseases.


[Lobular carcinoma of the breast in magnetic resonance tomography. A case report]. The invasive lobular carcinoma of the breast, the incidence of which is 10-15 per cent, occupies a special position in respect of histological differentiation and biological behaviour. No MR signal enhancement was seen after contrast medium application in the tumoral tissue in the case described here, namely, an invasive lobular carcinoma of the breast of 2 cm size. Hence, it is not always possible to exclude with absolute certainty the presence especially of an invasive lobular carcinoma of the breast in the absence of contrast medium uptake.


[Iopamidol-300/370 in galactography--a clinical comparative study]. From 12. 1988 to 6. 1990 we carried out on 27 patients at the Department of Gynaecology of the University of Freiburg an open study to compare the two water-soluble, nonionic, monomeric contrast agents (Iopamidol-300 corresponding to Solutrast-300 and Iopamidol-370 corresponding to Solutrast-370) with different osmolality (616 mosm/kg H2O resp. 799 mosm/kg H2O) and concentration (300 mg I/ml resp. 370 mg I/ml). It is a remarkable fact that the contrast quality in the x-rays was higher for Iopamidol-300. Complications such as hypersensitivity reactions or local irritations were not recorded. Iopamidol-300 was found to be the best tolerated of the two contrast media in respect of mildest intensity of pain.


[Advice on the x-ray positioning of the upper and the lower leg]. Roentgenographic images of the femur and tibia to demonstrate the bones in two true right-angled projections (anteroposterior, lateral view) can be obtained by using a small hydrostatic level with two levels positioned at right angles against each other. By taping the small plastic device to the skin of the leg under examination, rotation of the limb between the two x-ray exposures can be controlled and adjusted to exactly 90 degrees. Compared to other common positioning procedures (rotation of the leg to approximately 90 degrees by the patient; angulation of the x-ray tube to 90 degrees around the leg) this method yields the highest accuracy of adjustment.


The health assessment questionnaire 1992: status and review. Over 100 papers describing and utilizing the Stanford Health Assessment Questionnaire (HAQ) have been published since 1980. A brief overview of the HAQ is presented along with a guide to the accumulated literature. The topics covered include: studies using the disability, pain, economic, and drug side effect dimensions of the HAQ; reliability and validity studies; applications to various rheumatic diseases; language adaptations; modifications and derivative scales; studies correlating the HAQ with sociodemographic, health status, laboratory, and physical measures; and randomized controlled trials and observational studies using the HAQ. A few comments regarding future directions for research are also presented.


Sensitivity to change of the health assessment questionnaire (HAQ) and other clinical and health status measures in rheumatoid arthritis: results of short-term clinical trials and observational studies versus long-term observational studies. To obtain evidence concerning short-term and long-term efficacy of clinical and health status measures in rheumatoid arthritis (RA), we conducted two observational studies--a 6-month study of 233 patients receiving methotrexate and a 10-year study of 157 patients receiving multiple treatments in a rheumatic disease clinic. Results of the 6-month study yielded effect sizes for treatment similar to the meta-analyses reported by Felson [corrected] et al. (Arthritis Rheum 33:1449-1461, 1990) and the controlled trials of methotrexate reported by Weinblatt et al. (Arthritis Rheum 33:330-338, 1990), suggesting that observational studies provide valid measurements of treatment effect. The effect size for the Health Assessment Questionnaire (HAQ) was 0.5. By contrast, the 10-year study suggested that standard clinical variables changed little and were not useful in assessing RA outcome, while the effect size of the HAQ was -2.39. These data continue to underscore the differences between short-term trials and the long-term outcome of RA, and suggest an important place for the HAQ or similar instruments in all phases of RA evaluation and assessment.


Comparison and sensitivity to change of self-report scales to assess difficulty, dissatisfaction, and pain in performing activities of daily living over one and five years in rheumatoid arthritis. We analyzed the longitudinal sensitivity to change of three self-report activities of daily living (ADL) scales over 1 and 5 years in 982 patients with rheumatoid arthritis (RA) from 15 private practices. Over 1 year, the ADL difficulty status worsened in 28.3% of the patients, remained the same in 50.2%, and improved in 21.5%. Over 5 years, 41.3% worsened, 38.8% stayed the same, and 19.9% were improved. Similar percentages for 1- and 5-year changes were found for the ADL dissatisfaction and pain scales. The effect sizes for change over 1 and 5 years for the ADL difficulty, dissatisfaction, and pain scales were--(-)0.05, 0.01, and -0.02, and -0.28, -0.20, and -0.14, respectively, indicating small to moderate declines. These data indicate that the three ADL scales are sensitive to change in status, and ADL change status scores after 1 and 5 years were significantly correlated with each other (r = 0.49-0.68, all p < 0.001). Monitoring of these three constructs may be helpful in the longitudinal evaluation of some patients with RA.


Does musculoskeletal function deteriorate in a predictable sequence in the elderly? A variety of functions decline with aging, but whether losses occur in a predictable sequence is unknown. Improved understanding might facilitate the early detection and possible prevention of functional deterioration. We assessed self-reported difficulty with functional tasks in 288 community-dwelling elderly aged 65 to 97. We hypothesized that the ability to perform tasks involving strength, skill, and endurance (run errands, shop, yardwork or housework) would be lost first, followed by activities requiring less strength or mobility (rise from a chair with no hands, walk), followed by easier, but essential tasks (pick up clothes, rise from bed, lift a cup to the mouth). The patterns of decline were evaluated with Guttman scalograms. Picking up clothes and walking were reversed from the predicted order. Scale reliability was 0.92, indicating that functional decline is ordered; 75% of subjects fell into one of the modal sequence types. Analysis by self-reported presence of arthritis showed that 83% of nonarthritic subjects fit the predicted patterns (reliability = 0.95) versus 65% of arthritic subjects (reliability = 0.86), who tended to lose hand ability out of sequence. Sequential functional loss scales may tell more than the typical simple summation of functional loss, and may have predictive value to the clinician monitoring an elderly patient. If the sequence is accelerated or out of order, such as was seen in patients with arthritis, it may indicate the need for intervention. Examination of sequences of loss may help characterize adaptations to impairment and differences among subgroups.


Scoring methods and application of the activity record (ACTRE) for patients with musculoskeletal disorders. The National Institutes of Health (NIH) Activity Record (ACTRE) has been used to document daily activities in patients with musculoskeletal disorders. Quantification of the amount of time spent resting and physically active, the intensity of pain and fatigue associated with patterns of activities, and motivational considerations are possible with the ACTRE. Scoring has been streamlined to permit identification of the amount of pain, fatigue, and motivational factors as they relate to activity patterns (e.g., rest and physical activity). The ACTRE provides a performance-based, quantifiable measure of daily activity.


Arthritis problem indicator: preliminary report on a new tool for use in the primary care setting. Improving the quality of life for people with rheumatic disease involves timely identification of problem areas and application of appropriate interventions. In response to a 1987 Commonwealth of Pennsylvania study, which reported a wide variety of unmet needs in arthritis patients and their families, the Arthritis Problem Indicator (API) was developed. It is a single-page, self-report, low-cost tool. A mixed rheumatology population (n = 50) and their primary care physicians participated in a pilot study. The study revealed that the seven most common areas of patient concern were pain, weight control, sleep, mobility/walking, activities of daily living, community access, and depression/anxiety. The physicians reported that the patient's answers on the API led them to initiate new treatment or referral for 32% of the patients. The physicians also stated that for 80% of the patients, the API was helpful in providing information about the patient. The API is easily interpreted by health professionals and designed to be an indicator of problem areas frequently associated with arthritis.


Do self-reported arthritis symptom (RADAR) and health status (AIMS2) data provide duplicative or complementary information? This study assessed whether self-report measures of symptoms and functional health status provide unique outcome information, or whether functional status assessments primarily serve as a proxy for self-reported arthritis symptoms. Symptom scores of 138 individuals with rheumatoid arthritis (RA) collected with the Rapid Assessment of Disease Activity in Rheumatology (RADAR) measure were compared with same-day functional health scores collected with the recently revised Arthritis Impact Measurement Scales (AIMS2). Correlational and factor analyses revealed that self-assessed arthritis symptoms, physical function and work impact, psychological status, and social health each made independent contributions to outcome. Satisfaction with health status was shown not to be independent of symptoms, functional capacity, or psychological status. It is important to document that self-reported symptom and health status information, when collected concurrently, provides complementary rather than duplicative information.


Quality of life and policy analysis in arthritis. Problems in the American health care system have stimulated interest in cost-effectiveness methodologies. However, there is little consensus on how to define a common unit of health outcome. Many measures used in policy studies consider only mortality and do not fully capture the significant impact of disease-related dysfunction. The impact of conditions, such as osteoarthritis, that have little impact on mortality rates but substantial impact on functioning and well-being may be underestimated in these analyses. In this article, we propose a measurement and policy model that is based on a theoretical conceptualization of health outcome. The model considers the impact of disease and its treatment in terms of both morbidity and mortality. The value of the model for clinical trials, population assessments, and policy analysis is reviewed. A public policy application of the model in Oregon is briefly described.


Characterizing the meaning of psychological distress in rheumatoid arthritis. Symptoms of depression are frequently reported by people with rheumatoid arthritis (RA). To advance our understanding of how best to assess and treat these symptoms, their meaning must be elucidated. This article explores two possible meanings for the emotional distress of RA patients reported on the Center for Epidemiological Studies Depression (CES-D) scale: (1) Certain CES-D scale items may inflate actual depressive symptom scores. (2) Depressive symptoms are experienced and/or expressed in unique ways in an RA population due to the presence of chronic physical symptoms. In this study of 988 people with RA, it was found that there is some modest inflation of the CES-D scale due to the items of "having difficulty getting going" and "everything was an effort." However, irrespective of the modest inflation of the scale, there is evidence that distress in RA is not a static concept. Distress in this RA population was expressed differently from that of a community population, and within the RA population, distress was expressed differently over time.


Pathology of malignant lymphomas.

Pathology of malignant lymphomas. Although the subject is now seldom formally addressed, much of the pathologic research into malignant lymphoma is still tacitly directed at developing a rational and reproducible classification. Pure morphology, while remaining of critical importance in the diagnosis of malignant lymphomas, has been exhausted as a means of understanding the biology of these tumors, which must be the eventual basis of a firm, enduring and clinically relevant classification. Thus, histopathologists have turned first to immunohistochemistry and now to molecular genetics to make sense of their morphologic observations. Correlation of various genetic (including oncogenetic) rearrangements with morphology has preoccupied pathologists this past year and has led to important advances in the understanding of B- and T-cell lymphomas. Lymphomas occurring in a setting of immunodeficiency, whether therapeutically induced or acquired, have received special attention, and the possible role of the Epstein-Barr virus in their pathogenesis has induced pathologists to develop exciting in situ molecular hybridization techniques for its identification in tissues. The certainties underlying the diagnosis and classification of Hodgkin's disease (in which Epstein-Barr virus also appears to play a role), formally the only truly secure area for pathologists, have been disturbed, and the borderline between Hodgkin's disease and non-Hodgkin's lymphoma is now seriously blurred. The lymphoma pot has been well and truly stirred; we must now wait to see what the new sediment offers.


Advances in the treatment of Hodgkin's disease. Through the careful application of appropriate staging procedures and treatment modalities, at the beginning of the 1990s about 75% of patients with Hodgkin's disease can expect long-term remission or even cure. At present, radiotherapy remains the best therapeutic option for localized stages while advanced disease is cured by chemotherapy alone or chemotherapy combined with irradiation. In this decade, the challenge in the management of Hodgkin's disease will probably be represented by an optimal use of reasonably short-term chemotherapy regimens combined with limited-field irradiation in early stages and by an accurate evaluation of the best chemotherapy regimens for advanced disease. In the search for the optimal approaches to improve current therapeutic results, appropriate considerations should be given to the identification of effective treatment modalities with a minimum amount of acute and late toxicity.


T-cell leukemia-lymphoma and mycosis fungoides. Notable efforts have been made to relate aspects of the cell biology of T cells to the pathology, diagnosis, and treatment T-cell neoplasms. In particular, the application of molecular biologic tools to these areas has already allowed the generation of patient-specific markers for disease. A case can be made that a knowledge of the distinctive natural history of T-cell neoplasms should influence choices of treatment. Additional insights into the relevance of the human T-cell leukemia-lymphoma virus family to human disease have been recorded, and an important association of cutaneous T-cell lymphoproliferative disorders with human immunodeficiency virus infection has been documented.


Chemotherapy for non-Hodgkin's lymphoma. The term non-Hodgkin's lymphoma (NHL) refers to a diverse group of illnesses that have in common a high frequency of chemotherapy sensitivity. In fact, high-grade NHL was among the first cancers to be cured with chemotherapy. Although the curability of patients with low-grade NHL remains debatable, all patients with intermediate- and high-grade NHL should be approached with curative intent, even if they present with advanced disease. Our ability to treat patients with NHL is steadily improving. There have been significant advances in our understanding of the biology of the disease and our ability to predict treatment outcome. New treatments and innovative uses of already available treatments are regularly reported. This paper reviews the highlights of the past year's literature regarding the treatment of patients with NHL.


Biologic response modifiers: therapeutic approaches to lymphoproliferative diseases. Some biologic agents have proven effective in the treatment of lymphoproliferative diseases by stimulating host antitumor immunity or by applying active antitumor properties that specifically or nonspecifically effect tumor growth or tumor survival. These agents include interferons, which regulate cell gene expression, structure, and function; interleukin-2, which has several functions related to lymphoproliferation and mediation of lymphoid cell transport; anti-idiotype antibodies, which appear to cause a specific antiproliferative response against the patient's tumor; anti-idiotype vaccines, which produce cyclic complementary binding sites and idiotypes to induce specific immunity to tumors with resultant antitumor activity; radioisotope labeled monoclonal antibodies, which directly deliver tumoricidal doses of radiation to tumors, sparing normal tissue toxicity; and monoclonal antibody-immunotoxin conjugates, which directly deliver tumoricidal doses of radiation to tumors, sparing normal tissue toxicity. Encouraging results have been seen in clinical studies with these agents and much knowledge has been gained regarding the mechanisms involved. These findings dictate ongoing therapy modifications to produce continuing progress in the therapeutic applications of biologic agents in lymphoproliferative disease processes.


Prognostic factors in non-Hodgkin's lymphoma. There is an emerging consensus on the importance of identifying non-Hodgkin's lymphoma patients with different prognoses so that these patients can be optimally treated and the relative benefits of different therapeutic approaches can be adequately assessed. This review of recent publications on prognostic factors in lymphoma will summarize papers identifying: 1) clinical features associated with prognosis in specific subgroups of lymphoma patients; 2) the prognostic significance of pathologic and immunologic subclassification; 3) prognostic features predictive for relapse from complete response; and 4) newly identified prognostic features, including cytogenetic abnormalities, serologic parameters, and aberrant expression of adhesion molecules.


Clinical aspects of Kaposi's sarcoma.

Clinical aspects of Kaposi's sarcoma. Kaposi's sarcoma is the most common tumor found in patients with the acquired immunodeficiency syndrome. This opportunistic neoplasm has characteristics of a sexually transmitted disease. Growth factors, cytokines, immune suppression, and interaction with infectious organisms all appear to play a role in the pathogenesis of this enigmatic disorder. The manifestations of Kaposi's sarcoma are protean, and lesions may appear at any time in the course of human immunodeficiency virus disease, remain localized and asymptomatic, or spread aggressively and cause morbidity. Treatment, which must be individualized, ranges from observation, local therapy with cosmetic makeup, and cryotherapy with liquid nitrogen or local intralesional injection of agents, to radiotherapy and systemic therapy with interferon-alpha and cytotoxic chemotherapy.


The epidemiology of acquired immunodeficiency syndrome-related lymphomas. Approximately 3% of acquired immunodeficiency syndrome cases present with non-Hodgkin's lymphoma. By 6 to 8 years after human immunodeficiency virus infection, lymphoma risk is elevated 100-fold, and the risk approaches 1% per year following acquired immunodeficiency syndrome diagnosis. The proportions presenting as lymphoma differ by age, sex, and race, with relative rates being higher in older persons, males, and whites. The differences are similar in magnitude and direction to those seen in non-human immunodeficiency virus-infected persons and account for the variation by risk group. The relative risk of high-grade lymphoma is greatest, but significant increases are also seen for some intermediate-grade tumors. At diagnosis, persons with Burkitt's lymphoma, more common in children, have significantly higher average CD4 counts than those with immunoblastic tumors. Human immunodeficiency virus-associated lymphoma risk is probably related to dysregulation of the immune system leading to uncontrolled proliferation of transformed cell clones and subsequent genetic accidents. Environmental factors are unlikely to be important. By 1994, 10% of all lymphomas will be human immunodeficiency virus related, but this proportion will increase in the future. New approaches to the therapy of lymphoma are needed for this tumor, which we can neither prevent nor adequately treat.


Clinical aspects of human immunodeficiency virus-related lymphoma. As patients with human immunodeficiency virus infection live longer because of better antiretroviral therapy and infection prophylaxis, the incidence of non-Hodgkin's lymphoma has increased. The risk increases inversely with CD4 count--the most widely used surrogate marker for progressive immune suppression. Zidovudine itself does not appear to be a risk factor. Patients frequently present with extranodal advanced disease. The central nervous system is the primary site in 10% to 20% of cases. Important prognostic factors are performance status, a prior history of acquired immunodeficiency syndrome, and bone marrow involvement. Therapy is complicated by underlying immunosuppression, opportunistic infection, and poor bone marrow reserve. Progress has been made using colony-stimulating factors and less intensive chemotherapy regimens in systemic non-Hodgkin's lymphoma. Treatment of primary central nervous system lymphoma with radiation therapy has not improved survival.


Biologic aspects of human immunodeficiency virus-related lymphoma. A high frequency of lymphoma in human immunodeficiency virus-infected individuals has been reported since the outbreak of the acquired immunodeficiency syndrome (AIDS) epidemic in 1982. In the vast majority of cases, these lymphomas are highly aggressive B-cell, non-Hodgkin's lymphoma of intermediate or high grade of malignancy. AIDS-associated non-Hodgkin's lymphoma are histologically classified as small noncleaved cell lymphoma, large cell immunoblastic plasmacytoid lymphoma, or large noncleaved cell lymphoma. Host factors predisposing to lymphoma development in AIDS patients include decreased immunosurveillance as well as human immunodeficiency virus-induced chronic perturbation of the immune system leading to cytokine overproduction and increased B-cell stimulation. These alterations are associated with the development of multiple oligoclonal B-cell expansions, which are characterized by persistent generalized lymphadenopathy. The presence of Epstein-Barr virus within a persistent generalized lymphadenopathy clone further increases the risk of its neoplastic transformation. The appearance of non-Hodgkin's lymphoma is characterized by the presence of a monoclonal B-cell population displaying several genetic lesions, including monoclonal Epstein-Barr virus infection, c-myc rearrangements, Ras mutations, and p53 inactivation. The number and type of lesions varies among the different types of AIDS-non-Hodgkin's lymphoma, defining multiple alternative molecular pathways in AIDS-associated lymphomagenesis.


Human immunodeficiency virus as a risk factor in miscellaneous cancers. The association of malignancies, such as non-Hodgkin's lymphoma and Kaposi's sarcoma, with human immunodeficiency virus infection has been recognized since the beginning of the epidemic. However, an increasing number of tumors not diagnostic of acquired immunodeficiency syndrome has been described in this setting. Taking into consideration that survival of patients with human immunodeficiency virus infection is increasing because of improvement of supportive care and better control of human immunodeficiency virus and related opportunistic infections, oncogenic viruses such as human papillomavirus, hepatitis B virus, Epstein-Barr virus, in a setting of prolonged immunosuppression could increase the risk of a variety of malignant tumors.


Risk factors, epidemiology, screening, and prognostic factors in female genital cancer. This review, which due to limitations of space cannot be exhaustive, summarizes the recent literature on risk factors and epidemiology, screening and prognostic factors in a cervical, ovarian, and endometrial cancer. There have been a large number of pertinent publications during this period and this paper summarizes and highlights recent advances in the identification of women at particularly high risk of developing gynecologic cancer, analyzes studies on early detection and screening, and reviews prognostic studies with particular reference to selection of therapy according to risk of relapse and likelihood of benefit.


Surgery for gynecologic malignancies.

Surgery for gynecologic malignancies. The surgical management of invasive and preinvasive gynecologic malignancies continues to evolve at a brisk pace. Several good techniques are available for the treatment of preinvasive cervical disease, including cryotherapy, loop electrocautery excision, laser therapy, and standard knife conization. The use of radical surgery for early invasive cervical cancer has been extended to older women, and complications have been minimized. There has been a significant trend toward more conservative surgery in the management of invasive vulvar cancer. The new surgical staging system for endometrial cancer has generated much controversy. The importance of thorough surgical staging for ovarian cancer is clear, and our understanding of the role of cytoreduction has increased. The role of new techniques, including operative laparoscopy, is being defined in the management of gynecologic cancers.


Radiotherapy for gynecologic malignancies. This review highlights the curative potential of radiation in gynecologic malignancies. The controversies concerning the role of surgery in the management of bulky cervical cancer is discussed. Prognostic factors associated with improved pelvic control with radiation alone are described, particularly the bulk of pelvic disease, which is not accounted for in the current International Federation of Gynecology and Obstetrics staging system. The potential for integration of radiation and chemotherapy into the management of vulvar cancer to improve cosmesis and function as well as to reduce the risk of locoregional recurrence is described. The role of whole abdominal radiation in the management of advanced endometrial and ovarian cancers as well as the role of hyperfractionation to reduce acute morbidity of large abdominal fields is reviewed. Prognostic factors associated with locoregional and distant failure for endometrial cancer are outlined and the new pathologic staging system is critically analyzed. Finally, the treatment of vaginal cancer with radiation alone (external beam plus interstitial-intracavitary radiation) or surgery is reviewed and the prognostic importance of the present modifications to the vaginal staging system are emphasized.


Systemic therapy for gynecologic cancer. Over the past year, a number of important papers have appeared in the medical literature dealing with the chemotherapeutic management of gynecologic cancers. Among these papers, several studies have again demonstrated the superiority of platinum-based chemotherapy regimens for ovarian cancer compared with non-platinum-containing regimens, and have confirmed the equivalence of carboplatin to cisplatin in advanced disease. A number of trials have reported activity for intraperitoneal chemotherapy regimens in patients with small-volume residual disease. In endometrial cancer, combination cisplatin-based chemotherapy programs have been reported to achieve an overall 40% to 50% objective response rate. Although induction chemotherapy has been advocated in the management of advanced localized cervical cancer, this conclusion has yet to be supported by the results of randomized trials. The etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine regimen has been demonstrated to be highly effective in patients with high-risk gestational trophoblastic tumors. Finally, a recent report has demonstrated that it is possible to perform conservative surgery in patients with germ cell tumors to preserve fertility without compromising therapeutic efficacy.


Biology and therapy with biologic agents in gynecologic cancer. Growth of epithelial ovarian cancer is influenced by several factors including transforming growth factor-alpha and transforming growth factor-beta, macrophage colony stimulating factor, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, c-erb B-2 (HER-2/neu), and mutant p53. Continued expression of the epidermal growth factor receptor, new expression of c-fms, and overexpression of HER-2/neu are associated with a poor prognosis. A number of cytokines have been used to treat patients with ovarian cancer, including interferon-alpha, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2. Judging from preclinical models, interferon-gamma may be more active than interferon-alpha against human ovarian cancer. Although tumor necrosis factor-alpha can stimulate proliferation of some ovarian cancers, the cytotoxic activity of tumor necrosis factor-alpha has been amplified ex vivo by inhibitors of protein synthesis. Similar heterogeneity exists with regard to interleukin-1 where stimulation or inhibition of cell proliferation has been observed. Tumor-infiltrating lymphocytes from ascites fluid contain cells capable of major histocompatibility complex-restricted and major histocompatibility complex-nonrestricted cytotoxicity. Tumor-infiltrating lymphocytes and interleukin-2 have been combined with cytotoxic chemotherapy to treat advanced or recurrent disease. Bispecific monoclonal antibodies that react both with T cells and ovarian tumor cells have produced tumor inhibition in human tumor xenografts. Immunotoxins that contain OVB3 and pseudomonas exotoxin have been evaluated in a phase I clinical trial. Dose-limiting central neurotoxicity has been observed without tumor regression. A monoclonal antibody designated OVX1 has been developed against a high-molecular-weight mucinlike molecule associated with ovarian cancers.(ABSTRACT TRUNCATED AT 250 WORDS)


Biology of breast cancer and its clinical implications. Several established prognostic factors are used routinely in the clinical management of breast cancer. These factors include extent of axillary lymph node involvement, tumor size, histologic differentiation, and estrogen and progesterone receptor status. Unfortunately, these factors are not perfect predictors of outcome for the individual patient. This review highlights recent advances in the field of breast cancer biology that may ultimately improve our ability to predict prognosis more accurately, select therapy more appropriately, and possibly identify women who are at high risk for breast cancer development. In particular, studies addressing mechanisms of estrogen and antiestrogen resistance, clinical utility of flow cytometry, roles of certain oncogenes and tumor suppressor genes in breast cancer growth, and biologic factors involved in invasion and metastases are reviewed.


Early detection, epidemiology, and prevention of breast cancer. Control of breast cancer will ultimately be achieved through a better understanding of the epidemiology of the disease and application of primary prevention. Until then, use of screening mammography offers the promise of a 30% reduction in breast cancer mortality, which continues to be shown by screening studies with prolonged follow-up. Biologic markers of cancer risk, including nipple aspirates and cyst fluid, suggest that a complete risk profile can be developed using fluid and tissue obtained from the normal breast. Epidemiologic studies of dietary factors and geographic differences in breast cancer risk continue to provide promising leads relating to the etiology of the disease. Increasing evidence suggests that circulating androgens and estrogens affect breast cancer risk, whereas exogenous estrogen therapy does not increase risk except for small subgroups of women at risk. Increasing understanding of the genetics of breast cancer will have an impact on the disease in the near future. The greatest impact in the short term will come from the use of tamoxifen for primary prevention of breast cancer. The retinoids, particularly N-(4-hydroxyphenyl)retinamide, hold great promise as agents for primary prevention.


The surgery of early breast cancer.

The surgery of early breast cancer. This review highlights important issues for surgeons treating early breast cancer. The optimal use of ovarian ablation, the value and timing of radiotherapy for breast preservation, and axillary dissection are considered. New information on the importance of local surgery, even for older women, and the biology of small (up to 10 mm), screen-detected cancers has been recently reported. The value of support services for women having breast cancer surgery is stressed.


Systemic adjuvant therapy for breast cancer. Systemic therapy for operable breast cancer can delay the time to recurrence. Recurrence of breast cancer can follow a variable clinical course but will lead to death in virtually all cases. This delay is reflected in an accompanying improvement in overall survival with treatment. Almost 35 years have passed since the introduction of adjuvant chemotherapy, whereas adjuvant tamoxifen trials were begun 17 years ago. In that time, only in a minority of patients has a clear consensus emerged on the appropriate use of adjuvant therapies. Overview analysis from large numbers of controlled clinical trials has produced a much larger data base for examining the effects of hormonal and cytotoxic therapy on the outcome of patients with early-stage breast cancer and provides greater statistical power to detect small differences in particular subgroups of patients, which may not have been apparent in individual studies. Patients with involved lymph nodes are now routinely treated with chemotherapy if they are premenopausal and with tamoxifen if they are postmenopausal, especially if their tumors contain estrogen receptor. More recent trials attempt to examine the use of these therapies outside of these prescribed groups as well as the introduction of new chemotherapeutic agents and dosage regimens, some of which are based on biologic principles of alternating, non-cross-resistant therapy and dose responsiveness. Treatment of node-negative breast cancer remains controversial. Small but real differences in odds of relapse have emerged with adjuvant treatment, although the nature of the risks and benefits remains to be defined.


Metastatic breast cancer and its complications. Tamoxifen is now established for use in premenopausal as well as postmenopausal patients. Recent reports have not shown its activity to be enhanced by the addition of either prednisolone, progestogens, or interferon. Reversible ocular toxicity from tamoxifen appears to be more common than had been previously realized. Different schedules giving the same dose intensity of doxorubicin give markedly different pharmacokinetic profiles. Although this does not lead to differences in responses or physical toxicity, it seems to have important implications for quality of life. Taxol is showing impressive activity in advanced breast cancer, and significant response rates have also been reported for carboplatin and podophyllotoxin derivatives. To achieve maximum effectiveness from the cyclophosphamide, methotrexate, and fluorouracil combination, attention to schedule and dose intensity has been shown to be important. No new effective cytotoxic combinations have been described. High-dose chemotherapy requiring bone marrow support remains experimental. Further progress has been made in monitoring the response of metastatic bone disease to treatment. The precise significance for patients of the results in many of the papers reviewed is often uncertain because they lack quality-of-life measures; the importance of this approach is emphasized.


Psychosocial aspects of breast cancer.

Psychosocial aspects of breast cancer. Over the past year, several research areas have been noteworthy. This article discusses several reports on psychiatric morbidity and psychological factors of breast cancer, quality-of-life issues related to breast cancer treatment, and psychological factors in breast cancer screening. An area of increasing interest includes studies examining the psychological status and breast cancer screening practices of women at increased risk of developing breast cancer, primarily as a function of family history.


Cisplatin and platinum analogues: recent advances. Cisplatin is a critically important antineoplastic agent employed in treating patients who have a broad spectrum of neoplasms. Resistance to this agent poses a serious clinical dilemma. The objective of this review is to summarize the principal mechanisms that contribute to cytotoxicity by this agent and underlie resistance. Knowledge of these processes provides a rational basis for developing therapeutic strategies to circumvent resistance.


Antitumor antibiotics, epipodophyllotoxins, and vinca alkaloids. This paper reviews manuscripts published from June 1991 to June 1992 that, in the author's opinion, have added to the understanding and clinical use of a group of commonly used antineoplastic agents. New developments highlighted include 1) clarification of the mechanism of action of the anthracyclines and epipodophyllotoxins, 2) evaluation of tests used for the early detection of bleomycin pulmonary toxicity, 3) results of studies on the epidemiology and prevention of anthracycline-induced cardiomyopathy, 4) the potential use of therapeutic drug monitoring to predict etoposide toxicity, and 5) identification of drug interactions that alter the pharmacokinetics of the epipodophyllotoxins.


Antimetabolites.

Antimetabolites. Research efforts over the past year further elucidate the determinants of sensitivity and mechanisms of resistance to the antimetabolites fluorouracil, methotrexate, and cytarabine. Progress has been made in clarifying the complex regulation of target enzyme expression for these antimetabolites. Advances in analytical methodology should facilitate quantitation of thymidylate synthase content in tumor tissue prior to and following fluorouracil-based therapy. Information concerning the basis for certain drug interactions may guide rational dose rates and schedules for clinical trials. A better understanding of the clinical pharmacology of these agents has suggested strategies to minimize their toxicity while maintaining therapeutic activity.


Recent developments in radiotherapy.

Recent developments in radiotherapy. Radiation oncology is a dynamic discipline. The radiobiologic basis for understanding and anticipating treatment effects continues to grow. Improved understanding is permitting study of altered fractionation regimens and safer integration into the clinic of high-dose-rate brachytherapy. A new agent, SR 4233, may completely revise clinical approaches to tumor hypoxia, especially intermittent (or "dynamic") hypoxia. The availability of computer technology that permits three-dimensional treatment planning with unusual beam and treatment table orientations should result in isodose lines that conform very tightly to desired treatment volumes, permitting higher doses of treatment with acceptable normal-tissue risk. The biology of cytotoxic drug and irradiation interactions and of cytokine and irradiation interactions is an area of growing promise. Combined chemotherapy and radiotherapy treatments have, in the past year, suggested major improvements in the management of esophageal and laryngeal cancer. The importance of local and regional tumor control in contributing to clinical disease course is being understood with increasing clarity, validating the development of technically demanding new approaches to administering irradiation and the use of adjunctive radiotherapy following chemotherapy for selected neoplastic diseases.


Modulation of chemotherapy antineoplastic agents with biologic agents: enhancement of antitumor activities by interleukin-1. Cytokines or biologic response modifiers in combination with traditional chemotherapeutic agents can be used as therapeutics in patients with cancer. Biologic response modifiers, which are involved in the control and regulation of a wide variety of physiologic activities, have previously been used primarily to enhance or boost host immunologic function. Although immune modulatory therapeutic approaches are yet to be fully realized, biologic response modifiers have also been considered in combination with cytotoxic drugs for their effects on hematopoietic progenitor cells, tumor cells directly, and microvascular endothelial cells. Interleukin-1 is a multifunctional cytokine that not only activates the immune system but also plays a central role in regulating hematopoiesis, has potent effects on vascular function, and has shown significant antitumor activity alone or in combination with various chemotherapeutic agents. As a result, interleukin-1 is an excellent candidate for combination with conventional antineoplastic drugs toward the design of innovative therapeutic approaches to malignancy. This review examines the studies using preclinical animal tumor models as well as the recent phase I clinical trials and includes an overview of their potential for further application.


New biologic agents come to bat for cancer therapy. Biologic therapies are playing an increasingly important role in the treatment of patients with cancer. A better understanding of immune responses to tumors now exists, and more defined reagents are now available including new recombinant cytokines, cultured lymphoid cells of defined specificity, and most recently, vectors containing specific genes that can be introduced either into tumor cells or lymphoid effectors. During this past year, we have observed the reporting of new cytokines identified and tested in humans and the advent of cytokine gene therapy. The successful application of these new reagents either singly or in combination will require significant ingenuity, resources, and intuition over the next decade.


Immunotherapy with cytokine gene-transduced tumor cells: the next wave in gene therapy for cancer. Recently, new tumor vaccine approaches were developed in animal systems that modify tumor cells genetically to secrete certain cytokines. Engineering tumor cells to secrete cytokines in a paracrine fashion can induce powerful local cytokine effects without producing significant systemic toxicity. In addition to local inflammation, this approach can alter the presentation of tumor antigens or activation of tumor antigen-specific T lymphocytes, resulting in systemic antitumor immunity. The development of high efficiency gene transfer technologies such as defective retroviral vectors allows for the translation of these preclinical studies to clinical trials. However, before large investments are made in this area of gene therapy, it will be important to demonstrate that the actual gene transfer component of the strategy significantly enhances antitumor immune responses relative to alternative nongenetic approaches.


Targeted delivery of biologic and other antineoplastic agents. This review summarizes several strategies under investigation for targeted delivery of antineoplastic agents to tumor cells, which avoids normal tissue damage. Monoclonal antibodies remain the molecules of choice for targeted therapy, and several improvements to immunotargeting are discussed. These improvements include the use of novel radioisotopes, cytokines, new linkers for chemotherapeutic drugs, more potent drugs, and improved immunotoxins. Bifunctional antibodies, in which one antigen-binding site recognizes a tumor-associated antigen and the other an antineoplastic agent, have been investigated for radioimmunotherapy and for the activation of cytotoxic cells for targeted immunotherapy. The activation of relatively nontoxic prodrugs by antibody-enzyme conjugates is increasingly being investigated in an effort to reduce the systemic toxicity associated with conventional chemotherapy. Finally, the use of liposomes as carriers of drugs or as activators of macrophages is described.


[Pregnancy in renal transplant recipients. Long-term evaluation of their children]. The course of eight pregnancies in seven renal transplant patients was analyzed. Immunosuppression consisted of Azathioprine and Prednisone. Pregnancy lasted from 32 to 39 weeks and the fetal development corresponded to the gestational age in every case. There were three cases which had complications during the pregnancy. One case had severe arterial hypertension, proteinuria and pedal edema, which was thought to be due to pre-eclampsia. Another patient had cholestatic jaundice and premature fissure of membranes and the third patient also had this last complication. Four patients had vaginal deliveries and in four cesarean section was performed. Renal function did not deteriorate during any of the pregnancies nor during the follow-up period, but the expected increase in creatinine clearance was not found. Clinical evaluation of the children, 4 months to 8 years of age, did not disclose any abnormalities.


Successful pregnancy in a severe hypertensive patient treated with nitrendipine. Case report. Nitrendipine (NIT), a new potent calcium channel blocking agent, was administered to a patient with essential severe (191/119 mm Hg), refractory, and resistant hypertension (HT) to conventional triple drug regime. Three previous pregnancies had been unsuccessful in the past 4 years because of uncontrollable HT and repeated hypertensive crises. NIT (20 mg tablets) was given PO as a single morning dose and 15 months after BP control, she became pregnant again. With a 20 mg/day dose of NIT throughout pregnancy, a healthy 2400 g, 47 cm male boy was delivered by a non-emergency cesarean section at 37 weeks' pregnancy. Both mother and son remain normal months after birth. The results suggest NIT may be considered as an alternative for this type of patients and should be studied in clinical trials.


[Chronic manganese poisoning: autoradiographic quantification of cholinergic muscarinic receptors in mouse brain]. Chronic administration of manganese chloride (5 mg Mn/kg body weight/day) during nine weeks, did not affect the [3H]-quinuclidinyl benzilate binding to muscarinic cholinergic receptors in mouse brain. The quantitation and anatomical distribution of the receptors were determined by autoradiographic methods on coronal sections of midbrain and olfactory bulb. It is concluded that, in our experimental conditions, no alteration in the density of the muscarinic cholinergic receptors is produced in the brain of manganese intoxicated mouse.


[Teratogenic effect of the Venezuelan equine encephalitis virus: a review of the problem]. Clinical findings on Venezuelan Equine Encephalitis virus infection and the teratogenic effects of several Togaviruses are described. Similarities between the intrauterine alterations induced by Venezuelan Equine Encephalitis virus and rubella virus are pointed out. Findings described by Wenger in 1967 were those of massive cerebral necrosis in fetuses of women presumably suffering of encephalitis and they are commented along with the development of an animal experimental model at the end of 1970-1980. Pathogenesis of the intrauterine infection seemed to be related to changes in the placental vessels, vascular changes in the central nervous system were also described in rats surviving Venezuelan Equine Encephalitis experimental infection; similar changes were described in the brain of children with post rubella syndrome. The need for multidisciplinary studies in the endemic areas of Venezuelan Equine Encephalitis in order to detect sequelae of the viral effects in utero is emphasized. Finally, some experimental animal models are proposed to examine diverse aspects on intrauterine effect of Venezuelan Equine Encephalitis virus.


The use of computer-assisted diagnosis in cardiac-perfusion nuclear medicine studies: a review. The use of computer-assisted diagnosis has become widespread in cardiac nuclear medicine. Quantitative programs are commercially available for ventriculography, phase analysis, and thallium 201 perfusion studies. The goal of these programs is to eliminate interobserver variability by objectively analyzing the studies without causing a loss of accuracy. In addition, by using quantitative data not apparent on visual inspection, some programs attempt to increase sensitivity for disease above that possible by the visual reading of images. Programs that analyze perfusion studies to detect coronary artery disease have received the most interest. Results have varied, but sensitivities as high as 95% have been reported. This review discusses the techniques of computer-assisted diagnosis for thallium 201 myocardial-perfusion studies. The circumferential and washout profile methods are discussed in detail.


Cooperative image workstation based on explicit models of diagnostic information requirements. A medical image workstation designed to act as a cooperative dialogue partner in diagnostic radiology has been conceived, and a prototype has been made. The system can automatically select relevant information (eg, from current and previous examinations) and generate a meaningful and appropriate image arrangement on the display screen. For a number of routinely performed tasks in radiology, the users' interaction may be as simple as switching from one patient to the next. This is shown to considerably simplify and speed up radiological image access and presentation, saving the user time and effort. The cooperative system response is based on explicit (formalized and computer-accessible) models of diagnostic information requirements. These models are context dependent and take into account that diagnostic information needs vary with radiological work procedures, workstation users, and patient cases. Initial models have been acquired from expert radiologists in two European hospitals and were integrated in a cooperative workstation prototype. For the representation of models, rule-based and object-oriented techniques were applied. The rule base was designed with a distinct modular structure, separating between rule sets for general, task-dependent, and user-dependent information requirements. The installed rule-based mechanism also offers a solution for the automatic prefetching of images to avoid transmission delays in the course of diagnostic work sessions. The first part of the report reviews the objectives for the design of cooperative workstation user interfaces and explains the benefits from the users' point of view. In the second part, the acquisition, structuring, formalization, and representation of context-dependent information requirement models is described. The rule-based model is explained using examples. A layered workstation architecture consisting of model, object, and real-time layers is presented. Difficulties in the implementation of cooperative workstations are discussed that point to future research topics and standardization efforts.


Enhancement of chest images by automatic adaptive spatial filtering. Postprocessing of the image data is an exciting capability of digital radiography that may improve diagnostic performance. We present a new algorithm that selectively enhances edges and contrast in both lungs and mediastinum while minimally amplifying noise in chest images. Using different size kernels, two smoothed images are generated from the original chest image. The two regions of interest (lungs and mediastinum) are identified based on the distribution of pixel values in the image. A modified nonlinear unsharp mask subtraction technique is then applied. The resulting image has enhanced high- and middle-frequency information in the mediastinum without distorting lung parenchyma or significantly enhancing noise. We consider that the technique employed in this study could be suitable for routine use although its true effectiveness in improving diagnostic accuracy awaits observer-performance evaluation that is currently under way.


Three-dimensional display of hepatic venous anatomy generated from spiral computed tomography data: preliminary results. A new method is presented for generating three-dimensional images of the hepatic venous anatomy from helical computed tomography (CT) scans using volumetric rendering. The helical CT scans were obtained using peripheral injection of intravenous contrast via a power injector. Five patients with suspected liver tumors were studied from which one sample case was selected for illustration. Surgical planning of hepatic resection from three-dimensional images will soon become a practical part of patient care.


Demonstration of digital radiographs by means of ink jet-printed paper copies: pilot study. Different digital medical images have been printed on paper with a continuous ink jet printer, and the quality has been evaluated. The emphasis has been on digital chest radiographs from a computed radiography system. The ink jet printing technique is described as well as the handling of the image data from image source to printer. Different versions of paper prints and viewing conditions were compared to find the optimum alternative. The evaluation has been performed to maximize the quality of the paper images to make them conform with the corresponding film prints and monitor images as much as possible. The continuous ink jet technique offers high-quality prints on paper at a considerably lower cost per copy compared with the cost of a film print. With a future switch-over from diagnosing of digital images on film to diagnosing them on monitors, hard copies for demonstration purposes will occasionally be needed. This need can be filled by ink jet-printed paper copies.


Subsystem throughputs of a clinical picture archiving and communications system. We measured the throughtput rates of individual picture archiving and communications system (PACS) subsystems including the acquisition, archive, display, and communication network as a basis of evaluation the overall throughput of our clinical PACS. The throughput rate of each PACS subsystem was measured in terms of average residence time of individual images in the subsystem. The residence time of an image in a PACS subsystem was determined by the total time the image was required to be processed within the subsystem. The overall throughput of the PACS was measured as the total residence time of an image in the various subsystems. We also measured throughputs of the PACS subsystems using three types of networks (Ethernet; fiber distributed data interface; and UltraNet, UltraNetwork Technologies, San Jose, CA), and the results were compared. Approximately 200 gigabytes of data transactions including magnetic resonance, computed tomography and computed radiography images from our PACS were analyzed. Results showed that PACS throughput was limited by three major factors: (1) low-speed data interface used in the radiologic imaging devices and archive devices; (2) competition for systems processing time among the PACS processes; and (3) network degradation caused by heavy network traffic. We concluded that PACS performance could be improved with a well-designed network architecture, a job prioritizing mechanism, and an image routing strategy. However, device-dependent low-speed data interface has limited PACS performance.


Comparison of three different techniques for dual-energy subtraction imaging in digital radiography: a signal-to-noise analysis. Dual-energy subtraction imaging techniques allow the tissue and bone structures in the patient to be visualized and studied in two separate images, thus removing the obscurity associated with overlapping of the two structures. In addition, they allow the subtraction image signals to be used for quantifying the tissue and bone thicknesses. Thus, capability for dual-energy subtraction imaging is often incorporated with new digital radiography systems. There are three different approaches to dual-energy image subtraction imaging techniques. Among them, the dual-kilovolt (peak) [kV(p)] and sandwich detector techniques have been two widely used approaches. A third approach is the single-kV(p) dual-filter technique, which allows some flexible control of the spectra while avoiding the technical complexity of kV(p) value switching in slit-scan imaging. In this report, the noise properties associated with these three techniques are studied and compared by computing the noise variances in the subtraction image signals as a function of the kV(p) values and filter thicknesses. It was found that the dual-kVp technique results in the least noisy subtraction images, whereas the dual-filter technique results in slightly less noisy subtraction images than the sandwich detector technique. Following optimization of the kV(p) value and filter thicknesses, the dual-filter and sandwich detector techniques result in a noise level of approximately three and four times higher than that resulted from the dual-kV(p) technique, respectively.


Salmonella enteritidis in commercial layer farms in New York state; environmental survey results and significance of available monitoring tests. Seven hundred fifty-one environmental samples were collected from 76 chicken layer houses in a voluntary Salmonella enteritidis (SE) survey study carried out in New York state between January 15 and April 8, 1991. SE was recovered from both houses on 1 farm. Sampling of manure pits and mice in hen houses was useful for SE screening. Phage types of SE from the environment, birds, and mice were identical. The rapid whole-blood test was unreliable, and culture of cloacal swabs was inadequate for detection of SE carriers. Culture of organs from chickens did not correlate well with results of environmental samples.


Use of ELISA to detect toxigenic Pasteurella multocida in atrophic rhinitis in swine. The use of an enzyme-linked immunosorbent assay (ELISA) as a means of detecting dermonecrotoxin-producing strains of Pasteurella multocida was investigated. The assay was evaluated as a means to identify toxigenic P. multocida isolates recovered from nasal secretions of swine with atrophic rhinitis. The sensitivity and specificity of the ELISA for detecting dermonecrotoxin-producing P. multocida strains were compared to those of mouse-inoculation and cytotoxicity assays. The ELISA was highly sensitive and more specific than animal inoculation or tissue culture assay and is thus a more effective method for screening swine herds for the presence of toxigenic strains of P. multocida. The ELISA is a rapid, effective, economical way to identify toxigenic P. multocida isolates.


Mycobacterium bovis infection in North American elk (Cervus elaphus). A naturally occurring outbreak of Mycobacterium bovis infection in captive wild elk (wapiti) in Montana was confirmed by mycobacteriologic examination. Twenty-eight of 143 elk responded to M. bovis purified protein derivative (PPD) tuberculin injected intradermally in the cervical region (SCT). The results of comparative cervical tuberculin skin tests conducted within 9 days of SCT revealed greater responses to M. bovis PPD tuberculin than to M. avium PPD tuberculin in 23 of 28 elk responding. At necropsy, several grossly visible tuberculous lesions were observed in the parenchyma of the lung, thoracic lymph nodes, and submandibular lymph nodes. Microscopic examination of appropriately stained tissue sections revealed the presence of granulomatous lesions containing acid-fast bacilli. An enzyme-linked immunosorbent assay (ELISA) was developed using a sarkosyl extract of M. bovis (antigen) and peroxidase-labeled protein G (conjugate); reactions were detected in the sera of 8 of 9 elk responding to M. bovis PPD tuberculin. Lymphocyte blastogenic assay responses were detected using M. bovis antigens in 7 of 9 elk positive on skin tests using M. bovis PPD.


Gross and microscopic lesions of naturally occurring tuberculosis in a captive herd of wapiti (Cervus elaphus nelsoni) in Colorado. A Mycobacterium bovis-infected herd of captive wapiti (Cervus elaphus nelsoni) in Colorado was depopulated after lesions of bovine tuberculosis were confirmed in 8 of 10 tuberculin skin test reactors. Of the 43 animals > 1 year of age, 26 had gross lesions suggestive of tuberculosis, 24 had microscopic lesions of tuberculosis, and 23 had acid-fast bacilli associated with the lesions. Lungs and retropharyngeal lymph nodes were the most frequently affected sites. Most lesions grossly and microscopically resembled tuberculosis in cattle; however, some lesions resembled abscesses or ovine caseous lymphadenitis lesions. Special stains and immunohistochemical techniques labeled few to numerous mycobacteria associated with the lesions.


Bovine plasma beta-mannosidase activity and its potential use for beta-mannosidosis carrier detection. Plasma beta-mannosidase activities were determined for Salers cattle from 8 herds as an evaluation of this method for detection of beta-mannosidosis heterozygotes. Several biological factors, such as age, gender, herd, and risk of being a beta-mannosidosis carrier, were considered in this study. The mean enzyme activity for obligate heterozygotes (n = 8) was 55 U/ml (range = 43-65 U/ml), which was 59% of the mean enzyme activity for cattle that were low risk for being a carrier. These data indicate that bovine beta-mannosidosis is characterized by a gene dosage effect. The analytical and biological variation of plasma beta-mannosidase activity that was observed necessitates limiting the test to adult fullblood/purebred Salers cattle within a herd. Plasma beta-mannosidase analysis provides important information for intraherd selection of Salers cattle that are heterozygous for beta-mannosidosis.


Confirmation of indandione rodenticide toxicoses by mass spectrometry/mass spectrometry. Mass spectrometry/mass spectrometry (MS/MS) with collision-activated dissociation (CAD) was utilized to unequivocally distinguish 1,3-indandione rodenticides in 2 cases of anticoagulant toxicosis. Anecdotal evidence provided by the veterinarian in a case involving feedlot cows and physical evidence at the site of occurrence in a similar case involving lambs strongly implicated diphenadione (diphacinone; DP) in both instances. However, high performance liquid chromatography indicated chlorophacinone (CP), not DP, was present in the blood samples obtained from both cows and lambs. Intact 1,3-indandiones exhibit poor gas chromatographic properties, so procedures were developed for analysis by MS/MS using a direct exposure probe for sample introduction. The EI mass spectra of DP and CP contained a base peak at m/z 173, with molecular ions (M+) at m/z 340 and m/z 374 (Cl isotope cluster), respectively. Corresponding MS/MS CAD parent ion spectra of m/z 173 showed an ion of m/z 340 for DP and 374 (Cl cluster) for CP. CAD analysis of the blood extracts showed a parent ion scan of m/z 173 identical to that of CP, with the m/z 374 (Cl cluster). (Additional evidence was obtained by MS/MS examination of the CAD daughter ion spectrum of m/z 374.) Blood extracts from the affected animals revealed CAD daughter ion spectra for m/z 374 identical to that of reference CP. Positive confirmation of CP in both cases led to identification of the source of the toxicant and prevention of further animal exposures.


Transhiatal esophagectomy.

Transhiatal esophagectomy. THE is a versatile procedure that has become indicated for a variety of disease processes over the past two decades; amongst these indications are to treat many benign and malignant esophageal diseases, as well as for use in restoring gastrointestinal continuity after extensive pharyngeal or laryngopharyngeal resections. Careful and meticulous handling, formation, and transposition of the gastric tube are essential to the development of a well-perfused neo-esophagus. Present studies indicate acceptable morbidity and mortality of THE compared with transthoracic resections for carcinoma of the esophagus. There appears to be no significant detriment in overall long-term survival when THE is used as primary resection therapy for malignant esophageal disease.


Results of standard left thoracoabdominal esophagogastrectomy. The left thoracoabdominal incision is approaching its first century of use. Although less popular than the Ivor Lewis and transhiatal techniques, it continues to be a useful approach for esophageal or gastric tumors near the gastroesophageal junction. For these tumors, the incision provides excellent exposure, and maximizes reconstructive options during esophagogastrectomy. The incision has a proven track record of safety and is well-tolerated.


The BFM-protocol for HIV-negative Burkitt's lymphomas and L3 ALL in adult patients: a high chance for cure. During a period of 9 years we used the pediatric BFM-NHL protocol for treatment of 14 adult patients with Burkitt's lymphoma or L3 acute lymphoblastic leukemia. Ten of 14 patients obtained a complete remission including 5/8 with stage-IV disease or B-ALL. After a median follow-up of 55 months none of these ten patients relapsed. The projected survival after 8 years is 71%. Toxicity was moderate, with one early death; a tumor lysis syndrome occurred in four patients. From our experience we conclude that the BFM-NHL protocol is very effective in adult patients, with a high cure rate and acceptable toxicity, even in advanced stages of disease.


Increased risk of second cancers in managing Hodgkins disease: the 20-year Leiden experience. Between January 1969 and December 1988, 482 patients were treated for Hodgkin's disease at the Leiden University Hospital. All cases were routinely recorded in the Hospital Information System, which has an active annual follow-up. Of all patients, 57% remained relapse free. According to the kinds of treatment they received, the following major categories were established: radiotherapy only (28.2%), chemotherapy only (20.1%), only initial combination of radiotherapy and chemotherapy (34.2%), all other combinations of radio- and chemotherapy (15.4%), or not registered (2.1%). Twenty-seven second cancers were observed; six leukemias, five non-Hodgkin lymphomas, and 16 solid tumors. Of all solid tumors only nine occurred in relapse-free patients. The overall relative risk of second cancers increased with the duration of follow-up. Using general population incidence rates to calculate expected numbers, the risk for developing leukemia, non-Hodgkin lymphoma, and solid tumors was increased 36-fold, 31-fold, and 2.4-fold, respectively. The cumulative risk of developing a second cancer 10 years after diagnosis of Hodgkin's disease was 7% for both the radiotherapy-only and the initial combination of radio- and chemotherapy group. It was 16% and 17% for the chemotherapy-only and the other combinations of radio- and chemotherapy group, respectively. Multivariate analysis (using the Cox regression model) show an increased risk of second cancers (RR = 0.7) when a relapse of Hodgkin's disease resulting in increasing cumulative therapy occurred. Age at diagnosis of Hodgkin's disease was an important determinant for the risk of non-Hodgkin lymphoma and solid tumors. Cumulative chemotherapy intensity was an important factor in increasing leukemic risk in a dose-response fashion. Apart from this, the stage of Hodgkin's disease, although closely related to the kind of therapy, seemed to have an independent effect on leukemic risk.