Understanding the pathophysiology of intra-uterine growth retardation: the role of the 'lower limb reflex' in redistribution of blood flow. Doppler ultrasound was used to investigate the circulatory redistribution and underlying reflex responses of fetal cardiovascular compensation in 30 small-for-gestational age (SGA) fetuses. The utero-placental bed, umbilical artery and vein, thoracic and abdominal aorta, internal and external cerebral arteries were evaluated. The values were compared to reference ranges constructed from 135 normal pregnancies, correlated to fetal blood gases obtained by cordocentesis and compared to the outcomes. In Group I (mortality and morbidity), all fetuses had loss of end-diastolic frequencies (L-EDF) in the abdominal aorta (100%), but only 20 (87%) and 13 (56%) had L-EDF in the thoracic aorta and umbilical artery respectively. High vascular resistance in the placental bed and low impedance in the middle cerebral and common carotid arteries was found in 14 (61%), 12 (52%) and 20 (87%) fetuses, respectively. In Group II (Healthy infants) two fetuses had high utero-placental vascular resistance and one had brain-sparing. Doppler indices did not always reflect fetal hypoxaemia demonstrating that redistribution in SGA fetuses may not be triggered by a fall in pO2, and that hypoxaemia is an associated pathology but may not be the underlying cause. It is postulated that redistribution in SGA fetuses is regulated by reflex mechanisms (the 'lower limb reflex') which result in severe vasoconstriction in the abdominal aorta, mesentery and carcass, favouring the brain and cardiac muscles. This mechanism explains the good predictive value of L-EDF in the abdominal aorta for poor neonatal outcome (sensitivity, specificity and positive predictive value, all 100%).(ABSTRACT TRUNCATED AT 250 WORDS)


A comparative study of intramuscular ketorolac and pethidine in labour pain. A single dose block randomised double-blind study comparing intramuscular ketorolac, 50 mg of pethidine and 100 mg pethidine was carried out in multiparous women. Pain intensity and sedation effect were recorded at inclusion to the study, half hourly for the first 2 h, then hourly until 6 h after delivery. Maternal and neonatal side effects were noted including the Apgar scores and the baby's requirements for resuscitation. All three treatments are relatively ineffective in relieving labour pain. There was no difference in the analgesic efficacy between the two doses of pethidine but both doses of pethidine were statistically more effective compared with ketorolac. There was no difference in the retrospective assessment of the three groups or when comparison was made with the previous labour. A similar number of patients required further analgesia in each group. In all three groups, no adverse effect occurred in the mother or fetus. Maternal sedation and fetal depression were statistically less in the ketorolac group. Although ketorolac had inferior analgesic effect, its use was not associated with clinically significant sequelae and it showed a superior safety profile compared with either dose of pethidine. The study was not powerful enough to detect a difference between 50 mg and 100 mg of pethidine.


Reduced albumin binding of MADDS--a measure of bilirubin binding--during pregnancy and delivery. It was the purpose of the present study to investigate whether the decrease in the ability of plasma albumin to bind bilirubin, noted in pregnancy and during delivery, takes place in one step, during pregnancy alone, or in two steps, during both pregnancy and delivery. Furthermore, it was investigated whether a possible decrease during labor was related to the method of delivery itself. The material comprised (a) 17 pregnant women who delivered vaginally; (b) 25 women who were delivered by Cesarean Section; and (c) a group of 25 non-pregnant women. The reserve albumin concentration for binding of MADDS (a measure of the binding of unconjugated bilirubin), the total albumin concentration and the ratio between them were constant in the 6-week period up to birth and were significantly lower than the corresponding values in the non-pregnant group. During labor a significant decrease in reserve albumin and ratio of reserve albumin to total albumin was observed, while no change in the total albumin concentration was noted. No significant difference in reserve albumin concentration, total albumin concentration and ratio between them was found when the group of mothers who delivered vaginally was compared to the Cesarean Section group. It is concluded that the decrease in the ability of plasma albumin to bind unconjugated bilirubin takes place stepwise. The first step is a significant reduction during pregnancy followed by a further decrease during labor. The method of delivery is of no significance.


Some aspects of activation and inhibition of rat brain lipoxygenase. 1. Regulatory properties of lipoxygenase activity in rat brain cytosol were studied using linoleic acid (LA) as a substrate. 2. A change in the absorbance at 234 nm was biphasic when a mixture of LA and pre-formed hydroperoxide (LA-OOH) was incubated with freshly isolated native brain cytosol. Initially, a rapid depletion of LA-OOH was observed with a concomitant formation of LA-oxo compounds. This phase was followed by LA dioxygenation. 3. Both hydroperoxidase and dioxygenase activities of lipoxygenase were inhibited by micromolar concentrations of classic lipoxygenase inhibitors (phenidone, 5,8,11-eicosatriynoic acid and nordihydroguaiaretic acid). 4. The dioxygenase activity in dialysed cytsool was stimulated by nanomolar concentrations of H2O2 and micromolar concentrations of LA-OOH and it was inhibited by serotonin, dopamine and norepinephrine (IC50 25-43 microM).


Allosteric regulation of rat testis mitochondrial aldehyde dehydrogenase by capronaldehyde and magnesium ion. 1. The influence of Mg2+ on the kinetic behaviour of mitochondrial aldehyde dehydrogenase from rat testis has been investigated using capronaldehyde as substrate. 2. The kinetic data, obtained by numerical analysis of the progress curves of aldehyde oxidation, were fitted to a modified version of the Monod-Wyman-Changeux model and the fitting procedure resulted in a good correspondence between theoretical and experimental reaction rates over a wide range of capronaldehyde and Mg2+ concentrations. 3. According to the model, the tetrameric enzyme is in equilibrium between two conformational states R and T which display comparable affinities for capronaldehyde (the dissociation constants are 0.17 and 0.3 microM, respectively), but different catalytic power (VT = 2VR). The T state can bind with lower affinity a second molecule of aldehyde (K = 2.5 microM). 4. Mg2+ stabilizes the T state (the dissociation constants for the R and T states are 2.2 and 0.12 mM, respectively) and acts as a strong activator of the R state, but as a weak inhibitor of the T state. In the absence of substrates and Mg2+, the R<-->T equilibrium favors the R state ([T]/[R] = 0.16). 5. The model is able to predict the kinetic behaviour also when the NAD+ concentrations are not saturating and when inhibitory effects by NADH are taken into account.


Rat erythrocyte glycophorins can be isolated by the lithium diiodosalicylate method used for other glycophorins. 1. The lithium diiodosalicylate/phenol method, widely employed for the isolation of membrane sialoglycoproteins (glycophorins) from mammalian erythrocytes, was applied for the first time to the purification of homologous glycoproteins from rat erythrocyte membranes. 2. The resulting preparations showed to be composed of four components, fractionated on SDS-PAGE. All four were positive for periodic acid-Schiff's reagent stain, the two largest of them being major. 3. Isolated rat glycophorins accounted for 60% of the ghost sialic acid and 1.5% of their protein. The presence of O-acetyl groups was confirmed in one-third of the sialic acid residues. 4. The molecular masses of the four glycophorin components were determined by a method which takes into account the anomalous mobility of glycoproteins on SDS-electrophoresis. Estimated values thus obtained for the actual molecular masses were 74, 32, 25 and 17 kDa.


The condensing action of Mg2+, hexamminecobalt3+ and spermidine3+ on chromatin with gene regions activated by 17-beta estradiol. 1. Hepatic vitellogenin synthesis was induced by injecting 17-beta estradiol into fish. Liver nuclei were incubated with the endonuclease EcoRI at an increasing concentration of Mg2+ (0.15-1.50 mM), hexamminecobalt3+ or spermidine3+ (0.10-1.00 mM). Chromatin was separated into a 5000 g supernatant, S-fraction, and pellet fraction. 2. The release of chromatin into the S-fraction was higher for the induced than the control chromatin. Hybridization of the vitellogenin gene retained in the pellet fraction of the controls was unaffected by the individual cations. After activation of the vitellogenin gene, Mg2+ at its lowest concentration retained a high amount of the vitellogenin gene in the pellet fraction. The level of hybridization decreased by increasing the Mg2+ concentration. Retention of the gene rose by adding hexamminecobalt3+ and more so by adding spermidine3+. 3. The condensing action of spermidine3+ was extended to the activated vitellogenin gene regions of chromatin.


Gluconeogenesis from methylglyoxal in isolated murine hepatocytes. Does an alternative pathway exist in which pyruvate is not an intermediate? 1. Gluconeogenesis from alanine can be prevented by the addition of monoiodo acetic acid (an inhibitor of glyceraldehyde 3-phosphate dehydrogenase), while glucose production from methylglyoxal is only partially inhibited by this compound. 2. It is supposed that methylglyoxal can enter gluconeogenic sequence not only at pyruvate.


Metabolic utilization of muscular L-proline in 24-hr starved rats. 1. The aim of this paper was to study the in vivo skeletal muscle L-proline related to its destination to other key tissues such as liver and intestine as well as to give some insight into the role of blood cells in proline handling. 2. L-U-[14C]Proline was injected intramuscularly and following by sampling of blood, liver, intestine and contralateral muscle at 20 and 30 min after injection. 3. The distribution of radioactivity between blood cells and plasma and in total and individual amino acids, protein and glycogen fractions was determined in the above tissues. 4. The pattern of well fed rats was compared with those submitted to 24-hr complete starvation. 5. During starvation a minor degree of proline oxidation occurs. 6. The main destruction of proline in the liver seem to be the synthesis of proteins. 7. The radioactivity recovered in the blood proline fraction of starved rats is twice that of the fed rats and that it could be attributed mainly to plasma protein. 8. We have obtained in vivo evidence for the role of erythrocyte in the interorgan proline transport.


Purification and characterization of glutathione S-transferase isozymes in dog lens. 1. Two isozymes of glutathione S-transferase (GST-dl1 and GST-dl2) were purified to homogeneity from dog lens. 2. The subunit size and the isoelectric point were determined to be 24,000 and > pI 9.5 for GST-dl1 and 22,000 and pI 8.1 for GST-dl2. 3. It was judged that GST-dl1 is a class alpha enzyme and GST-dl2 belongs to class pi on the basis of their immunological properties and N-terminal amino acid sequences. 4. The expression pattern of glutathione S-transferase isoenzymes in dog lens is different from that in pig, rat and bovine lenses.


Steady-state kinetic properties of FoF1-ATPase: the pH effect. 1. The kinetic properties of FoF1-ATPase from submitochondrial particles isolated from rat heart were studied, with emphasis to the pH effect. The velocity data were treated according to the Hill equation, and the results were discussed on the basis of the knowledge on the soluble F1-ATPase properties. 2. Three kinetic phases were observed in the range of pH 6.0-8.5, with apparent dissociation constant values (K0.5) of 0.001, 0.04 and 1.5 mM (respectively sites I, II and III) at pH 7.0. Their contribution to the total activity of the enzyme were pH-dependent on the range of 6.0-7.0, but not from 7.0 to 8.5, where the maximal velocity (V) for site III was some 4-fold larger than for site II, and the total V of sites II and III was some 40-fold larger than V assumed for site I. Therefore, two catalytic sites seem to participate significantly in the catalysis at steady-state condition. 3. Azide increased the sites II and III K0.5 values as well as decreased the site III V. In the presence of bicarbonate these two sites were not distinguishable, and the kinetic parameters at pH 7.0 were similar to those for sites II and III combined. Both azide and bicarbonate did not have a significant effect on site I, and this behavior was not pH-dependent. 4. The studies on the effect of pH on the kinetic parameters showed the following results: (1) the optimum pH for V was around 8.5; (2) decrease in the K0.5 values at pH below 7.0 for site II, and increase at pH over 7.0 for sites II and III; (3) in the pH range of 6.0-8.5 the Hill coefficient increased for site II, decreased for site III, and an intermediary effect was observed for the sites II and III combined, with a Michaelis-Menten behavior in the highest affinity pH, which was found in the physiological range.


Characterization of rat liver nuclear proteins which recognize the cAMP responsive element. 1. The data herein reveal the existence of cAMP-responsive element (CRE)-binding factors (CRF) in the nuclear extracts from cAMP-treated rat liver. 2. DNAase I and DMS footprinting analysis showed that the CRFs protected the CRE (-77 to -92) in the phosphoenolpyruvate carboxykinase (PEPCK) promoter and the TGACGTCA motif in a consensus oligodeoxynucleotide based on the sequence of the CRE's of 6 cAMP-regulated genes (C32mer). 3. Competition assays indicate that the CRF(s) is a CGTCA-specific, ATF/CREB-like factor(s). 4. Southwestern (SW) blot analysis detected 2 apparent CRFs which have molecular weights of about 30 and 32 kDa, respectively. 5. Based on the comparison of the size and binding specificity of the CRFs with the CREBs reported to date, the CRFs appear to be novel CRE-binding nuclear factors.


Differential effects of aluminum ion on smooth muscle calpain I and calpain II activities. 1. In millimolar Ca2+, smooth muscle calpains I and II were inhibited by aluminum ion. 2. At sub-millimolar Ca2+, calpain II, but not calpain I, was activated by low millimolar aluminum ion. 3. Calpastatin inhibited aluminum ion-activated calpain II. 4. Aluminum ion-activated and Ca(2+)-activated calpain II gave almost identical patterns of desmin cleavage. 5. Aluminum-activated calpain II, unlike the Ca(2+)-activated enzyme, did not autolyze and retained its proteolytic activity over extended periods of time.


Fluorescamine-induced membrane permeability in mitochondria. 1. Addition of fluorescamine (75 microM) to mitochondria induced an increase in membrane permeability. 2. The leakiness of the inner mitochondrial membrane is characterized by extensive release of accumulated Ca2+, collapse of the transmembrane potential, mitochondrial swelling and efflux of matrix proteins, among them, malate dehydrogenase. 3. These effects were diminished by supplementing the media with 1 mM phosphate, and partially prevented by Mg2+. 4. These results indicate that the primary amino groups of membrane components contribute, partially, to the maintenance of the permeability barrier in mitochondria.


Protein kinase NII from calf thymus chromatin. Isolation, characterization and some functional properties. 1. A protein kinase type II was purified from calf thymus chromatin using ammonium sulphate fractionation, ion exchange chromatography on DEAE and phosphocellulose and affinity chromatography on phosvitin- and casein-sepharose columns. 2. The enzyme moves as a single band in non-denaturing gel electrophoresis at pH 8.3, which coincides with the enzyme activity assayed on gel slices. 3. Sodium dodecyl sulphate gel electrophoresis shows three separate polypeptide chains having M(r) of 40,000, 38,000 and 25,000, respectively. The native M(r) was about 130,000, as measured by HPLC on Superose 12 column, suggesting a subunit structure of alpha, alpha', beta 2 type. The enzyme incubated with [gamma 32P]ATP or [gamma 32P]GTP as phosphoryl donors undergoes autophosphorylation in the M(r) = 25,000 subunit. 4. The enzyme phosphorylates casein (Km = 7 microM) and phosvitin (Km = 5 microM) but not histones and was strongly deactivated by Zn2+ ions (I50 = 0.05 mM) and heparin (I50 = 0.1 micrograms/ml). 5. The enzyme seems to be the major phosphorylating system present in the 0.35 M NaCl chromatin extract of calf thymus. The RNA polymerase II from calf thymus and RNA polymerase from E. coli are both phosphorylated by protein kinase NII. The effect of phosphorylation, which causes a remarkable increase of DNA transcription rate, was studied in vitro and extensively discussed.


Lysosomal beta-hexosaminidase is highly resistant towards proteolytic degradation in vitro. 1. A partially purified enzyme preparation of beta-hexosaminidase from human fibroblasts was treated with proteases and the effect on its molecular weight and enzymatic activity was studied. 2. Both the forms A and B of the enzyme appeared to be resistant to a protease treatment that degraded the majority of the contaminating proteins to a large extent. 3. The same result was obtained with enzyme preparations from cells treated with tunicamycin. 4. Also the molecular weights of the individual polypeptide chains of the enzyme were not decreased, as was shown by SDS-PAGE, followed by immuno-blotting.


pH dependent kinetic studies of lipoamide dehydrogenase catalysis. 1. Kinetic studies of lipoamide dehydrogenase and its modified enzymes catalyzing lipoamide oxidoreduction and ancillary reactions at various pH are compared. 2. The asymptotic kinetics of lipoamide oxidoreductions switch between the ping pong and ordered mechanisms by varying pH of the reactions. 3. pH-rate profiles of these reactions are bell-shaped suggesting the participation of 2 ionizable residues with pK values of 6.6 +/- 0.5 and above 8 respectively. 4. The unusually high pK value for the catalytic site histidine is attributed to its involvement in an ion-pair formation. 5. In the absence of the catalytic site histidine, the pH-rate profile for the lipoamide reduction of the photooxidized enzyme is no longer bell-shaped but it is similar to those of the transhydrogenation and NADH-oxidation of the native enzyme. 6. This implies the participation of a low-pK protonated group in these reactions.


Cytotoxicity and cytokinetic effects of mitomycin C and/or photochemotherapy in a human colon adenocarcinoma cell line. 1. The cytotoxicity and cytokinetic effects of Mitomycin C (MC) and/or photochemotherapy (PCT) in cultured human colon adenocarcinoma (WiDr) cells were investigated using colony formation to determine cell survival and DNA flow cytometry to analyze cell kinetics. 2. A low concentration of MC (0.01 micrograms/ml) caused accumulation of cells in late S and early G2 phase; higher concentrations (0.05-0.5 micrograms/ml) induced accumulation of the cells in mid and early S phase. 3. The effects of the lowest concentration of MC (0.01 micrograms/ml) were reversible upon removal of the drug, whereas a higher concentration of MC (0.1 micrograms/ml) resulted in a permanent inhibition of cell cycle progression. 4. The sensitivity of Photofrin II-loaded cells to PCT can be enhanced significantly by the addition of MC. 5. The MC-induced accumulation of the cells in S phase may be one reason for the increased cytotoxicity of PCT combined with MC. 6. The data suggest that MC may also inhibit repair of PCT-induced DNA damage.


Conversion of skeletal tartrate-sensitive acid phosphatases into tartrate-resistant isoenzymes in vitro. 1. Chicken skeletal tartrate-sensitive (TsACP) and -resistant (TrACP) acid phosphatase isoenzymes could be separated from each other by carboxylmethyl-sepharose ion exchange chromatography. 2. Chicken skeletal TsACP showed a gradual time-dependent loss of sensitivity to tartrate inhibition when incubated at room temperature, but not at 4 degrees C. 3. The loss of sensitivity to tartrate inhibition was associated with an activation of the enzyme activity. 4. These changes were accompanied with a shift in the electrophoretic mobility of the enzyme activity from a large molecular sized form to a smaller molecular sized form that resembled the freshly prepared TrACP on the native acidic polyacrylamide electrophoresis gels, and on molecular sieve Superose-12 Fast Protein Liquid Chromatography. 5. Kinetic evaluations of the biochemical properties of the "converted" TsACP activity resembled the TrACP. 6. The apparent "conversion" was not unique to chicken TsACP, since similar "conversion" was observed with partially purified preparations of bovine bone matrix TsACP and of human osteoblastic TsACP. 7. Addition of several serine protease inhibitors did not prevent the "conversion". 8. These findings are consistent with the possibility that skeletal TsACPs are precursors of skeletal TrACPs.


The effects of exercise and feeding on the activity of lipoprotein lipase in nine different adipose depots of guinea pigs. 1. The activity of lipoprotein lipase (LPL) was measured in whole adipose tissue from 9 identified adipose depots of sedentary, fasting adult guinea pigs and following 30 min of exercise or voluntary ingestion of chow, and in adipocyte and stromal-vascular fractions from exercised specimens. 2. In sedentary, fasting specimens, LPL activity was up to 4 times higher in the small intermuscular depots than in the perirenal and epididymal depot (Table 1). 3. LPL activity increased significantly after feeding only in the large superficial depot, groin, and in the perirenal depot. LPL activity decreased after exercise only in the 2 intermuscular depots and in small anterior superficial depots. These effects of exercise were consistently greater in males than in females (Table 3). 4. Following exercise, there was up to twice as much LPL in the adipocytes as in the stromal-vascular fraction of the intermuscular depots, about 50% more in adipocytes from the minor superficial depots and about equal quantities in the 2 fractions of the intra-abdominal and groin depots (Table 2). 5. The data demonstrate the physiological inhomogeneity of both superficial and internal adipose depots, and are consistent with the hypothesis that LPL originating from adipose tissue may enter the circulation.


Vegetable foods in weaning.

Vegetable foods in weaning. Vegetable foods (cereals, non-starchy vegetables, legumes) make a unique nutritional and metabolic contribution during weaning. They provide proteins that are of low biological value individually but whose value can be raised by consuming appropriate combinations: minimal amounts of lipids, mostly essential polyunsaturated fats; complex carbohydrates; and soluble fibre, which are fermented by colonic flora to short-chain fatty acids that have beneficial effects. Insoluble fibre, minerals, trace elements and vitamins are also nutritionally important components of vegetable foods. Vegetable foods lower the calorific density of meals, modulate nutrient and antigen absorption, and promote a physiological copropoiesis. Recent nutritional surveys have shown that 12-month old children eat an excessive amount of animal proteins. Whole cereals and non-starchy vegetables, including whole legumes, should be routinely eaten during weaning to improve nutritional balance and to make children accustom to eating fibre, which has prophylactic properties. The daily intake of fibre should be progressively increased to 5 g during the first year of life.


The effect of Vivida cream as compared with placebo cream in the treatment of sun-damaged or age-damaged facial skin. Vivida when used orally has been previously shown to be effective in treating degenerated skin of women. In the present study, 30 women with moderate to severe sun-damaged facial skin applied Vivida cream twice daily for 120 days on one side of the face and placebo to the other. Vivida was significantly (P < 0.001) more effective than placebo in improving wrinkles. The effects of Vivida cream on mottles and telangiectasis were also significantly (P < 0.01) greater than those of placebo. Scanner measurement showed that epidermal thickness increased from 0.13 mm to 0.29 mm and dermal thickness from 0.91 mm to 1.29 mm on the Vivida-treated side; only minimal changes were observed on the placebo-treated side. The elasticity index increased from about 50% to 69% on the Vivida-treated side and from 49% to 50% on the placebo-treated side.


Pregnancy by means of tubal insemination and subsequent spontaneous pregnancy in rabbits. The purpose of the study was to determine whether or not physical stimulation by tubal insemination had any unfavourable influences upon the tubal fimbria. Tubal insemination was carried out on 14 rabbits and subsequent pregnancy results were monitored. After a period of 69-123 days following tubal insemination, 10 of the rabbits were mated spontaneously and these rabbits were then monitored for pregnancy. Newborn were obtained, with normal gestation periods in six out of the 14 rabbits, following tubal insemination and all 10 of the rabbits that were mated spontaneously with males following tubal insemination subsequently delivered. It is concluded that physical stimulation by tubal insemination does not produce adhesive changes on the tubal fimbria.


Onset and duration of the effects of three antihistamines in current use--astemizole, loratadine and terfenadine forte--studied during prolonged, controlled allergen challenges in volunteers. In a three-way, double-blind, crossover study the onset of action and effects at the end of the dosing interval of 10 mg/day astemizole, 10 mg/day loratadine and 120 mg/day terfenadine forte given for 3 days to six atopic volunteers were assessed using the Vienna challenge chamber (VCC). With each treatment, two long-term pollen challenges were performed in the VCC: the first to assess the onset of action started 1 h before the first dose and lasted continuously for 5 h; the second to assess the effects at the end of dosing took place 21 h after the last of the three doses and lasted 3 h. All three drug treatments initiated 1 h after the beginning of challenge with grass pollen reversed the adverse effects of challenge on the subjective symptoms (runny, blocked or itchy nose, sneezing, itchy eyes, tears) and the objective parameters (nasal secretions, nasal resistance, nasal flow, flow increase, nasal peak flow) within 1-3 h. The mean time to onset of action was 107 min for astemizole, 117 min after treatment for loratadine and 153 min for terfenadine forte. During the second allergen challenge, 21-24 h after intake, astemizole consistently provided better protection for all parameters than did loratadine or terfenadine forte; however the differences were not statistically significant.


Clinical appraisal of vinpocetine for the removal of intractable tumoral calcinosis in haemodialysis patients with renal failure. Previous studies have shown that vinpocetine [14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamenine] scavenges minerals and/or metals in the soft tissues of rabbits with artificially induced arteriosclerosis. The present study was carried out to determine whether or not vinpocetine would bring about the removal of intractable tumoral calcinosis in haemodialysis patients with renal failure. After administration of 15 mg/day vinpocetine for 3-12 months in haemodialysis patients with X-ray evidence of tumoral calcinosis, calcinosis was completely eliminated in all eight cases. Serum alkaline phosphatase and bone osteocalcin concentrations tended to decrease after treatment with vinpocetine compared with before treatment. Vinpocetine thus appears to be an effective scavenger of tumoral calcinosis in haemodialysis patients with renal failure without any side-effects during treatment.


Low-dose sultamicillin oral suspension in the treatment of mild to moderate paediatric infections in Turkey. A total of 101 children (47 males, 54 females; age range, 3 months-16 years) with mild to moderate upper or lower respiratory tract infections, or skin and soft tissue infections entered a clinical study conducted at two centres in Izmir, Turkey. The children received a mean daily dose of 25 mg/kg sultamicillin oral suspension administered as two equal doses approximately 12 h apart. In total, 100 children met all requirements for evaluability and were included in the clinical efficacy assessment, and 49 children were evaluated for bacteriological efficacy. Clinical cure was reported by the investigators in 93 patients, improvement in six and failure in only one. The bacteriological eradication rate of isolated pathogens was 100%. Of the 101 patients evaluated for drug safety, four experienced adverse drug-related or possibly drug-related reactions. All side-effects were gastro-intestinal and diarrhoea was reported in three patients. No discontinuation of therapy was reported, nor were any significant laboratory abnormalities recorded.


An open non-comparative pilot study of the safety and efficacy of oral sultamicillin in the treatment of mild to moderate upper respiratory tract infections in children. A total of 49 children (20 females, 29 males; age range, 6 months-12 years) with upper respiratory tract infections (otitis media, sinusitis, pharyngitis and/or tonsillitis) were treated orally with 25 mg/kg.day sultamicillin suspension in two equal doses for an average of 9.2 days. There was bacteriological evidence of sultamicillin-sensitive pathogens in 44 patients prior to treatment. On completion of treatment, 42 (85.7%) patients were rated as clinically cured and there was improvement in the remaining seven (14.2%) patients. Pathogens were totally eradicated in 32/44 (73.7%) cases but were still present in two (4.5%) and in 10 cases follow-up bacteriological evaluation was not possible. Tolerability of sultamicillin was good and only three possible or probable treatment-related adverse events were recorded.


An open comparative study of the efficacy and safety of sultamicillin versus cefaclor in the treatment of acute otitis media in children. In an open study, children (age range 6 months-12 years) with otitis media due to a bacterial infection were treated orally with 50 mg/kg sultamicillin (n = 30) in two equal doses each day for a mean of 10 days, or 40 mg/kg cefaclor (n = 30) in three equal doses each day for a mean of 11 days. Earache was rapidly improved by either treatment; none of the 27 evaluable sultamicillin-treated or the 29 evaluable cefaclor-treated patients had earache after 8-10 days. Other signs and symptoms (reddened eardrums, perforated eardrums, middle ear fluid, hearing loss) gradually improved during treatment. All the pathogens isolated from patients in the sultamicillin treatment group were eradicated, as were all but one of the pathogens isolated from patients in the cefaclor treatment group. In the sultamicillin treatment group 65.4% of patients were cured and 34.6% were improved, and in the cefaclor group 65.5% were cured and 31.0% improved, but there was one treatment failure. Study drug-related adverse events were experienced by 33.3% of sultamicillin- and 40.0% of cefaclor-treated patients, all but one (urticaria in a cefaclor-treated patient) were gastro-intestinal. The dose administered was reduced by approximately 50% in patients experiencing adverse effects. This did not lead to any reduction in efficacy and no patient was withdrawn due to adverse events.


Relative bio-availability of sultamicillin in healthy volunteers following administration of two tablet formulations. The pharmacokinetics of both ampicillin and sulbactam obtained from a balanced, open two-way crossover study in 20 normal adult volunteers receiving a single 375 mg oral tablet of sultamicillin administered as two different formulations--the original product (Duocid) and a generic formulation that is commercially available in Turkey--were compared. Pharmacokinetic parameters for the two formulations and for both ampicillin and sulbactam were tested for bio-equivalence by the two one-sided Student's t-test (80-120% range; P < 0.1). Area under concentration--time curves and maximum concentrations for both components were found to be non-equivalent for the two formulations, the generic formulation having consistently lower mean values. The results were consistent with studies of the in vitro release of sultamicillin from the two tablets. It is concluded that the generic formulation is pharmacokinetically inferior to the original product.


Treatment of lower respiratory tract infections with sultamicillin. Oral tablets containing 375 mg sultamicillin were used to treat 30 adult patients of either sex suffering from lower respiratory tract infections. The dose used was one tablet every 12 h for 22 cases and one tablet every 8 h for eight cases. The duration of therapy varied between 5 and 14 days (mean 8.6 days). The therapeutic response was rated as cure in 23 (76.6%) patients, with complete disappearance of pretreatment signs and symptoms, and as improvement in seven (23.3%) patients, with amelioration of the pretreatment manifestations. All 52 microorganisms isolated before treatment were eradicated. No adverse effects were reported in 25 (83.3%) patients, whereas the remaining five (16.7%) patients reported mild loose stools with normal bowel motion. There were no abnormal changes in blood count and liver and renal functions following sultamicillin treatment.


An open multicentre study to compare the efficacy and safety of sultamicillin with that of cefuroxime axetil in acute ear nose and throat infections in adults. A total of 110 adults with acute ear, nose and throat infections were treated orally with 750 mg/day (n = 9) or 1500 mg/day (n = 46) sultamicillin, or 500 mg/day (n = 51) or 1000 mg/day (n = 4) cefuroxime axetil for a minimum of 5 days. Variations in dose and duration of treatment were due to severity of symptoms. After treatment with sultamicillin for 8.1 +/- 1.5 days or with cefuroxime axetil for 7.9 +/- 1.6 days, local pain, erythema, exudate, oedema and adenopathies were improved in both treatment groups and all sultamicillin-treated patients were apyretic. All sultamicillin-treated and all but three cefuroxime axetil-treated patients experienced cure or improvement; only one cefuroxime axetil-treated patient discontinued treatment due to treatment failure. Gastrointestinal adverse events occurred in both treatment groups (eight sultamicillin-treated patients and three cefuroxime axetil-treated patients); one patient receiving cefuroxime axetil discontinued treatment due to nausea. Pruritus was reported by one sultamicillin-treated patient.


Sultamicillin in the treatment of obstetric and gynaecological infections. A total of 40 adult females were studied suffering from different obstetric and gynaecological infections. In 30 patients two 375 mg sultamicillin tablets were taken twice daily, whereas 10 patients received one 375 mg sultamicillin tablet twice daily. The duration of treatment ranged from 5 to 12 days, with a mean of 6.6 days. Cure or improvement was reported in 35 (87.5%) cases, whereas five (12.5%) patients did not respond to therapy. Of the 61 pathogens isolated before treatment, 56 (91.8%) were eradicated. Clinical tolerability of the therapy was excellent, with no adverse effects being observed in any of the studied patients. The absence of significant differences between the mean values of blood count, hepatic and renal function tests performed before and after treatment confirmed the safety of treatment. It is concluded that sultamicillin is a suitable and useful additional antibiotic therapy for the treatment of obstetric and gynaecological bacterial infections.


Myelomeningocele: a review of the orthopaedic aspects of 206 patients treated from birth with no selection criteria. Two hundred and six consecutive children with spina bifida who have been treated since the first day of life were analysed in terms of walking ability, motor level, orthopaedic deformities, operative procedures and balance deficit. The authors found that: (1) ambulation was quite delayed compared with the normal population; (2) sitting balance was a useful predictor of future walking; (3) almost all patients with quadriceps function were able to walk and were community ambulators; and (4) a significant number of congenital and acquired orthopaedic deformities required surgical intervention.


Perceptions of pediatricians' helpfulness: a national study of mothers of young disabled children. A national sample of 503 mothers of young children (up to six years of age) with developmental disabilities was surveyed to determine the extent to which their family pediatricians are helpful in providing information and support. The respondents ranged from lower-middle to upper class, with the mean SES reflective of middle socio-economic status. Their children had a variety of disabilities that qualified them to receive early intervention services. The majority of the mothers found their pediatricians helpful about issues related directly to their child's medical condition. However, few found them helpful with issues relating to the effect of the disability on their child's development, or to their own personal or family needs.


The effects of maternal epidural anesthesia on neonatal behavior during the first month. The effects of maternal epidural anesthesia with bupivacaine on the infant's performance on the Neonatal Behavioral Assessment Scale (NBAS) over the first month of life were examined. 20 non-medicated infants were matched for biomedical and demographic variables with 20 infants delivered with bupivacaine epidural anesthesia. The NBAS was administered on days 1, 3, 7 and 28. The epidural group showed poorer performance on the orientation and motor clusters during the first month of life. Epidural mothers reported spending less time with their infants while in the hospital; post hoc analyses showed that they had longer labor, more forceps deliveries and a greater amount of oxytocin. Controlling for the effects of these medical variables, a dose effect was found for the mean orientation and motor cluster scores. The results are discussed in terms of possible effects of the infant's early disorganization on the mother-infant interaction.


Fanconi anemia: a model for genetic causes of abnormal brain development. Fanconi anemia is an autosomal recessive disease resulting in bone-marrow failure, phenotypical abnormalities and predisposition to malignancy. The authors reviewed 257 clinical and neuropathology results from the International Fanconi Anemia Registry at The Rockefeller University. Two patients had hydrocephalus and ventriculoperitoneal shunts. Of 15 neuropathology reports, 10 found CNS abnormalities, with the most common--ventriculomegaly--seen in six, two of whom required shunts. Aqueductal stenosis, agenesis of the corpus callosum and septum pellucidum, and holoprosencephaly were found. The authors conclude that neurological derangements are probably more common in Fanconi anemia than previously recognised. Fanconi anemia cells in culture are highly sensitive to oxidative stress and alkylating agents; Fanconi anemia may provide a model for a genetic disorder potentially predisposing to environmental insults.


Antecedents and outcome of simple and complex febrile convulsions among Saudi children. Of 215 Saudi children seen with their first febrile convulsion (FC) at the King Khalid University Hospital, Riyadh, between January 1984 and December 1988, the index FC was simple for 133 children and complex for the remaining 82. History of adverse antecedent factors, particularly perinatal asphyxia, birth injuries and pre-existing neurological deficits, were significantly more associated with complex FC, as was occurrence of first FC before the age of 12 months. Recurrence of FCs and development of epilepsy were also more common among the group of children with complex FC. Complex FCs were less benign in the present study population than has been reported in some Western studies.


Magnetic resonance imaging in pseudotumor cerebri. The pathophysiology of pseudotumor cerebri is unclear, but may relate to an abnormality in water transport in the brain. The authors performed MR imaging in seven children with pseudotumor cerebri; the signal intensity in the white matter was normal in all patients. These data suggest that periventricular brain water content is not increased markedly in children with pseudotumor cerebri. The authors speculate that this may relate to the establishment of an equilibrium between increased resistance to cerebrospinal fluid outflow and increased brain stiffness, occurring as a consequence of increased cerebral blood-volume and/or interstitial pressure.


Epidemiology of headache and childhood migraine in an urban general practice using Ad Hoc, Vahlquist and IHS criteria. In a survey conducted by a UK urban general practice, 98.1 per cent (1083) of the children registered aged three to 11 years took part in an interview. Possible migraine subjects took part in an extended interview, the results of which were recorded using three different sets of diagnostic criteria: Vahlquist, Ad Hoc and International Headache Society. The prevalence of migraine ranged from 3.7 to 4.9 per cent, depending on the criteria used. The prevalence of migraine with aura (1.5 per cent) was similar by all criteria, whereas that for migraine without aura ranged from 2.2 to 3.4 per cent. The prevalence of migraine increased with age. The IHS criteria appeared less sensitive than the Ad Hoc for migraine without aura. Operational criteria using three attacks lasting longer than one hour may be more specific for the diagnosis of migraine in young children.


Transient loss of speech followed by dysarthria after removal of posterior fossa tumour. The authors report three children who suffered transient loss of speech during six to eight weeks following removal of a large midline cerebellar tumour. None manifested speech difficulties immediately after surgery, but all developed mutism within 24 to 48 hours. The speech of all children slowly but completely recovered, after a period of severe dysarthria. The re-organization of speech functions is discussed in relation to the functioning of musculature.


Pathological left-handedness and preserved function associated with a slowly evolving brain tumor. The authors report the serial neuropsychological evaluations of a patient with acquired left-handedness who had a massive brain tumor that infiltrated the entire temporal and posterior parietal lobes of the left hemisphere. Although the patient had pre-operative impairment of non-verbal memory, follow-up assessment 31 and 66 months after the tumor was resected revealed cognitive functions to be in the high-average to superior range. This case demonstrates the sparing of neuropsychological functions that can be seen with a slowly evolving lesion. The authors suggest that such functional sparing may be due to transfer of function rather than to the residual function of tumor-infiltrated neuronal tissue. Possible mediators of functional preservation include slow lesion growth, the patient's youth at disease onset and the large size of the lesion.


Magnetic resonance imaging of the kidney in type 1 (insulin-dependent) diabetes mellitus. Reductions in the physiological cortical to medullary signal intensity ratio are found in magnetic resonance scans of the kidney in non-diabetic glomerular disease. Whether this abnormality can also characterise patients with Type 1 (insulin-dependent) diabetes mellitus and nephropathy is not known. We measured the cortical to medullary signal intensity ratio in magnetic resonance images of the kidney in 34 patients with Type 1 diabetes (ten with either clinical proteinuria or raised serum creatinine or both, nine with microalbuminuria, seven with normal urinary albumin excretion and long duration of diabetes and eight with Type 1 diabetes of short duration). The cortical to medullary signal intensity ratio showed a trend to cluster at lower values in the normoalbuminuric patients with normal serum creatinine rather than in the nine healthy individuals, independent of Type 1 diabetes duration (1.47 +/- 0.06 and 1.41 +/- 0.13 vs 1.63 +/- 0.16; five groups Scheffé F-test p = 0.05-0.1). Among the Type 1 diabetic patients, significant reductions in the cortical to medullary signal intensity ratio characterised overt nephropathy (1.19 +/- 0.15, p less than 0.05 vs all groups), but not microalbuminuria (1.47 +/- 0.13, p = NS), concomitantly with low glomerular filtration rate and elevated fractional excretion of uric acid, but independent of glycaemic control. The determinants of the renal cortical to medullary signal intensity ratio in Type 1 diabetes are uncertain. Reductions in the cortical to medullary signal intensity ratio may be a late finding in diabetic nephropathy, and parallel the accompanying impairment in kidney haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)


Protective effect of vitamin E supplementation on increased thermal stability of collagen in diabetic rats. Products similar to non-enzymatic glycation end products are known to arise from the interactions between proteins and lipid peroxides in vitro. In this study, we assessed the effect of vitamin E, which possibly modifies lipid peroxide, on advanced glycation end products or similar products in vivo by measuring the fluorescence and thermal rupture time of tail tendon collagen in streptozotocin-induced diabetic rats. The diabetic rats and non-diabetic rats were fed a vitamin E supplemented diet, and a control diet starting 3 days after the streptozotocin injection. After the 4-week treatment, the serum lipid peroxide levels expressed as thiobarbituric acid reactants in the diabetic rats on control diet (15.9 +/- 2.6 mumol/l[SEM]) were significantly (p less than 0.05) higher than in the non-diabetic rats (7.9 +/- 1.3 mumol/l on control diet and 3.3 +/- 0.4 mumol/l on supplemented diet), but the levels in the diabetic rats on supplemented diet (7.9 +/- 2.3 mumol/l) were reduced to the normal levels. No significant differences were found in serum glucose and glycated haemoglobin levels within the diabetic rats on control and supplemented diets. Both the fluorescence and thermal rupture time of collagen were significantly (p less than 0.05) increased in the diabetic rats on both diets compared with those in the corresponding non-diabetic rats. Although there was no significant difference in the collagen-linked fluorescence within the diabetic rats on control and supplemented diets, the thermal rupture time was significantly (p less than 0.01) shortened with supplemented diet (10.8 +/- 0.7 min on supplemented diet vs 15.0 +/- 0.7 min on control diet).(ABSTRACT TRUNCATED AT 250 WORDS)


Insulin secretion by rat islet isografts of a defined endocrine volume after transplantation to three different sites. We have analysed the graft function of rat islet isografts of identical and well-defined endocrine volumes after transplantation to three different sites (kidney, liver and spleen). Graft endocrine mass was determined by measuring the total islet volume prior to transplantation and was chosen to be similar to the endocrine volume in the normal adult rat pancreas. Graft function was tested in unanaesthetized, unstressed rats by the responses to glucose infusion and to a meal. All transplanted animals returned to normoglycaemia within one week after transplantation. At one month, basal glucose and insulin levels were similar to controls in rats with grafts to the spleen, but higher in rats with grafts to the kidney or liver. Irrespective of the transplantation site, recipients had higher glucose and lower insulin levels than controls in response to glucose infusion, but in response to a meal these differences from normal were less obvious. Finally, recipients showed both an acute insulin response to glucose infusion as well as a pre-absorptive insulin release after food ingestion, irrespective of the transplantation site. Our findings indicate that the insulin response to glucose infusion and to a meal is quantitatively reduced, but qualitatively intact after transplantation to the kidney, liver or spleen.


Role of infiltrating T cells for impaired glucose metabolism in pancreatic islets isolated from non-obese diabetic mice. Pancreatic islets isolated from non-obese diabetic (NOD) mice, all of which have insulitis, exhibit an impaired glucose metabolism. In order to investigate the role of infiltrating lymphocytes for this altered metabolism, we injected 12- to 13-week-old female NOD mice with monoclonal antibodies directed against either the alpha beta-T cell receptor, CD4+ or CD8+ T cells. Control NOD mice were injected with normal rat IgG or with the vehicle (phosphate buffered saline) alone. Injection of the three different monoclonal antibodies markedly reduced the mononuclear cell infiltration. An intravenous glucose tolerance test showed no differences between the groups. Islet insulin release in response to glucose was similar in all groups. In contrast, islets isolated from the control NOD mice with insulitis showed a high basal (1.7 mmol/l glucose) glucose oxidation rate and a small increase in the glucose oxidation rate in response to a high glucose concentration (16.7 mmol/l glucose). The monoclonal antibodies counteracted the elevated basal glucose oxidation rate of the islets. Parallel studies of stimulated mononuclear cells suggested that the contribution of glucose oxidized by islet-infiltrating lymphocytes could only partially explain the observed alterations in NOD mouse islet metabolism. Culture of islets obtained from NOD mice in the presence of the cytokine interleukin-1 beta induced a similar pattern of glucose metabolism as seen earlier in IgG or phosphate-buffered saline treated control NOD mice. In conclusion, alterations in the glucose oxidation rates seem to be an early sign of disturbance in islets isolated from NOD mice. These early alterations in glucose metabolism can be reversed in vivo by monoclonal antibodies directed against effector lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute actions of insulin-like growth factor II on glucose metabolism in adult rats. The metabolic potency of recombinant human insulin-like growth factor II was studied in anaesthetized adult rats by obtaining dose-response curves for the hypoglycaemic action and for the stimulation of glucose metabolism during euglycaemic clamping. Compared to insulin, about 50 times higher doses of insulin-like growth factor II were required to result in identical in vivo responses, with half-maximally effective serum concentrations for the stimulation of glucose disposal during clamp studies of about 0.8 and 50 pmol/ml, respectively. A similar difference in potency was observed for the dose-dependent stimulatory actions on glucose metabolism in individual target tissues. Half-maximally effective serum concentrations in the range of 0.8 to 3.0 pmol/ml for insulin and of 40 to 70 pmol/ml for insulin-like growth factor II were seen to be required for 2-deoxyglucose uptake, glycogen formation in skeletal muscle and lipogenesis in epididymal fat. Maximal responses were identical with both peptides. These data suggest that in vivo acute metabolic actions of insulin-like growth factor II on carbohydrate metabolism occurred through insulin receptors.


Persistent reduction of pancreatic beta-cell mass after a limited period of protein-energy malnutrition in the young rat. Kwashiorkor, the human disease of protein-energy malnutrition, has been implicated in the aetiology of malnutrition-related diabetes mellitus, a form of diabetes not uncommon in developing countries. We have previously demonstrated that temporary protein-energy malnutrition in young rats causes a persisting impairment of insulin secretion. The present study investigates whether this secretory deficiency is accompanied by structural alterations of the endocrine pancreas. Three-week-old rats were weaned onto semi-synthetic diets containing either 15% or 5% protein and these diets were maintained for 3 weeks. From 6 weeks of age all rats were fed a commercial chow containing 18% protein. The endocrine pancreas was investigated by light and electron microscopic morphometry at 3, 6 and 12 weeks of age. In rats not subjected to protein-energy malnutrition there was a progressive increase, with age, of total pancreatic Beta-cell weight and individual Beta-cell size. In 6-week-old rats fed the low protein diet total pancreatic Beta-cell weight and individual Beta-cell size were diminished. In 12-week-old rats previously fed the low protein diet total Beta-cell weight remained lower compared to control rats. It is concluded that protein-energy malnutrition early in life may result in a diminished reserve for insulin production. This may predispose to glucose intolerance or even diabetes in situations with an increased insulin demand.


Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. The effect of 2 months aminoguanidine treatment on nerve conduction abnormalities was studied in streptozotocin-diabetic rats. Treatment with aminoguanidine from the induction of diabetes mellitus prevented a 22% decrease in sciatic motor nerve conduction velocity (p less than 0.001), and a 10% deficit in sensory saphenous conduction velocity (p less than 0.01). There was a 49% increase in resistance of sciatic nerve to hypoxic conduction failure in vitro. This was not significantly affected by aminoguanidine treatment. Sciatic nerve polyol pathway metabolites, sorbitol and fructose, were elevated 10-fold by diabetes (p less than 0.001). Myo-inositol levels were 18% decreased by diabetes. Aminoguanidine treatment had no significant effect on sorbitol, fructose or myo-inositol levels. Aminoguanidine has been identified as both an inhibitor of the formation of advanced glycation end products, and an aldose reductase inhibitor. The data suggest that beneficial actions on nerve function do not depend on the latter property. They support the notion that advanced glycation end products contribute to the aetiology of early diabetic neuropathy, possibly acting via a vascular mechanism, and that aminoguanidine treatment may have therapeutic applications.


Life table analysis of the risk of type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers. An 8-year prospective study. To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2-29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p less than 10(-5)) than HLA-identity (10% and 7%, respectively, p less than 0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4%, 3% and 4.4%, respectively, NS). C4BQO also conferred significant risk (11% vs 3% in non-C4BQO siblings, p less than 0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7% for HLA-identity, 9% for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41%, risk 56% after 8 years, p less than 10(-7)). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4+ subjects had the highest risk (70% after 8 years, predictive value 58%, p less than 10(-7)) compared with islet cell antibody-positive DR3,4- (37% and 20%, respectively) and islet cell antibody-negative DR3,4+ (5% and 3.6%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Nine healthy subjects were studied on two separate occasions, at least two weeks apart, using the glucose clamp technique to produce a gradual hypoglycaemia. Glucose thresholds for neuroendocrine and symptom responses varied up to 1.5 mmol/l between subjects. There was a significant correlation between individual glucose thresholds on day 1 and 2 for adrenaline (p = 0.0008), growth hormone (p = 0.007) and pancreatic polypeptide (p = 0.02), and for autonomic (p = 0.018) and neuroglycopoenic (p = 0.023) symptoms, whereas no significant correlations were found for glucagon and cortisol. The mean intra-individual differences in glucose thresholds between day 1 and 2 were 0.22 mmol/l for the hormones and 0.25 mmol/l for the symptoms. We conclude that healthy subjects differ in hypoglycaemic thresholds, and that the difference reflects individual variation.


Factors associated with basal metabolic rate in patients with type 2 (non-insulin-dependent) diabetes mellitus. To examine determinants of basal metabolic rate we studied 66 Type 2 (non-insulin-dependent) diabetic and 24 healthy age- and weight-matched control subjects with indirect calorimetry and infusion of [3H-3-] glucose. Eight Type 2 diabetic patients were re-studied after a period of insulin therapy. Basal metabolic rate was higher in Type 2 diabetic patients than in control subjects (102.8 +/- 1.9 J.kg LBM-1.min-1 vs 90.7 +/- 2.8 J.kg LBM-1.min-1; p less than 0.01) and decreased significantly with insulin therapy (p less than 0.01). The basal rate of hepatic glucose production was higher in Type 2 diabetic patients than in control subjects (1044.0 +/- 29.9 vs 789.3 +/- 41.7 mumol/min; p less than 0.001) and decreased after insulin therapy (p less than 0.01). Hepatic glucose production correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.49; p less than 0.001) and in control subjects (r = 0.50; p less than 0.05). Lipid oxidation was increased in Type 2 diabetic patients compared with control subjects (1.68 +/- 0.05 vs 1.37 +/- 0.08 mumol.kg LBM-1.min-1; p less than 0.01) and decreased significantly after insulin therapy (p less than 0.05). The rate of lipid oxidation correlated positively with basal metabolic rate both in Type 2 diabetic patients (r = 0.36; p less than 0.01) and in control subjects (r = 0.51; p less than 0.01). These data demonstrate that basal metabolic rate, rates of hepatic glucose production and lipid oxidation are interrelated in Type 2 diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Oral contraceptive use and the risk of type 2 (non-insulin-dependent) diabetes mellitus in a large prospective study of women. We examined the association between oral contraceptive use and incidence of Type 2 (non-insulin-dependent) diabetes mellitus among 115117 female nurses free of diabetes, cardiovascular disease and cancer in 1976 and followed-up for 12 years. During 1237440 person years of follow-up, 2276 women who provided information on oral contraceptive use were clinically diagnosed with Type 2 diabetes. Women who used oral contraceptives in the past had only a slight and marginally increased relative risk of 1.10 (95% confidence interval 1.01, 1.21) compared to those women who had never used oral contraceptives after controlling for known risk factors of disease. We found no evidence of increased risk with longer duration of use or with shorter interval since last use. Current users did not have an increased risk of Type 2 diabetes (relative risk = 0.86, 95% confidence interval 0.46, 1.61) when compared to women who had never used the drug. There was no effect modification by obesity, family history of diabetes, or physical activity. These data suggest that past or current oral contraceptive use does not substantially influence subsequent risk of Type 2 diabetes.


Trends in mortality from diabetes mellitus in Taiwan, 1960-1988. The increasing trends of mortality from diabetes mellitus in Taiwan are becoming a public health concern. The age-adjusted death rate for diabetes was 3.7 per 100,000 population in 1960, which increased to 23.2 per 100,000 in 1988, a 6.3-fold increase over the past 30 years. The mortality data for diabetes in Taiwan from 1960 to 1988 for both sexes are presented and analysed using an age-period-cohort model in order to gain a better understanding of the possible determinants of the time trends of this disease. Steeply increasing trends which are particularly prominent in the elderly are found in the periods studied. Females and urban dwellers demonstrated greater risks for developing the disease. Significant cohort effects were found which peaked in the birth-cohort 1910-1917. This declined thereafter for females but has levelled since then for males. Further study is necessary to assess the aetiological implications of diet and urbanization on time trends of diabetes.


An increased level of antibodies to beta-lactoglobulin is a risk determinant for early-onset type 1 (insulin-dependent) diabetes mellitus independent of islet cell antibodies and early introduction of cow's milk. Using a case-control design we have studied whether antibodies to cow's milk proteins are risk determinants for childhood-onset Type 1 (insulin-dependent) diabetes mellitus independent of early exposure to cow's milk formula and islet cell antibodies. Sera from 116 recent-onset diabetic children and 112 age- and sex-matched control children were analysed for cow's milk protein IgA, IgG and IgM antibodies, beta-lactoglobulin IgA and IgM antibodies and islet cell antibodies. The titres were compared to questionnaire data on duration of breast-feeding and introduction of formula feeding. Most antibody levels tended to be increased among diabetic compared to control children. This was statistically significant for cow's milk protein IgA antibodies (p less than 0.001) and beta-lactoglobulin IgA antibodies (p less than 0.01) as well as for islet cell antibody-positivity which was found among 92% of the diabetic and 3% of control children. The differences in cow's milk protein antibodies as well as beta-lactoglobulin antibodies were more pronounced among children with an early onset of Type 1 diabetes. Breast-feeding duration was significantly inversely related to the log of beta-lactoglobulin IgG (r = -0.16, p = 0.04) and the log of cow's milk protein IgA antibodies (r = -0.17, p less than 0.001). A positive correlation was found between formula feeding and the logarithm of beta-lactoglobulin IgG antibodies (r = 0.22, p = 0.01) and the log of cow's milk protein IgA antibodies (r = 0.16, p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)


Disease-associated anti-bovine serum albumin antibodies in type 1 (insulin-dependent) diabetes mellitus are detected by particle concentration fluoroimmunoassay, and not by enzyme linked immunoassay. We recently developed a particle concentration fluoroimmunoassay for the measurement of serum antibodies to bovine serum albumin in patients with Type 1 (insulin-dependent) diabetes mellitus. We observed elevated IgG-anti-bovine serum albumin antibodies in 100% of newly-diagnosed diabetic children and in 2.5% of matched control children. Here we compare the fluoroimmunoassay and the more commonly available enzyme linked immunoassay technique, exchanging coded serum samples from 40 newly-diagnosed diabetic children and 179 control children between two laboratories. Particle concentration fluoroimmunoassay detected elevated IgG-anti-bovine serum albumin antibodies in all diabetic children, enzyme immunoassay in 25% (p less than 0.0001). Fluoroimmunoassay detected elevated levels in 2.2% and enzyme immunoassay in 10% of control children (p less than 0.002). Elevated IgA-anti-bovine serum albumin antibodies in patients were slightly more often detected by fluoroimmunoassay than by enzyme immunoassay, while in control children enzyme immunoassays detected elevated levels three times more often (p less than 0.01). Values measured in either assay showed overall no correlation in either patient (IgG:rs = 0.28; IgA:rs = 0.11) or control sera (IgG:rs = 0.02; IgA:rs = -0.05). Fluoroimmunoassay for IgG was 100% disease-sensitive (enzyme immunoassay: 25%, p less than 0.0001) and more disease-specific (IgG; p less than 0.02). Our findings demonstrate that these assay techniques detected distinct subsets of anti-bovine serum albumin antibodies with little (IgG) or some (IgA) overlap. In fluoroimmunoassay procedures, antigen:antibody binding occurs within 1-2 min while hours are allowed in an enzyme immunoassay.(ABSTRACT TRUNCATED AT 250 WORDS)


Increases in plasma lysosomal enzymes in type 1 (insulin-dependent) diabetes mellitus: relationship to diabetic complications and glycaemic control. Lysosomal enzymes degrade membrane glycoconjugates, and increased circulating enzyme activity may be an important mechanism in the pathogenesis of diabetic microangiopathy. We have assayed a profile of seven lysosomal enzyme activities (nmol.h-1.ml-1) in platelet-free plasma from 54 Type 1 (insulin-dependent) diabetic subjects (median age 31 years) and 42 matched normal control subjects. A significant increase in median (interquartile range) enzyme activity was measured in diabetic compared to control subjects for beta-D-glucuronidase, 121 (97.7-171) vs 88.8 (62.8-113), p less than 0.001; beta-D-Nacetylglucosaminidase, 693 (568-799) vs 568 (462-686), p less than 0.001; alpha-D-mannosidase, 23.8 (16.7-28.9) vs 14.5 (10.1-20.0), p less than 0.001; and beta-D-galactosidase, 6.94 (6.11-9.99) vs 6.66 (4.78-8.33), p less than 0.04. In contrast, alpha-L-fucosidase, alpha-D-galactosidase and beta-D-mannosidase activities were similar in diabetic and control subjects. None of the enzyme activities differed significantly (p less than 0.05) between 24 diabetic patients with clinical complications and 30 complication-free diabetic patients with similar glycaemic control which does not support the hypothesis that enzyme increases in diabetes arise simply by leakage from damaged tissues. In the diabetic subjects HbA1, median (interquartile range) 9.10 (7.40-10.60), was significantly related to beta-D-glucuronidase (rs = 0.56, p less than 0.001) and beta-D-Nacetylglucosaminidase (rs = 0.55, p less than 0.001). We have therefore demonstrated in diabetic subjects an increase in certain lysosomal glycosidases, that correlates with glycaemic control.(ABSTRACT TRUNCATED AT 250 WORDS)


The small heat shock protein hsp25 is accumulated in P19 embryonal carcinoma cells and embryonic stem cells of line BLC6 during differentiation. Murine embryonal carcinoma and embryonic stem cell lines were investigated with regard to the occurrence of the small heat shock protein hsp25 during cell growth and differentiation. In the embryonal carcinoma cell line F9 considerable constitutive levels of hsp25 were observed which could be slightly increased by treatment with retinoic acid. No hsp25 was found, however, in the embryonal carcinoma cell line PCC4. When analyzing the pluripotent embryonal carcinoma cell line P19 and the pluripotent embryonic stem cell line BLC6, both characterized by high differentiation capacity, no hsp25 was observed under cell culture conditions maintaining the undifferentiated state. Induction of differentiation caused by prolonged cell culture, retinoic acid treatment, or embryoid body formation, however, resulted in an increase of the level of hsp25. The finding that hsp25 is accumulated in a differentiation-dependent manner suggests that this protein is associated with processes involved in differentiation. Therefore, hsp25 can be regarded as a marker of differentiation in the investigated embryonal carcinoma cell line P19 and the embryonic stem cell line BLC6.


The hamster cheek pouch as a convenient ectopic site for studies of uterine morphogenesis and endocrine responsiveness. The Syrian hamster cheek pouch was evaluated as a convenient transplantation site for studies of estrogen-dependent uterine growth and morphogenesis. At one month of age, hosts were either ovariectomized (Ovex) or ovariectomized and estrogen implanted (Ovex+E2), and at the same time the uterus from a 7-day old untreated donor was transplanted into the host's right cheek pouch. Periodic inspection (by simple eversion of the pouch) revealed viable transplants in the majority of hosts for both groups, and clear evidence of estrogen-dependent transplant growth that continued for at least 9 months. At that time, weight of the transplanted uterus was comparable to that of a given host's own in situ uterus, but uteri at both sites weighed six to eightfold more in Ovex+E2 hosts than in Ovex hosts. Histological analysis also revealed similar degrees of endometrial atrophy in Ovex hosts and hypertrophy/hyperplasia in Ovex+E2 hosts for both in situ and transplanted uteri. Furthermore, while only scant and rudimentary endometrial glands developed in both in situ and transplanted uteri within Ovex hosts, uteri at both sites within the Ovex+E2 hosts were riddled with cystic glandular structures and exhibited marked leukocytic infiltration. These data demonstrate that neonatal uteri transplanted to the hamster cheek pouch will grow, differentiate and follow an endocrine-responsive morphogenetic program that is quantitatively and qualitatively consistent with that of the host's in situ uterus. Lastly, we were able to cleanly separate epithelium from the stroma of 5-day old hamster uteri, reassociate the two tissues in vitro, transplant the recombinants into cheek pouches of adult female hamsters and subsequently observe growth and maintenance of a generally normal uterine morphology and differentiated function.


Immunohistochemical study of secretory proteins in the developing human exocrine pancreas. We have studied, by immunohistochemical methods using specific antisera, the development of three glycoproteins of human pancreatic secretion: lipase, carboxyl ester hydrolase (CEH) and the P19 protein (precursor of the non glycosylated protein X or "pancreatic thread/stone protein"). We have compared their development to that of trypsinogens (Tgs) and chymotrypsinogen A (ChTgA), as well as to that of FAP (feto acinar pancreatic protein), a glycoprotein associated with the differentiation of human pancreas. Our studies show the characteristic appearance and development of lipase, the immunoreactivity of which appears later (at the 21st week of pregnancy) than it does for Tgs and ChTg (at the 16th week of pregnancy). Moreover, the lipase labelling is first observed in a few acini dispersed in the pancreas and then spreads out progressively to be present in all the acini after the age of 15 days. By contrast, as soon as they appear, Tgs and ChTg are observed uniformly in all acinar cells. The intensities of the lipase, Tgs and ChTg labellings increase greatly at birth. The ontogenesis of CEH does not follow that of lipase but that of Tgs and ChTg. The ontogenesis of P19 is parallel to that of Tgs. As previously observed, FAP presents a maximal immunoreactivity at the 24th-27th weeks of pregnancy, which decreases slowly up until birth.


Modulation of differentiation markers in human choriocarcinoma cells by extracellular matrix: on the role of a three-dimensional matrix structure. During spontaneous or chemically induced differentiation human choriocarcinoma cells express typical characteristics of the normal differentiating trophoblast: 1) increased production of peptide and steroid hormones (chorionic gonadotropin, placental lactogen, estrogens, progesterone); 2) increased activity of cellular alkaline phosphatase; 3) morphological transition from cytotrophoblast to syncytiotrophoblast-like cells; and 4) arrested cell proliferation. Since the extracellular matrix is known to control gene expression we have examined the effects of different substrates composed of matrix macromolecules on the differentiation of BeWo choriocarcinoma cells. Matrices tested were: fibronectin, laminin, collagens type I and type IV, the basement membrane-like complex matrix Matrigel, and a complex matrix extracted from human term placenta. Irrespective of the type of molecule(s), it was consistently found that, whenever the matrix molecules were presented as three-dimensional structures (as opposed to protein coatings on tissue culture plastic) the response of affected differentiation markers monitored was highly pronounced. Morphology was changed from monolayers to rounded colonies, cell proliferation was reduced, and the secretion of chorionic gonadotropin was increased up to tenfold. Heterogeneous effects were observed on progesterone secretion and on the activity of cellular alkaline phosphatase. Cell adhesion to matrix molecules, however, did not depend on the structure of the matrix. This study demonstrates that gene expression in these tumor cells can be modified by extracellular matrix and highlights that not only the presence of effector molecules in the matrix but also the three-dimensional structure of the matrix is important for the induction of differentiation.


Predictors of outcome in patients with achalasia treated by pneumatic dilation. This prospective study investigates whether the effect of pneumatic dilation in patients with achalasia can be predicted on the basis of patient characteristics, type of treatment, or results of postdilation investigations. Over a period of 10 years, 54 consecutive patients with newly diagnosed achalasia were treated with pneumatic dilation and underwent pretreatment and posttreatment manometric, radiographic, and scintigraphic investigations. They were followed up every 2 years until the fall of 1991. Among the factors evaluated in the initial examination, only young age adversely affected outcome (P < 0.05). With the exception of the diameter of the dilating balloon, the treatment characteristics had a low predictive value. Postdilation lower esophageal sphincter pressure was the single most valuable factor for predicting the long-term clinical response (P < 0.0005). However, patients with high sphincter pressures and poor treatment results benefited from repeated dilations by having progressively longer remissions. It is concluded that young patients are poor candidates for pneumatic dilation, that treatment should be aimed at near complete inflation of the dilating bag, and that postdilation sphincter pressure may guide further treatment.


Patchy expression of lactase protein in adult rabbit and rat intestine. Enzymatic and immunohistological analyses of lactase were performed at different stages of development and within different regions of the small intestine of the rabbit and rat. As previously reported, there seems to be a sharp decline of lactase activity on weaning but variable and higher levels of activity are seen in adult animals. Two monoclonal antibodies to rat lactase were available to study the protein in rats. Four monoclonal antibodies to human lactase were shown to cross-react with rabbit lactase and used for the rabbit studies. Immunohistological analysis of small intestine of adult rabbits and rats showed residual lactase protein within the enterocytes throughout the small intestine. In the middle of the small intestine (lower jejunum, upper ileum), uniform staining of the brush border was observed. In the proximal and distal regions, a patchy pattern of staining was observed. This pattern, which resembles that observed in adult hypolactasic humans, indicates an underlying heterogeneity of enterocyte differentiation.


Activation of human phagocyte oxidative metabolism by Helicobacter pylori. A characteristic feature of chronic antral gastritis is the abundant inflammatory response in close association with Helicobacter pylori, but the immunopathological mechanisms of tissue damage are unknown. Because reactive oxygen radicals have been implicated in the tissue damage of other chronic inflammatory disorders, we investigated the potential ability of H. pylori sonicate to influence the oxidative burst responsiveness of human polymorphonuclear leukocytes and monocytes. For both cell types, a dose-dependent stimulation in a chemiluminescence system was observed. Furthermore, preincubation in sonicate caused a marked priming of the cells to subsequent stimulation with the oligopeptide N-f-methionyl-leucyl-phenylalanine and phorbol-myristate-acetate. The sonicate activity was nondialysable, completely destroyed by proteinase and resistant to heat treatment. However, dialysis of boiled sonicate significantly reduced the activity, suggesting the breakdown of a larger molecule(s) to smaller fragments still biologically active. Preliminary experiments suggest that the activity is 25-35 kilodaltons. The demonstration of a protein with stimulatory activity for production of reactive oxygen radicals by human phagocytes may contribute to the understanding of the immunopathology associated with H. pylori infection.


Adaptive changes in the pyloric motor response to intraduodenal dextrose in normal subjects. Gastric emptying of glucose is faster after dietary supplementation of glucose, suggesting specific adaptation to changes in nutrient intake. In the present study, the effects of a continuous long-term (0-120-minute) and two short-term (0-20- and 80-100-minute) intraduodenal infusions of dextrose (2.4 kcal/min) on antropyloroduodenal motility and blood glucose, plasma gastric inhibitory polypeptide, and insulin concentrations were evaluated in nine volunteers. In four volunteers, an intraduodenal infusion of triglyceride (2.4 kcal/min) was administered immediately after the long-term dextrose infusion. The long-term dextrose infusion initially increased isolated pyloric pressure waves (IPPWs) and basal pyloric pressure (P < 0.05 for both), but after about 30 minutes IPPWs and basal pyloric pressure decreased and returned to baseline within 80 minutes. Each short-term infusion increased IPPWs and basal pyloric pressure (P < 0.05 for both). Antral pressure waves remained suppressed during the long-term dextrose infusion. Intraduodenal triglyceride increased IPPWs and basal pyloric pressure (P < 0.05 for both). The long-term dextrose infusion was associated with a sustained increase, and both short-term dextrose infusions were associated with peaks in glucose, insulin, and gastric inhibitory polypeptide levels. There was no significant relationship between biochemical measurements and antropyloroduodenal motility. It is concluded that specific adaptive changes occur rapidly in the phasic and tonic pyloric motor response, but not the antral motor response, to intraduodenal dextrose.


Uremia increases gastric mucosal permeability and acid back-diffusion injury in the rat. The possibility that chronic uremia renders the gastric mucosa more susceptible to acid injury was investigated. A rat model of chronic renal failure was induced by subtotal nephrectomy. [H+] back-diffusion across the mucosa, following intragastric perfusion of 0.15N HCl or 15% ethanol in 0.15N HCl, was significantly greater in uremic than in sham-operated rats. Gastric mucous gel thickness and transmural potential difference were significantly lower in rats with renal insufficiency. Furthermore, a significantly greater acidification rate of the surface epithelial cells was found in uremic rats than in sham-operated rats during superfusion with pH 1.7 buffer. Intragastric administration of acidified ethanol or aspirin solutions markedly increased gastric mucosal blood flow (68% and 89% respectively) in the sham-operated group producing mild injury, in contrast to uremic rats, where a lesser increase in mucosal blood flow (7% and 14% respectively) was associated with more pronounced mucosal injury. It was concluded that enhanced susceptibility to acid injury in uremia is due to a reduction of function of pre-epithelial, epithelial, and postepithelial elements of the gastric mucosal barrier.


Differential induction of major histocompatibility complex molecules on mouse intestine by bacterial colonization. The aim of this study was to determine what factors induce major histocompatibility complex (MHC) molecules on the mouse small intestinal epithelium by using immunohistochemical methods. In germ-free mice, although MHC class I molecules such as H-2K and thymus leukemia antigen (TLa) were expressed on the small intestinal epithelium, class II molecules were absent. The introduction of microorganisms into germ-free mice induced characteristic MHC molecules on the small intestinal epithelial cells. The I-A molecule was induced on the villus tip and crypt epithelial cells 7 days after conventionalization, and the I-E molecule was induced on the mid villus and crypt epithelial cells 14 days after conventionalization. The staining intensity of the H-2K molecules was increased 4 days after conventionalization. In contrast, TLa did not change during conventionalization of germ-free mice. These results suggest that the expression of MHC molecules, except for the TLa, is greatly dependent on the presence of intestinal microorganisms.


Subepithelial collagen table thickness in colon specimens from patients with microscopic colitis and collagenous colitis. Microscopic colitis and collagenous colitis are similar conditions that are differentiated by the presence or absence of subepithelial collagen table thickening. To better understand the relationship between these two disorders and the role of collagen table thickening in the pathogenesis of diarrhea, colonic mucosal biopsy specimens from 24 patients with microscopic or collagenous colitis and 9 control subjects were analyzed using a computer-assisted morphometric method to evaluate the average thickness of the subepithelial collagen table. The collagen table thickness in colitis patients taken together formed a multimodal rather than a unimodal distribution. There was no tendency for collagen table thickening to increase with age or with duration of symptoms. In general, the types and distribution of inflammatory cells were similar in patients with normal and thickened collagen tables. Stool weight correlated with lamina propria cellularity but not with collagen table thickening. The multimodal distribution of collagen table thickening and the lack of correlation with age, duration of symptoms, or inflammation suggest that microscopic colitis and collagenous colitis are discrete conditions, although the inflammatory changes in the two conditions are similar. Moreover, because stool weight correlates with lamina propria cellularity but not with collagen table thickening, diarrhea probably is caused by the inflammatory changes and not by collagen table thickening per se.


Stimulation of acid secretion increases the gastric gland luminal pressure in the rat. The gastric mucosal gland luminal pressure was measured in vivo with a pressure-sensitive microelectrode technique (servo-null) in anesthetized rats. A microelectrode was inserted into a gland lumen by means of a micromanipulator at an angle of 30 degrees to the mucosal surface. Acid secretion was estimated by measuring the pH in the solution covering the mucosa. During control conditions, when the mucosa was secreting acid spontaneously, gland luminal pressure was 12.3 +/- 1.2 mm Hg. At about 9 minutes after starting pentagastrin administration, the luminal pressure stabilized at 17.2 +/- 1.7 mm Hg. In the rats given impromidine (500 micrograms.kg-1.h-1) luminal pressure gradually increased (during 9-10 minutes) from a control level of 9.0 +/- 1.9 to 17.3 +/- 2.6 mm Hg. During the majority of experiments, the luminal pressure oscillated at 3-7 cycles per minute. The results show that intraluminal pressure increases during stimulated acid secretion, indicating that a resistance to the volume secretion exists in the upper part of the gastric crypts. This hydrostatic pressure may well be the driving force for creating channels for acid and pepsin to cross the mucus layer covering the mucosal surface.


Sex differences in gastric alcohol dehydrogenase activity in Sprague-Dawley rats. The effects of sex differences and of fasting on gastric alcohol dehydrogenase activity were determined in Sprague-Dawley rats. Gastric alcohol dehydrogenase activity and enzyme protein levels were higher in female than in male rats. Ovariectomy and orchiectomy had no effect on alcohol dehydrogenase and did not alter the sex difference in enzyme activity. Fasting decreased the enzyme activity more in female than in male rats, abolishing the sex difference. Serum gastrin levels measured in female rats decreased on fasting and returned to normal levels within 24 hours of refeeding. Short- and long-term administration of pentagastrin to fasted and fed female rats did not affect the enzyme activity or enzyme protein level, except for a transient increase in enzyme activity but not in enzyme protein level 12 hours after administration to fasted fats. Omeprazole, which increased serum gastrin levels and decreased enzyme activity but not enzyme protein levels, was found to be a competitive inhibitor of the enzyme with a Ki of 0.40 mmol/L. The mechanisms for the sex differences and changes with fasting in rat gastric alcohol dehydrogenase activity remain unknown.


Human gastric myoelectric activity and gastric emptying following gastric surgery and with pacing. Postoperative gastric myoelectric activity, gastric emptying, and clinical course were correlated in 17 patients at high risk of developing gastroparesis after gastric surgery. In addition, an attempt was made to pace the stomach with an electrical stimulus and determine the effect of pacing on early postoperative gastric emptying. Gastric dysrhythmias (bradygastria, slow wave frequency < 2 cycles/min; tachygastria, slow wave frequency > 4 cycles/min) persisted beyond the first postoperative day in 6 patients (35%). Delayed gastric emptying was identified by a radionuclide meal in 15 patients (88%), but symptoms of gastroparesis developed in only 6 of 15 (40%). Patients with postoperative gastroparesis had more frequent dysrhythmias than asymptomatic patients (67% vs. 18%), but these differences were not significant, although we cannot exclude a type II statistical error. Gastric rhythm was entrained in 10 of 16 patients (63%). Pacing increased the gastric slow wave frequency (3.1 vs. 4.1 cycles/min; P < 0.01) but did not improve gastric emptying (gastric retention at 60 minutes, 86% +/- 6% for control and 90% +/- 2% for paced). In conclusion, gastric dysrhythmias do not appear to play a major role in the development of postsurgical gastroparesis. Although gastric rhythm could be entrained in the majority of patients, pacing did not improve gastric emptying overall.


Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA. The mitogenic role of estradiol on the growth of colon cancer was examined in mice. Sham-operated or ovariectomized mice were injected with cancer cells and received estradiol treatment. Tumor growth was noted: tumor weights were higher in female than male mice. The growth of the tumors was least in ovariectomized mice and highest in estradiol-treated ovariectomized mice. Tumor messenger RNA (mRNA) levels for ornithine decarboxylase (ODC) and proto-oncogenes c-myc, c-fos, and H-ras were examined. Two transcripts (2.2 and 2.7 kilobase pairs) of ODC were observed. The steady-state mRNA levels for ODC paralleled the changes observed in the weight of the tumors in all groups of animals. Less dramatic changes were observed in c-myc mRNA levels. No significant differences were observed in the mRNA levels for H-ras and c-fos. It thus appears likely that an increase in the ODC mRNA levels and, to a lesser extent, an increase in c-myc mRNA levels may be some of the important mechanisms by which estradiol mediates its growth effects on colon cancer cells in vivo.


Modulation of salivary secretion by acid infusion in the distal esophagus in humans. To examine the relationship between esophageal acid exposure and development of salivation and heartburn, 15 healthy subjects underwent perfusion of the distal esophagus with varying concentrations of hydrochloric acid, different-osmolality saline solutions, and deionized water. In five study subjects, hydrochloric acid was infused in the body of the stomach only. During the study, timed samples of whole and parotid saliva were collected and analyzed for flow rate and bicarbonate concentration. Only hydrochloric acid concentrations of 20 mmol/L or greater (pH 1.8 or lower) induced a rapid (within 2 minutes) and significant (P < 0.05) increase in salivation. The hydrochloric acid-induced salivation was associated with significant (P < 0.05) increase in bicarbonate secretion in both parotid and whole saliva samples. Intravenous atropine administration completely inhibited hydrochloric acid-induced salivary secretion in all six subjects. Changes in osmolality of saline solution infused in the esophagus and hydrochloric acid infused in the stomach did not significantly alter parotid and whole saliva flow rates. These data suggest that in humans, rapid salivation in response to esophageal mucosal exposure to intraluminal hydrochloric acid is a pH-dependent and osmolality-independent phenomenon that is most likely mediated by pH-sensitive chemoreceptors located in the esophageal mucosa.


Decreased expression of transforming growth factor alpha during differentiation of human pancreatic cancer cells. The relationship between cell differentiation and transforming growth factor alpha (TGF-alpha) expression in human pancreatic cancer cells was analyzed in Capan 1 cells. These cells differentiate either spontaneously or after butyrate treatment. During differentiation (spontaneous or butyrate induced), TGF-alpha messenger RNA (mRNA) levels decreased, whereas the TGF-beta 1 mRNA levels remained unchanged. TGF-alpha was present in cells as proTGF-alpha, which decreased after butyrate treatment. Secretion of TGF-alpha was not found. Under the two conditions of differentiation, the membrane-bound protein kinase C activity was also reduced. Conversely, long-term phorbol ester treatment increased both membrane-bound protein kinase C activity (260%) and TGF-alpha mRNA level (500%), a not significant increase of TGF-beta 1 mRNA was observed. However, phorbol 12-myristate-13-acetate did not induce TGF-alpha synthesis or secretion. These data suggest that expression of TGF-alpha can be reduced in cancer cells; they also suggest the existence of a relationship between TGF-alpha expression and cell differentiation. In addition, the protein kinase C-induced TGF-alpha mRNA level was not followed by the increase of TGF-alpha biosynthesis, suggesting a translational control. Finally, the expression of TGF-alpha and -beta 1 messengers appears to be differently regulated.


Immunoglobulin A antibody to a 200-kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis. Considerable clinical and experimental evidence points to the importance of immune responses in the development of alcoholic liver disease. In the present study it was investigated whether circulating antibodies from patients with alcoholic liver disease recognize acetaldehyde-liver protein adducts. Cytosolic and microsomal fractions from livers of Wistar rats or from normal human liver were incubated with acetaldehyde (0.5-2.5 mmol/L) and/or cyanoborohydride (100 mmol/L) then analysed by immunoblotting. Cytosolic fractions that had been incubated with acetaldehyde and cyanoborohydride expressed a 200-kilodalton protein antigen not present in untreated fractions or fractions incubated with acetaldehyde or cyanoborohydride alone. The 200-kilodalton antigen was recognized by immunoglobulin (Ig)A antibodies in a large proportion of sera from patients with alcoholic hepatitis (70%, n = 23), but in significantly smaller proportions of sera from patients with alcoholic cirrhosis without hepatitis (30%, n = 10; P < 0.05), heavy drinkers without overt liver disease (20%, n = 10; P < 0.02), patients with nonalcoholic liver disease (35%, n = 17; P < 0.05), or normal control subjects consuming moderate quantities of alcohol (25%, n = 20%; P < 0.005). These results indicate that IgA antibodies to a 200-kilodalton acetaldehyde-protein adduct are present in a large proportion of patients with alcoholic liver disease and in a significantly smaller proportion of other individuals.


Increased gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy. To characterize gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy, 34 cirrhotics with this lesion and 24 noncirrhotics were studied by reflectance spectrophotometry and laser-Doppler flowmetry during endoscopy. A significant correlation was observed between the hemoglobin content of the gastric mucosa, measured by reflectance spectrophotometry, and the serum hemoglobin concentration both in cirrhotics (r = 0.72) and in noncirrhotics (r = 0.87). IHb ratio (hemoglobin content of gastric mucosa divided by blood hemoglobin concentration) was higher in cirrhotics with portal hypertensive gastropathy than in noncirrhotics (P < 0.001), whereas the oxygen content of the gastric mucosa was similar in both groups. This pattern indicates that cirrhotics with portal hypertensive gastropathy have increased gastric perfusion without congestion. Gastric blood flow estimated by laser-Doppler was significantly higher in cirrhotics with portal hypertensive gastropathy than in noncirrhotics (P < 0.001). In cirrhotic patients, gastric areas with cherry red spots showed a significantly higher IHb ratio than areas with a mosaic or scarlatina pattern (P < 0.05). The magnitude of changes in gastric perfusion and the endoscopic severity of portal hypertensive gastropathy had no relationship with the degree of portal hypertension or the azygos blood flow.


Cytological changes in the pancreas of transgenic mice overexpressing transforming growth factor alpha. Transgenic mice overexpressing human transforming growth factor alpha (TGF-alpha) predictably develop an enlarged, firm pancreas. The present study investigated the changes that occur in the different components of the pancreas in these animals. The increase in size of the pancreas may be accounted for by increased connective tissue. The added collagen is mainly type I. Thin, elongate fibroblasts are frequently bordered by a basal lamina, a relationship that is normally restricted to the perineurium. Collagen is intimately associated with epithelial cells. Fingers of connective tissue extend close to acinar lumina. Redifferentiation of acinar cells produces tubular complexes. In some cases, acinar cells take on the appearance of ductular cells. In some, there is a transition to mucin-producing cells. Intermediate forms between acinar and mucin-producing cells are present. The growth factor is localized in acinar cells and decreases with redifferentiation. The pancreas of these animals routinely displays characteristics that also are observed in diseases of the exocrine pancreas in humans, including fibrosis and redifferentiation. It is likely that the changes are the result of both direct and indirect effects of TGF-alpha, some of which may parallel altered control mechanisms in human pancreatic disease. Study of this model may provide clues to understanding the initiation of fibrosis and redifferentiation in human pancreas.


Primary sclerosing cholangitis: refinement and validation of survival models. The natural history of primary sclerosing cholangitis was studied in 426 patients from five medical centers. The median follow-up time was 3.0 years (range, 0.01-16.6 years); 100 patients had died by the time of last follow-up. Survival analysis (Cox proportional-hazards regression) was used to identify the variables most useful in predicting survival of patients with primary sclerosing cholangitis. Serum bilirubin concentration, histological stage on liver biopsy, age, and the presence of splenomegaly were independent predictors of a high risk of dying. A mathematical model to predict survival of patients with primary sclerosing cholangitis (based on referral values of those predictors) was statistically validated using two methods. Confidence intervals for predicting patient-specific survival probabilities are also presented. This model to predict survival could be used to stratify participants in therapeutic trials, counsel patients and their families, decide on candidacy for and timing of liver transplantation, and provide mathematical controls for evaluating the efficacy of therapies for primary sclerosing cholangitis, including transplantation.


Human pancreatic tissue concentration of bactericidal antibiotics. Pancreatic infection represents the most important cause of fatal outcome in human acute pancreatitis. In a comparative analysis, human pancreatic tissue concentrations of 10 different bactericidal antibiotics were determined in 89 patients undergoing pancreatic surgery. Concentrations of the antibiotics were determined in the blood and pancreatic tissue using high-pressure liquid chromatography. Pancreatic tissue concentrations 120 minutes after intravenous administration were as follows: mezlocillin, 19.0 mg/kg; piperacillin, 20.3 mg/kg; cefotaxime, 9.1 mg/kg; ceftizoxime, 7.9 mg/kg; netilmicin, 0.4 mg/kg; tobramycin, 0.4 mg/kg; ofloxacin, 1.7 mg/kg; ciprofloxacin, 0.9 mg/kg; imipenem, 6.0 mg/kg; metronidazole, 3.5 mg/kg. Three groups of antibiotics were established: group A, substances with low tissue concentrations (netilmicin, tobramycin), which were below the minimal inhibitory concentrations of most bacteria found in pancreatic infection; group B, antibiotics with pancreatic tissue concentrations which were sufficient to inhibit some but not all bacteria in pancreatic infection (mezlocillin, piperacillin, ceftizoxime, cefotaxime); group C, substances with high pancreatic tissue levels as well as high bactericidal activity against most of the germs present in pancreatic infection (ciprofloxacin, ofloxacin, imipenem). These data could serve as the basis for adequate antibiotic prophylaxis or treatment of pancreatic infection.