Human insulin-receptor gene

The human insulin-receptor (hINSR) gene spans a region of greater than 120,000 base pairs (bp) on the short arm of chromosome 19. It is comprised of 22 exons or coding regions that vary in size from 36 to greater than 2500 bp. To a large degree, the introns appear to divide the hINSR gene into segments that encode structural and/or functional elements of the hINSR protein. The exon-intron organization of the hINSR gene provides a clue to the evolutionary history of this gene and suggests that it is a mosaic constructed from protein-coding regions recruited from other genes. Eight mutations in the hINSR gene that result in expression of structurally abnormal proteins have been described. These mutations are associated with insulin resistance and provide insight into the role of the hINSR gene in the development of diabetes mellitus.     

Recognition and treatment of hypercholesterolemia in a family practice center

Elevated levels of serum cholesterol are a major risk factor for coronary artery disease, yet few studies have investigated the extent to which practicing physicians recognize and treat their patients with hyperlipidemia. A retrospective chart review was performed on 93 patients who had documented cholesterol levels greater than or equal to 6.20 mmol/L (240 mg/dL) in an outpatient setting to determine the degree of recognition and treatment of hypercholesterolemia. Hypercholesterolemia was diagnosed in 66 percent of patients, dietary recommendations were made in 46 percent, and lipid-lowering medication was prescribed in only 6 percent. Lipid profiles or high-density lipoprotein levels were determined in 22 percent, and thiazide diuretics were being prescribed for 32 percent. There was a trend toward greater recognition and treatment in patients with cholesterol levels greater than 7.75 mmol/L (300 mg/dL) and in patients less than 70 years of age. These results suggest that physician recognition of hypercholesterolemia is greater when compared with previous studies, but more aggressive diagnosis and intervention are needed. Greater utilization of lipid-profile analysis in hypercholesterolemic patients should also be encouraged.     

Age-matching improves the results of renal transplantation with older donors

Whilst HLA matching is routine for renal transplantation, the possible benefits of matching donor and recipient age have not been previously examined. In this study we examined the simultaneous effect of donor to recipient age difference on the graft survival of 141 consecutive first cadaver transplant recipients treated by cyclosporin immunosuppression. Multivariate regression analysis, taking into account other variables of moderately matched recipients (i.e. dialysis time and type, donor/recipient sex, local/imported kidneys, recent sensitivity, total ischaemic time, preoperative transfusions), indicated that age-difference was the single most important variable (P less than 0.05). Individually there was no significant effect of recipient age, whilst older donors (aged greater than 50 years) were associated with significantly worse graft survival than those younger (P less than 0.01). When dealing with donors aged greater than or equal to 50 years the corresponding recipient 1-year graft was improved when the donor was no more than 5 years older than the transplant recipient. Donor age to recipient age difference is a potentially important selection criterion in renal transplantation.     

Inhibition of hepatic glucose production by SDZ 51641

The new oral hypoglycemic agent SDZ 51641 was evaluated in nondiabetic rats and a rat model of human non-insulin-dependent diabetes mellitus. Diabetes was induced with a single injection of 37.5 mg/kg streptozocin, and the rats exhibited hyperglycemia in the fed state with normal insulin levels. Treatment of nondiabetic animals with 100 mg/kg SDZ 51641 given orally significantly decreased serum glucose and ketone levels within 4 h without affecting insulin levels. Nonesterified fatty acids increased more than twofold during the same period. Its effect on ketone and fatty acid levels suggests that SDZ 51641 acts as an inhibitor of fatty acid oxidation. Diabetic rats treated with SDZ 51641 exhibited a significant acute hypoglycemic response, which was more pronounced after 3 days of treatment. The compound also significantly decreased serum cholesterol and triglyceride levels 27 and 53%, respectively. When endogenous hepatic glucose production was assessed in nondiabetic and diabetic animals via continuous infusion of [3-3H]glucose, we found that hepatic glucose production was elevated 43% in diabetic compared with control animals. When diabetic rats were treated with 100 mg/kg SDZ 51641, hepatic glucose production decreased to normal levels within 6 h. Hyperinsulinemic-euglycemic clamp studies indicated that SDZ 51641 had no effect on insulin-stimulated glucose utilization. Measurement of [1-14C]oleate oxidation in isolated hepatocytes demonstrated that SDZ 51641 inhibited long-chain fatty acid oxidation in a concentration-dependent manner. The compound was ineffective at inhibiting long-chain fatty acid oxidation in epitrochlearis or soleus muscles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early changes in hemoglobin and hematocrit levels after packed red cell transfusion in patients with acute anemia

BACKGROUND: Equilibration of hemoglobin concentration after transfusion has been estimated to take about 24 hours, but some studies have shown that earlier measurements reflect steady-state values in persons who have not bled recently. This study was aimed at assessing the changes over time in hemoglobin concentration after transfusion in acutely anemic patients because of recent bleeding. STUDY DESIGN AND METHODS: Thirty-two normovolemic patients recovering from an acute bleeding episode who were no longer thought to be bleeding and who received a 2- unit red cell transfusion were studied. At baseline and 15, 30, 60, and 120 minutes and 24 hours after transfusion, hemoglobin concentration and hematocrit values were measured. RESULTS: The administration of 2 units of packed red cells elicited a 24-hour increase of 22.4 +/− 6.8 g per L in hemoglobin concentration. Hemoglobin values were not different at any of the defined posttransfusion times. Hematocrit levels experienced similar changes over time. Agreement between 15-minute and 24-hour values was excellent, as only 6 percent of patients exhibited a clinically significant difference (> 6 g/L) between the hemoglobin measurements. CONCLUSION: Hemoglobin and hematocrit values rapidly equilibrate after transfusion in normovolemic patients who are recovering from an acute bleeding episode. This fact would allow a rapid assessment of the effects of transfusion and of the recurrence of bleeding in patients remaining at risk.     

CHARACTERISTICS OF MEMBRANE TRANSPORT PROCESSES OF MACULA DENSA CELLS

1. Macula densa (MD) cells are located within the thick ascending limb (TAL) and have their apical surface in contact with tubular fluid and their basilar region in contact with the glomerulus. These cells sense changes in luminal fluid sodium chloride concentration ([NaCl]) and transmit signals resulting in changes in vascular resistance (tubuloglomerular feedback) and renin release. 2. Current efforts have focused on understanding the cellular transport mechanisms of MD cells. Progress in this area has benefited from the use of the isolated perfused TAL-glomerular preparation, which permits direct access to MD cells. 3. Using microelectrodes to measure basolateral membrane potential (V_BL) of MD cells, it was found that VBL was very sensitive to changes in luminal fluid [NaCl]. As [NaCl] was elevated from 20 to 150mmol/L, V_BL was found to depolarize by over 30 mV. 4. Basolateral membrane potential measurements were also used to identify an apical Na⁺: 2CI^?: K⁺ cotransport pathway in MD cells that is the major pathway for NaCl entry into these cells. 5. Other work identified a basolateral chloride channel that is presumed to be responsible for changes in V_BL during alterations in luminal [NaCl]. This channel, which is the predominant conductance across the basolateral membrane, may be regulated by intracellular Ca²⁺ and cAMP. 6. An apical Na⁺: H⁺ exchanger in MD cells was detected by measuring changes in intracellular pH using the fluorescent probe 2′,7′-bis-(2-carboxyethyl)-5(and-6) carboxyfluorescein. 7. Using patch-clamp techniques, a high density of pH- and Ca²⁺-sensitive K⁺ channels was observed at the apical membrane of MD cells. 8. Other studies found that, at the normal physiological conditions prevailing at the end of the TAL (luminal [NaCl] of 20–60 mmol/L), reabsorption mediated by MD cells is very sensitive to changes in luminal [NaCl].     

Utilization and clinical manifestations of human immunodeficiency virus type 1-infected children presenting to a pediatric emergency department

A retrospective review was conducted of 22 human immunodeficiency virus type 1 (HIV-1)-infected children under 13 years of age presenting to an inner city pediatric emergency department to determine their clinical manifestations of disease and utilization of emergency department services. When compared with a population of 78 normal children, the infected children were more likely to present with cough, difficulty in breathing, and lethargy. Pneumonia, diarrhea, and dehydration were more common diagnoses in the infected children, who were more likely to be admitted, had more invasive procedures, and required more professional staff to provide care. There was no significant difference in the frequency of visits (visits/month of age) when comparing the two groups. As expected, the infected children presented with problems associated with pediatric HIV-1 infection. Our results suggest that HIV-1-infected children require an increased level of care in the emergency department and subsequent admission to the hospital. These children did not visit the emergency department more frequently than the controls. This may be the result of an active outpatient HIV clinic in our hospital, which is available to both scheduled and unscheduled patients.     

Effect of the 5-lipoxygenase inhibitor ZD2138 on allergen-induced early and late asthmatic responses.

BACKGROUND--Leukotrienes are lipid mediators generated from arachidonic acid by the 5-lipoxygenase pathway which may play an important part in the pathophysiology of asthma. Previous studies have demonstrated attenuation of the allergen-induced early and late asthmatic responses by leukotriene receptor antagonists. The effect of the 5-lipoxygenase inhibitor ZD2138, a non-redox lipoxygenase inhibitor which inhibits leukotriene synthesis for 24 hours after single doses of 350 mg, on allergen-induced early and late asthmatic responses has been assessed. METHODS--Eight asthmatic subjects with baseline FEV1 > 70% were studied. On screening, all subjects developed an allergen-induced biphasic asthmatic response to grass pollen, cat dander, or house dust mite. ZD2138 (350 mg) or placebo was given on two occasions separated by two weeks in a randomised double blind fashion. Allergen inhalation challenge was performed four hours after dosing and FEV1 was measured for eight hours. The inhibitory activity of ZD2138 on the 5-lipoxygenase pathway was assessed by measurements of calcium ionophore-stimulated generation of LTB4 in whole blood ex vivo and by analysis of urinary LTE4 levels before administration of drug or placebo and at regular intervals after oral drug dosing and allergen challenge. RESULTS--ZD2138 produced no significant bronchodilatation or attenuation of the early or late asthmatic response, although there was 82% inhibition of whole blood generation of LTB4 in response to calcium ionophore stimulation and 52% reduction in urinary excretion of LTE4. CONCLUSIONS--In asthmatic subjects the 5-lipoxygenase inhibitor ZD2138 did not protect against allergen-induced asthmatic responses, despite substantial inhibition of 5-lipoxygenase.     

Weekly subcutaneous recombinant human erythropoietin corrects anemia of progressive renal failure

PURPOSE: The purpose of this study was to analyze data retrospectively from our use of weekly subcutaneous recombinant human erythropoietin (rHuEPO) in predialysis and peritoneal dialysis patients with anemia. PATIENTS AND METHODS: All anemic patients with progressive renal failure (12 predialysis and seven home peritoneal dialysis) in whom subcutaneous rHuEPO therapy was begun at, or was reduced to, a weekly dose were studied retrospectively. Patients were not selected for, nor excluded from, these observations for any other reason. Hematocrit and endogenous creatinine clearance were monitored regularly, and no other new treatment for anemia was given except oral iron. Iron-deficiency anemia was considered improbable because of normal red blood cell mean corpuscular volume. Unfortunately, iron parameters were not monitored. RESULTS: The hematocrit increased 4 to 9 percentage points in 4 to 13 weeks in all but two patients who were initially treated with weekly doses, and a hematocrit of 31% was achieved in these patients within 6 to 12 weeks. The mean effective dose to accomplish this was 150 U/kg. All but three patients could be maintained on weekly doses at a hematocrit of 31% or higher. The mean effective dose was 75 U/kg. CONCLUSION: It is concluded that subcutaneous rHuEPO administered weekly can correct the anemia of predialysis and peritoneal dialysis patients. Weekly dosing is more convenient for patients and may be less costly for Medicare providers.     

Narrative and procedural discourse in temporal lobe epilepsy.

It is well established that some individuals with temporal lobe epilepsy (TLE) demonstrate language deficits at the single word level. However, discourse production rarely has been examined quantitatively within this group. This study compared adult TLE patients with an early seizure onset (< or = age 14 years, n = 27) to a control group (n = 28) on narrative and procedural discourse tasks. As a group, the TLE patients performed normally on the procedural discourse task, but differed significantly from the controls on several narrative discourse variables. At the individual level, 30% of the TLE patients versus 4% of the controls demonstrated impaired discourse ability (p and 0.01). Within this early onset TLE group, discourse performance was not associated with demographic or seizure history variables. Considering the cognitive domain, discourse performance correlated significantly with working memory. In summary, mild discourse dysfunction was present in a significant minority of early onset TLE patients, but this deficit was not closely associated with other language measures. Discourse ability and its neuropsychological, neuroanatomical and conversational speech correlates deserve further study in TLE patients.