Pharmacological studies on lappaconitine: possible interaction with endogenous noradrenergic and serotonergic pathways to induce antinociception.

Systemic and intracerebroventricular (i.c.v.) injections of lappaconitine (LA) produced a dose-dependent inhibition of the response to thermal stimulation in sham-operated mice as assayed by the tail-immersion test. After spinal transection, the antinociceptive potencies of s.c.- or i.c.v.-administered LA were markedly reduced. Antinociception induced by systemically administered LA was clearly reduced by pretreatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine through the i.c.v. and intrathecal (i.t.) routes. When LA was administered by i.c.v.-injection, the LA-induced antinociception was reduced by pretreatment with timolol, a beta-adrenergic antagonist, and ketanserin, a 5-HT2 antagonist. Administration of LA by the i.t. route resulted in a significant antinociceptive activity, which was also reduced by pretreatment with phenoxybenzamine, an alpha-adrenergic antagonist, and mianserin, a 5-HT1 antagonist. The results of these studies suggest that the central noradrenergic and serotonergic systems may be involved in the antinociception of systemically administered LA, and these pathways are mediated by beta-adrenoceptors and 5-HT2 receptors in the brain and alpha-adrenoceptors and 5-HT1 receptors in the spinal cord.


Difference between halothane and barbiturate anesthesia in the influence of cerebral ischemia on the vagal baroreflex in dogs.

In halothane-anesthetized dogs, a decrease in baroreflex sensitivity (BRS) of approximately 20% was observed during the reperfusion period following 5-min global cerebral ischemia. When compared with our previous study on animals under pentobarbital anesthesia, the extent of the decrease in BRS was smaller and apparently more severe ischemia was necessary to damage the vagal component of the baroreflex. Substitution of halothane with pentobarbital during the reperfusion period failed to affect either BRS or the ratio of the vagal component. In another group, pre- and post-ischemic measurements of BRS was performed under halothane anesthesia, but the ischemic insult was given under thiopental anesthesia. In these animals, the extent of decrease in BRS (about 50%) was greater than that in animals subjected to ischemia under halothane anesthesia. The present results suggest that the anesthetics used during the ischemic insult may affect the extent of post-ischemic dysfunction of the baroreflex. The vagal component of the baroreflex may be more resistant to ischemia under halothane anesthesia than under barbiturate anesthesia.


Novel derivatives of 5-fluorouridine and 5-fluorouracil having potent antitumor and lower immunosuppressive activities.

We studied the biological activities of several 5-fluorouridine (5-FUR) and 5-fluorouracil (5-FU) derivatives to find novel antitumor drugs with lower immunosuppressive effects. We examined 5-FUR and 5-FU derivatives acylated with (2-n-propyl-n-pentanoyl)glycine (KN-539). Among the examined compounds, we found satisfactory activities in a derivative of 5-FUR, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), and a derivative of 5-FU, 1-(6-[N-(2-n-propyl-n-pentanoyl)glycyl] amino-n-hexylcarbamoyl)-5-fluorouracil (UK-25). UK-21 (0.05-0.2 mmole/kg, p.o., 10 days) and UK-25 (0.1-0.4 mmole/kg, p.o., 10 days) suppressed Meth A and E.L.4 tumor growths in the corresponding syngeneic hosts (BALB/c mice and C57BL/6 mice, respectively) without decreasing body weight and blood leukocyte count. UK-21 and UK-25 suppressed the proliferation of KB tumor cells in vitro (IC50: 3.0 x 10(-11) M and 4.4 x 10(-7) M, respectively) at concentrations almost equivalent to those of 5-FUR and 5-FU, respectively. These results suggest that UK-21 and UK-25 express their antitumor activity as 5-FUR and 5-FU, respectively. Neither UK-21 nor UK-25 suppressed thymus weight and humoral antibody production against sheep red blood cells (SRBC) in ddY mice, although 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and 5-FU suppressed them in their respective therapeutic dose ranges for tumors. Thus, UK-21 and UK-25 are expected to develop into anticancer drugs with lower immunotoxicological effects.


Comparison of eicosanoids production between rat polymorphonuclear leukocytes and macrophages: detection by high-performance liquid chromatography with precolumn fluorescence labeling.

We developed a procedure for serial measurement of fluorescent derivatives of eicosanoids in biological samples by HPLC. The 9-anthryldiazomethane (ADAM)-derivatized sample was first fractionated through SEP-PAK silica into fraction 1 (eluate of chloroform:toluene) and fraction 2 (eluate of acetonitrile:methanol). Both fractions were loaded separately onto an ODS column, and eluted with a step-gradient of 85% and 95% acetonitrile for Fr-1 (HETE's and arachidonic acid) and with 70% acetonitrile for Fr-2 (PG's and LTB4). The method was applied to the arachidonate products of rat peritoneal leukocytes which were stimulated with A23187. The polymorphonuclear leukocytes (PMNL), which were collected after stimulation with casein, released mainly LTB4, 5-HETE, 6-K-PGF1 alpha, but little arachidonic acid. In contrast to PMNL, rat macrophages, which were collected after peritoneal injection of soluble starch and bacto peptone, released 5-HETE, arachidonic acid, and 6-K-PGF1 alpha, but no LTB4. These differences might be partly caused by the differential rates of uptake or turnover of arachidonic acid into their membrane phospholipids.


Thrombolytic effects of a novel modified tissue plasminogen activator, E6010, on coronary thrombosis in the pig.

This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical stimulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t-PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respectively. The time to recanalization after 0.4 mg/kg of E6010 was 22 +/- 11 min (mean +/- S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 +/- 0.3 vs. 9.4 +/- 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, alpha 2-plasmin inhibitor and plasminogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic action of E6010 following single intravenous bolus injection.


Cisplatin-induced emesis in Suncus murinus.

Emetic responses to cisplatin and participation of vagal innervation in emesis were studied in suncus. Intraperitoneal and intravenous administration of cisplatin caused dose-dependent emesis. ED50 values, latencies and frequencies were not significantly different between the two administrations. Cis-diaqodiammineplatinum (DAP), an active metabolite of cisplatin, also induced emesis, but with significantly shorter latency. Vagotomy completely abolished both types of vomiting. These results suggest that cisplatin is metabolized to DAP that subsequently causes emesis through stimulation of the vagus afferent.


Reduced activity of antioxidant enzymes underlies contrast media-induced renal injury in volume depletion.

Oxidant-mediated renal injury has been suggested as an important mechanism of acute renal failure induced by contrast media. Since volume depletion has been recognized as a predisposing factor for contrast media nephropathy, the present study was designed to characterize host-defense mechanisms against oxidant-mediated renal injury during volume depletion. Antioxidant enzyme activities in renal cortex were compared between acutely water deprived (WD, 72 hours) and non-WD rats. WD rats had reduced activities of catalase and superoxide dismutase activities (on average, 48% and 60% of values in non-WD, respectively). In separate groups of WD rats, saline or one of three different contrast media, namely diatrizoate meglumine/diatrizoate sodium (DTZ), ioxaglate meglumine/ioxaglate sodium (IXG), and iohexol (IHX) was injected. Both GFR and renal plasma flow rate, measured 24 hours later, was some 50% less in DTZ-injected than saline-injected WD rats. WD rats treated with IXG and IHX had similar GFR to saline-treated rats. In DTZ-treated WD rats, specific products of membrane lipid peroxidation, phosphatidylcholine and phosphatidylethanolamine hydroperoxide, determined by chemiluminescent HPLC, were more than two-fold higher than saline, IXG, or IHX-treated WD rats. DTZ did not induce renal dysfunction and enhance lipid peroxidation in non-WD rats. Therefore, DTZ appeared to induce oxidant-mediated injury only in WD rats. When WD rats were pretreated with polyethylene glycol-coupled catalase (1.4 mg x 2 days), renal cortical catalase activity remained at a level similar to that of non-WD rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Nutritional status and muscle amino acids in children with end-stage renal failure.

Nutritional status, assessed by anthropometric and biochemical methods, and muscle water, protein and amino acid composition, were evaluated in a control group of 10 children with normal renal function who were undergoing elective surgery, and in 15 children with end-stage chronic renal failure. Samples of the rectus abdominis muscle were taken when surgery was performed in the control children and when a peritoneal catheter was implanted in the uremic children. Height and body weight were reduced in the uremic children compared to the controls but skinfold thickness, arm muscle circumference and serum proteins (total protein, albumin, transferrin, pseudocholinesterase) were essentially normal. The muscle contents of total, extracellular and intracellular water, and of alkali-soluble protein (ASP), DNA and the ASP-DNA ratio were not significantly different in uremic children from those in the controls. Plasma leucine, isoleucine, tyrosine, valine, and serine levels were significantly decreased, whereas plasma citrulline, 1-methylhistidine and 3-methylhistidine levels were increased. Muscle isoleucine and valine levels and the valine/glycine ratio were low in the uremic children. Our results demonstrate that children with chronic renal failure and growth retardation may maintain a satisfactory nutritional status but exhibit amino acid abnormalities typical of uremia.


Hemodialysis prescription and delivery in a metropolitan community. The St. Louis Nephrology Study Group.

The National Cooperative Dialysis Study attempted to determine adequacy of hemodialysis based on kinetic modeling of urea. Based on this study, it has been recommended that a dimensionless term quantitating the amount of dialysis delivered (KT/V) be greater than 1.0 to avoid adverse outcomes. With the declining duration of dialysis treatments in the United States, there has been concern that a significant proportion of patients may be receiving inadequate therapy. The purpose of this study was to survey hemodialysis practices and treatment outcomes in our metropolitan area. Sixteen area nephrologists volunteered to study their outpatient hemodialysis patients (N = 617). Demographic data and urea kinetic modeling results were then analyzed at the lead center. The mean length of dialysis was 3.2 +/- 0.4 (SD) hours with dialysis blood flow rates of 333 +/- 74 ml/min. The mean KT/V was 1.03 +/- 0.25 with nearly half of patients failing to attain a KT/V of 1.0. In 55% of patients the reason for a low KT/V was the prescription of an insufficient amount of dialysis treatment. In the remainder, insufficient delivery of prescribed dialysis contributed to the low KT/V. Only 1 of 33 patients undergoing dialysis twice a week achieved the recommended quantity of treatment on a weekly basis. Patients undergoing dialysis in non-profit units had a higher KT/V than those treated in proprietary units (1.1 +/- 0.26 vs. 0.92 +/- 0.22, P less than 0.001). In addition, patients dialyzed in units that performed urea kinetic modeling on all or selected patients had a higher KT/V compared to those in units where urea kinetics were not done (1.12 +/- 0.25 vs. 0.95 +/- 0.23, P less than 0.001). If these findings reflect practices elsewhere in the United States, many hemodialysis patients fail to receive the current recommended quantity of treatment.


Simultaneous analysis of morbidity and mortality factors in chronic hemodialysis patients.

The Cox stepwise logistic regression model was applied to analyze 22 factors potentially affecting morbidity and mortality (MM) in a cohort of 104 patients on chronic hemodialysis (CHD). Two groups of predictor variables were considered: patients' characteristics at the start of the study, and treatment-related factors recorded throughout the observation period. End points were either failure (death or admission to a hospital) or success. Patients were followed for 24 months. Thirty-nine patients were hospitalized and seven died in the interval. The two leading causes of failure were cardiovascular and infectious complications. Variables significantly associated with the result were: cardiac status (score greater than 2, beta = 1.16), mean predialysis blood pressure (greater than 115 mm Hg, beta = 0.94), total dialysis dose (greater than 0.90, beta = -0.59) and age (greater than 55 years, beta = 0.51). The probability of failure was 0.13 for patients who presented the four variables in the lowest risk class. This increased to a maximum of 0.60 with one risk factor, to 0.91 with two risk factors, and to 0.99 with three or more risk factors. We conclude that, given the conditions for this study, two treatment-related variables of CHD (mean predialysis blood pressure and total dialysis dose) are MM factors even when simultaneously analyzed with other well-established predictors (cardiac status and age). Mean arterial pressure (MAP) is the most important CHD treatment-related MM predictor.


Comparison of hemodialysis and hemodiafiltration: a long-term longitudinal study.

Although hemodiafiltration is purported to provide better cardiovascular stability for dialysis patients; other possible benefits of this therapy have not been well defined. We have compared treatment with hemodialysis (HD) and hemodiafiltration (HDF) in 20 stable patients over a period of 18 months. Dialysis parameters (dialysate composition and flow, duration, dialyzer) were the same in the two periods except for the added convection of HDF and a higher tolerated blood flow in HDF. Cardiovascular parameters were remarkably similar in the two treatment periods, indicating that stable patients do not benefit further from this therapy in terms of these factors. The clearance of urea was significantly improved with HDF, which was reflected in a higher Kt/V and lower TACurea. We observed a significant correlation between Kt/V and PRU in both HD and HDF modes. This correlation was linear and the regression line was similar in both modes. The clearance of beta 2-microglobulin was also significantly improved by HDF compared to HD. Thus the benefit of HDF in stable dialysis patients is the improved clearance of small molecules and beta 2-microglobulin without increasing dialysis time. Further clinical benefits due to the improved clearance may only become apparent with longer follow-up.


Intravenous 1,25 dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients.

The effects of intravenous 1,25 dihydroxycholecalciferol [(OH)2D3] on glucose tolerance and insulin secretion were studied in eleven uremic patients on regular hemodialysis and compared with eleven healthy controls. Intravenous glucose tolerance tests (IVGTT) were used to assess glucose tolerance, and the hyperglycemic clamp technique was used to quantitate endogenous insulin secretion. Three days after they had discontinued oral 1,25(OH)2D3, the dialysis patients were then studied with (+D) and without (-D) a single intravenous dose of 1,25(OH)2D3 at 2 micrograms/m2, given two hours before the IVGTT or clamp studies. During the -D studies, the uremic patients were glucose intolerant but not hyperinsulinemic. Intravenous 1,25(OH)2D3 in dialysis patients increased glucose uptake (K values) during IVGTT by 38% (P less than 0.02) and increased early component of insulin secretion during hyperglycemic clamps by 48% (P less than 0.01) and the late component by 32% (P less than 0.01). After intravenous 1,25(OH)2D3, the dialysis patients became hyperinsulinemic and regained glucose tolerance. Intravenous 1,25(OH)2D3 did not change the K values during IVGTT nor the insulin secretion during hyperglycemic clamps in the control subjects. During the -D studies, serum concentrations of 1,25(OH)2D3 were significantly lower in uremic patients compared with controls. Serum 1,25(OH)2D3 during the +D studies increased to supraphysiological levels in both uremic patients and controls. Serum concentrations of intact parathyroid hormone, total and ionized calcium, magnesium, potassium, urea nitrogen and creatinine were not different between the +D and -D studies in neither the uremic patients nor the controls. These results suggest that 1,25(OH)2D3 deficiency, independent of parathyroid hormone and calcium, may contribute to the abnormalities in glucose tolerance and insulin secretion in dialysis patients.


Ventilatory and metabolic changes during high efficiency hemodialysis.

Ventilatory and metabolic changes were measured in seven patients undergoing high efficiency hemodialysis using a cuprophane dialyzer and bicarbonate-containing dialysate. At an HCO3 concentration of 35 mEq/liter and a mean in vivo urea clearance of 3.6 ml/kg/min, hypoxemia was not detected during dialysis (PaO2 was 14.00 and 13.60 kPa before and during dialysis). The new findings, related to high efficiency bicarbonate dialysis, include a sustained rise in minute ventilation (VE, 6.1 to 6.8 liter/min, P less than 0.01), an increase in CO2 excretion (VCO2, 194 to 214 ml/min, P less than 0.05), and O2 consumption (VO2, 215 to 246 ml/min, P less than 0.05). The increment in VE and VCO2 was attributed to the high flux rate of bicarbonate while the rise in VO2 is likely the result of metabolic alkalosis. Arterial pH rose from 7.40 to 7.49 mm Hg and serum HCO3 increased from 23.8 to 29.2 mEq/liter, while pCO2 remained normal at 5.07 kPa throughout the study. The acid-base status of the blood changed from that of a metabolic acidosis to that of a respiratory acidosis across the dialyzer where the pH decreased from 7.47 to 7.41 and pCO2 rose from 5.31 to 7.72 kPa. These data indicate that a healthy ventilatory response is needed to excrete the excess CO2 generated during high efficiency bicarbonate hemodialysis. The significance and etiology of the elevated O2 consumption is undetermined.


Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus.

Heparan sulfate proteoglycans (HSPG) are negatively charged constituents of the renal extracellular matrix including the glomerular basement membrane (GBM) and mesangial matrix. Biochemical and functional studies of patients with type-1 insulin dependent diabetes mellitus (IDDM) suggest that alterations of HSPG may occur in diabetic nephropathy. We have utilized a specific cytochemical method and electron microscopy to quantitate the distribution of HSPG in the GBM of 10 normal people and in 16 IDDM patients with a spectrum of clinical and structural changes. Enzyme incubation studies of normal infant kidney demonstrated that heparitinase removed 94% of the stainable anionic sites in the lamina rara externa (LRE) and 77% of the sites in the lamina rara interna (LRI) of the GBM. In contrast, incubation in the enzyme chondroitinase ABC did not reduce the number of sites in the LRE but reduced the number of sites in the LRI by 26%. The HSPG anionic sites in normal subjects were distributed in the LRE as 20.9 +/- 1.3, and in the LRI as 13.1 +/- 2.2 per micron GBM length. Anionic sites were slightly reduced (19.6 +/- 1.3, P less than 0.04) in the LRE of IDDM patients with normal urinary albumin excretion rates (UAE), or microalbuminuria, and were reduced in both the LRE and LRI of IDDM patients with clinical proteinuria (13.1 +/- 2.3, P less than 0.001 and 8.9 +/- 2.1, P less than 0.001, respectively). The number of anionic sites in the LRE and LRI, respectively, correlated with UAE (r = +0.78, P less than 0.001, r = +0.58, P less than 0.02), with GBM thickness (LRE, r = +0.81, P less than 0.001; LRI, r = +0.67, P less than 0.01) and with the volume fraction of mesangium (LRE, r = +0.59, P less than 0.02; LRI, r = +0.58, P less than 0.03). These data confirm earlier biochemical findings of a reduction of HSPG in the GBM in advanced diabetic nephropathy but do not provide evidence for the loss of HSPG in the GBM as a mechanism for early microalbuminuria.


Estimation of glomerular volume: a comparison of four methods.

Methods for estimating glomerular volume were compared in Zenker-fixed, paraffin-embedded biopsies from 10 patients with insulin-dependent diabetes mellitus and 6 normal kidney donors. Two methods of measurement of individual glomerular volumes were used: the Cavalieri method (considered the "gold standard") and the maximal profile area (MPA) method. Also studied were the method of Weibel and Gomez and a method based on the disector principle; both estimate mean volume (VG). MPA and Cavalieri showed strong correlation (r = 0.93; P less than 0.001), although the MPA method consistently overestimated the true volume; six glomeruli were necessary for a reliable estimate of VG. The disector method did not correlate with VG determined by Cavalieri. Weibel-Gomez did correlate with Cavalieri (r = 0.68; P less than 0.05), but overestimated VG. At least 15 profiles were needed to provide a dependable estimate of VG by Weibel-Gomez. The Cavalieri, MPA, and Weibel-Gomez methods all can provide reliable estimates of VG, the latter two with appropriate correction factors. The individual glomerular volume methods, while more time consuming, provide information on variation and distribution of the glomerular population and are the methods of choice for studies of glomerular volume.


Is diabetic nephropathy an inherited complication?

For yet unidentified reasons less than 50% of patients with insulin-dependent mellitus develop diabetic nephropathy. Genetic factors have been suggested as risk markers for development of nephropathy in diabetes. To further evaluate this hypothesis we studied the prevalence of nephropathy in diabetic siblings of diabetic patients with and without nephropathy. From a representative sample of 619 patients with insulin-dependent diabetes, we identified 20 patients with and 29 patients without nephropathy having diabetic siblings. Diabetic nephropathy (defined as urinary albumin excretion greater than 300 mg/24 hr) was found in 7 out of 21 siblings to patients with nephropathy and 3 out of 30 siblings to normoalbuminuric patients (P less than 0.04). No significant differences between the two groups of siblings with respect to age, diabetes duration, sex distribution, blood pressure or glycosylated hemoglobin A1c-levels were found. A significant correlation within sib-pair of glycosylated hemoglobin A1c was found (r = 0.47; P less than 0.001). We conclude that familial clustering of diabetic nephropathy does occur. This clustering may either be due to genetic inheritance or to sib-similarities due to shared environment, as indicated by the correlation of glycosylated hemoglobin A1c within sib-pairs.


Predisposition to hypertension: risk factor for nephropathy and hypertension in IDDM.

Less than a quarter of the patients with juvenile-onset IDDM develop diabetic nephropathy during the first 20 years of diabetes. To study the determinants of this complication, we selected patients who had come with newly diagnosed IDDM to the Joslin Clinic between 1967 to 1972, and we examined them in 1986 to 1988, that is, 15 to 21 years after onset of diabetes. Using a case control design we compared three groups of cases, that is, advanced nephropathy (N = 43), only microalbuminuria (N = 41), and hypertension alone (N = 17), with a group of controls who remained normoalbuminuric and normotensive despite the long duration of IDDM (N = 61). In comparison with controls, patients with advanced nephropathy had more parents with hypertension (odds ratio 3.8), higher Vmax values of Na/Li countertransport in red blood cells (odds ratio 10.0 for the highest tertile), and higher mean arterial pressure during adolescence and early adulthood (odds ratio 3.1 for those above the median). They also had significantly poorer glycemic control during their first 12 years of diabetes. Patients with hypertension alone were similar to those with advanced nephropathy with regard to markers of predisposition to hypertension but differed from them with regard to glycemic control, having the best glycemic control of all the study groups. Patients who developed only microalbuminuria during 15 to 21 years of IDDM (some of whom will progress to overt proteinuria later) did not differ significantly from controls with regard to predisposition to hypertension. In conclusion, predisposition to hypertension is a major risk factor for the development of advanced diabetic nephropathy and essential hypertension during the first 20 years of IDDM.


Eight to nine year mortality in known non-insulin dependent diabetics and controls.

Microalbuminuria is known to predict mortality in elderly, non-insulin dependent diabetic individuals. To test whether this is also so when studied prospectively and over a longer period, we followed 228 persons with known diabetes mellitus and an age and sex matched, non-diabetic cohort for eight to nine years. Both cohorts were found during a population screening in 1981-1982 of 5292 citizens aged 60 to 74 years. At ascertainment extensive clinical and biochemical examinations including determination of urinary albumin were carried out. At May 15, 1990 111 diabetic and 46 non-diabetics had died (P less than 0.0001). In the diabetic cohort the median value of urinary albumin excretion (UAE) was 17.40 micrograms/min. In the group with values at or above 17.40 micrograms/min 62 died, compared with 40 deaths in the group with values below (P = 0.003). In the non-diabetic cohort the median UAE value was 7.52 micrograms/min. In the upper group 26 died, in the lower 15 (P = 0.05). Cox regression analyses showed coefficients of regression for ln(UAE) of 0.333 (P less than 0.001) for the diabetic group and 0.236 (P = 0.048) for the non-diabetic group. In the Cox model for the diabetics, ischemic heart disease was also of independent significance to mortality. The final model for the non-diabetics included hypertension and sex as significant variables. It is concluded that in a prospective study of elderly diabetics urinary albumin excretion rate is the best prognostic factor for long-term mortality.(ABSTRACT TRUNCATED AT 250 WORDS)


Relationship of systemic blood pressure to nephropathology in insulin-dependent diabetes mellitus.

Although hypertension is an important complication of diabetes it is unclear whether its association with other diabetic complications represents cause or consequence. Our study is a cross sectional evaluation of the relationship of blood pressure to renal structural and functional parameters. In 139 patients with insulin dependent diabetes for 18.9 +/- 7.4 years (mean +/- SD), we divided the patients into those with markedly increased mesangial volume fraction [Vv(mes/glom) greater than or equal to 0.37] and those with less [Vv(mes/glom) less than 0.37]. Hypertension (systolic BP greater than or equal to 160 and/or diastolic BP greater than 90 mm Hg or receiving BP medications) occurred in 29/40 with Vv(mes/glom) greater than or equal to 0.37. All 40 had clinical nephropathy with urinary albumin excretion (UAE) greater than 200 mg/24 hr. By two-way ANOVA creatinine clearance was lower and albuminuria was increased with both hypertension and the expanded mesangium. Also other measures of renal structure including filtration surface, index of interstitial fibrosis and index of arteriolar hyalinosis were increased by hypertension and mesangial expansion. Most patients with hypertension had other criteria for clinical nephropathy. Since, in these studies, we could not determine if hypertension contributed to or resulted from the renal lesions, we developed an estimate of the rate of mesangial expansion. We found that patients with normal BP (119 +/- 11/78 +/- 7 mm Hg) can be rapidly developing mesangial expansion. These studies support the view that the development of serious renal lesions can be independent of hypertension in IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)


Glomerular structure in type-1 (insulin-dependent) diabetic patients with normo- and microalbuminuria.

Kidney biopsies from 15 type-1 (insulin-dependent) diabetic patients with a range of albumin excretion (AER) were analyzed. Nine patients had normal AER, and six had microalbuminuria. Basement membrane thickness, BMT, and mesangial matrix volume fraction, Vv(mat/glom), were obtained from at least three glomeruli per biopsy. Mesangial structures were estimated with electron microscopic analysis at three levels in each glomerulus. Glomerulopathy parameters were significantly increased in micro- versus normoalbuminuric patients with the following means and (CV): BMT 571 nm (0.12) and 442 nm (0.25), P = 0.03; Vv(mes/glom) 0.31 (0.20) and 0.22 (0.14), P = 0.002; Vv(matrix/glom) 0.17 (0.25) and 0.11 (0.28), P = 0.006; matrix star volume 56 microns 3 (0.47) and 22 microns 3 (0.43), P = 0.02. A positive correlation obtained between AER and each of the glomerulopathy parameters, BM thickness, Vv(mes/glom) and Vv(matrix/glom), as well as between AER and a structural index expressing the sum of changes in the peripheral BM and in the mesangium (r = 0.62, P = 0.01). The results indicated a parallel course of mesangial and peripheral BM changes: a positive correlation obtained between BM thickness and mesangial parameters [BMT versus Vv(matrix/glom): r = 0.82, P = 0.0001] and the ratio of the two subsets of glomerular BM material (PBM:matrix) did not show significant difference between normo- and microalbuminuric groups. The data give strong support to the contention that the transition from normo- into the microalbuminuric phase is linked to progressing glomerulopathy.


An electron microscopic study of glomeruli in Japanese patients with non-insulin dependent diabetes mellitus.

Renal biopsy specimens of 29 Japanese non-insulin dependent diabetes mellitus (NIDDM) patients were examined by quantitative electron microscopic morphometry. In NIDDM the relative increase of percent total mesangium and mesangial capillary surface density (S/Vb) and the relative decrease of peripheral capillary surface density (S/Va) were compared with disease controls. However, mesangial-GBM-epithelial surface density (S/Vc) was not different between both groups. These results suggest that the increased mesangial matrix expands directly towards the capillary lumen as well as along the inner surface of GBM, and narrows the capillary lumen and filtration surface. The duration of diabetes mellitus (DM) did not correlate with all morphological parameters. The mesangial expansion correlated with urinary protein excretion and decreased creatinine clearance (CCr). GBM thickening correlated with proteinuria, but not with CCr. The degree of these morphological changes could be the indicators of hypertension of NIDDM patients. Areas of thin GBM were occasionally noticed in glomeruli which revealed thick GBM extensively, although the mechanism of GBM thinning is not known at the present time.


Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients.

A prospective study of the prevalence and causes of persistent albuminuria (greater than 300 mg/24 hr) was conducted in non-insulin-dependent diabetic (NIDDM) patients, age less than 66 years, attending a diabetic clinic during 1987. All eligible patients (N = 370) were asked to collect at least one 24-hour urine sample for albumin analysis. Urine collection was obtained in 224 males and 139 females (98%). Fifty patients (7 women) suffered from persistent albuminuria (13.8%). The prevalence of albuminuria was significantly higher in males (19%) than in females (5%). A kidney biopsy was performed in 35 patients (70%). The kidney biopsies revealed diffuse and/or nodular diabetic glomerulosclerosis in 27 patients (77%), while the remaining eight patients (23%) had a variety of non-diabetic glomerulopathies, such as minimal lesion and mesangioproliferative glomerulonephritis. Diabetic retinopathy was present in 15 of 27 patients (56%) with diabetic glomerulosclerosis, while none of the eight patients with a non-diabetic glomerulopathy had retinopathy. Our cross sectional study has revealed a high prevalence of albuminuria and of non-diabetic glomerulopathy as a cause of this complication in NIDDM patients. Presence of diabetic retinopathy strongly suggests that a diabetic glomerulopathy is the cause of albuminuria. Albuminuric non-insulin-dependent diabetic patients without retinopathy require further evaluation, that is, kidney biopsy.


Inhibition of glomerular glucosaminyl N-deacetylase in diabetic rats.

The enzyme glucosaminyl N-deacetylase plays a key role in heparan sulphate biosynthesis since N-deacetylation is a prerequisite for N- and further O-sulphation of the carbohydrate polymer. Diabetes induced inhibition of this enzyme could be an important factor in the development of diabetic nephropathy. In this study glomerular glucosaminyl N-deacetylase activity and urinary albumin excretion were measured in insulin-treated streptozotocin-diabetic rats. Furthermore, in an attempt to provide evidence of genetically dependent differences in the vulnerability of the N-deacetylase enzyme, two closely related rat strains (H and U) were studied. A significant 10% inhibition in enzyme activity was found among rats with mean blood glucose values between 9 and 17 mmol/liter, P less than 0.05. There was a pronounced difference between the two rat strains in the vulnerability of the enzyme against blood glucose alterations. The U rat appeared highly sensitive to short-term blood glucose control judged by the correlation between blood glucose and N-deacetylase activity (r = -0.73, P = 0.005, N = 16), where no such correlation was found in the H rat (r = 0.02, P = 0.9, N = 14). Urinary albumin excretion was increased in diabetic H rats and significantly correlated to glomerular N-deacetylase activity (r = -0.62, P = 0.02, N = 14). The U rats developed a 10-fold rise in albumin excretion compared to H rats, but this albuminuria was apparently not related to the presence of diabetes or correlated to glomerular N-deacetylase activity. It is concluded that the diabetes induced inhibition of glucosaminyl N-deacetylase may play an important role in the pathogenesis of diabetic nephropathy.


Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+.

These studies were undertaken to examine effects of elevated glucose levels on glycolysis, sorbitol pathway activity, and the cytosolic redox state of NADH/NAD+ in isolated glomeruli. Blood-free glomeruli were isolated from kidneys of male, Sprague-Dawley rats using standard sieving techniques, then incubated for one hour at 37 degrees C, pH 7.4, pO2 approximately 500 torr, in Krebs bicarbonate/Hepes buffer containing 5 or 30 mM glucose. Elevated glucose levels increased glucose 6-phosphate, fructose 6-phosphate, total triose phosphates, lactate, the lactate/pyruvate ratio, sorbitol, and fructose, but did not affect sn-glycerol 3-phosphate, pyruvate, or myo-inositol levels. The more reduced glomerular cytosolic redox state (manifested by the tissue lactate/pyruvate ratio) induced by 30 mM glucose was completely abrogated by aldose reductase inhibitors added to the diet two to seven days prior to glomerular isolation. These observations, coupled with evidence linking glucose- and diabetes-induced glomerular dysfunction to increased sorbitol pathway metabolism, support the hypothesis that metabolic imbalances associated with a more reduced ratio of cytosolic NADH/NAD+ (resulting from increased glucose metabolism via the sorbitol pathway) play an important role in mediating glucose- and diabetes-induced glomerular dysfunction.


Effects of diabetes and insulin on expression of kallikrein and renin genes in the kidney.

We previously showed that renal prokallikrein synthesis is reduced in streptozotocin (STZ)-diabetic rats. Plasma renin activity is also reduced in diabetic rats. To investigate the molecular mechanisms underlying these changes, we examined the effects of diabetes and insulin treatment on renal kallikrein and renal renin mRNA levels and the activities of these enzymes. Rats made diabetic by STZ were either treated with 1.5 to 1.75 U PZI insulin daily to maintain moderate hyperglycemia (plasma glucose 200 to 300 mg/dl, D + I) or left untreated to produce severe hyperglycemia (plasma glucose greater than 400 mg/dl, D). Control (C) rats were also studied. After three weeks, renal kallikrein mRNA was reduced 50% in D rats. A proportional reduction in immunoreactive kallikrein was also observed (37.8 +/- 2.5 vs. 55.8 +/- 6.8 ng/mg protein, D vs. C, P less than 0.001). Kallikrein mRNA and immunoreactive kallikrein levels in D + I rats were not different from C rats. Renin mRNA level was also markedly reduced in D rats, compared to C rats. This was associated with reduced plasma renin concentration (4.5 +/- 0.2 vs. 10.5 +/- 1.6 ng Ang I/ml/hr, D vs. C, P less than 0.01). However, renal renin concentration was unchanged (0.84 +/- 0.17 vs. 0.84 +/- 1.3 micrograms Ang I/mg protein/hr, D vs. C). In D + I rats, renin mRNA level and plasma renin concentration were not different from C levels. However, renal renin concentration was increased (1.49 +/- 0.27 micrograms Ang I/mg protein/hr) compared to C rats (P less than 0.05). beta-actin mRNA levels were unchanged in either diabetic rat group.(ABSTRACT TRUNCATED AT 250 WORDS)


Renin and angiotensinogen gene expression in experimental diabetes mellitus.

The renin-angiotensin system may play a role in the initiation and progression of diabetic kidney disease. In this study, the local intrarenal renin-angiotensin system was examined in streptozotocin-treated rats maintained moderately hyperglycemic by daily low-dose insulin injection. Four weeks after induction of diabetes, plasma renin activity was significantly lower in the diabetic compared to a non-diabetic control group (diabetes: 2.30 +/- 0.30 vs. control: 6.93 +/- 1.36 ng Al/ml/hr; P less than 0.01). Renal tissue renin content (diabetes: 1.81 +/- 0.46 vs. control: 2.05 +/- 0.27 micrograms Al/mg protein/hr; P less than 0.05) and renal renin mRNA (diabetes: 2.32 +/- 0.16 vs. control: 1.89 +/- 0.12 pg/micrograms RNA; P = NS) were not different between diabetic and control rats. Renal and liver angiotensinogen mRNA were lower in the diabetic group. Glomerular renin mRNA was not different between the diabetic and sham group. The dissociation between systemic renin activity (a decrease), and in renal renin content or mRNA in the diabetic rats (no change), suggests a post-translational alteration in renin processing and/or renin secretion.


Octreotide administration in diabetic rats: effects on renal hypertrophy and urinary albumin excretion.

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.


Increased glomerular filtration rate as a predictor of diabetic nephropathy--an 8-year prospective study.

The objective was to study the natural history and the predictive value of glomerular filtration rate, albumin excretion rate, blood pressure, and hemoglobin A1c for diabetic nephropathy. A cohort of 75 type-1 diabetic adolescents with a diabetes duration of 8 years was studied. Thirty-one females, 33 males, mean age 16.9 +/- 0.3 (SEM) participated in the follow-up study. Glomerular filtration rate, albumin excretion rate, blood pressure, and hemoglobin A1c were measured every second year during 8 years to determine the predictive value of glomerular filtration rate for future nephropathy. Initial differences and patterns of changes in glomerular filtration rate, albumin excretion rate, and hemoglobin A1c were examined in patients who did (group 1) and did not (group 2) develop incipient or overt nephropathy. Five of 64 patients developed overt nephropathy. They had an initial glomerular filtration rate of greater than 125 ml/min/1.73 m2. Fifteen of 53 initially normoalbuminuric patients developed incipient and three of 53 overt nephropathy. Age, age at onset, diabetes duration, initial albumin excretion rate, initial blood pressure, and hemoglobin A1c were similar in groups 1 and 2. Glomerular filtration rate was initially higher in group 1 than in group 2 (P = 0.01). The positive predictive value for combined incipient and overt nephropathy of an initial glomerular filtration rate greater than 125 ml/min was 53%. The negative predictive value of glomerular filtration rate less than 125 ml/min was 95%. In initially normoalbuminuric patients multiple regression revealed initial glomerular filtration rate as the only significant independent predictor for nephropathy when also corrected for hemoglobin A1c (P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)


Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus.

Little information is available regarding renal hemodynamics in non-insulin dependent diabetics (NIDDMs), despite their numerical significance to renal support programs. Therefore, simultaneous determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) (expressed to 1.73 m2 surface area) was performed in 110 newly presenting normotensive NIDDMs [mean (SD) age: 52.5 (10.1) years] and compared with 32 normal subjects of similar age range [age: 52.2 (11.3) years]. Mean (SD) GFR, ERPF and filtration fraction (FF) for the NIDDMs were: 117 (22) ml/min (range: 74 to 178), 534 (123) ml/min and 22.4 (3.0)%, and for the normals: 95 (12) ml/min (range: 75 to 119), 472 (70) ml/min and 20.2 (2.2%), respectively. As a group, NIDDMs demonstrated significantly greater GFR (P less than 0.001), ERPF (P less than 0.005) and FF (P less than 0.001). GFR values above 140 ml/min were observed in 16% of the NIDDMs, while 45% had GFRs in excess of mean +/- 2 SD of the normals. NIDDMs demonstrated a positive relationship for GFR with ERPF (P less than 0.001) and an inverse association for both GFR and ERPF with age (P less than 0.001). Multivariable regression analysis revealed ERPF as the strongest explanatory variable for GFR in the NIDDMs (P less than 0.001), followed by age (P less than 0.01). Significant contributions to the regression analysis were not observed for body mass index, systolic or diastolic blood pressures, glycosylated hemoglobin nor fasting levels of plasma glucose, cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides. Urinary albumin excretion rates were not correlated with GFR, ERPF or FF. Microalbuminuria was detected in 7% of the NIDDMs in this study.(ABSTRACT TRUNCATED AT 250 WORDS)


Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study.

A cohort of 63 Type 1 insulin-dependent diabetic patients were first characterized for overnight urinary albumin excretion rate (AER) in 1967. In 1981, seven out of eight (87%) patients with initial AER greater than or equal to 30 less than or equal to 140 micrograms/min (microalbuminuria) developed clinical proteinuria compared to only 2 out of 55 (4%) patients with initial AER less than 30 micrograms/min. The same cohort of patients was reassessed in 1990 after a total follow-up period of 23 years. The aim was to investigate the role of microalbuminuria in the prediction of total/cardiovascular mortality and the development of renal failure, in addition to clinical proteinuria. The initially microalbuminuric patients had a significantly higher risk of developing not only clinical proteinuria (relative risk 9.3, 95% C.I. 1.36 to 3.10, P less than 0.05), but also of dying from a cardiovascular cause (relative risk 2.94, 95% C.I. 1.18 to 7.34, P less than 0.05). The rate of progression to renal failure was higher but not significantly so in the microalbuminuric (2 of 8) compared to the normoalbuminuric (4 of 53) group (relative risk 3.31, 95% C.I. 0.72 to 15.24, NS). In insulin-dependent diabetic patients microalbuminuria is a powerful predictor of clinically overt diabetic renal disease as well as cardiovascular mortality.


Ambulatory blood pressure in microalbuminuric type 1 diabetic patients.

Twenty-four-hour ambulatory blood pressure (AMBP) was performed in microalbuminuric (micro.) type 1 diabetic patients, with the aim of comparison with a matched group of normoalbuminuric patients (normo.) and healthy controls. Thirty-four patients without antihypertensive medication were investigated in each group. Urinary albumin excretion (UAE) for micro. was (geometric mean, tolerance factor microgram/min) 51.7 x/divided by 1.94, 5.1 x/divided by 1.88 for normo. and 5.2 x/divided by 1.75 for controls. Twenty-four-hour AMBP (mean systolic/diastolic mm Hg +/- SD) was significantly higher in micro. (131 +/- 10/78 +/- 7) than in normo. (122 +/- 8/73 +/- 6; P less than 0.001/P less than 0.01). No 24-hour AMBP difference between normo. and controls (120 +/- 9/71 +/- 7) was found. No difference in the night/day ratio of blood pressure was found between the diabetic groups. Coefficient of variation for day time systolic measurements did not show any intergroup difference. Systolic day time blood pressure for the pooled diabetic group correlated significantly with UAE (r = 0.45, P less than 0.001), whereas no significant correlation with auscultatory systolic values in the clinic was found (r = 0.21; P = 0.09). In conclusion, blood pressure in micro. as compared to normo. is not more labile but is elevated day and night without significant alteration of the diurnal rhythm. AMBP reflects the association between UAE and blood pressure more precisely than clinical measurements and may be preferable for identifying candidates for antihypertensive treatment.


Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport.

Diabetic nephropathy is more common in patients with a positive family history of hypertension and with elevated red blood cell sodium-lithium countertransport, a marker of risk for essential hypertension. To evaluate whether there is a relationship between this cation transport system and indicators of risk of renal and cardiovascular complications in diabetic patients before the development of clinical proteinuria, we studied 31 type 1 (insulin-dependent) diabetic patients with arterial hypertension, without clinical proteinuria and 12 normotensive normoalbuminuric diabetic patients. Sodium-lithium countertransport activity was significantly higher in hypertensive patients (0.43 +/- 0.03 mmol/l RBC x hr) than in normotensive patients (0.23 +/- 0.03; P less than 0.001). To better explore the nature of the association between this transport system and arterial hypertension, hypertensive patients were divided in two groups, with high (greater than 0.41 mmol/l RBC x hr) or normal (less than 0.41) sodium-lithium countertransport activity. The two groups of hypertensive diabetics were similar in age, sex, body mass index and blood pressure levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Is increased erythrocyte sodium-lithium countertransport a useful marker for diabetic nephropathy?

Genetic predisposition to essential hypertension has been proposed as a risk factor for the development of diabetic nephropathy in type 1 (insulin-dependent) diabetes mellitus. An increased sodium-lithium countertransport activity (NaLiCT) has been suggested as a genetic marker for essential hypertension. We therefore evaluated NaLiCT in diabetic patients with (N = 39) or without (N = 23) diabetic nephropathy (DNP), patients with non-diabetic renal diseases (N = 42) and in healthy controls (N = 24). The NaLiCT was elevated in both diabetic patient groups compared to healthy controls (median 244; range 134 to 390 mumol.liter cells-1.hr-1), but was not different in patients with DNP (median 314; range 162 to 676), without DNP (median 325; range 189 to 627) and patients with non-diabetic renal disease (median 300; range 142 to 655). The genetic predisposition to DNP is illustrated by the fact that diabetic sibs of probands with DNP showed a higher occurrence of DNP than diabetic sibs of patients without DNP. We analyzed whether familial DNP clustered with an increased NaLiCT. The NaLiCT in sibs concordant for the presence of DNP (N = 10; median 307; range 217 to 428 mumol.liter cells-1.hr-1) was not significantly different from that in sibs concordant for absence of DNP (N = 15; median 279; range 189 to 442). We conclude that erythrocyte sodium-lithium countertransport activity cannot be used as a marker to identify patients at risk for the development of diabetic nephropathy.


Prevalence of raised sodium-lithium countertransport activity in type 1 diabetic patients.

The prevalence of raised Na+/Li+ countertransport (CT) activity (greater than 0.41 mmol/liter RBC/hr) was assessed in 185 consecutive insulin-dependent diabetic patients attending an outpatient diabetic clinic. Normoalbuminuria was defined as an overnight albumin excretion rate (AER) of less than 20 micrograms/min (N = 121), microalbuminuria as AER between 20 and 150 micrograms/min (N = 35) and macroalbuminuria as AER greater than or equal to 150 micrograms/min (N = 29). The prevalence of elevated Na+/Li+CT (greater than 0.41 mmol/liter RBC/hr) was 21.5, 42.8 and 51.7% (P = 0.0005), in patients with normo-, micro- and macroalbuminuria, respectively. In the whole group, Na+/Li+CT was significantly related to mean blood pressure (MBP; rs = 0.37, P less than 0.001) and AER (rs = 0.38, P less than 0.001). In a multiple regression analysis the significant correlates of AER, as a continuous variable, or of proteinuria (micro + macroalbuminuria), as a categorical variable, were Na+/Li+CT, MBP, duration of diabetes and glycosylated hemoglobin (HbA1). The frequency of normoalbuminuric patients with high Na+/Li+CT activity fell with duration of diabetes. The risk of proteinuria was significantly greater in patients with raised Na+/Li+CT compared to those with Na+/Li+CT within the normal range (odds ratio 3.8, 95% CI, 1.9 and 7.8). A relative excess of patients with proteinuria (micro + macroalbuminuria) was found in the group with elevated Na+/Li+CT and HbA1 above the median value (8.05%) of the whole population (chi 2 = 9.7, P less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)


Antihypertensive therapy in a model combining spontaneous hypertension with diabetes.

We have compared the effects of the angiotensin converting enzyme inhibitor, perindopril, and a conventional antihypertensive regimen (triple therapy: hydralazine, reserpine and hydrochlorothiazide) on kidney function and albuminuria in hypertensive diabetic rats. Diabetes was induced with streptozotocin in spontaneously hypertensive (SHR) rats and they were randomized to receive no treatment, perindopril or triple therapy. Antihypertensive drugs were commenced at the time of induction of diabetes and continued for 16 weeks. Blood pressure reduction was equal in the groups treated with perindopril or triple therapy. All groups had similar severity of diabetes as determined by body weight, serum glucose and glycated hemoglobin levels. Whereas plasma renin activity rose in both the perindopril and triple therapy groups, it is likely that the effects on angiotensin II levels were opposite since perindopril but not triple therapy was associated with a significant reduction in plasma angiotensin converting enzyme activity. Diabetes was associated with an increase in glomerular filtration rate. At 12 weeks, glomerular filtration rate was higher in the perindopril treated group when compared to the triple therapy group, but neither group treated with antihypertensive therapy was different to untreated diabetic rats. Both drug regimens reduced albuminuria in the diabetic rats to a similar degree apparently independently of their effects on the renin-angiotensin system. Studies in diabetic subjects are warranted to evaluate different classes of antihypertensive drugs with respect to their effects on kidney function, proteinuria and glomerular morphology.


Angiotensin converting enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy. The Melbourne Diabetic Nephropathy Study Group.

Small increases in blood pressure are a feature of incipient diabetic nephropathy, and mean blood pressure often correlates with the degree of albuminuria in such patients. Antihypertensive therapy with angiotensin converting enzyme inhibitors (CEI) or calcium channel blockers (CCB) has been assessed in several studies to determine if either form of treatment modifies incipient diabetic nephropathy and its evolution to established nephropathy. The acute renal hemodynamic effects of CEI differ from those of CCB under certain circumstances. In incipient diabetic nephropathy, therapy with CEI but not CCB tends to reduce filtration fraction, especially in hyperfiltering patients. In hypertensive patients with incipient diabetic nephropathy, both treatments result in a decrease in albuminuria and the responses are mainly dependent on the lowering of systemic blood pressure. In normotensive patients with incipient diabetic nephropathy, a lowering of mean blood pressure with CEI or CCB is not found consistently while effects on albuminuria are difficult to interpret. Short- and long-term therapy with CEI lowers or stabilizes albuminuria. Short-term administration of CCB has at times been associated with increases in albuminuria, but a comparison of CEI and CCB over 12 months in the Melbourne Diabetic Nephropathy Study (MDNS) has shown that both drugs stabilize albuminuria with no significant differences in their effects. Serial analysis of urinary sodium excretion in the MDNS shows that the hypotensive response to CEI in incipient nephropathy is highly dependent on sodium intake, and that sodium intake may modulate albuminuria during both CEI and CCB therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term glycemic control and kidney function in insulin-dependent diabetes mellitus.

In this paper we examined the relationship between blood glucose control and initiation and progression of increased urinary albumin excretion. In this seven year Oslo study 45 insulin-dependent diabetes mellitus patients were initially randomized into three different modes of treatment: continuous subcutaneous insulin infusion (CSII), multiple injections, or two injections a day. After four years, the patients were free to choose their treatment, and therefore the data were analyzed according to mean HbA1 during seven years. The mean HbA1 was 11.2% (2.2) (SD) at start, and 9.5% (1.5) at seven years, which was a significant long-term improvement (P less than 0.001). Eight out of 10 patients with mean seven year HbA1 less than 8.5% improved their albumin excretion rate, and patients with mean HbA1 greater than 10% had an increased albumin excretion rate (from 26 mg/24 hr to 91 mg/24 hr, P less than 0.02). The glomerular filtration rate decreased slightly regardless of mean HbA1 level. Systolic blood pressure increased significantly regardless of mean HbA1. Diastolic blood pressure was unchanged in the patients with mean HbA1 less than 10%, but increased slightly (NS) in patients with HbA1 greater than 10%. We conclude that mean blood glucose as measured by glycosylated hemoglobin is a main determinant in the progression of urinary albumin excretion in insulin dependent diabetics, and near normoglycemia improves urinary albumin excretion.


Simultaneous pancreas-kidney transplant versus kidney transplant alone in diabetic patients.

The decision for simultaneous pancreas-kidney (SPK) versus kidney transplant alone (KTA) in diabetic patients with renal failure depends on the potential risks and benefits for each procedure. The purpose of this study was to compare the morbidity, mortality, and renal allograft survival in diabetic patients who underwent SPK versus KTA, and to discern the added risks associated with pancreas transplantation. Between 7/1/86 and 9/30/90, 69 primary cadaver SPK and 59 primary cadaver KTA were performed in type I diabetic patients with chronic renal failure. Antilymphocyte globulin or OKT3 was used for induction therapy, followed by standard triple therapy (prednisone, azathioprine, and cyclosporine). Patient and graft survivals were retrospectively analyzed. In addition, a detailed comparison of morbidity in those patients treated after 7/1/87 was performed (53 SPK, 49 KTA). For those less than 45 years of age (65 SPK, 42 KTA), there were no significant differences (P greater than 0.6) in the actuarial patient survival at one year (SPK 92%, KTA 95%), or two years (SPK 89%, KTA 92%), or actuarial renal allograft survival at one year (SPK 82%, KTA 83%) or two years (SPK 77%, KTA 83%). However, for those greater than 45 years old, actuarial renal allograft survival was significantly higher (P less than 0.03) in the KTA group. The mean serum creatinine levels were similar at one year (SPK 1.8, KTA 1.9 mg/d).(ABSTRACT TRUNCATED AT 250 WORDS)


Intrarenal distribution of clusterin following reduction of renal mass.

Clusterin is a multifunctional protein isolated from a number of tissues in several different species. In a variety of renal diseases, clusterin appears in the glomerulus and tubules in association with the membrane attack complex of complement. It is also transiently expressed after several forms of acute renal injury. In this study, we examined the expression and intrarenal distribution of clusterin following subtotal renal ablation. Male rats were subjected to either 1-1/3 nephrectomy (1-1/3 NX), uninephrectomy (UNX) or sham operation (SHAM). Two weeks after surgery, clusterin mRNA was elevated in the 1-1/3 NX group (1-1/3 NX: 1215 +/- 88; UNX: 208 +/- 11; SHAM: 207 +/- 19 OD units; P less than 0.001). Clusterin mRNA increased between 3 and 24 hours after 1-1/3 NX, plateaued, and remained elevated for at least seven weeks. The increased clusterin mRNA in 1-1/3 NX was localized to the tissue adjacent to the infarctive scar (scar 858 +/- 173 vs. non-scar 98 +/- 27 OD units; P less than 0.001). Clusterin protein followed a similar pattern of localization, being increased in most tubules and some peritubular capillaries in the peri-infarct zone. Only occasional tubules were positive for clusterin in the renal tissue distant from the scar or in the kidneys of sham operated rats. Co-localization of clusterin and C5b-9 was not detected. Evidence for apoptosis was found in the peri-infarct zone but not elsewhere in 1-1/3 NX kidney or in the normal kidney following sham operation. Infarction of 1/3 of the left kidney without contralateral nephrectomy, a maneuver which eliminates the compensatory growth, and uremia seen with 1-1/3 NX still resulted in increased clusterin mRNA in the infarcted left kidney compared to the intact right kidney (LK: 790 +/- 112 vs. RK: 128 +/- 25 OD units; P less than 0.001), although the amount of clusterin mRNA was less than that found following 1-1/3 NX. In conclusion, persistently increased clusterin mRNA and protein was seen in the peri-infarct zone following 1-1/3 NX. This increased expression of clusterin may be playing a role in the ischemia-related apoptosis present in the scar-adjacent tissue.


HIV infects glomerular endothelial and mesangial but not epithelial cells in vitro.

The infectivity of human immunodeficiency virus (HIV-1) in human glomerular cells was evaluated by exposing homogeneous cultures of human glomerular capillary endothelial, mesangial and epithelial cells to HIV in vitro. Infectivity and HIV expression was assessed by: 1) the measurement of p24 antigen production from culture supernatants; 2) the presence of p24 antigen intracellularly by immunofluorescence; 3) levels of P24 antigen production or syncytia formation following the cocultivation of glomerular cells exposed to HIV with normal human peripheral blood mononuclear cells or MT-2 lymphocytes; and 4) the presence of intracellular HIV DNA by polymerase chain reaction. The results indicate that HIV can infect and replicate in glomerular capillary endothelial cells and in a small percentage of mesangial cells, but not in human glomerular epithelial cells in vitro.


Improved left ventricular contractility with cool temperature hemodialysis.

Cool temperature dialysis (CTD) has been shown to sharply decrease the frequency of intradialytic hemodialysis hypotension, but the mechanism of this hemodynamic protection is unknown. Therefore, we performed two-dimensional echocardiographic studies of left ventricular contractility in six stable hemodialysis patients before and after hemodialysis at 37 degrees C (RTD) and 35 degrees C (CTD). Left ventricular function was assessed by plotting the rate-corrected velocity of circumferential fiber shortening (Vcfc) against end-systolic wall stress (sigma es) at four different levels of afterload. Linear regression was used to calculate Vcfc at a common afterload of 50 g/cm2. Changes in weight and dialysis parameters were similar following RTD and CTD. Mean arterial pressure and heart rate did not change significantly following RTD or CTD. The Vcfc - sigma es relation was shifted upward in each patient after CTD, indicating increased contractility as compared to RTD or pre-dialysis baseline. Pre-dialysis Vcfc at an afterload of 50 g/cm2 was similar during RTD and CTD (0.94 +/- 0.24 circ/sec vs. 0.92 +/- 0.22 circ/sec). Postdialysis Vcfc at an afterload of 50 g/cm2 was significantly higher for CTD than for RTD (1.13 +/- 0.29 circ/sec vs. 0.98 +/- 0.30 circ/sec, P = 0.0004). Thus, cool temperature dialysis increases left ventricular contractility in hemodialysis patients, which may be a potential mechanism whereby hemodynamic tolerance to the dialysis procedure is improved.


Renal hypertrophy in streptozotocin diabetic rats: role of proteolytic lysosomal enzymes.

Renal protein mass increases in diabetic renal hypertrophy. Accretion of protein may be the result of increased protein synthesis and/or decreased protein degradation. The lysosomal proteases, cathepsins B and L, are key enzymes in cellular protein catabolism. To evaluate the role of protein degradation in diabetic renal hypertrophy, the activities of cathepsins B and L were measured in microdissected proximal tubule segments and in kidney cortex homogenates. In rats four and ten days following induction of diabetes by streptozotocin, the kidney weight was increased and the cathepsin activities were reduced in proximal tubule segments. Treatment with insulin prevented both changes. The liver weight in diabetic rats was decreased and the activity of cathepsins B and L was increased, while the activity in kidney cortex was reduced. This excluded that diabetes per se may be accompanied by decreased cathepsin activities independent of organ hypertrophy. Renal hypertrophy as a cause rather than as the consequence of reduced cathepsin activities was excluded by the finding of unchanged cathepsin activities in proximal tubule segments from rats with compensatory renal hypertrophy four days and ten days following unilateral nephrectomy. Decreased activities of cathepsins B and L may reflect decreased intracellular protein degradation. Decreased protein breakdown in proximal tubules may contribute to diabetic renal hypertrophy. In agreement with this interpretation are the results from rats six months following induction of diabetes. Renal hypertrophy is complete at that time. No further accretion of protein occurs and the cathepsin activities in the proximal tubule were not different from controls.


Sphingomyelin and cholesterol modulate sodium coupled uptakes in proximal tubular cells.

Sphingomyelin (SM) and cholesterol are major lipid species of apical membranes in renal proximal tubular cells and confer to these membranes a low fluidity. Changes in membrane fluidity and/or lipidic composition were shown to affect the activity of cotransport systems of renal apical membranes. We evaluated the effect of decreasing membrane SM content on lipidic composition, membrane fluidity and sodium (Na)coupled uptakes in rabbit proximal tubular cells in primary culture. Sphingomyelinase (SMase) (30 to 250 mU/ml) decreased [3H]choline-labeled SM content, decreased cholesterol content, and increased cholesterol esterification. SMase did not modify membrane fluidity on isolated brush border membranes. SMase decreased Vmax of Na-dependent uptake of phosphate and alpha-methyl-D-glucoside, but not of alanine. SMase did not influence protein kinase C-induced inhibition of phosphate and glucose uptake. Increasing membrane cholesterol content with cholesterol-enriched liposomes subsequently to SMase action restored in part glucose uptake, but not phosphate uptake. In conclusion, SM degradation affected Na-phosphate and Na-glucose cotransports through changes in both SM and cholesterol contents of apical proximal membranes; these changes seemed to occur independently from changes in bulk membrane fluidity. These results suggest that SM and cholesterol have distinct and intricated roles in accessibility and/or activity of apical cotransport systems.


[Vision disorders in children with acquired severe brain damage].

27 children with severe brain injuries were examined by an ophthalmologist and had several paediatric examinations during an eight or ten weeks' course of rehabilitation. With highly reduced levels of consciousness they had hardly any cortical visual function but frequently had brainstem controlled reactions of eyelids, pupils and eyeballs. The development of these reactions was followed up and correlated to the recovering visual functions. Some of the palpebral reflexes seemed to be of prognostic significance to the reappearance of cortical visual functions.


[Corneal sensibility following epikeratophakia].

The postoperative rate of reinnervation following corneal surgery is widely considered to be a useful indicator of the healing process. This study reports the corneal sensitivity of 14 patients following epikeratophakia for different indications (myopia, aphakia and keratoconus) after time periods ranging from 7 to 104 weeks. All transplants were clear at the time of measurement. A newly developed aesthesiometer (using a low electric current for stimulation) was employed. Nine positions on the operated eye were chosen for the measurements, five locations of the non-operated fellow eye served as controls. On the operated eye the corneal sensitivity peripheral to the trephination were significantly reduced at the 9 and 12 o'clock positions as compared to the other eye. The 3 and 6 o'clock locations showed no significant difference. On the epikeratophakia lenticule the sensitivity was significantly reduced at all points, the center showing the largest difference (p less than 0.001). No correlation with age, sex or the indication for the procedure was observed. Although there was a trend of a positive correlation between the postoperative time period and the central corneal sensitivity, the follow-up was too short to reach significant levels. The nearly complete lack of corneal sensitivity, particularly in the center of the transplant is therefore well compatible with its long-time survival, even when the lenticule has been prepared with the cryolathe and lyophilized for transportation.


[Localization disorders in squint amblyopia: horizontal line bisection and relative vertical localization].

We used two different procedures for the evaluation of spatial localization errors in strabismic and anisometropic amblyopes, strabismic alternators and normal control subjects: partitioning of horizontal lines and vertical alignment. We found defective spatial localization in the amblyopic eyes of squinters with both procedures. However, in the horizontal partitioning experiment, the control subjects also showed asymmetries between the two hemifields. Thus, there is no good baseline under these conditions for the results of the amblyopic eyes of squinters. Our results show that vertical alignment is the more appropriate procedure to quantify defective spatial localization in strabismic amblyopes.


[The influence of some ophthalmologists of German origin on the development of American ophthalmology].

German-speaking immigrants came to America at the end of the seventeenth century from Central Europe, in the 19th century predominantly from Germany, in the 20th century from the Austro-Hungarian Monarchy. Herrmann Knapp (1839-1911), 1859 member of Eye Department in Heidelberg, 1867 immigration, 1879 foundation of American Archives of Ophthalmology, continued to be Editor together with his son Arnold until 1948. Julius Homberger (1839-1872), born in Frankfurt, 1861 immigration, foundation of American Journal of Ophthalmology (1862-1865). Favored specialisation in medicine, Secretary of Section of Surgery in the new American Medical Association 1864, expelled 1868. Adolf Alt (1851-1920), 1875 graduation at the University in Heidelberg, 1875 immigration, 1879 publication of his book in English and German "The Normal and Pathological Histology of the Human Eye". In 1883 second foundation of the American Journal of Ophthalmology, 1896 first president of Western Ophthalmological Society, 1882 member of American Ophthalmological Society. Karl Koller (1857-1944) from Bohemia, 1882 graduation in Vienna, 1884 discovery of anaesthetic effect of cocaine, 1888 immigration, 1889 chief of Mount Sinai Hospital, 1922 Howe-Medal, member of American Ophthalmological Society. Ludwig von Sallman (1892-1975), 1919 graduation in Vienna, 1939 immigration, head of Laboratories of Hermann Knapp Memorial Hospital, New York, 1956 chief of National Institute of Neurological Diseases and Blindness, Bethesda, 1947 member of American Ophthalmological Society, 1959 Howe-Medal. Bertha A. Klien-Montcreiff (1898-1978), 1925 graduation in Vienna, 1928 immigration to Chicago, 1959 Professor at the University of Chicago, clinicopathological correlation of ophthalmoscopic and histologic findings in oil paintings.(ABSTRACT TRUNCATED AT 250 WORDS)


[Christmas tree ornament cataract--an indication for disordered lipid metabolism?].

Cataract combined with Christmas tree decoration crystals in the lens is a relatively rare but very impressing cataract formation. The aim of this controlled study was to give an answer to the question, whether cholesterol level in blood is as important for local cholesterol accumulation in the lens as it is for the mechanism of arteriosclerosis. The blood levels of cholesterol, triglyceride, HDL and LDL were examined in 35 patients (average age 83.5 years; 26 women, 9 men). There was no significant difference between these parameters and those of a control group, which is similar in age and sex proportion. Therefore it is presumed, that these crystals of cholesterol are a result of lens metabolism and not of hypercholesterolemia.


[Taenia crassiceps in the anterior chamber of the human eye. A case report].

An otherwise healthy 15-year-old girl developed an iridocyclitis in her right eye. A contractable living parasite measuring two millimeter could be detected in the anterior chamber, the other parts of the eye remained uninvolved. The patient had close contact with the young dog of the family. By using a viscoelastic substance the parasite could be removed alive without any complications. The tapeworm was found to be too young for having developed the characteristic scolex. Western-immunoblotting gave indirect evidence for infection with Taenia crassiceps, a dog's tapeworm. During an observation period of two years no evidence for any other ocular or general Taenia crassiceps infestations could be found.


[Surgical treatment of hyperplastic persistent pupillary membrane].

Clinical findings of two patients with persisting pupillary membranes are described and therapy is discussed. The indication for excision of the pupillary membrane was constituted in one patient (age 6 weeks) by complete occlusion of the optic axis, in the second (age 4 months) by absence of any recordable fixation. In both cases the pupillary membrane could be separated from the anterior lens capsule without lens damage. No strabismus or lens opacification were detected postoperatively. Surgery was undertaken with the intention of avoiding primary lentectomy, since pupillary membranes can usually be separated easily from the anterior lens capsule with viscoelastic substances.


[Cysteamine eyedrops for treatment of corneal cysteine deposits in infantile cystinosis].

A two-year-old boy with nephropathic cystinosis was successfully treated with cysteamine eye drops. Using topical cysteamine 0.1% every two hours in the right eye we found a clearance of crystals from the cornea after 26 weeks. In the left eye, treated with topical cysteamine 0.5% the same result was reached after 12 weeks.


[Arthur von Hippel--100 years motorized trepanation].

The introduction of a new motorized trepan in ophthalmic surgery by Arthur v. Hippel in 1891 was a very important achievement. The corneal incision became much safer and the unintentional injury of the iris, the lens and the vitreous body could be avoided considerably. Following a statement on corneal grafting in the 2. part of the 19. century the development of the trepan, the technical data and the experiences and reactions of other ophthalmic surgeons are discussed. The innovations of Arthur v. Hippel were appreciated by the A. v. Gräfe-Prize of the Society of Ophthalmology/Heidelberg.


[The cycloplegic effect of atropine in comparison with the cyclopentolate-tropicamide-phenylephrine combination].

Atropine is thought to produce the most effective cycloplegia in early childhood. Cyclopentolate and Tropicamide are the best known short acting cycloplegic agents. Phenylephrine is an adrenergic agent and has also a cycloplegic effect. In this study we compared a combination of Cyclopentolate, Tropicamide and Phenylephrine with Atropine and observed no difference between them.


CAD-design, stress analysis and in vitro evaluation of three leaflet blood-pump valves.

The computer-supported development of valves for cardiac-assist devices or artificial hearts is shown in relation to plastic technology. A CAD-system is used for the design development, whereas the dimensioning of the critical and highly stressed membranes is examined by FEM-analyses. Economic manufacture is permitted by the combined thermoforming-dip moulding technique; the blood-side components are made from biocompatible polyurethane to minimize blood damage. The first long-term results in the test set-up are compared to the FEM results.


Blood analysis using black and white digital images.

Image processing offers a powerful tool for medical diagnosis by visual inspection. Our proposed system considers the blood analysis problem. The system processes black and white blood images obtained from a CCD camera through a microscope. Different categories of cells are recognized, counted and classified into white cells, red cells and blood petals. The white cells are further treated for their classification, according to the morphological characteristics of their nuclei. The final classification is printed in special format for the physician.


Bending moments in lower extremity bones for two standing postures.

The goal of this paper is to study how external gravitational forces stress the lower extremity bones and to ascertain and study how muscle activation compensates for the external load. For these purposes relatively accurate anatomical and biomechanical modelling is necessary. For a comparison of the calculated results to the naturally occurring muscular activity, seven-channel surface EMG activity was recorded. For simplicity a two-dimensional model was developed for the sagittal plane including 19 lower extremity muscles relevant to human standing and walking. In the calculation procedure of muscle forces an optimization procedure is also included. The results give rise to the expected assumption that muscle action is covered by two main requirements: first, to stabilize the joint actively (moment equilibrium) and, second, to compensate efficiently for bending moments produced by gravitational and external forces.


Non-invasive optical monitoring of cerebral blood oxygenation in the foetus and newborn: preliminary investigation.

Near infra-red spectroscopy was applied as a non-invasive and continuous technique for the in vivo monitoring of blood and tissue oxygenation in human neonates. Monitoring of cerebral blood oxygenation in the wavelength range 775-904 nm was carried out on preterm infants after inducing a transient mild hypoxic change; the measurements were performed either by the transmission or reflection (backscattering) mode of monitoring. The results of these investigations were used to assess the application of the technique to foetal monitoring. A series of foetal monitoring studies was performed to investigate the influence of maternal contractions on foetal cerebral blood oxygenation. Although only changes in haemoglobin concentration can be monitored at present, the results suggest that near infra-red monitoring could provide a non-invasive, real-time monitoring method in intensive neonatal and intrapartum care.


Periodic posture stimulation of the baroreceptors and the local vasomotor reflexes.

In a supine subject, lowering of the foot from heart level to 50 cm below is known to stimulate the local reflex response and the baroreceptor outflow. We lowered and raised the leg of a supine subject periodically, with the leg stationary between movements (square wave). The Traube-Hering-Mayer wave (THM congruent to 0.1 Hz) was captured by or locked on to the leg movement over a certain frequency range, this is usually called the entrainment range. Square wave periodic leg movement in this manner on 10 male subjects, mean age 22 years, demonstrated that the THM frequency can be entrained. The lower limit of the entrainment bandwidth is 0.0841 (SD 0.0030) Hz and the upper limit is 0.1176 (SD 0.0013) Hz. Further examination showed that this phenomenon is independent of the breathing input. Comparison with the Traube-Hering-Mayer entrainment techniques of breathing and periodic neck suction using the Eckberg collar which stimulates the baroreceptors showed similar results. This work supports the hypothesis that the local reflex response and the baroreceptor outflow entrain the THM frequency.


Patterns of relations between lower limb angle excursions during normal gait.

This paper deals with the analysis of data from a kinematic study of limb angle during normal gait. The first set of data deals with the variation of femur angle to the vertical, and of knee and ankle flexion-extension. The data are recorded on the System of Gestual Automatic 3D Analysis with a 50 Hz sampling rate. The second data set concerns morphological parameters. The data are obtained from 35 subjects. The time angle data are raw and are not to be related to a base position. The first stage of the angle analysis shows that a walking cycle can be characterized by 25 values. A factor analysis is then applied to these values for each angle in order to underscore the more informative instants. From this study, eight measurements are preserved. In the third stage, the same method is applied to both angles. It illustrates four ways to differentiate healthy subjects' walk. It also shows that the angles of femur and knee are strongly correlated and that there is a priori no clear relationship between the ankle and the two previous angles. The last stage is analysis of the morphological and angle parameters together. It brings to the fore the influence of sex and height for two groups of subjects.


Artificial vision approach to the understanding of heart motion.

To overcome the major drawbacks of conventional descriptive methods, we have developed a computer vision approach to aid understanding of heart motion from a series of sequential X-ray images. The computation is addressed of local descriptors of the heart pumping function from ventricular contours. Physical constraints are exploited such as spatial smoothness of the displacement field and shape correspondence between ventricular boundaries during the beat. A computational method is proposed for the estimation of the displacement field of the left ventricular boundary. Moreover, the spatial arrangement of the estimated motion field is rendered explicit so that it may be utilized in the medical clinic (or for high-level symbolic processing). This is achieved using a grouping criterion which allows the clustering of contiguous points of the left ventricular outline into curve segments which have homogeneous motion properties.


Effects of tibial rotations on patellar tracking and patello-femoral contact areas.

The object of this study is to determine the effect of tibial rotations on the three-dimensional patello-femoral motions and contact areas during a physiological loading condition, the knee-extension exercise. A commercially available device, the 3-SPACE digitizer and tracker system, was used to collect the motion data, utilizing cadaveric human lower limbs as well as the geometric measurements describing the articular surfaces at the patello-femoral joint. It was found that tibial rotations caused statistically significant differences, at the 0.05 level, in patellar tilt, patellar rotation and patellar medial-lateral shift. It was also found that while the magnitude of the total contact area at a given knee flexion angle did not change significantly with tibial rotations, medial and lateral components of the total contact areas were affected by tibial rotations. Medical femoral contact areas increased with internal tibial rotations at all flexion angles; lateral femoral contact areas increased with external tibial rotations at all flexion angles. This correlates well with the kinematic data since it was found that the patella shifted medially with internal tibial rotations at all flexion angles, and titled more medially near full-extension causing an increase in the medial contact areas and a decrease in the lateral contact areas.


Energetics of paraplegic walking.

A group of 35 paraplegic subjects using reciprocating walking orthoses have been examined in order to gain an insight into the potential functional benefits of using such devices. Measurements have been made of walking speeds and of the energy costs of ambulation using an established technique based on heart rate recordings. It was found that orthotically aided walking for paraplegics was slow and energy costly compared with both normal walking and wheelchair propulsion and, as it additionally requires the use of a walking aid in both hands, cannot be considered to confer the functional benefits frequently claimed for it. Nevertheless, the majority of the subjects studied liked their orthosis and did well in it, with many subjectively reporting improvements in mobility and independence.


Self-propelled weight-relieving walker for gait rehabilitation.

This paper describes a novel walking aid, the weight relieving walker (WRW), which partially relieves the body weight of an ambulating patient. The device incorporates a pneumatic weight relief mechanism, a restraint mechanism and a forward propulsion mechanism. Weight relief facilitates stance on an affected lower limb as well as the swing of that same limb. Restraint of the patient by the walker adds to trunk stability thereby facilitating walking movements of the lower extremities. A motorized, self-propelled walker neutralizes the effect of the walker's own weight on patient's locomotion. Additionally, it contributes to step symmetry. Data gathered from 26 patients with severe locomotion problems, point to a substantial contribution of the device to ambulation.


Finger tremor and the central nervous system.

It is well known that normal physiological tremor of the fingers and alpha rhythm in the EEG, may share a common frequency band in the region of 10 Hz; that these two characteristics may be in some way related as a function of their frequencies, is a hypothesis which needs to be tested, as one element in establishing the physiology of physiological tremor. Bilateral occipital EEGs and simultaneous measurements of acceleration from the terminal phalanx of the middle finger of both hands were recorded from eight subjects. The data were analysed to produce power spectral densities and coherence functions, the latter being used to reveal the presence or absence of frequency elements common to both signals. No evidence was found that would support a hypothesis that the two characteristics were in any way frequency related, from which it can be inferred that the tremor is not under central control. In addition, tremor of the right and left hands does not show a synchronous relationship.


Ventricular assist devices for postcardiotomy cardiogenic shock. A combined registry experience.

Data submitted voluntarily to the combined registry since its inception in 1985 to December 31, 1990, on the use of ventricular assist devices for postcardiotomy cardiogenic shock in 965 patients were analyzed. Approximately 45% of patients were weaned from temporary circulatory assistance and 24.6% reached hospital discharge regardless of the original operation. In 90% of patients who were discharged from the hospital, circulatory support was able to be discontinued by 1 week. Rates of weaning and discharge were statistically different and favored those patients requiring univentricular support only. Results were equal whether nonpulsatile centrifugal or pulsatile pneumatic devices were used for support. Although complications were frequent and multiple during assist pumping, patient variables including age greater than 70 years rather than direct complications caused by circulatory support were likely to affect overall outcome. In patients achieving hospital discharge, 2-year actuarial survival was 82% with 86% of patients being in New York Heart Association functional class I or II. In rare instances of device dependency in 43 patients (4.5%) with no contraindications to transplantation, 32 (74.4%) underwent bridge to cardiac transplant and 20 (62.5%) were discharged. This multi-institutional experience would continue to support the use of ventricular assist devices in postcardiotomy cardiogenic shock.


Experience with the Sarns centrifugal pump in postcardiotomy ventricular failure.

The reported clinical use of the Sarns centrifugal pump (Sarns, Inc./3M, Ann Arbor, Mich.) as a cardiac assist device for postcardiotomy ventricular failure is limited. During a 25-month period ending November 1988, we used 40 Sarns centrifugal pumps as univentricular or biventricular cardiac assist devices in 27 patients who could not be weaned from cardiopulmonary bypass despite maximal pharmacologic and intraaortic balloon support. Eighteen men and nine women with a mean age of 60.4 years (28 to 83) required assistance. Left ventricular assist alone was used in 12 patients, right ventricular assist in 2, and biventricular assist in 13. The duration of assist ranged from 2 to 434 hours (median 45). Centrifugal assist was successful in weaning 100% of the patients. Ten of 27 patients (37%) improved hemodynamically, allowing removal of the device(s), and 5 of 27 (18.5%) survived hospitalization. Survival of patients requiring left ventricular assist only was 33.3% (4/12). Complications were common and included renal failure, hemorrhage, coagulopathy, ventricular arrhythmias, sepsis, cerebrovascular accident, and wound infection. During 3560 centrifugal pump hours, no pump thrombosis was observed. The Sarns centrifugal pump is an effective assist device when used to salvage patients who otherwise cannot be weaned from cardiopulmonary bypass. Statistical analysis of preoperative patient characteristics, operative risk factors, and postoperative complications failed to predict which patients would be weaned from cardiac assist or which would survive.


Mechanical assistance of the left ventricle: acute effect on cardiac performance and coronary flow of different perfusion patterns.

Mechanical circulatory assistance by ventricular assist devices provides an opportunity to influence the aortic pressure pattern, which may affect ventricular loading and coronary perfusion. The effect of synchronous, pulsatile coronary perfusion of an assist device-supported left ventricle has not been studied. To analyze the effect of different perfusion patterns on left ventricular performance and on coronary flow, independent of pressure and volume loading, we used three different modes of aortic perfusion in an isometric, contracting, isolated canine heart model. The effect of nonpulsatile, counter-pulsatile, and copulsatile coronary perfusion was analyzed in four subgroups to simulate different, clinically relevant situations (using two different ventricular end-diastolic volumes [normal and high] and two mean perfusion pressures [normal and critically low]). Our experiments demonstrated that total coronary flow is optimized by making the perfusion pressure pulsatile and by synchronously timing the pump systole with ventricular diastole (counterpulsation). Under identical conditions of preload and mean perfusion pressure, coronary flow and left ventricular contractility were decreased during non-pulsatile and copulsatile aortic perfusion when compared with counterpulsatile flow. There were no significant differences between the nonpulsatile and copulsatile modes. We conclude from these data that a nonejecting, but contracting, left ventricle will have improved systolic function and coronary blood flow if the coronary perfusion pressure is synchronized in a counterpulsatile manner. This is a significant implication for mechanical left ventricular assist devices when used to promote myocardial recovery.


Right heart function during prosthetic left ventricular assistance in a porcine model of congestive heart failure.

A left ventricular assist device was used to produce a 90% reduction in peak systolic left ventricular pressure in pigs with congestive heart failure, and the resultant effects on right ventricular function were determined. Initially, eight farm pigs underwent rapid ventricular pacing at 230 beats/min for 7 days to produce congestive heart failure. When compared with an independent series of normal pigs, cardiac output in the paced animals was 33.3% less (2.2 +/- 0.2 versus 3.3 +/- 0.5 L/min; p less than 0.05), left ventricular end-diastolic pressure was elevated (13.8 +/- 3.5 versus 6.6 +/- 1.8 mm Hg; p less than 0.05), and the slope of the right ventricular global stroke work curve was significantly depressed (0.004 +/- 0.001 versus 0.033 +/- 0.003 joules/mm Hg; p less than 0.05). Next, the left ventricular assist device was connected between left ventricular apex and ascending aorta and left ventricular pressure was reduced from 92.0 +/- 3.8 to 10.5 +/- 2.2 mm Hg, while systemic arterial pressure was maintained constant. This led to a further impairment in cardiac output (-14%), mean arterial pressure (-15%), and the slope of the right ventricular global stroke work curve (-50%). Under each condition, right ventricular preload recruitable stroke work and end-systolic pressure-dimension relationships were studied in three different regions on the right ventricle during both steady-state and transient inferior vena caval occlusion. In the right ventricular septal-free wall dimension, left ventricular pressure unloading resulted in a 47.5% +/- 5.4% (p less than 0.05) reduction in the slope and 20.1% +/- 4.8% (p less than 0.05) increase in the dimension intercept of the preload recruitable stroke work relationship. There was also a 44.6% +/- 4.8% (p less than 0.05) reduction in the slope and 15.6% +/- 2.8% (p less than 0.05) increase in the dimension intercept of the end-systolic pressure-dimension relation. These slope changes plus reductions in cardiac output and in global stroke work, which are indicative of impaired right ventricular function during left ventricular pressure unloading in the congestive heart failure pigs, are not seen in normal hearts, whereas the intercept changes associated with leftward septal shift are present in both. These results suggest that anatomic ventricular interactions have a more significant role in heart failure than in the normal heart in determining overall right ventricular function during left ventricular assist device support.


Venoarterial extracorporeal membrane oxygenation--how safe is it? Evaluation with a new experimental model.

This study was undertaken to find out if about 25% right cardiac output is sufficient for preservation of lung function during prolonged periods of venoarterial extracorporeal membrane oxygenation. Six healthy pigs weighing 57 kg were subjected to 18-hour venoarterial extracorporeal membrane oxygenation. During this period 1200 ml/min venous blood was delivered to the lungs through the pulmonary artery with the help of a separate roller pump and with use of the animal's own right ventricle to generate the pulse. Animals were observed for 6 hours after weaning from the venoarterial extracorporeal membrane oxygenation. At the sixth hour after extracorporeal membrane oxygenation, arterial oxygen tension, venous oxygen tension, lung compliance, and cardiac output had decreased significantly. Pulmonary vascular resistance and pulmonary clearance of technetium 99m-diethylenetriamine pentaacetic acid increased significantly also. The systemic arterial and venous carbon dioxide tensions, pH, and the base excess remained unchanged, as did the blood pressure and the systemic vascular resistance. Histopathology of the lung specimens revealed focal alveolar wall thickening and alveolar capillary congestion. The major portion of the pulmonary parenchyma looked normal. Alterations in pulmonary parameters cited were, to a major extent, explained on the basis of the experimental protocol followed and were believed to be reversible. This study suggests that about 25% of the systemic cardiac output should be diverted into the pulmonary artery for prevention of irreversible physiologic and histopathologic changes in the lungs during 18-hour normothermic venoarterial extracorporeal membrane oxygenation in healthy juvenile pigs.