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Biosystems Engineering and Control Group 20

8043913

Characterization of hematology lysing reagents containing quaternary ammonium halides using fast-atom bombardment mass spectrometry.

Positive- and negative-ion fast-atom bombardment (FAB) mass spectrometry has been employed to characterize pure dodecyl-, tetradecyl- and hexadecyl-trimethylammonium chlorides and bromides, compounds of high interest as lysing agents in hematologic analyses. In parallel, the same approach has been used for some commercially available lysing reagent products. While in positive-ion FAB mass spectra the presence of the abundant ions corresponding to the intact quaternary ammonium cations (Q+) is accompanied by the presence of [Q2X]+ (X = Cl, Br) species, in the negative-ion mode cluster ions such as [QX2]- are the sole ionic species that are easily evident. The mechanism for the formation of [Q2X]+ and [QX2]- species has been studied and some suggested explanations are given.

8043912

Energetic state of the postischemic myocardium and its relation to contractile failure.

We used the isolated working rabbit heart preparation as a model to study the relationship between postischemic myocardial dysfunction and the energetic state of the heart in terms of mitochondrial function and myocardial high energy phosphate (HEP) contents. Normothermic global myocardial ischemia (10, 20 and 30 min) was induced. Cardiac function, mitochondrial function and myocardial HEP contents were measured. Viability of the postischemic myocardium was assessed by electron microscopy. Myocardial tissue was found to be intact up to 20 min of ischemia plus reperfusion. Areas of irreversibly damaged myocardium were found after 30 min of ischemia. Myocardial contractile function was significantly depressed after 10 and 20 min of ischemia and severely depressed after 30 min of ischemia. Postischemic myocardial dysfunction was associated with normal mitochondrial function and HEP content after 10 min of ischemia, with near-normal mitochondrial function and HEP content after 20 min of ischemia and with pathologic values after 30 min of ischemia. It is concluded that postischemic myocardial stunning is not associated with a disturbance of the energy producing processes. More severe ischemia however leads to progressive deterioration of mitochondrial function which may contribute to complete deterioration of myocardial contractile function upon reperfusion.

8043911

Flow dependence of factor X activation by tissue factor-factor VIIa.

Blood coagulation is initiated after blood is exposed to the transmembrane glycoprotein Tissue Factor (TF). The continuous flow reactor has been used to study the flow-dependent activation of factor X by the complex of TF and factor VIIa. The apparent Km value of X for TF-VIIa in vesicles of 16 nM is low compared to the value of > 600 nM on a macroscopic surface. At 17 to 70 fmoles TF-VIIa/cm2, the steady state Xa production rate was fairly insensitive to the enzyme density, which is in contrast with classical Michaelis-Menten kinetics. The X activation rate was linear with the cube root of the flow rate. These results show that X activation is limited by transport of factor X across a boundary layer towards the enzyme complex.

8043910

Origin of circulating acute phase cytokines: modified proteins may trigger IL-6 production by macrophages. Preliminary report.

Human peripheral blood monocytes isolated by centrifugation with Mono-Poly resolving medium, and human alveolar macrophages obtained by lung lavage during fiberoscopic bronchoscopy, were cultured in RPMI containing 2% foetal calf serum. The cultures were exposed to modified human proteins: alpha-1-antitrypsin cleaved with papain, fibrinogen degradation products (fraction D) purified from plasmin digest, and non-enzymatically glycosylated (glycated) serum albumin. Conditioned macrophage media were tested for the contents of acute phase cytokines by bioassay with hepatoma cells, and the concentration of interleukin-6 was determined with ELISA. Modified proteins stimulated macrophages to produce acute phase cytokines and the response was not abrogated by polymyxin B in distinction to stimulation of macrophages by endotoxin. Our data indicate that some proteolytically damaged proteins or the end glycosylation products formed in pathological states (acute inflammation, diabetes) may be responsible for the appearance of cytokines in the circulation.

8043909

Thrombinogenesis and its pharmacological modulation in atherosclerosis.

Appearance of thrombin in circulating blood can be monitored in the clinical setting by measuring specific thrombin markers, such as fibrinopeptide A, thrombin-antithrombin III or prothrombin fragment 1 + 2. In myocardial infarction monitoring of thrombin activity is of growing clinical interest. High levels of thrombin markers indicate an increased risk to a patient with myocardial infarction. Persistent, high thrombin marker levels, despite heparin anticoagulation, point to ongoing thrombin generation that may necessitate more anticoagulation, increased antiplatelet treatment, angioplasty or, in the future, use of new antithrombotic drugs. Recently, new sensitive methods have been developed to study the reaction of thrombin generation in clotting blood. These methods permitted to demonstrate that, aspirin, contrary to several other antiplatelet drugs, delay the process of thrombin formation. Continuous dampening of thrombin formation by aspirin might be one of the mechanisms responsible for its prophylactic and therapeutic efficacy. Hypercholesterolemic subjects might profit less than others from this type of treatment, since aspirin dampening effects are not so evident in hypercholesterolemia.

8043908

Prostaglandins and arterial wall lipid metabolism--in vitro, ex-vivo and in-vivo radioisotopic studies.

It is the aim of this paper to review our findings in vitro, in experimental animals and in human on arterial wall lipid metabolism. Radiolabelling of LDL indicates that experimentally induced lesions in hypercholesterolemic rabbits do show less lipid accumulation if treated with prostaglandins (PGI2, PGE1, 13,14-dihydro-PGE1) or stimulators of prostaglandin synthesis (isradipine, a calcium channel blocker of the dihydropyridine family). Endogenous blockade of cyclooxygenase by ASA-pretreatment results in a complete abolishing of this apparently PG-mediated benefit. In-vivo studies using autologous 123I-labeled LDL without therapeutic intervention exhibit a quite good reproducibility of the imaging technique. While PGE1 (at 2 different therapeutic regimens) is inducing lipid lesion regression, the comparable benefit induced by isradipine again disappears with concomitant ASA-therapy. Quantitative estimation of arterial wall lipid metabolism in patients undergoing vascular surgery demonstrates that PGI1- (and cAMP-) increase are paralleled by a several-fold increase of acid and neutral cholesterol ester hydrolase and a decrease in net arterial cholesterol ester content. This benefit again disappears with concomitant ASA-therapy. These findings are allowing to conclude that (exogenously added or endogenously stimulated) prostaglandins do significantly improve arterial wall lipid metabolism.

8043907

A note on distribution of human plasma levels of ascorbic and dehydroascorbic acid.

Ascorbic acid concentrations in 102 human plasma samples ranged from 1 to 15 micrograms ml-1 with a mean concentration at about 8 micrograms ml-1, corresponding to the results of other authors. Dehydroascorbic acid was found only in traces, independent of ascorbic acid concentrations. The ascorbic acid concentrations in plasma of four persons, examined twice with a four-years interim period revealed no obvious differences over time. It is suggested that the variability of plasma ascorbic acid concentrations is mainly determined by long-term dietary habits.

8043906

Reducing effect of atrial natriuretic factor on Na, K-ATPase activity in rat kidney.

This study was designed to examine the effect of the rat atrial extract (RAE) and synthetic rat ANF123-150 (rANF) on the renal Na, K-ATPase activity in Wistar anesthetized rats. Na, K-ATPase activity was assayed by measuring the amount of inorganic phosphate liberated from ATP. RAE from 40.3, 80.6 mg of tissue and rANF in the following doses: 0.043, 0.087, 0.173, 0.260 nM/kg/min reduced Na, K-ATPase activity by 59, 64 and 11, 34, 37, 45% respectively in the renal medulla but not in the cortex. It was associated with the increase in diuresis and natriuresis. Five and ten minutes after the end of rANF administration, Na, K-ATPase activity was decreased by 78 and 57% respectively, diuresis and natriuresis were significantly higher than the control. After fifteen minutes enzyme activity returned to normal, diuresis and natriuresis were increased. After thirty minutes there was a 37% increase in Na, K-ATPase activity but diuresis and natriuresis were still higher than control values. We conclude that the inhibition of Na, K-ATPase in the medulla of the rat kidney is one of the mechanisms of ANF action.

8043905

Effects of vasopressin and analogue [d(CH2)1(5), Tyr (Me)2, Val4, delta 3Pro7)] AVP on learning and memory in rats chronically treated with ethanol.

Rats with impaired active and passive avoidance induced by chronic administration of ethanol were studied. Vasopressin (AVP) and analogue (d(CH2)1(5), Tyr (Me)2, Val4, delta 3Pro7] AVP (icv, 2 micrograms) eliminated the toxic effect of ethanol, and analogue AVP improved retrieval of passive avoidance situation in both control and postalcohol groups of rats. Chronically administered ethanol markedly depressed the ability to learn. AVP administered icv markedly delayed extinction of conditioned avoidance situation in both groups of rats, and did not influence acquisition in this test. Analogue AVP has no influence on extinction and acquisition in the control and post-alcohol groups of rats.

8043904

The melting of native domain structure in effector activation of IgG studied by using congo red as a specific probe.

The nature of structural changes in IgG molecules associated with the binding to antigen and/or heat aggregation was studied using bis azo dye (Congo Red) as the specific probe. It was found, that protein conformation responsible for binding the dye represents an unfolding intermediate with properties corresponding to a molten globule state. The properties of the dye-protein complex reveal the signs of an unfolding of the peptide chain with simultaneously preserved relatively compact packing. Immunoglobulins which were induced by heating, or binding to antigen in order to form the complex with dye ligands, become more susceptible for digestion. The main peptide of molecular weight 30,000 D which appears in products was suggested to originate from a heavy chain after its splitting in the region of CH1 domain. The energetic evaluation of stability of IgG domains also indicates that CH1 is the least stable fragment of the heavy chain and its conformation may be destabilized first. It was concluded that destabilized tertiary packing of antibodies bound to antigen may favour the association of closely situated immunoglobulin molecules increasing the stability of the immune complex and influencing in the result its effector activity.

8043903

Mechanism of inhibition of smooth muscle of guinea-pig taenia coli by chloramphenicol.

The effects of antibiotic chloramphenicol (CAP) on Ca(2+)-ATPase activity and muscle tension were examined in guinea-pig taenia coli. In general, when CAP was added to the resting tissue no inhibition was observed except when a tonus was present, caused by either ouabain, high K+ or acetylcholine. Ouabain and high K(+)-induced sustained contractions were concentration-dependently inhibited by CAP. The sustained contraction induced by high K+ was more strongly inhibited by CAP than ouabain (IC50 value: high K+ 0.29 mumol/ml; ouabain 0.34 mumol/ml). In Ca(2+)-free solution, inhibition of ouabain-induced sustained contracture by CAP was more pronounced. CAP increased the activity of Ca(2+)-ATPase in taenia coli in all experiments. In presence of cystine, CAP-induced inhibition and increase in Ca(2+)-ATPase activity could not be observed. CAP analogue thiamphenicol (TAP), devoid of p-NO2 group, showed insignificant response on smooth muscle inhibition and Ca(2+)-ATPase activity. These findings suggest that CAP inhibits smooth muscle contractility by decreasing cytosolic Ca2+ ([Ca2+]i) level through a cGMP mediated increase in Ca(2+)-ATPase activity and this action is possibly related with the p-NO2 group present in its molecule like other nitro-compounds.

8043902

Angiotensin converting enzyme inhibitors and atherosclerosis.

This study was designed to evaluate possible antiatherosclerotic effects of angiotensin converting enzyme inhibitors in mini-pigs. Experimental hypercholesterolemia and atherosclerosis were produced in mini-pigs of the Göttingen strain by adding 11% egg yolk and 1% cholesterol to the diet for 52 weeks. The animals were divided into three groups. One group was fed the atherogenic diet alone and served as control. The second group was treated with captopril in a dose of 80 mg/kg/day added to the atherogenic diet on an individual basis. The third group was treated with fosinopril in a dose of 8 mg/kg/day. Both drugs produced a significant reduction in serum ACE activity associated with a reactive rise in plasma renin activity and a slight fall in serum aldosterone concentration. The drug treatment had only minor effects on plasma lipids. The aorta and the carotid and coronary arteries were examined for atherosclerotic lesions. Atherosclerotic plaques developed in the abdominal aorta whereas fatty streaks were present in the thoracic aorta and the coronary arteries. Both drugs significantly reduced the percent visible atherosclerosis in the abdominal aorta. Furthermore, the accumulation of cholesterol in the thoracic and abdominal aorta was significantly reduced. The effect of captopril and fosinopril on endothelium-dependent relaxation of iliac arteries was examined. After addition of 3 x 10(-7) M acetylcholine strips from basal diet fed mini pigs showed a remaining tension of 7.0% +/- 7.1 (p < 0.05 compared to cholesterol-high diet), cholesterol-high diet 36.4% +/- 10.2, captopril 16.9% +/- 4.9 (p < 0.01) and fosinopril 31.7% +/- 4.6 (n.s.). It is concluded that the ACE inhibitors captopril and fosinopril inhibited the development of atherosclerosis in hypercholesterolemic mini-pigs.

8043901

Effect of endothelin-3 on blood pressure in conscious spontaneously hypertensive [SHR] and DOCA-salt hypertensive rats.

The aim of the study was to investigate blood pressure responses and changes in heart rate after bolus administration of endothelin-3 [ET-3] in conscious, freely moving SHR and WKY rats and DOCA-salt hypertensive and normotensive Wistar rats. The effect of ET-3 on blood pressure and heart rats was investigated for four doses equal to 250 ng, 500 ng, 1000 ng and 2000 ng of ET-3. Our study shows that in experimental models of hypertension changes in blood pressure were predominantly characterized by the pronounced hypotensive phase with no significant raises in blood pressure. In normotensive animals cardiovascular responses to ET-3 were biphasic, with initial depressor phase followed by long-lasting, significant pressor effect.

8043900

The effect of an antilipolytic agent (acipimox) on the insulin resistance of lipid and glucose metabolism in hypertriglyceridaemic patients.

Hypertriglyceridaemia is associated with insulin resistance of both lipid and glucose metabolism. It is not known whether the insulin resistance affects both glucose oxidation and glycogen formation. To study the oxidative and non-oxidative pathways of non-esterified fatty acids (NEFA) and glucose metabolism, eight male hypertriglyceridaemic subjects were studied during insulin infusion (75 and 340 pmol/m2.min) in combination with indirect calorimetry and infusions of [3-3H]glucose and [1-14C]palmitate before and after 4 weeks of treatment with the antilipolytic agent acipimox (250 mg three times daily). Compared with eight healthy subjects the hypertriglyceridaemic subjects were resistant to the antilipolytic effect of insulin, both in the basal state (P < 0.05) and during insulin infusion (P < 0.05). This was associated with impaired insulin-stimulated glucose uptake (P < 0.05), predominantly in the non-oxidative pathway (P < 0.05). Acipimox decreased basal NEFA concentrations (P < 0.01) and reduced lipid oxidation during low-dose insulin infusion (P < 0.05). Glucose uptake, predominantly glycogen formation, was stimulated by acipimox (P < 0.05). In conclusion, the insulin resistance of glucose metabolism associated with hypertriglyceridaemia is largely due to a defect in non-oxidative glucose metabolism. Acipimox improves glucose metabolism both by affecting glucose oxidation (low-dose insulin) and non-oxidative glucose metabolism (high-dose insulin).

8043899

Impairment of T-cell growth-promoting lymphokines in human insulin-dependent diabetes mellitus.

T-cell growth factor (TCGF) activity was studied in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) from 10 type-1 diabetic patients who had been diagnosed within the previous 12 months (group A), from 9 diabetic patients in whom the duration of disease was more than 1 year (group B) and from 12 healthy controls (group C). The effects of indomethacin on PHA-induced TCGF activity and the effects of adherent cells (macrophages) from group A and group C on TCGF production of normal group-matched non-adherent cells (lymphocytes) were also studied. TCGF activity was assayed on TCGF-dependent blast cells and calculated as a stimulation index (SI). TCGF activity in group A (SI 0.86 +/- 0.8) was significantly different from that in group B (SI 1.75 +/- 1.02; P = 0.037) and in group C (SI 1.91 +/- 1.29; P = 0.023). Following the addition of indomethacin, TCGF SI was 1.35 +/- 0.74 in group A, 1.85 +/- 0.73 in group B and 2.06 +/- 1.19 in group C. The responses to indomethacin were found to correlate with the basal TCGF activity in all subjects (r = -0.48; P = 0.006) independently of the disease process studied or its duration. No correlation was found between TCGF activity and parameters of metabolic control (HBA1c and fructosamine). Interestingly, a significant inverse correlation was found between TCGF activity and the required dose of insulin only in group A (r = -0.66; P < 0.05). Adherent cells from diabetic patients were found not to inhibit TCGF production.(ABSTRACT TRUNCATED AT 250 WORDS)

8043898

Resting energy expenditure and body composition in morbidly obese, obese and control subjects.

Resting energy expenditure (REE) was investigated by indirect calorimetry in relation to body composition and to different degrees of obesity in order to assess if a defective energy expenditure contributes to extra body fat accumulation. Differences were found between control subjects (group C; BMI 23 +/- 0.5 kg/m2, REE 5890 +/- 218 kJ/day; mean +/- SEM) and obese subjects (group O; BMI 34.2 +/- 0.9 kg/m2, REE 7447 +/- 360 kJ/day; P < 0.0001) and between group C and morbidly obese subjects (group MO; BMI 49.9 +/- 1.6 kg/m2, REE 8330 +/- 360 kJ/day; P < 0.0001); REE was not significantly different between groups O and MO. Body composition data were obtained by means of body impedance analysis. Even though group MO had a fat mass higher than group O, body cell mass, the metabolically active body compartment, was similar in groups O and MO, and this fact may have contributed to the similar REE in the two groups. Multiple regression analysis gave the following equation as the best predictor of REE: REE (kJ/day) = 1591 +/- 49BW + 74BCM - 737G (R2 = 0.88), where BW is body weight, BCM is body cell mass and G is a dummy variable coding group membership (group C = 1; group O = 2; group MO = 3). Thus the analysis showed a negative impact of obesity on REE beyond body composition variables.

8043897

Thiobarbiturate and fructosamine assays: significance and interest of the borohydride blank.

The acute-phase reaction (APR) induces the production by the liver of short-lived glycoproteins. The carbohydrate moiety of these proteins is thought to interfere with the thiobarbiturate (TBA) and nitroblue tetrazolium colorimetric tests which are used for assaying non-enzymatic glycosylation (NEG) of serum proteins. The aim of the present study was to assess the effect of the APR on the specificity of the colorimetric tests in non-diabetic and diabetic subjects. A positive correlation was found between C-reactive protein (CRP), an APR glycoprotein, and non-specific TBA reactivity as determined after borohydride reduction (BH4-resistant TBA, BR-TBA), both in non-diabetics (r = 0.61; P < 0.01) and diabetics (r = 0.68; P < 0.01). The BH4-sensitive specific TBA (SP-TBA) was not influenced by glycoproteins, and its increase in diabetics was correlated with the nitroblue tetrazolium assay (r = 0.89; P < 0.01). An independent effect of diabetes and APR on non-specific TBA was also demonstrated, suggesting an effect of hyperglycaemia on both protein glycation and glycosylation. TBA with borohydride reduction is an attractive tool for the study of complex glycoproteins in diabetes.

8043894

Effects of glipizide on glucose metabolism and muscle content of the insulin-regulatable glucose transporter (GLUT 4) and glycogen synthase activity during hyperglycaemia in type 2 diabetic patients.

To examine whether sulphonylureas influence hyperglycaemia-induced glucose disposal and suppression of hepatic glucose production (HGP) in type 2 diabetes mellitus, a 150-min hyperglycaemic (plasma glucose 14 mmol/l) clamp with concomitant somatostatin infusion was used in eight type 2 diabetic patients before and after 6 weeks of glipizide (GZ) therapy. During the clamp a small replacement dose of insulin was given (0.15 mU/kg per min). Isotopically determined glucose-induced glucose uptake was similar before and after GZ administration which led to improved glycaemic control (basal plasma glucose 12.2 +/- 1.3 vs 8.9 +/- 0.7 mmol/l; P < 0.01). Glucose-induced suppression of HGP was, however, more pronounced during GZ treatment (0.96 +/- 0.14 vs 1.44 +/- 0.20 mg/kg per min; P < 0.02). Following GZ treatment hyperglycaemia failed to stimulate glycogen synthase activity. Moreover, GZ resulted in a significant increase in the immunoreactive abundance of the insulin-regulatable glucose transport protein (GLUT 4) (P < 0.02). In conclusion, these results suggest that GZ therapy in type 2 diabetic patients enhances hepatic sensitivity to hyperglycaemia, while glucose-induced glucose uptake remains unaffected. In addition, GZ tends to normalize the activity of glycogen synthase and increases the content of GLUT 4 protein in skeletal muscle.

8043895

Incidence of type I diabetes in the district of Catania, Sicily.

The incidence of type I (insulin-dependent) diabetes was determined in the district of Catania (eastern Sicily) in children under 15 years of age over a 3-year period (1 January 1989 to 31 December 1991). Two independent sources of information were used. The primary source was contact with all medical services in the province, and the secondary source was the personal identification cards issued to all diabetic patients by the National Health System necessary for obtaining free medical care. The information obtained was 99.6% complete. The overall incidence was 10.2/10(5) per year. This study provides the first standardized data on the incidence of type I diabetes in Sicily and is consistent with the possibility of regional deviations from the proposed north to south gradient.

8043892

Sodium retention and insulin treatment in insulin-dependent diabetes mellitus.

The hypothesis that total body exchangeable sodium (ENa) is elevated in type 1 (insulin-dependent) diabetic patients with short-duration diabetes and no signs of microangiopathy was tested. Also tested was whether peripheral hyperinsulinaemia, in terms of the amounts of insulin injected subcutaneously, contributes to the increased ENa. Three studies were performed. Study 1 was a cross-sectional study comprising 28 type 1 diabetic men (aged 18-35 years) with short-duration diabetes (< 5 years) and no signs of diabetic complications, and 22 control subjects. Study 2 was a prospective study of 17 newly diagnosed diabetic patients (aged 20-35 years, median 27 years) who were studied on two occasions on different insulin doses. Study 3 was a 12-month prospective intervention study of 21 type 1 diabetic patients with incipient nephropathy, who had been randomized either to receive continuous subcutaneous insulin infusion for improvement of glycaemic control or to remain on conventional insulin treatment. In study 1, ENa was higher in short-duration type 1 diabetic men than in controls (3003 +/- 325 vs 2849 +/- 207 mEq/1.73 m2, P < 0.05) and was correlated significantly with the insulin dose (r = 0.38, P < 0.05). In study 2, of the newly diagnosed diabetic patients, 11 received a reduced insulin dose and 6 an increased dose as compared with the initial study. ENa was reduced in all patients receiving less insulin (P < 0.001) and remained unchanged in patients receiving more insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

8043891

Long-term treatment with nifedipine reduces urinary albumin excretion and glomerular filtration rate in normotensive type 1 diabetic patients with microalbuminuria.

The aim of the present study was to investigate the renal effects of long-term treatment with the calcium channel blocker nifedipine in normotensive type 1 diabetic patients with microalbuminuria. In a randomized, double-blind trial, 15 type 1 diabetic patients were treated with either nifedipine (n = 8; dosage 30 mg/day) or placebo (n = 7) for 12 months. At baseline and after 6 and 12 months of therapy, the albumin excretion rate (UAER, radioimmunoassay), glomerular filtration rate (GFR, chromium 51 ethylenediamine tetra-acetic acid clearance) and renal plasma flow (RPF, iodine 125 hippuran clearance) were determined. Nifedipine treatment caused a significant reduction of UAER after 6 and 12 months (median, Q1/Q3 in mg/24 h): baseline 84 (65/163); 6 months 35 (23/90), P < 0.02; 12 months 39 (15/79), P < 0.05). GFR was significantly decreased by nifedipine treatment (baseline 157 +/- 15, 6 months 122 +/- 8, 12 months 111 +/- 47 ml/min; P < 0.05, mean +/- SEM), whereas RPF remained constant. Nifedipine treatment did not influence systolic (baseline 121 +/- 7, 12 months 124 +/- 2 mmHg, mean +/- SEM) or diastolic (baseline 72 +/- 2, 12 months 74 +/- 3 mmHg) arterial blood pressure. With placebo treatment no significant alterations of UAER, GFR, RPF and arterial blood pressure were observed. Metabolic control was constant throughout the whole study period. Thus, 1 year's treatment with nifedipine reduces the UAER and GFR in normotensive type 1 diabetic patients without influencing the systemic arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

8043890

Clinical reliability of multi-drug intracavernous vasoactive pharmacotherapy for diabetic impotence.

The aim of this study was to assess the effectiveness and safety of intracavernous injections of a four-drug vasoactive mixture in diabetic patients with organic impotence. A group of 60 diabetic patients with either pure neurogenic, pure vasculogenic or mixed neurovasculogenic impotence were treated with intracavernous injections of a combination of 12.1 mg/ml papaverine hydrochloride, 1.01 mg/ml phentolamine mesylate, 10.1 micrograms/ml prostaglandin E1 and 0.15 mg/ml atropine sulphate ('full-dose' mixture). A mixture of the same drugs but at one-third concentrations ('reduced-dose' mixture) was also used. The mean (+/- SEM) volumes of the full-dose and reduced-dose mixtures used were 0.21 +/- 0.03 ml and 0.31 +/- 0.02 ml, respectively. All the patients were able to sustain a rigid erection at the end of the titration phase of the study. At a mean follow-up of 18 months, 48 patients (80%) were successfully using the mixture, 6 patients (10%) were using the mixture at a dose lower than the initial dose and 6 patients (10%) had dropped out from the injection therapy. No major complications were seen. The association of multiple vasoactive drugs which use different mechanisms of action, thus exerting a pharmacological synergism, is an effective and safe procedure in intracavernous pharmacotherapy for diabetic patients with organic impotence.

8043889

Assistive devices in an elderly population studied at 70 and 76 years of age.

The longitudinal Intervention Study of the Elderly in Göteborg, Sweden (IVEG), has provided an opportunity to report on the use of assistive devices in activities of daily living (ADL) in a subsample of elderly persons living in their own homes, who were interviewed at the ages of 70 and 76 (n = 371). Type, frequency, usage rate and effectiveness of assistive devices was studied among all 76-year-olds involved in the IVEG study (n = 595). One-fifth at the age of 70 and almost half of the population at 76 had assistive devices, most frequently in connection with bathing and mobility. A higher percentage of females and subjects living alone used assistive devices compared to men and cohabitants. The longitudinal study showed that 31% developed a need for assistive devices between 70 and 76 years of age, 15% used assistive devices both at 70 and 76 years, while 50% had no devices at 70 or at 76 years of age. The usage rate was high (90%), and a high degree of effectiveness was found, particularly in the form of an increment in safety and a decrement in effort in the various activities.

8043888

Medical activity during an international sporting competition for the physically disabled: Saint-Etienne World Handicapped Sport Championships.

This paper describes the medical activity performed during the 1990 World Games for the Disabled, in Saint-Etienne, France. These Games were attended by 1200 athletes, 229 consultations were performed, and 175 treatments were administered by the medical team. This activity represents a rather high frequency of medical problems, linked either to the disabling disease or to sports injuries. There is a need for specific equipment, for better training of disabled athletes and for improved preparation.

8043887

Disease, impairment, disability and social handicap: a community based study of people aged 70 years and over.

The aim of this research was to investigate the prevalence of disability in a total population-based sample aged 70 years and over, the social handicap resulting from the disability and the diseases and impairments contributing to disability in the most disabled subjects. From the initial sample of 856 subjects, 782 (91.4%) participated. Disability in the tasks examined varied from 1.3% of subjects unable to feed themselves to 24.4% unable to carry out housework. In the 74 most disabled subjects comorbidity was common. The major clinical disorders that contributed to impairment and disability were heart failure, osteoarthritis, stroke and dementia. Those who were disabled were considerably more likely to be handicapped than those not disabled (odds ratio 6.65, 95% confidence interval 4.73-9.36). When social support was considered, the estimated risk of handicap associated with disability ranged from 3.19 (95% CI 1.92-5.30) for the subset of subjects who had a spouse, to 52.00 (95% CI 4.03-670.6) for subjects without emotional support.

8043886

Inter-rater agreement of two functional independence scales: the Functional Independence Measure (FIM) and a subjective uniform continuous scale.

The needs and clinical decisions of care centres are related to patients' ability to carry out daily living activities. Most of the functional scales are not easy to use. This study examined the inter-rater agreement of the Functional Independence Measure (FIM) and a subjective uniform continuous scale (UCS) (the rating varied between 0 = complete dependence and 9 = complete independence) between 'educators', physiotherapists and occupational therapists. Two hundred and fifty-four patients aged below 20 in a rehabilitation centre were rated by professionals who were most familiar with them. For the two scales, inter-rater agreement was very good for all activities except for locomotion outside the centre for the UCS. The rating differences were slightly smaller for the FIM than for the UCS. Physiotherapists rated similarly to occupational therapists. The educators rated slightly though significantly lower than the other raters. The differences could be explained by their professional activities.

8043885

Age-related changes in balance performance.

The postural stability of 1280 healthy subjects (640 males and 640 females) between the ages of 6 and 85 years was measured using a modified single limb stance timed test. Balance performance for both sexes increased with chronological age but peaked at different ages. The males' performance with eyes opened and eyes closed peaked at the third decade of life, after which a progressive decline was found. The females' performance with eyes opened and eyes closed peaked at the fourth decade of life and thereafter progressively declined. Except for the first decade of life, males performed better (p < 0.001) than females at all ages. The results of the stepwise regression analyses revealed that stature and body weight were the two viable anthropometric determinants of balance performance; the contribution of body surface area and body adiposity to the prediction of balance performance was negligible.

8043884

Differences in job placements between men and women with mental retardation.

Thirty-three men and women with mental retardation living in the New York metropolitan area (USA), who entered a supported employment programme were followed during their first 9 months in competitive employment. Differences in placement outcomes were consistently associated with gender differences. The implications of these findings are discussed in terms of providing employment services to men and women with mental retardation and developmental disabilities.

8043879

Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is an uncommon but potentially fatal complication of immunosuppression in solid-organ transplant recipients. A semiquantitative DNA polymerase chain reaction assay was developed to amplify a unique 269-bp region of the EBNA-1 gene in peripheral blood lymphocytes (PBL) using the primers described by Telenti et al (J Clin Microbiol 28:2187, 1990). Serial samples were studied from 23 transplant recipients, 12 of whom were diagnosed with PTLD. The majority of transplant recipients who were EBV seropositive at the time of transplant surgery and who did not develop PTLD (5 of 7, 71%) exhibited less than a 10-fold increase in the levels of EBV-infected PBL over the 0.1 to 5 EBV genomes/10(6) PBL observed in immunocompetent EBV seropositive controls. Transplant recipients who were seronegative at the time of transplantation and who underwent a primary EBV infection but did not develop PTLD exhibited a reduced capacity to control viremia because the levels of EBV-infected PBL were up to 400 times greater than the 1.0 to 50 EBV genomes/10(6) PBL observed in individuals undergoing acute infectious mononucleosis (Rocci et al: N Engl J Med 296:132, 1977). However, all transplant recipients who developed PTLD exhibited a marked elevation of EBV-infected PBL independent of their serologic state at the time of transplantation. Six of the 10 transplant recipients with PTLD exhibited > or = 300,000 EBV genomes/10(5) PBL, two exhibited 10,000 to 50,000 EBV-infected genomes/10(5) PBL, and one each exhibited 2,500 and 500 EBV genomes/10(5) PBL. However, the latter two samples were obtained 4 to 5 weeks after the diagnosis of PTLD and may reflect a decrease in viral load resulting from immunomodulation. Marked decreases in the levels of EBV nuclear antigen-1 (EBNA-1), EBNA-2, and EBNA-LP antibodies correlated with the increase in EBV-infected PBL. Hence, a quantitative difference in circulating EBV viral load and EBNA antibody levels is evident between transplant recipients with and without PTLD and may be useful as a noninvasive prognostic marker with which to monitor and/or predict the development of PTLD.

8043878

Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation.

T-cell depletion of donor bone marrow has been associated with an increased risk of disease relapse after allogeneic bone marrow transplantation (BMT). Recombinant interleukin-2 (IL-2), which is capable of increasing the antileukemic activity of peripheral blood lymphocytes obtained from patients who have undergone BMT, has been proposed as a potentially useful agent to reduce the risk of relapse post-BMT. We have previously shown that IL-2 administered to patients at very low doses after BMT is both clinically tolerable and immunologically active. We now report on the clinical outcome of 29 patients treated with low-dose IL-2 after CD6-depleted allogenic BMT for hematologic malignancy. IL-2 was administered by continuous infusion for up to 3 months beginning at a median of 67 days post-BMT. Eligibility requirements for IL-2 therapy included demonstration of stable engraftment and absence of acute grade 2-4 graft-versus-host disease (GVHD). Low-dose IL-2 was well tolerated by the majority of patients, with only 4 of 29 subjects withdrawn early. Acute GVHD developed in only one individual. After 12 weeks of treatment, the mean number of circulating natural killer cells in patients increased 10-fold without any significant change in T-cell number. Of the 25 patients who received > or = 1 month of IL-2, only 6 have relapsed. Relapse rate and disease-free survival (DFS) were determined in the 25 patients who completed at least 4 weeks of IL-2 treatment and compared with historical controls transplanted at our institution for the same conditions and treated with an identical ablative regimen and method of T-cell depletion. Only control patients who had survived disease free for 100 days post-BMT were included in this analysis. Cox's proportional hazards regression model suggested that, compared with control patients without a history of GVHD, patients treated with IL-2 had a lower risk of disease relapse (hazard ratio 0.34; range, 0.14 to 0.82) and superior DFS (hazard ratio 0.39; range 0.18 to 0.87). A randomized controlled trial of IL-2 immunotherapy after T-cell-depleted BMT should now be undertaken.

8043877

Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non-Hodgkin's lymphoma.

Over a 6-year period, 275 patients were treated with autologous bone marrow transplantation (auto-BMT) for advanced-stage malignant lymphoma. After BMT, clonal chromosomal abnormalities were detected in hematopoietic cells from 10 patients. All 10 had morphologically and cytogenetically normal BMs at the time of stem cell harvest. The cytogenetic changes were first detected 1.8 to 6.5 years (mean, 3.9) after induction chemotherapy, and 0.5 to 3.1 years (mean, 1.4) after transplantation, and were characteristic of those reported for therapy-related myelodysplastic syndrome (MDS) in 9 of the patients: abnormalities of chromosome 5 or 7 (classical-form) were present in 4, 11q23 or 21q22 abnormalities (topoisomerase II-related form) were detected in 3, and a combination of both forms was seen in 2 patients. Clonal 2p abnormalities were found in the 1 remaining patient. The abnormal karyotypes were associated with morphologically recognizable MDS in 3 patients and with acute myeloid leukemia (AML) arising in MDS in 2. Four of these patients have died: 3 of AML and 1 of infection. One patient is still alive with cytopenia. The clonal cytogenetic abnormalities were not associated with MDS in 5 patients: 1 has died of recurrent lymphoma, 2 have cytopenia, and 2 still have no morphologic or clinical evidence of MDS after short follow-up (4 and 13 months). Compared with a control group matched for disease, length of follow-up, and treatment with auto-BMT, there were no statistically significant associations between the development of clonal chromosomal abnormalities and age, number of chemotherapeutic regimens, prior local radiation, BMT conditioning regimen (with or without total body irradiation), or type of lymphoma. These studies show that the risk of developing clonal cytogenetic changes after auto-BMT for malignant lymphoma is approximately 9% at 3 years, even when pre-BMT karyotypic studies are normal. The exact significance of these cytogenetic abnormalities in the absence of MDS or AML is unclear.

8043876

Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia.

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor's peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

8043875

Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta-thalassemia.

Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta-thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta-thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.

8043874

An increased HLA DR2 frequency is seen in aplastic anemia patients.

The underlying etiology of aplastic anemia is unknown in the majority of patients, although medications, chemical exposure, or viral infections can be implicated in some. Genetic susceptibility to a variety of diseases has been shown and it has recently been suggested that aplastic anemia is more common in individuals who are HLA DR2+ than in the general population. To examine this question, we retrospectively analyzed the results of HLA-DR typing in 75 aplastic anemia patients who received antithymocyte globulin (ATG) therapy or an HLA-matched sibling bone marrow transplant at UCLA between 1978 and 1989. Thirty-one patients were DR2+, a 1.9-fold higher incidence than the expected number of 16.6 patients (P < .0005). Of the 37 patients who received ATG, 33 were evaluable for a response; 14 patients had either a complete (4 patients) or partial (10 patients) response, for an overall response rate of 42.4%. Of the 14 DR2+ patients who received ATG, 7 responded, for a 50% response rate, which is not significantly higher than the response rate for the DR2- patients (7 of 19 [36.8%]; P = .50). The median survival of patients who are DR2+ was slightly, but not significantly, longer than that of the DR2- patients in the ATG group (P = .19). Although the incidence of HLA DR2 was clearly increased in these patients with aplastic anemia, response rates to ATG were not significantly different in the DR2+ and DR2- patients.

8043873

Altered band 3 structure and function in glycophorin A- and B-deficient (MkMk) red blood cells.

The anion transport activity of the human erythrocyte anion transporter (band 3; AE1) has been examined in both normal and glycophorin A (GPA)-deficient (MkMk) human red blood cells (RBCs). The sulfate transport activity of MkMk cells (from two ethnically diverse sources) was approximately 60% that of normal erythrocytes under the transport assay conditions used. However, MkMk and normal RBCs contained similar amounts of band 3. The reduction in sulfate transport activity was shown to be caused by an increase in the apparent Km for sulfate in MkMk RBCs, suggesting the band 3 in the MkMk RBCs has a lowered binding affinity for sulfate anions. The size of the N-glycan chain on band 3 of the MkMk cells was larger than that on band 3 from normal RBCs. In contrast, the size of the N-glycan chain on the glucose transporter (GLUT1) from MkMk cells was smaller than that on GLUT1 from normal cells. The possible role of GPA in the biosynthesis and anion transport activity of band 3 in normal RBCs is discussed.

8043872

Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis.

Iron chelation treatment of red blood cells infected with Plasmodium falciparum selectively intervenes with iron-dependent metabolism of malaria parasites and inhibits their development. Highly permeant hydroxamate iron chelator RSFileum2 affects all parasite stages when cultures are continuously exposed to drug, but affects primarily ring stages when assessed for irreversible effects, ie, sustained inhibition remaining after drug removal. On the other hand, the hydrophilic and poorly permeant desferrioxamine (DFO) affects primarily trophozoite/schizont stages when tested either in the continuous mode or irreversible mode. Unlike parasites, mammalian cells subjected to similar drug treatment show complete growth recovery once drugs are removed. Our studies indicate that parasites display a limited capacity to recover from intracellular iron depletion evoked by iron chelators. Based on these findings we provide a working model in which the irreversible effects of RSFs on rings are explained by the absence of pathways for iron acquisition/utilization by early forms of parasites. Trophozoite/schizonts can partially recover from RSFileum2 treatments, but show no DNA synthesis following DFO treatment even after drug removal and iron replenishment by permeant iron carriers. At trophozoite stage, the parasite uses a limited pathway for refurnishing its iron-containing enzymes, thus overcoming iron deprivation caused by permeant RSFileum2, but not by DFO because this latter drug is not easily removable from parasites. Their DNA synthesis is blocked by the hydroxamate iron chelators probably by affecting synthesis of ribonucleotide reductase (RNRase). Presumably in parasites, prolonged repression of the enzyme leads also to irreversible loss of activity. The action profiles of RSFileum2 and DFO presented in this study have implications for improved chemotherapeutic performance by combined drug treatment and future drug design based on specific intervention at parasite DNA synthesis.

8043871

Normal cations and abnormal membrane lipids in the red blood cells of dogs with familial stomatocytosis-hypertrophic gastritis.

Examination of the red blood cells (RBCs) of eight dogs with familial stomatocytosis-hypertrophic gastritis (FS-HG), a multiorgan disease associated with hemolytic anemia, hereditary stomatocytosis (HSt), and hypertrophic gastritis resembling Ménétrier's disease in man, showed abnormal osmotic fragility, normal mean corpuscular volume, slightly increased cell water, and normal cation content and cation fluxes. Cholesterol was decreased in RBC and increased in plasma. In both RBCs and plasma, total phospholipid (PL) was normal, phosphatidylcholine (PC) decreased, and sphingomyelin increased. The palmitic acid content of PC was increased, and the stearic acid content of PC was decreased. Sodium dodecyl sulfate electrophoresis of RBC membrane proteins was normal. These findings have not been described previously in HSt. They suggest that in FS-HG, abnormal composition of the PL in RBCs secondary to abnormal PL in plasma causes defective membrane function and stomatocytic shape-change. This conclusion was supported by a shortened half-life of 51Cr-labeled RBCs from normal dogs after transfusion in dogs with FS-HG. It was concluded (1) that not all hereditary forms of stomatocytosis are necessarily associated with an intrinsic structural defect of the RBC membrane, but that the change in shape of RBC may also be induced by abnormal composition of the plasma; (2) that stomatocytosis may be caused by loss of membrane surface area rather than by the increased cation uptake such as has been shown in some human kindreds with HSt, (3) that FS-HG is a disorder of lipid metabolism, and by consequence, (4) that abnormal lipid metabolism might be involved in the pathogenesis of Ménétrier's disease.

8043870

Identification of new mutations in two phosphoglycerate kinase (PGK) variants expressing different clinical syndromes: PGK Créteil and PGK Amiens.

Phosphoglycerate kinase (PGK) deficiency is generally associated with chronic hemolytic anemia, although it can be accompanied by either mental retardation or muscular disease. Genomic DNAs of two PGK-deficient patients previously described in France were sequenced directly after polymerase chain reaction amplification. The PGK Créteil variant arises from a G-->A nucleotide interchange at position 1022 in cDNA (exon 9), resulting in amino acid substitution 314 Asp-->Asn in the C-terminal domain, which contains the nucleotide binding site. It is associated with rhabdomyolysis crises but not with hemolysis or mental retardation. In the other case, which is associated with chronic hemolytic anemia and mental retardation (PGK Amiens), an A-->T nucleotide interchange was found at position 571 in cDNA (exon 5); this leads to amino acid substitution 163 Asp-->Val in the N-terminal domain, which contains the catalytic site for phosphoglycerate binding. These results corroborate the kinetic data observed. In the two cases, the mutations are distinct from others previously reported and no significant relationship could be observed between the location of the amino acid substitution and its clinical consequences.

8043869

Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas.

We have analyzed 30 cases of high- and intermediate-grade acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma (AIDS-NHL) for mutations in the c-myc coding region. In addition, in these same tumors, we have sought the presence of mutations in a regulatory region within the first c-myc intron defined by the binding to a factor that inhibits c-myc transcription (MYC intron factor, or mif). Mutations in the c-myc coding region were present in 10 of 16 small noncleaved cell lymphoma (SNCL), but in only 3 of 14 other histologic subtypes tested (0/3 large non-cleaved cell, 2/8 immunoblastic, and 1/3 anaplastic large cell lymphomas). Nineteen of the AIDS-NHLs analyzed contained a c-myc rearrangement and in 10 of these the c-myc gene was mutated in its coding region. In contrast, we could detect a mutation in the coding region in only 2 of 8 AIDS-NHL without a c-myc rearrangement. Mutations in the mif region were detected in 5 of 16 SNCL. Among AIDS-NHL carrying mutations in the c-myc coding region, only 4 carried mutations in the regulatory region. These results suggest that the mutations in the coding region of the c-myc protein may either be a consequence of the translocations involving c-myc, or may be necessary only in tumors where c-myc is deregulated as a result of a c-myc/lg translocation.

8043868

Hairy cell interactions with extracellular matrix: expression of specific integrin receptors and their role in the cell's response to specific adhesive proteins.

Integrin/extracellular-matrix interactions are central to the migration, localization, and subsequent function of lymphocytes within tissues. In hairy cell leukemia (HCL) the malignant cells display a highly characteristic tissue distribution in which interactions with extracellular matrix (ECM) are often prominent. Therefore, we used HCL as a model in which to investigate the poorly understood integrin/ECM interactions that underlie the migratory behavior of malignant B lymphocytes. Using a combined approach involving immunocytochemistry, flow cytometry, and immunoprecipitation analysis, hairy cells (HCs) were shown to have a consistent and distinctive phenotype (mainly alpha 4 beta 1, alpha 5 beta 1, alpha v beta 1, and alpha v beta 3). Furthermore, functional studies utilising adhesion assays, time-lapse video-microscopy and image analysis showed that the HCs displayed very specific adhesive behaviour in response to relevant adhesive protein ligands. HCs were able to adhere to different extents on all the adhesive proteins examined, but, on laminin and collagen, binding was weak with little cytoplasmic spreading. In contrast, the cells showed strong adhesion both to fibronectin (FN) and to vitronectin (VN). On FN, the cells spread extensively with nonpolarized cytoplasmic projections, whereas on VN cytoplasmic projections were markedly polarized. This polarized morphology was shown to reflect cell motility. Investigation of the role of individual integrin receptors in the cell movement response suggested that alpha v beta 3 is the major integrin responsible for this motile behavior. These results are discussed in relation to the limited previous data on leukemic and activated B-cell integrins, and we suggest that the HC integrins play a significant role in the characteristic behavior of HCs within tissues.

8043867

Human t(4;11)(q21;q23) acute lymphoblastic leukemia in mice with severe combined immunodeficiency.

Mice with severe combined immunodeficiency (SCID) were injected intravenously with primary bone marrow blasts from 12 children with newly diagnosed t(4;11)(q21;q23) acute lymphoblastic leukemia (ALL). Blasts from eight patients caused overt disseminated leukemia, whereas blasts from the other four patients produced occult leukemia that was detectable only by the polymerase chain reaction (PCR) technique. Only one patient among eight whose blasts caused disseminated leukemia in SCID mice remains alive and disease-free at 48.4 months postdiagnosis. In contrast, three of the other four patients whose blasts did not cause overt leukemia in SCID mice remain alive and disease-free at 6.1, 23.6, and 35.9 months, respectively. Thus, the occurrence of overt leukemia in SCID mice may be a predictor of patients' disease-free survival. The described SCID mouse model system may prove useful for designing more effective treatment strategies against therapy-refractory t(4;11) ALL.

8043866

Clinical importance of extraordinary integration patterns of human T-cell lymphotropic virus type I proviral DNA in adult T-cell leukemia/lymphoma.

The proviral DNA of human T-cell lymphotrophic virus type I (HTLV-I) is known to be integrated monoclonally in the malignant cells of adult T-cell leukemia/lymphoma (ATL), which is a peripheral T-cell malignancy caused by this virus. We studied the relationship between the integration patterns of HTLV-I and clinical characteristics in 89 patients with ATL. The proviral DNA of HTLV-I was examined by the standard Southern blot analysis using the endonucleases EcoRI and Pst I. One clear band of greater than 9 kb was detected in most of the patients (83 case) when cellular DNA was digested with EcoRI. On the other hand, extraordinary integration patterns of HTLV-I proviral DNA were detected in 6 patients; 3 of them showed two bands, while the other 3 showed one band smaller than 9 kb. When cellular DNA was digested with PstI, the band patterns of these patients were quite different from those of typical patients. The patients with the extraordinary integration patterns had clinical characteristics dissimilar to those of the other 83 patients with the ordinary integration pattern. The patients with two bands by EcoRI digestion always had severe hypoxemia with extremely high levels of serum lactate dehydrogenase at first presentation and showed peculiar organ infiltrations, such as retina and muscle, which were less frequent in the other ordinary 83 patients. They all died within 8 months after the onset. In contrast, the patients with one smaller band by EcoRI digestion always had small and mature T lymphocytes with bilobulated nuclei without lymphadenopathy and showed a favorable clinical course, which was uncommon in the ordinary cases. They were alive 20 to 38 months after diagnosis. Rearranged bands of the T-cell receptor gene were detected in all patients with unusual integration. These findings indicate that the integration patterns of HTLV-I proviral DNA have a clinical implication and may be one of the explanations for heterogeneity in the behavior of this disease.

8043865

Coxsackievirus B3 infection in human leukocytes and lymphoid cell lines.

Although coxsackie B viruses (CBVs) are known to cause viremia during acute infection, the role of the blood cells as a target for virus replication is poorly understood. We have analyzed the susceptibility of human peripheral blood mononuclear cells (PBMCs), granulocytes, bone marrow (BM) cells, and lymphoid cell lines to coxsackievirus B3 infection. Lymphoid cell lines with B- and T-cell characteristics (Raji and Molt-4, respectively) supported virus replication to high titers and virus protein synthesis was detected by metabolic labeling and immunoprecipitation. CBV3 synthesis in the U937 cell line with mononuclear phagocytic characteristics was very limited. The virus was able to infect a small proportion of leukocytes and BM cells, and intracellular virus antigens were detected by immunofluorescent staining. However, only a diminutive amount of infectious virus was produced in isolated PBMCs and granulocytes, and no virus protein synthesis was detected by metabolic labeling and immunoprecipitation in these cells.

8043864

Effects of butyrate on the erythropoietin receptor of cell line IW201.

The murine erythroleukemic cell line, IW201, normally expresses only low-affinity erythropoietin receptors. Exposure of these cells for 48 hours to sodium butyrate results in a change in receptor kd from about 600 pmol/L to 100 to 200 pmol/L. This change in affinity is accompanied by downregulation of both receptor number and receptor mRNA. Cells exposed to sodium butyrate for 2 hours show a similar change in kd but no change in receptor number. The butyrate effect on kd at 2 hours is abrogated by either cycloheximide or actinomycin D. These data indicate that an accessory protein induced by sodium butyrate is responsible for high-affinity binding of erythropoietin.

8043863

Efficient retrovirus-mediated gene transduction into murine hematopoietic stem cells and long-lasting expression using a Transwell coculture system.

The neomycin phosphotransferase (neo) gene was transduced into murine hematopoietic stem cells by culturing a recombinant retrovirus-producing cell line in a Transwell (Costar, Cambridge, MA) (bottomed with a porous membrane) hung into a Dexter-type long-term bone marrow (BM) culture. Gene transduction into stem cells retaining long-term reconstitution ability was successfully performed by using protocols of total 15 to 18 days of culture including establishment of the Dexter culture, transduction, and G418 selection. In the irradiated recipients of these cells, a large majority of the BM, thymus, and spleen cells as well as peripheral blood (PB) leukocytes were of donor origin and the neo gene was present in these organs up to 21 weeks after cell transfer. One third to two thirds of the in vitro colony-forming cells in the BM of the recipient mice were resistant to cultivation with G418. It was further found that the hematopoietic system of secondary recipients given BM cells from a primary recipient mouse was predominated by original donor-type cells. The transduced neo gene was detected in the PB, BM, thymus, and spleen cells of these secondary recipients. These results indicate that our procedure of retroviral vector-mediated gene transfer is highly effective in safely introducing a gene into pluripotent hematopoietic stem cells.

8043862

Mac-1 (CD11b/CD18) and CD45 mediate the adhesion of hematopoietic progenitor cells to stromal cell elements via recognition of stromal heparan sulfate.

Hematopoiesis is regulated by two sets of signals, those generated by cytokines and those generated when precursor cells interact with bone marrow (BM) stroma. The intimate contact between precursors and stroma appears to be mediated by multiple, different receptor-ligand binding events. To identify receptor-ligand pairs mediating the adhesion of hematopoietic precursor cells to stroma, an in vitro model of hematopoiesis was used. This involved coculturing the BM-derived, interleukin-3 (IL-3)-dependent, multipotential cells, FCDP-mix A4 (A4) with a stromal equivalent embryonic mesenchymal cell line, Swiss 3T3 (3T3). In coculture, A4 cells survive, proliferate, and differentiate in the absence of exogenous IL-3, providing they are attached to the 3T3 cell surface. By using detergent lysates of surface-biotinylated A4 cells, A4 cell molecules that bind to the stroma could be detected by either fluorescein isothiocyanate (FITC)-streptavidin or FITC-antibody staining and flow cytometry. Using this approach the beta 2 integrin, Mac-1, and CD45, a receptor-type tyrosine phosphatase, were identified as molecules on the A4 cell surface that bind 3T3 cells. Various glycosaminoglycans (GAGs), particularly heparin and heparan sulfate, blocked binding of A4 cell surface molecules to the 3T3 cells. The binding of CD45 and Mac-1 to the 3T3 cells was similarly blocked by these GAGs. Removal of heparin-binding molecules from A4 cell lysates diminished binding to the 3T3 cells and digestion of the 3T3 cell surface with heparinase abolished the binding of CD45 and Mac-1. The data suggest that heparan sulfate on the 3T3 cell surface is a ligand for both CD45 and Mac-1, but the two molecules recognize different heparan sulfate structural motifs.

8043861

Autografting with cultured marrow in chronic myeloid leukemia: results of a pilot study.

Incubation of chronic myeloid leukemia (CML) marrow for 10 days in vitro causes a marked and selective loss of very primitive Philadelphia chromosome (Ph)+ as compared with Ph- progenitors. We have autografted 22 patients with CML (16 in first chronic phase [group 1] and 6 with more advanced disease [group 2]) with marrow treated in this way to facilitate restoration of Ph- hematopoiesis after intensive therapy. Hematologic recovery to greater than 0.5 x 10(9)/L neutrophils occurred in 16 patients, and to greater than 20 x 10(9)/L platelets in 15 of 21 evaluable patients at a median of 29 and 48 days postautograft, respectively. Regenerating marrow cells were 100% Ph- in 13 patients and 75% to 94% Ph- in 3. Between 4 and 36 months (median 12) postautograft, Ph+ cells became detectable in all but 1 (who died in remission) of the 13 patients who achieved complete cytogenetic remission. Four of 7 evaluable patients treated with low-dose interferon alpha were returned to complete cytogenetic remission. Thirteen group 1 patients (81%) are alive 1.0 to 5.7 years (median 2.6) after autografting: 4 in complete cytogenetic remission, 2 in hematologic remission, 6 in chronic phase, and 1 in myeloid blast phase. Three group 2 patients (50%) are alive at 2.6, 3.8, and 4.3 years after autografting: 1 in partial cytogenetic remission, 1 in chronic phase, and 1 in accelerated phase. Thus, autografts of cultured marrow can result in prolonged restoration of Ph- hematopoiesis for some patients with CML.

8043860

Detection of cytarabine resistance in patients with acute myelogenous leukemia using flow cytometry.

Cytarabine (Ara-C) is currently used in the treatment of adult acute myeloid leukemia (AML). To predict the results of induction chemotherapy, it could be useful to detect leukemic cells that are resistant to Ara-C in patients with AML. Using a bromodeoxyuridine/DNA (BrdUrd/DNA) staining method in flow cytometry (FCM), we have developed a cell resistance index to Ara-C (RI). The technique has been applied to 121 bone marrow (BM) samples from patients with de novo AML treated by a regimen containing Ara-C and daunorubicin (DNR). Ninety-seven patients achieved a complete remission (CR), and 24 patients did not and were considered drug-resistant (DR). The BM cells collected at diagnosis were cultured for 48 hours and underwent BrdUrd/DNA analysis. Among 25 patients with no or very low proliferative activity (<3% of cells in S-phase), the proportion of DR patients (nine of 25) was significantly higher than in a second group of 96 patients with detectable proliferative activity (15 of 96) (P < .025). Within this second group, there was a first group of nine patients with high RI values, which included only DR patients; a second group of 63 patients with low RI values, which included 62 CR patients; and a third group of 24 patients with intermediate RI values, which included 19 CR and five DR patients. In view of this series, our results show that it is possible to detect a majority of DR patients treated by Ara-C.

8043859

Hodgkin's disease with a B-cell phenotype often shows a VDJ rearrangement and somatic mutations in the VH genes.

The nature of Hodgkin and Reed-Sternberg (HRS) cells remains in question. Immunophenotypic studies favor a relation to the lymphoid lineage with the existence of B- and T-cell types. However, studies on the detection of antigen (Ag) receptor gene rearrangements provided inconsistent results. They concur in that rearranged Ig and T-cell receptor (TCR) genes are not demonstrable in most Hodgkin's disease (HD) cases. To clarify whether this is because of the insensitivity of the method of detection or a real absence of clonal Ig heavy chain (IgH) rearrangements, a polymerase chain reaction (PCR) method with high sensitivity was applied, allowing the detection of less than 50 cells with clonally rearranged IgH genes in a mixture of 100,000 germline or individually rearranged cells. In 67 cases of HD, most of those (67%) with B-Ag+ HRS cells express clonal VDJ rearrangements of the IgH gene. No cases with T-cell Ag+ HRS cells harbored detectable clonal VDJ rearrangements. Of 10 sequenced rearranged IgH genes, the VH segment of six contained considerable somatic mutations. These results suggest that the demonstrated VDJ rearrangements stem from the HRS cells themselves and that the HRS cells of cases with rearranged IgH genes are B-cell related and correspond in their differentiation stage either to naive pregerminal center B cells or (more commonly) to germinal center/postgerminal center-derived memory B cells.

8043858

Loss of membrane-dependent factor Va cleavage: a mechanistic interpretation of the pathology of protein CVermont.

Clinical manifestations of arterial and venous thrombosis in a family with protein C deficiency was associated with two mutations in the light chain of protein C: Glu20-->Ala and Val34-->Met. Further studies showed that the mutation Glu20-->Ala which eliminated a gamma-carboxylation site was exclusively responsible for the anticoagulant defect of activated protein C (APC). Membrane-bound human factor Va is inactivated by APC after two sequential cleavages of the heavy chain at Arg506 and Arg306. Human factor Va inactivation by human recombinant APC (rAPC) and a mutant molecule with an alanine instead of a glutamic acid at position 20 (rAPC(gamma 20A)) was investigated in the presence and absence of phospholipid vesicles. During a 2-hour incubation period of the cofactor with either rAPC or rAPC(gamma 20A). In the absence of a membrane surface, factor Va is cleaved quantitatively at Arg506 and retains approximately 60% of its initial cofactor activity. After a 2-hour incubation period with rAPC membrane-bound factor Va has no cofactor activity, whereas in the presence of a membrane surface and rAPC(gamma 20A) factor Va retains 60% of its initial cofactor activity. The completed loss in factor Va cofactor activity upon incubation of the membrane-bound cofactor with phospholipid vesicles and rAPC is associated with cleavages at Arg506 and Arg306, whereas membrane-bound factor Va cleavage at Arg306 by rAPC(gamma 20A) is impaired, resulting in a cofactor that is cleaved at Arg506. Slow cleavage at Arg306 occurs when membrane-bound factor Va is incubated with rAPC(gamma 20A) and only small amounts of fragments of M(r) = 45,000 and 30,000 are noticed. Our data show that the genetic defect which leads to the absence of a gamma-carboxylation site at Glu20 impairs membrane binding of human APC, which in turn is required for cleavage of factor Va at Arg306 and inactivation of the cofactor. The consequence of impaired membrane-dependent cleavage at Arg306 is manifested in vivo by venous and arterial thrombosis.

8043854

[Morphofunctional characteristics of the cat spiral ganglion in neurosensory hypoacusis].

Morphofunctional disorders in spiral ganglion in animals of different groups of age with neurosensory hardness of hearing due to ototoxic antibiotics have been shown. Antibiotic intoxication in kittens in early postnatal period arouses essential deviation from normal process of development of neurocytes in spiral ganglion. In the first rate low level of their metabolic activity must be shown. Delay of differentiation of neurocytes makes essential influence on the development of spiral ganglion as the unit of transmission of audio-information. The main feature of morphofunctional disorders in neurocytes of ganglion of grown-up animals is inhibition of protein synthesis mechanism activity.

8043853

[Microcirculatory bed of the auricle floor in rabbits after blood substitution].

Microvessels of rabbit ears chamber and blood samples drawn from the internal ear vein have been studied after blood substitution. It has been shown that the left microvessel bed responds to the hemodilution with 38% decrease of its length and 5.9% decrease of the mean diameter of its vessels, decrease apparent viscosity of outflowing blood, but RBC concentration per volume unity of blood (N) being preserved. The right one--with 7.8% increase of microvessel diameter, their length being preserved and 10% increase of the N.

8043852

[Comparative structural analysis of the liver and kidneys in experimental chronic renal insufficiency].

The enzymatic activity/succinate-, lactate-, NADP-H2- and NAD-H2-dehydrogenase, alkali and acidic phosphatase/in renal and hepatic tissues has been studied on subtotally nephrectomized rats. Activation of hepatic functions and metabolism has been shown to occur during the development of experimental chronic renal insufficiency.

8043851

[Ultrastructure of chromatin in nuclei of hepatocytes of regenerating guinea pig liver after administration of vitamin B12].

Experiments have been carried out on 10 male guinea-pigs (0.5 kg, 6 month old). The experimental animals have been submitted to partial hepatectomy of the left lobe of the liver (lobus externus sinister) with and without the administration of vitamin B (0.8 mgr/kg). 10 nuclei of hepatocytes have been expressed in conventional units.

8043850

[Ultrastructural study of explants of carcinoma of the large intestine during prolonged organ cultivation].

The electron microscopical study on organ cultures of colonic carcinoma has shown that tumour cells form typical for this kind of tumours glandular-like structures which consist of ultrastructural differentiated cells with organospecific features of brush-border and goblet cell types. Depending on the terms of cultivation the consecutive stages of ultrastructural differentiation have been retraced starting from undifferentiated cells (the 5th day of the experiment) up to structurally matured differentiated cells (the 7th-9th days of experiment). The tumour growth in the organ cultures is realized mainly by an explant itself building up processes from its peripheral cell lining and its invagination inside a piece. Glandular-like structures which are forming on the ends of processes and invaginations have undergone further separation. The question of monoclonal origin of colonic carcinoma in organ cultures is discussed.

8043849

[Chromatin ultrastructure in hepatocyte nuclei of dogs as affected by adrenaline].

The study of the chromatin's ultrastructure in the nuclei of hepatocytes under the adrenalin influence is very essential (e.g., the square of the perimembrane chromatin-PmCh). The experiments have been carried out on 10 male dogs. Experimental dogs received adrenalin intravenously--100 mkg per 1 kg of weight during 5 days. The pieces of tissue have been fixed by 2.5% glutaraldehyde solution ("Serva"--FRG) and postfixed by 2% four-oxide osmium, dehydrated in spirts and acetone, and poured into exposed mixtures. The ultrathin cuts have been got on ultramicrotome "LKB" (Sweden) Microscopic sections examined by electronic microscope "JEM-7" (Japan) increasing 10,000 times. Morphonutrical working have been carried out by Student method and expressed in conventional units. The relation of the area of perimembrane chromatin to the nucleus's area in hepatocytes of the controlled animals, is equal--to 0.21 and of the experimental ones--to 0.13 (decreased 1.6 times, 0.02 p 0.05).

8043848

[Species specificity of serum factors in rabbits with acute pancreatitis in stimulated regeneration of pancreatic islet B-cells in experimental diabetes].

The experiment has shown that the serum of rabbits with acute pancreatitis produces proliferative effect on pancreatic islets' B-cells in rats with the acute form of experimental diabetes. The stimulation of miotic activity of B-cells, processes of acino-insular transformation, compensation of the insular function in rats with alloxan diabetes proved to be lower than in rabbits under the same experimental conditions. This testities to relative species specificity of factors in the serum of rabbits with pancreatic gland trauma.

8043847

[Dynamics of destructive and reparative processes in organs of the immune system in acute experimental peritonitis of varying course].

A quantitative characteristics of destructive and reparative processes in the organs of immune system is given on the model of acute peritonitis running under different conditions. During the usual course of inflammation in the abdominal cavity in the first 24 hours a sharp increase of lymphocyte destruction is noted, while proliferative changes decrease. Two days later the cell destruction decreases but proliferative changes increase. While using levamisole the destructive phenomena are not highly marked but proliferative processes persist at a high level during all periods of the experiment. In azathioprine immunosuppression the process of destruction increases intensively during all periods of the experiment with the simultaneous suppression of reparative manifestation. It results in devastation of the organs of the immune system and can be considered as an equivalent to the secondary immunological insufficiency.

8043846

[Electron microscopic study of erythrocyte form after extracorporeal ultraviolet and red coherent irradiation of blood].

The results of these experiments demonstrate that extracorporeal ultraviolet and red coherent blood irradiation make the energetics of erythrocyte membrane broken. This deviation has been manifested in changing of erythrocyte's form. The degree of these disorders and of inertia of the recovering process of the erythrocyte's form was greater under ultraviolet blood irradiation.

8043845

[Effect of various levels of hypothermic ischemia on ATPase activity of the functional element of the myocardium].

Activity of ATPase in functional element of myocardium (its qualitative and quantitative aspects) has been researched in normal tissue and in one with various levels of hypothermic ischemia (28-30 degrees C and 10-12 degrees C) by methods of electron microscopic histochemistry on dogs. It has been found that hypothermia of myocardium (10-12 degrees C) optimally prevents ischemic disorders of energetic processes. Reproduction activity of ATPase during reperfusion of myocardium after that hypothermia maintains contractile function of heart in proper high level.

8043844

[Serum factors in rabbits with acute pancreatitis as stimulators of regeneration of pancreatic islet B-cells in experimental diabetes].

The experiment reveals the stimulating effect of pancreatic rabbits' serum on the reparative regeneration of pancreatic islets' B-cells of rabbits with alloxan diabetes. Serum, got 12 hours after mechanical pancreatic gland trauma proves to be most effective. The maximum rise of mitotic activity is in 24 hours after 3 daily injections of serum. In the experiment with the decrease of the level of proliferation of B-cells compensation of insulinary function by acinoinsulary transformation prevails.

8043843

[Dynamics of cell proliferation in rat kidney and effect of endogenous inhibitors].

The age dynamics of albino rat kidney cell proliferation in conditions of compensatory hypertrophy and influence of endogenous inhibitors on this process have been studied. The lack of influence of repeated injection of inhibitors on kidneys cell division of 1-month old rats has been shown, while the level of kidney proliferation of 3-month old rat and 12-month old rat decreased of about 50% and of 24-month old rat decreased of about 34%.

8043841

[Effect of T-activin on macrophage 5'-nucleotidase activity and blood cortisol level depending on the time of day].

Peculiarities of T-activin influence on macrophage 5-nucleotidase and blood cortisol in dependence of day time have been investigated on CBA and C57/B16 mice. It has been established that T-activin influence on already studied indexes in broad range of doses; from 10 to 1 mkg for 1 mouse.

8043840

[Analysis of hydroxypyridine cross-links of collagen from human rib cartilage].

Ion-paired reversed-phase high performance liquid chromatography (HPLC) has been used for the analysis of the content of mature collagen crosslinks--hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) in biopsy specimens of human rib cartilage from healthy donors (n = 14) and patients with inherited diseases of the connective tissue complicated with funnel chest (n = 17). Analysis of normal tissues reveal the presence of LP (alongside with HP) in embryonal rib cartilage. LP has been found in the rib cartilage of 4 out of 6 patients with funnel chest (FC) associated with Ehlers-Danlos syndrome (EDS); with no signs of this pathology detected in individuals with isolated FC. In rib cartilage of 2 patients with recurrent isolated FC LP has been discovered alongside with the presence of type I collagen. A significant increase of LP content in rib cartilage in a child with clinical phenotype of EDS type VI has been discovered.

8043839

[Comparative study of mechanisms of antiproliferative action of low concentrations of mafosfamide and cyclosporin A].

Exact mechanisms of Mf and CsA effect have been investigated in BALB/c, DBA/2, CC57BR, and C57BL/6 mice. Different sensitivity of spleen cells of mice of different strains to Mf and CsA antiproliferative effect has been demonstrated. These interstrain variations have not been related with an inhibition of interleukin-2 (IL-2) release but, perhaps depended on the IL-2 receptor (IL-2R) expression differences. The p75 chain of IL-2R as a possible target for Mf, has been discussed.

8043838

[Biotransformation of sodium nitroprusside in tumor-bearing animals].

The interaction of sodium nitroprusside with tissues of solid tumour bearing animals (S-180; S-Worker; spontaneous adenomatosis) have been studied in vivo by means of EPR-method. The tumour subjected animals in distinction from healthy animals elicits appearance of paramagnetic nitrosyl iron complexes in blood plasma. Thus, the previously found phenomenon of specific reaction of nitroprusside with ascitic forms of tumours is confirmed on solid tumours in vivo.

8043836

[Production of interleukin-1 and interleukin-6 in a culture of mononuclear cells of peripheral blood and bone marrow in multiple myeloma].

Constitutive and lipopolysaccharide (LPS)--induced production of interleukin (IL)-1 and IL-6 have been investigated in peripheral blood (PB) and bone marrow (BM) of patients with multiple myeloma (MM) and PB of health donors. The level of these cytokines has been higher in MM in comparison with norm. Monocytes of PB of patients with MM have been more stimulated by LPS than those of health people. When adherent and nonadherent cells have been cultured apart, there not have not been any differences in constitutive IL-6 production between compared groups. The important role of cell-cell interactions in regulation of IL-6 production is proposed. High level of IL-6 in BM of patients with MM is conditioned by mutual stimulation of adherent and nonadherent cells.

8043837

[Immunoregulatory properties of human recombinant angiogenin].

Rosette formation, hypersensibility of slow type and humoral reaction as an answer to immunization by ram erythrocytes in c conditions of normal and changed angiogenin level have been studied in CBA mice.

8043835

[Cytostatic activity of soluble factors secreted by inactivated peritoneal macrophages of Syrian hamsters, relative to normal, transformed and tumor cells].

Two strains of RSV-SR in vitro transformed hamster embryo cells appeared to be significantly less susceptible to cytostatic factor (CSF) produced by non-activated macrophages (Mph) of Syrian hamsters as compared with normal hamster embryo cells (HE), or HE cells spontaneously transformed in vitro (STHE). Three out of four highly malignant variants of STHE cells selected in vivo were significantly less susceptible to CSF of Mph as compared with parental STHE cells. The possible role of CSF of non-activated Mph in the regulation of proliferation of normal, transformed and tumour cells is discussed.

8043833

[Plasma erythropoietic activity in children with sepsis].

The low plasma erythropoietic (Epo) activity which is non-adequate to manifestation of anemia, and the lack of correlation between Epo activity and the degree of anemia and hypoxia were found in children with sepsis. The lowest Epo activity was determined in plasma of patients after repeatedly blood transfusion and in emaciated children. The non-specific Epo activity inhibitor was determined in acute period of sepsis in majority of patients. We suppose that the low Epo activity was due to the violation of Epo synthesis regulation mechanism or was connected with the presence of non-specific inhibitors. These results suggest recombinant Epo for the treatment of anemia in children with sepsis.

8043832

[Sensitivity of immunocompetent cells to a hormonal signal in the presence of mitogen].

The chorionic gonadotropin (Cg) effects on the ability of intact and mitogen-activated splenocytes to form the adoptive immune response have been studied in a short-term cell culture. It has been established, that an hour incubation of non-fractionated spleen cells with CG (40 or 200 IU) leads to plaque-forming cell (PFC) suppression. The culture, deprived of macrophages, does not react on the hormone depressive effects, but its low dose, on the contrary, stimulates the PFC formation. Lipopolysaccharide addition into the culture of non-fractionated splenocytes does not influence the PFC level, while the CG addition leads to intensification of PFC formation processes. In the cell culture, deprived of macrophages, hormone abolishes the immunostimulating effect of lipopolysaccharide. The simultaneous addition of non-fractionated CG splenocytes and monoclonal anti-IgM antibodies does not influence the immunostimulating effect of mitogenic antibodies. The possible mechanisms of CG effect and the problem of hormonal immunocompetent cell regulation, depending on their functional activity are under consideration.

8043831

[Effect of plague microbe fraction 1 protein-polysaccharide complex and pure protein on metabolic parameters of macrophages].

The investigation reveals different influence of the plague microbe's fraction 1 polysaccharide-protein complex and of it's purified protein on the 5'-nucleotidase activity and on the chemiluminescence response of peritoneal macrophages. Both of these metabolic indexes were found to be dependent on the dose of fraction 1 and duration of time till examination.

8043830

[Effect of preliminary administration of phenobarbital on the toxicity of GABA-lytics in mice].

The toxicity of picrotoxin bicuculline, but not of 3-mercaptopropionic acid decreased in mice pretreated during three days with phenobarbital and benzonal. The antidotal effectiveness of diazepam by picrotoxin and bicuculline exposure increased significantly. It has been suggested, that the modulation of detoxication systems may be the cause of increased tolerance against GABA-antagonists.

8043829

[Antiarrhythmic effect of estradiol-dipropionate in animals of different sexes].

Repetitive injections of estradiol, performed for many days, caused a diminution of resting potential of ventricular cardiomyocytes; spontaneously reversible ventricular fibrillation aroused 2 times more often, and the latent period of development of aconitine-induced ventricular fibrillation increased for 3 times in males, and for 5 times--in females. The antiarrhythmic effect of estradiol may be caused by its action on potassium current.

8043828

[Remote effects in the mutagenic action of chrysotile asbestos and zeolite dusts in vivo].

It was proposed that there are a generalized mutagenic actions of chrysotile-asbestos fibers and zeolite particles in vivo. Chrysotile-asbestos fibers and different species zeolite particles in doses 50 mg/kg, intraperitoneally, increased the levels of damaged chromosomes not only in peritoneal cells, but also in bone marrow of C57BL/6 mice. Cytogenetic effect of chrysotile-asbestos does not depends on the time exposure of animals with mutagenic factor. In four weeks followed after administration chrysotile-asbestos fibers there were revealed 19-22% peritoneal cells with damaged chromosomes and 3.2-4.4% aberrant cells of bone marrow. Cytogenetic effect of zeolite particles was observed on 14-28 days after the administration, with peaks at 35.6% in peritoneal and 3.6-4.2% in bone marrow cells. Our data indicate the mutagenic action is realised as in cells contacted with dusts as in cells of other tissues. Probably, these effects are mediated by products of lipid peroxidation.

8043827

[Change in systemic hemodynamics after acute administration of diazepam binding inhibitor (DBI) and after autoimmunization against DBI].

Endogenous peptide DBI inhibits the activity of HABA-ergic system and that is why can be a factor of arterial hypertension development. We investigated DBI influence on cardiac index (CI), arterial pressure (AP) and heart rate (HR) in rats. I.v. administration of DBI caused dose--dependent increase in CI, AP but HR did not change. High dose (150 mg/kg) caused a biphasic answer: hyperkinetic reaction reversed to cardiodepressive one. Long-term immunization against DBI led to decrease of AP and systemic vessel's resistance.

8043826

[Effect of low doses of emoxipine and pyridoxine hydrochloride on the status of patients with cataract and glaucoma].

It has been shown that eyes instillation of pyridoxine hydrochloride low doses during 20 days affects the vision and tonographic characteristics of patients with glaucoma and earlier stage of cataract. Light eyes have been shown to be more sensitive to treatment than dark ones. From 10 to 40 min after emoxipin or pyridoxine hydrochloride low doses instillation, some pupil constriction has been registered. The data obtained suggest that low doses of this substances affect eyes cholinoreactive structures and may be useful for treatment glaucoma and early stage cataract.

8043825

[Role of the lipid matrix of plasma membranes in the process of transmission of information by regulatory peptides].

Role of lipid matrix of target cell plasma membrane in the process of regulatory peptides information message has been considered. The calculation of information quantity of regulatory peptide molecule in solution and excess coefficient at peptide transition from extracellular volume to membrane surface have been carried out. Possible ways of using of excessing for regulatory peptides receptors information by lipid matrix have been proposed.

8043824

[Correlation of protein content in salivary gland tissue, oral mucosa and saliva in experimental staphylococcal sialoadenitis].

The dependence between the total content and excretion of protein (P) in salivary gland tissue (SGT), oral mucosa (OM) and saliva has been investigated. The difference between P contents in intact gland and during staphylococcus sialoadenitis has been shown. After 2 hours of staphylococcus toxin injection in non-stimulated SGT P contents are not changed, and in saliva--are increased. After 24 hours in non-stimulated SGT P contents are decreased, in OM P contents are increased. By stimulation of SGT, P contents increases, in OM--decreases.

8043823

[Effect of the somatosensory cortex on the development of deafferentation pain syndrome].

Effects of somatosensory cortex ablation and electrical stimulation on development of deafferentation pain syndrome in rats with sciatic nerve section have been studied. It has been demonstrated that both ablation and stimulation of somatosensory cortex delay the development of pain syndrome. The possible mechanisms of cortical effect on development of deafferentation pain are discussed.

8043821

[Role of the striatal serotoninergic apparatus in Parkinsonian syndrome].

Injected into the rat caudate nuclei (CN) serotonin promotes the generator of pathologically enhanced excitation (GPEE) in CN and parkinsonian symptoms, induced by MPP+ injection into substantia nigra. Serotonin antibody injected in CN decreases the GPEE activity and partly suppresses the parkinsonian symptoms. The role of serotoninergic system in parkinsonism is discussed.

8043822

[Effect of stress on the development of deafferentation pain syndrome in rats after sciatic nerve transection].

Effect of immobilization and painful stress on the development of deafferentation pain syndrome, appeared after sciatic nerve section, has been studied in Wistar rats. It has been determined that both immobilization and painful stress favour the appearance of pain syndrome in rats without clinical signs of pain syndrome up to the moment of stress influence. There has been made a conclusion that both immobilization and painful stress favour the appearance of pathologic algic system, which is the basis of pain syndrome. The fact that stress can cause analgesia in normal animals in contrast to those with potential pain syndrome is explained to different mechanisms of physiological and pathological pain.

8043820

[Decrease in constrictor response and increase in dilator response of the resistant artery in experimental myocardial infarction: effect of adaptation to hypoxia on this phenomenon].

After adaptation to hypoxia experimental myocardial infarction does not result in enhanced vasodilatory responses of isolated tail artery from rat to acetylcholine and isoproterenol. At the same time the vascular reactivity to norepinephrine and phenylephrine is enhanced. These data may explain the previously described improvement in postinfarction time course of the blood pressure due to preliminary adaptation to hypoxia.

8043819

[Electric activity in the dorsal horns of the spinal cord and somatosensory cortex in rats with and without development of pain syndrome after sciatic nerve transection].

Bioelectric activity in dorsal horn of spinal cord and somatosensory cortex have been studied in rats with and without pain syndrome after sciatic nerve section. The results show that in rats with pain syndrome (the development of pain syndrome determined in appearance of autotomies on the limb with cutting nerve and decrease of pain threshold) simultaneous increase of amplitude of evoked potentials (EPs) in contralateral somatosensory cortex and ipsilateral dorsal horn of lumbal segments by electrical stimulation of the injured limb are to be observed. In rats without pain syndrome (rats without autotomies and hyperalgesia) the EPs increase have been registered only in dorsal horn of spinal cord. The results are discussed on the basis of the theory of generator and systemic mechanisms of formation of neurogenic pain syndrome: the pain syndrome is clinical manifestation of the pathologic algic system (PAS) which includes the neurons of the dorsal horn and of the somatosensory cortex.

8043818

[Alimentary modification of catecholamine levels and status of the thiol-dependent protective system in the brain in convulsive syndrome].

Alimentary modification of CA metabolism and the activity of thiol-depended protective systems in corazol seizures have been studied. Chronic seizures causes the decrease in tissue CA levels. Rations enriched with regulators of inhibitory neurotransmitters metabolism significantly diminished above mentioned effect. Protective influence of rations could be attributed at least partly to the activation of thiol-depended mechanisms prevented the excess CA oxidation.

8043817

[Modulating action of neurotensin on the parasympathetic regulation of cardiac rhythm].

In 8 experiments on anaesthetised cats bursts stimulation of the peripheral cut end of right vagus nerve leads to synchronisation of cardiac and vagus rhythms. Alterations of burst sequence frequency within definite limits has been synchronously reproduced by heart thus creating managed brady-cardia possibility. Neurotensin (4.10(-8) M intravenously) accelerate heart rate and potentiate total vagal chronotropic effect. Vagotropic effect of the neurotensin is due to enlargement of the tonic component's strength in the vagal chronotropic effect. On the other hand, extent of the synchronizing vagal influences upon heart rhythm is unaffected. Mechanisms of the participation of neurotensin in organisation of the vegetative control of the cardiac rhythm are discussed.

8043816

[Tonus of the sympathetic nervous system].

According to some investigators, tonus of sympathetic nervous system is not observed at all or marked a little, according to others--it is marked well. Tonus of sympathetic nerve has not been discovered at all in our experiments. The experiments have been made on narcotized and non-narcotized pigeons, guinea pigs, rats and dogs. The frequency of heart beats is regulated by n. vagus and humoral substances in rest.

8043815

[The effect of low-intensity laser radiation on rat brain capillaries].

The dose-dependent action of the low-intensive He-Ne laser on the capillaries of the temporal area of the brain which were revealed by Mg ATPase has been determined. Laser radiation during 0.5-15 min provoked a complex of the activity of the enzymes in the vessels with density latent action of the factor. Subsequent increasing of the exposition (from 30 min to hours) bring to the opposite effect.

8043814

[Dual-factor correlation analysis of the distribution of morphofunctional properties of mitochondria].

Judging by double-factorial correlative analysis of mitochondrial morpho-functional property distribution during the treatment of organism with radioactive rays, it has been established that there is a high correlation between mitochondrial dimensions in population and known structural-functional types. To detect the force and tightness of this parameters' connection, there lists a method of double-factorial correlative analysis. The value of correlation coefficient lets assume that mitochondrial functional activity depends on mitochondrial dimensions and is described by straight regression equation. It has been established that dimension's increase is accompanied by mitochondrial functional activity decrease and vice versa, though some functionally inactivated mitochondria can have little dimensions. Thus, knowing mitochondrial dimensions in population we can detect it's functional properties and detect mitochondrial dimensions knowing the functional properties by straight regression curves.

8043813

[Rhythmic changes in morphometric parameters of fiber structure of myocardial connective scar tissue in rats].

The results of morphometrical and stereological analysis of cardiomyocytes and rats' cardiac scar conjunctive tissue are stated in this article. It was shown that during the myocardial construction, the collagen fibril tension occurs. When diastole ensues, they goes back to point of departure. The author supposes that such a rhythmical, synchronous with systole changes of scar conjunctive tissue collagen fibres indicates the conjunctive tissue scar participation in cardiac contractile activity.

8043812

[Membrane potential of resting muscle fibers from the rat diaphragm in total ischemia].

Membrane potential (MP) of the diaphragm muscle fibers of the rats was registered in the different periods of ischemia in vitro. The ability to normalization of MP up to 6 h of ischemia and an irreversible decrease of MP after 6.5 h of ischemia was revealed. It is concluded that the ability of diaphragm muscle fibers to restore their MP lost beginning from 6 h of artificial ischemia.

8043811

[Morphological and computer-tomographic analysis of reparative regeneration of the tibia by distraction osteosynthesis].

Morphological & computerized tomography analysis of tibial reparative regeneration in distraction osteosynthesis was performed in 12 & 25 patients consequently. The authors discuss the correlation between the two kinds of the data & show that development of bone regeneration with restoration of anatomical form & structure of the reconstructing tubular bone occurs in the place of osteotomy.

8043810

[Persistence of physiological hydrocephaly in newborns].

During intratubal development of the brain the reduction delay of the fetal ventricular system is marked as persistence of the physiological hydrocephalus (PPH). PPH was revealed in 26.9%, 30.3% and 21.9% observations of premature and mature infants. The criteria of PPH are the extending of the posterior cornua of lateral ventricle and the absence of the interthalamus commissure in normal indexes of mass and anatomically formed brain. In pathogenesis of PPH the influence of teratogenic factors which enables to put it down to the minimal brain dysplasia is possible. PPH, though it is not of a clinical importance itself, can be favourable background for the developing of the hydrocephalus, but in the majority of the cases during postnatal period it liquidates.

8043809

[Monitoring blood pressure. A chronobiological approach to diagnosis of hypertension].

In spite of time-depended variability of blood pressure (BP), the applied medicine uses fixed limits of standards, recommended by ROH for diagnostics of arterial hypertonia (AH). Such approach is nominally untenable. To interpret monitorizing of BP in it's time-depended variability during 24 hours, the analysis procedure should be changed. The new analysis method including comparison of BP-monitorizing results with respective standard time limits is called chronodiagnostics. Chronodiagnostical process is described in procedures of macro- and microanalysis of daily BP-curve. Each procedure has it's own statistical description and clinical significance.

8043808

[Increased sensitivity of hypophyseal cells from neonatal rats to bromocriptine and melatonin].

Age-related peculiarities of the bromocriptine and melatonin effect on macromolecule biosyntheses in cultured rat pituitary cells were studied during long-term (3 day) incubation. Bromocriptine (10(-9)-10(-7) M) caused dose-dependent inhibition of DNA synthesis in pituitary cells of neonatal rats, but only in maximal dose (10(-7) M) it decreased significantly this parameter in pituitary cells of adult animals. Melatonin (10(-8)-10(-6) M) caused significant inhibition of DNA synthesis in cultured cells of neonatal rat pituitaries. However, melatonin did not change DNA biosynthesis in pituitary cells of adult rats. The results obtained permit us to suggest certain contribution of dopaminergic tone and melatonin to the control of proliferative activity of rat pituitary in neonatal period of development.

8043807

[The effect of a suspension of brain cells from mice of varying age on the growth of tumors, transplanted under the capsule].

Antitumour activity of cerebral cells at different stages of ontogenesis (embryonic, new-born, adult) has been studied. Researches have been carried out at killer-activity patterns in vitro with target-cells and tumour transplantation under mice kidney's capsule in vivo. It has been established that mice cerebral cells' suspension can decrease the tumour transplants' growth under kidney's capsule. Antiproliferative activity of embryonic and new-born mice cerebral cells was much higher than adult one. The kidney and liver new-born mice cells had no antiproliferative activity at all.

8043806

[The role of prostaglandins type E in tumor cells during their contact with NK-cells in vitro].

Active PGE--secretion by malignant tumour cells of Syrian hamsters was demonstrated 30 min after their contact with NK-cells in vitro. The duration of PGE--secretion depended upon the ratio of tumour cells and NK--cells, engaged in contact. Increase of the number of NK--cells (bound to tumour cells) up to 10:1-20:1 led to rapid release of PGE from majority of tumour cells; in this case PGE release was continued not longer than 1.5-2.0 hours. The active release of PGE can be stopped after the contact of tumour and NK--cells by indomethacin at any moment of its secretion.

8043805

[The effect of prostaglandin E2 on chemiluminescent activity of peritoneal exudate cells of intact animals and animals, inoculated with various materials].

Changes in the normal cellular content and chemiluminescence (CL) activity of peritoneal exudate cells at the first hours after intraperitoneal injection of thioglycollate, casein, mineral oil and BCG were studied, as well as the influence of PGE2 on the CL activity of such cells. It has been shown, that 3-5 hours after intraperitoneal inoculation with these materials, independently from the type of the material used, the enrichment of peritoneal cell population with neutrophils, up to 90% or more, takes place. PGE2 induced the significant inhibition of the CL activity of peritoneal exudate cells from the animals, injected with thioglycollate and BCG, but did not influence the CL activity of peritoneal cells from the intact animals and animals injected with casein. The possible connection of these differences with the level of PGE2 receptors expression on the intact and stimulated peritoneal cells is discussed.

8043804

[Effect of synthetic fragments of immunodominant regions of HIV viral proteins on the oxygen metabolism of human neutrophils].

Influence of synthetic peptides identical to fragments of natural human immunodeficiency virus (HIV) glycoproteins gp 120 and gp 41, on luminol-enhanced chemiluminescence (CL) of human neutrophils has been studied. It was established that some of peptide analogs of gp 120 and gp 41 immunodominant regions are able to suppress spontaneous CL: but when being used with dimethylsulfoxide they dramatically stimulate it and deteriorate opsonized zymosan-induced CL. Conclusions about the necessity of possible side effects considering during use of peptide vaccines against HIV have been made. It is also possible to explain some neutrophil dysfunction in HIV infected subjects as the result of HIV glycoproteins direct influence on this cells.

8043803

[Interconnection of interleukin-1 and glucocorticoid hormones in regulating the immune response].

IL-1 and hydrocortisone have an opposite and competitive effect on the lymphocyte proliferation in cell culture. In mice recombinant human IL-1 beta dose-dependently induces high level serum corticosterone. Injection of IL-1 beta or hydrocortisone led to a similar alterations in the thymus: reduction of cellularity and decrease in spontaneous thymocyte proliferation. On the other hand in the same doses IL-1 beta stimulates spleen cell proliferation. IL-2 production and enhances serum antibody titres and the number of antibody producing cells in spleen of mice immunized with T-dependent antigen.