Influence of physiologic hyperglucagonemia on basal and insulin-inhibited splanchnic glucose output in normal man

To evaluate the effects of physiologic hyperglucagonemia on splanchnic glucose output, glucagon was infused in a dose of 3 ng/kg per min to healthy subjects in the basal state and after splanchnic glucose output had been inhibited by an infusion of glucose (2 mg/kg per min). In the basal state, infusion of glucagon causing a 309 +/- 25 pg/ml rise in plasma concentration was accompanied by a rapid increase in splanchnic glucose output to values two to three times basal by 7-15 min. The rise in arterial blood glucose (0.5-1.5 mM) correlated directly with the increment in splanchnic glucose output. Despite continued glucagon infusion, and in the face of stable insulin levels, splanchnic glucose output declined after 22 min, returning to basal levels by 30-45 min. In the subjects initially receiving the glucose infusion, arterial insulin concentration rose by 5-12 muU/ml, while splanchnic glucose output fell by 85-100%. Infusion of glucagon causing an increment in plasma glucagon concentration of 272 +/- 30 pg/ml reversed the inhibition in splanchnic glucose production within 5 min. Splanchnic glucose output reached a peak increment 60% above basal levels at 10 min, and subsequently declined to levels 20-25% below basal at 30-45 min. These findings provide direct evidence that physiologic increments in plasma glucagon stimulate splanchnic glucose output in the basal state and reverse insulin-mediated inhibition of splanchnic glucose production in normal man. The transient nature of the stimulatory effect of glucagon on splanchnic glucose output suggests the rapid development of inhibition or reversal of glucagon action. This inhibition does not appear to depend on increased insulin secretio.     

Increased nitrotyrosine in the diabetic placenta: evidence for oxidative stress

OBJECTIVE: To evaluate the presence of nitrotyrosine (NT) residues in placental villous tissue of diabetic pregnancies as an index of vascular damage linked to oxidative stress. RESEARCH DESIGN AND METHODS: Villous tissue was collected and flash frozen after delivery from 10 class C and D IDDM patients (37.9+/-3.2 weeks) and 10 normotensive pregnant individuals (37.5+/-3.8 weeks). Serial sections of tissue were immunostained with specific antibodies to NT, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and manganese superoxide dismutase (MnSOD). Sections were scored for intensity of immunostaining (0-3) by three observers blinded to the identity of tissue. RESULTS: All tissues demonstrated immunostaining for eNOS in both syncytiotrophoblast and stem villous vascular endothelium with no apparent differences between groups. Immunostaining for iNOS was seen in the villous stroma, but again was not different between the two groups. Significantly more intense NT staining was apparent in vascular endothelium and villous stroma (both P < 0.02) of diabetic placentas. The endothelium of large villous vessels of diabetic tissues also showed more intense immunostaining for MnSOD (P < 0.01). CONCLUSIONS: In these diabetic pregnancies, we were unable to show increased eNOS, unlike previous findings in preeclamptic pregnancies. The presence of NT may indicate vascular damage in the diabetic placenta due to peroxynitrite action formed from increased synthesis/interaction of nitric oxide and superoxide. The apparently paradoxical increase in MnSOD expression may be an adaptive response to increased superoxide generation.     

Modulation of fatty acid metabolism by glucagon in man. IV. Effects of a physiologic hormone infusion in normal man

This study was done to explore the role of physiologic elevations of glucagon concentration in plasma ketone body concentration in normal man. During the period of hormone elevation, plasma free fatty acids were pharmacologically elevated to ensure adequate free fatty acid substrate delivery to the liver to support hepatic ketogenesis. Eighty-minute infusions of glucagon resulted in a plasma hormone concentration of approximately 300 pg./ml. During the infusion, ketone bodies declined from their basal concentration and remained below basal for the duration of the infusion. An acute heparin-induced pharmacologic elevation of plasma free fatty acid concentration resulted in a transient rise in plasma ketone body concentration, but at no time did it attain the concentration observed during the control saline infusion. Plasma glucose concentration was not altered by glucagon infusion, but plasma insulin concentration rose by approximately 2.5 muU./ml. These results suggest that glucagon is not ketogenic in normal man as has been previously reported in insulin-deficient diabetics. The glucagon-induced rise in plasma insulin concentration may participate in the observed reduction in plasma ketone body concentration.     

The effect of partial portal decompression on portal blood flow and effective hepatic blood flow in man: a prospective study

We evaluated the effectiveness of current strategies for educating patients in routine clinical practice in three related studies. (1) A study of overall knowledge in 100 patients with rheumatoid arthritis (RA) and osteoarthritis (OA) showed knowledge of diagnosis and treatment effects were high (86% and 83% respectively) but only a minority (37%) were well informed about side effects. (2) Patients' detailed knowledge of drug therapy was assessed in 50 RA and OA patients. Between 56%-92% knew why drugs were given, their use and their likely effects. But many patients were unaware of the main adverse reactions and also how to avoid or limit them. (3) The relationship of patient education to overall disease management was evaluated in 89 RA patients with 5-10 years disease duration using validate guidelines for specialist care. Those patients who had been give inadequate education about drug therapy had a reduced level of overall care. Although education is considered important by patients, it is often inadequate, and this is associated with a less effective overall treatment.     

Effects of metformin on glucose and glucagon regulated gluconeogenesis in cultured normal and diabetic hepatocytes

The effects of glucose and glucagon on the anti-gluconeogenic action of metformin were investigated in normal and diabetic hepatocytes. Glucose production from lactate was elevated by 88% in hepatocytes from fasted normal rats compared with hepatocytes from fed animals. Diabetes caused 3.5- and 2.1-fold increases in hepatic gluconeogenesis under fasting and fed conditions, respectively. Metformin (250 microM) suppressed glucose production by 37% in normal and by 30% in diabetic hepatocytes from fed rats. This drug was more effective (up to 67%) with increasing concentrations of glucose in the medium. Potentiation by metformin of insulin action on gluconeogenesis was elevated significantly (P < 0.01 to 0.001) by glucose in vitro. Metformin (75-250 microM) also counteracted the effects of glucagon at optimal concentrations in normal (32-68%) as well as diabetic (8-46%) hepatocytes. The findings of this study indicate that (i) the anti-gluconeogenic effect of metformin is enhanced by glucose in vivo and in vitro; and (ii) the suppression of glucagon-induced gluconeogenesis by metformin could play a role in its glucose-lowering effects in diabetic conditions.     

The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs

BACKGROUND: Irritable bowel syndrome is a common cause of abdominal pain and discomfort and may be related to disordered gastrointestinal motility. Our aim was to assess the effects of long-term treatment with a prokinetic agent, cisapride, on postprandial jejunal motility and symptoms in the irritable bowel syndrome (IBS). METHODS: Thirty-eight patients with IBS (constipation-predominant, n = 17; diarrhoea-predominant, n = 21) underwent 24-h ambulatory jejunal manometry before and after 12 week's treatment [cisapride, 5 mg three times daily (n = 19) or placebo (n = 19)]. RESULTS: In diarrhoea-predominant patients significant differences in contraction characteristics were observed between the cisapride and placebo groups. In cisapride-treated diarrhoea-predominant patients the mean contraction amplitude was higher (29.3 +/- 3.2 versus 24.9 +/- 2.6 mm Hg, cisapride versus placebo (P < 0.001); pretreatment, 25.7 +/- 6.0 mm Hg), the mean contraction duration longer (3.4 +/- 0.2 versus 3.0 +/- 0.2 sec, cisapride versus placebo (P < 0.001); pretreatment, 3.1 +/- 0.5 sec), and the mean contraction frequency lower (2.0 +/- 0.2 versus 2.5 +/- 0.4 cont./min, cisapride versus placebo (P < 0.001); pretreatment, 2.5 +/- 1.1 cont./min] than patients treated with placebo. No significant differences in jejunal motility were found in the constipation-predominant IBS group. Symptoms were assessed by using a visual analogue scale before and after treatment. Symptom scores relating to the severity of constipation were lower in cisapride-treated constipation-predominant IBS patients [score, 54 +/- 5 versus 67 +/- 14 mm, cisapride versus placebo (P < 0.05); pretreatment, 62 +/- 19 mm]. Diarrhoea-predominant IBS patients had a higher pain score after cisapride therapy [score, 55 +/- 15 versus 34 +/- 12 mm, cisapride versus placebo (P < 0.05); pretreatment, 67 +/- 19 mm]. CONCLUSION: Cisapride affects jejunal contraction characteristics and some symptoms in IBS.     

Influence of glucagon replacement on the hyperglycemic and hyperketonemic response to prolonged somatostatin infusion in normal man

Somatostatin was infused for 6 h into seven normal subjects with and without a replacement dose of glucagon. The addition of glucagon to somatostatin resulted in a 30-40% rise in plasma glucagon, whereas plasma insulin declined by 40-50% in both treatment groups. Plasma glucose and glucose production initially increased 2-fold with glucagon replacement, and subsequently declined by 2-3 h to levels comparable to those observed with somatostatin alone. After 6 h plasma glucose and glucose kinetics were no different whether or not glucagon was present. The rise in blood ketones after somatostatin was not exaggerated by glucagon replacement. We conclude that glucagon lack is not a modifying factor in the late hyperglycemic and hyperketonemic response to prolonged infusions of somatostatin.     

Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin

OBJECTIVES: To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN: Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING: Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS: 17 patients with insulin dependent diabetes mellitus of more than five years' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES: Glycaemic control and frequency of hypoglycaemic episodes during two months' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS: Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS: These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.     

Increased lipase inhibition in uremia: identification of pre-beta-HDL as a major inhibitor in normal and uremic plasma

The hypertriglyceridemia commonly observed in uremia has been attributed to an abnormally high inhibitor activity in plasma for lipoprotein lipase (LPL) and hepatic lipase (HL), both of which have a key role in lipoprotein metabolism. The purpose of this investigation was to establish a relationship between plasma lipase inhibitor activity and hypertriglyceridemia, identify the main plasma lipase inhibitor, and determine the basis for the greater inhibitor activity in uremia. In a mixed population of normal (N = 8) and uremic subjects (N = 12), log-transformed plasma triglycerides correlated with both inhibitor activity and uremic status. However, inhibitor activity was the only retained predictor variable for triglycerides in a multiple linear regression model (r = 0.91; P < 0.0001). An inhibitor isolated from normal plasma was identified as a particle containing apolipoprotein A-I (apo A-I) and 3% phospholipid. This particle, which has pre-beta electrophoretic mobility and a Stokes' radius of 54 A, therefore corresponds to a form of the previously described pre-beta-HDL (free apo A-I) in the non-lipoprotein fraction of plasma. Comparison of normal and uremic plasma indicated that the greater lipase inhibitor activity in the latter could be attributed to an increased concentration of apo A-I in the non-lipoprotein fraction of plasma (pre-beta-HDL), as well as to increased inhibition by the uremic lipoproteins. The increased plasma lipase inhibitor activity may be important in the pathogenesis of hypertriglyceridemia in chronic renal failure.     

Purpose in life as a mediator of adjustment after spinal cord injury.

Objective: Determine how purpose in life influences adjustment after spinal cord injury (SCI). Study Design: Cross-sectional survey with mediation analysis. Subjects: 1,391 adults with traumatic SCI 1 or more years prior. Main Outcome Measure: Ladder of Adjustment (N. M. Crewe & J. S. Krause, 1990). The Purpose in Life scale (PIL: .J. C. Crumbaugh, 1968), the Zuckerman-Kuhlman Personality Questionnaire (M. Zuckerman, D. M. Kuhlman, J. Joireman, P. Teta, & M. Kraft, 1993), and the Multidimensional Health Locus of Control scale (K. A. Wallston, B. S. Wallston, & R. DeVellis, 1978) were assessed. Results: PIL mediated between most measures and adjustment. Conclusions: Logotherapy is effective in strengthening purpose in life. Its use with persons with SCI may improve their adjustment and quality of life. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Carotid arterial blood flow in the ovine fetus as a continuous measure of cerebral blood flow

Principles derived from a group of 46 ML of the mantle zone are presented: Mantle pattern of a ML and its cytological structure are mostly sufficient for positive basic diagnosis. Diffuse mantle zone ML need detection of BCL-1 and CD5 hyperexpression which are characteristic for small-cell and centrocytoid forms when compared with BCL-2 positive centrofollicular lymphomas. B monocytoid lymphomas from the parafollicular subgroup as well as plasmacytoid ML from the marginal subgroup retain faint BCL-1 positivity but lose CD5 positivity. That may results in attempt of problematic narrowing of mantle zone definition because of existence of the mixed cellularity forms of mantle zone ML. Nodular mantle zone ML are clinically recognized late and are unsensitive to treatment which is opposite to the original idea of their relative benignity. M-coding of mantle zone ML is very defective because the codes do not separate nodular (perifollicular) and diffuse variants.     

Cerebral blood flow velocity and vasomotor reactivity before and after shunting surgery in patients with normal pressure hydrocephalus

The purpose of this study was to evaluate pre- and post-shunting haemodynamic changes and their correlation with the clinical results in normal pressure hydrocephalus (NPH). Accordingly, eleven demented patients with clinical signs suggestive of NPH received examinations of cerebral blood flow velocity (BFV) and vasomotor reactivity (VMR) by transcranial Doppler sonography with carbogen testing before and after shunt treatment. Computerized tomography (CT), clinical assessment and neuropsychological grading were performed prior to and at 3 months following surgery. A control group consisting of 10 patients was included to establish baseline data. The pre-operative CBF studies in the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) revealed the NPH patients did not have significant decreases of BFVs, but had significant decreases of carbogen VMR (P < 0.05). After shunting, there were no significant changes of the BFVs as compared with the pre-shunting data. The post-shunting VMR of the ACA was significantly higher than the pre-shunting one (p < 0.05), but there was no variation in that of the MCA. Both the values of post-shunting VMR in ACA and the post-shunting increase in VMR in MCA of the 7 shunt-responsive patients who improved mentally and in other symptoms were significantly higher than those of patients without improvement (p < 0.05). In addition, the five patients with gait improvement showed significantly higher values of post-shunting VMR of ACA and the post-shunting increase of VMR for both ACA and MCA when compared with those patients without gait improvement (p < 0.05, respectively). Our study supports the view that patients with NPH had various degrees of impaired VMR in both the ACA and the MCA, but showed insignificant reduction in BFVs, indicating a compensatory mechanism of CBF over time to accommodate the subnormal state of cerebral perfusion pressure. Shunt placement would improve the VMR in responsive patients. Postoperatively, an increase of VMR tends to accompany improvement of the functional state: that in the MCA alone is associated with symptomatic improvement in mental function and that increase in VMR in both the ACA and the MCA with improvement in gait, respectively.     

Hepatic blood flow and splanchnic oxygen consumption in patients with liver failure. Effect of high-volume plasmapheresis

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia was not present.     

Maternal renal artery blood flow velocimetry in normal and hypertensive pregnancies

OBJECTIVE: To investigate the effect of normal pregnancy and hypertensive disorders of pregnancy on the maternal renal artery Doppler blood flow velocity indices. METHODS: The patient material consisted of 30 normal pregnant women, 29 women with pregnancy induced hypertension, 43 women with preeclampsia and 22 pregnant women with chronic hypertension. Blood flow velocities in the segmental renal arteries from the right kidney were analysed by pulsed and color Doppler. The systolic/diastolic (s.d.) ratio, resistance index (RI) and pulsatility index (PI) were used for Doppler waveform analysis. RESULTS: In all of the groups of hypertensive pregnant women renal artery Doppler indices were significantly lower compared to the normal pregnant women group. There was a significant negative relationship between renal artery PI and mean arterial pressure in the preeclampsia group and in the chronic hypertension group. CONCLUSION: The present results demonstrate that the mechanism of renal autoregulation in preeclampsia might be altered, leaving glomerulus unprotected from increased blood pressure. It seems that the concept of renal vasoconstriction in preeclampsia might be disputed and needs further investigation.     

Anti-diabetic drugs as a cause of hypoglycaemia among acute medical admissions in Hong Kong and Singapore--relationship to the prescribing patterns in diabetic patients

By a reaction of salicylaldehyde (Scl) with the corresponding amino acids and by the next complexation reaction of the formed Schiff bases with Cu2+ ions in an aqueous-alcoholic medium, aqua (N-salicylideneaminoalkanoato)copper(II) complex chelates of the composition Cu(Scl-DL-Asp(2-)) (H2O)2, Ip and Cu(Scl-L-Asn(2-)(H2O), In were prepared. The monodiazole complexes with pyrazole IIp and IIn (as monohydrate) as well as with 3,5-dimethylpyrazole IIIp a IIIn were prepared by replacing the molecule of H2O in the parent aquacomplexes with the diazoles under the same reaction conditions. Using a routine dilution micromethod, the antimicrobial activity of the prepared complexes and free diazoles was tested against Staphylococcus aureus, Escherichia coli and Candida albicans. Only a significant antistaphylococcus activity was found (highest for the complex IIn; MIC = 39 micrograms/cm3). All chelates (Ip,n-IIIp,n) were more effective (MIC = 39-156 micrograms/cm3) than both pyrazole (312 micrograms/cm3)and 3,5-dimethylpyrazole (625 micrograms/cm3) alone. The relationship between the coordination-chemical properties and the biological effects of the complexes studied is discussed.     

Stress-response-dampening effects of alcohol: Attention as a mediator and moderator.

The present study sought to characterize alcohol's stress-response-dampening (SRD) effects on multiple measures of stress and whether these effects are mediated by reductions in sustained attention and, further, whether baseline levels of sustained attention moderate SRD. One hundred six men consumed either an alcohol (0.70 g/kg) or a placebo beverage prior to learning that they would deliver a self-disclosing speech. Structural equation models controlling for multiple baseline periods indicated that alcohol directly reduced self-reported anxiety and skin conductance levels in response to the stressor. Alcohol's effect on reducing heart rate response, in contrast, was indirect and mediated by effects on prestress baseline. As hypothesized, differences in sustained attention partially mediated the effects of alcohol on skin conductance (but not heart rate or self-reported anxiety) and served as a moderator of alcohol's effects on skin conductance response. Findings are discussed in terms of theoretical links among alcohol consumption, specific cognitive abilities, and stress reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fluorophotometry and the rate of aqueous flow in man. I. Instrumentation and normal values

A new objective fluorophotometer, based on a previous model but with changes in electronic circuitry, was designed and built. The fluorometric method was applied to 38 normal eyes to obtain the aqueous outflow rate and fluorescein decay constant. Aqueous outflow rate has a direct correlation with the anterior chamber depth and an inverse correlation with age. The aqueous flow rate is higher in whites than in blacks, but in our sample, mean pressure was lower in whites. Acetazolamide decreases the aqueous flow rate and the fluorescein constant; the mean decrease in 10 eyes of 5 patients was approximately 38% and 22%, respectively. Fluorophotometry gives a higher value for the aqueous outflow rate than that calculated by tonography.     

Cold-induced vasodilatation and peripheral blood flow under local cold stress in man at altitude

The cold-induced vasodilatation (CIVD) response was studied on 17 lowlanders (20-30 years) at Delhi, using a water bath maintained at 4 degrees+/-0.2 degreesC. The temperatures were measured at the tip of the index finger, centre of the palm, over a prominent wrist vein, and orally. Then the subjects were air-lifted to an altitude of 3500 m, where the measurements were repeated at weekly intervals for a period of 3 weeks. After this, they were flown back and retested. For comparison, the study at altitude was done on 10 acclimatised lowlanders and on 10 high-altitude natives. The peripheral blood flow under a local cold stress was calculated. Three types of CIVD responses--viz. typical hunting, proportional control, and continuous rewarmin--were observed. At altitude, the pattern was more or less the same but there was a significant reduction in the response. The responses of the natives were more or less identical to those of the lowlanders at sea level, and responses of the acclimatized lowlanders were better than the fresh inductees, but much less than the natives. The changes in peripheral blood flow was in accordance with the CIVD response.