Reconstruction of the anterior cruciate ligament in patients over 50 years.

The records of patients aged 50 years or over who underwent primary reconstruction of the anterior cruciate ligament between 1990 and 2002 were reviewed. There were 35 knees in 34 patients that met the inclusion criteria. The mean age of the patients was 57 years (50 to 66) and the mean clinical follow-up was for 72 months (25 to 173). A total of 23 knees were reconstructed with patellar tendon allograft, and 12 with patellar tendon autograft. The mean pre-operative knee extension was 1 degrees (-5 degrees to 10 degrees) and flexion was 129 degrees (125 degrees to 150 degrees) and at follow-up these values were 0 degrees (-5 degrees to 5 degrees) and 135 degrees (120 degrees to 150 degrees), respectively. Pre-operatively there were 31 knees (89%) with a Lachman grade 2+ or 3+. Post-operatively, 33 knees (94%) were Lachman grade 0 or 1+. The mean pre- and post-operative International Knee Documentation Committee scores were 39 (23 to 72) and 90 (33 to 100) respectively. The mean pre- and post-operative Lysholm scores were 50 (18 to 68) and 92 (28 to 100) respectively and the mean University of California Los Angeles activity scores were 8.5 before injury (4 to 10), 4.3 (3 to 6) after injury and 8.3 (4 to 10) post-operatively. There were three graft failures (8.6%) requiring revision. We conclude that reconstruction of the anterior cruciate ligament in carefully-selected patients aged 50 years or over can achieve similar results to those in younger patients, with no increased risk of complications.

Red blood cell sorbitol lowering effects and tolerance of single doses of AL 1576 (HOE 843) in diabetic patients.

The safety and biochemical effects of AL 1576 (HOE 483), a recently developed aldose reductase inhibitor, were evaluated. In a double-blind, placebo-controlled, clinical trial, AL 1576 (HOE 483) was administered to diabetic patients for the first time. Four single, orally administered dose levels were tested, (2, 5, 10, and 20 mg). No clinically important adverse effects were seen in any of the patients. AL 1576 (HOE 483) suppressed red blood cell (RBC) sorbitol concentrations in a dose-related fashion. Also found were statistically significant inverse correlations between the plasma drug concentration and both RBC sorbitol concentrations as well as RBC sorbitol/serum glucose ratios. In single doses up to 20 mg, AL 1576 (HOE 483) is well tolerated and decreases RBC sorbitol, a biochemical marker of pharmacologic activity, in diabetic patients.

High-performance liquid chromatographic assay of the aldose reductase inhibitor spiro-(2-fluoro-9H-fluorene-9,4'-imidazolidine)-2',5'-dione (AL01567) in plasma and urine and its pharmacokinetics in humans.

Two selective high-performance liquid chromatographic (HPLC) methods have been developed for the quantitative determination of spiro-(2-fluoro-9H-fluorene-9,4'-imidazolidine)-2',5'-dione (AL01567; 1) in plasma and urine, with an assay sensitivity of 0.25 micrograms/mL for plasma and 0.13 micrograms/mL for urine. The plasma assay procedure involved precipitation of proteins with acetonitrile followed by dilution with water. The diluted supernatant was analyzed on an ODS column eluting with acetonitrile:0.5% phosphoric acid (30:70) adjusted to pH 7.2 with concentrated ammonium hydroxide. The urine assay procedure involved extraction of 1 with 10% n-butanol in hexane, followed by back extraction with 0.05 M sodium hydroxide. The basic extract was neutralized and analyzed on a phenyl column eluting with acetonitrile:10 mM potassium phosphate (30:70; monobasic, pH 5.6). The pharmacokinetics of 1 was investigated in humans following single and multiple oral doses. The elimination half-life from 12 normal subjects following single 100-400-mg oral doses was independent of dose, and the overall mean half-life was 66 +/- 9 h. The overall mean oral clearance (assuming a bioavailability of 100%) was 11 +/- 3 mL/min, and the mean apparent volume of distribution was 59 +/- 13 L. The mean urinary recovery of intact drug during the first 24 h after dosing was 1.2 +/- 0.4% of the administered dose. During once daily 100-mg oral dosing of 1 to five subjects for 21 d, plasma concentrations of 1 reached apparent steady-state by 7 d.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term follow-up of lens changes with Scheimpflug photography in diabetics.

This study was designed to document and quantify changes in lens clarity over 24 months in a group of diabetic patients. One hundred thirty-four type I and type II diabetics of 3 months' to 45 years' duration with an average age of 53.5 +/- 7 years volunteered to participate in this prospective study. Patients were evaluated upon entry and at 6-month intervals. Scheimpflug lens photographs (Topcon SL45) were taken at each visit. All photographs were evaluated by densitometry which allowed quantification of the light scattering in the various lens layers. A significant and progressive (4-7% every 6 months) increase in light scattering was observed in the lens anterior superficial lens cortex over 24 months. The rate of change in lens clarity was similar in all patients regardless of the clinically observable lens change type (nuclear, cortical, posterior subcapsular, or mixed). Patients who were younger at enrollment, having diabetes of shorter duration and higher glycosylated hemoglobin values (a measure of long-term glucose control), were identified to be at greater risk of having increased densitometry values in the anterior superficial lens cortex. Only a few patients had significant changes in visual acuity during 24 months, and the correlation of superficial cortical lens clarity changes to clinical cataract formation and visual impairment remains to be established.

Evaluation of cataract-related risk factors using detailed classification systems and multivariate statistical methods.

The well-known different morphological features observed in so-called senile cataract are probably symptoms of various pathogenetic mechanisms in the lens. In order to identify a relationship between type of cataract and special risk factors, a cataract classification system using Scheimpflug photography has been developed. Data of 288 cataract patients (case histories and blood chemistries) have been grouped according to differences in cataract morphology. The multivariate analyses showed the following five variables to be important and to contribute independently to the differentiation of cataract types: cholelithiasis, allergy, heart insufficiency, pneumonia, and age. A case-control study without consideration of cataract morphology showed the following variables to be important and to associate independently with the risk of developing cataracts: age, allergy, diabetes, hypotension, hypertension, use of analgesics, and coronary disease.

Hypothalamic lesions in the weanling rat alter pancreatic response to glucose.

Circulating levels of insulin and glucagon were monitored daily in weanling rats bearing bilateral radiofrequency lesions of the hypothalamic region comprising the ventral pole of the dorsomedial nucleus and at least one third of the dorsal pole of the ventromedial nucleus (V-DMH). Plasma insulin levels in the animals with lesions were significantly elevated by the eighth post-lesion day while plasma glucagon levels were significantly reduced by the 13th day. An intravenous glucose bolus administered to conscious unrestrained animals with lesions had no significant effect on circulating insulin levels but resulted in a dramatic increase in circulating glucagon levels. The IV glucose injections had no significant effect on circulating glucagon levels in the sham-lesioned and unoperated controls while the plasma insulin levels in both control groups were significantly elevated. After a glucose challenge in vitro (300 mg%), insulin release by islets from the lesioned animals showed only a slight increase whereas glucagon release was paradoxically increased. These results provide evidence for an abnormal glucose-sensing function of the pancreatic islet after hypothalamic lesions.

Effect of 2-deoxy-D-glucose on plasma somatostatin levels in conscious dogs.

The effects of 2-deoxy-D-glucose (2-DG) on plasma levels of somatostatin-like immunoreactivity (SLI) were examined in conscious normal dogs. After an iv infusion of 2-DG (400 mg/kg . h for 15 min), plasma SLI rose significantly from a mean baseline of 130 +/- 5 pg/ml (mean +/- SEM) to a mean peak of 204 +/- 25 pg/ml (P less than 0.005) at 25 min. Plasma insulin and glucagon also increased significantly. Atropine (200 microgram/kg . h for 35 min, iv) and hexamethonium (5 mg/kg, iv) markedly suppressed the SLI response to 2-DG, suggesting that it might be mediated, at least in part, by the autonomic nervous system. In contrast, the plasma insulin and plasma glucagon responses to this glucose analog were only slightly affected by atropine or hexamethonium pretreatment. Carbachol (0.2 mg, sc) caused a mean maximal increase in SLI of 43 +/- 14% (P less than 0.005) and atropine (200 micrograms/kg . h, iv) caused a mean maximal decrease of 25 +/- 2% (P less than 0.001) from the respective baseline levels. Plasma insulin and glucagon rose promptly after carbachol and were unchanged by atropine. To assess th contribution of 2-DG-stimulated gastric acid secretion in the 2-DG-induced SLI rise 2-DG was infused during the infusion of the H2-receptor antagonist cimetidine (3.0 mg/kg . h). Plasma SLI, nevertheless, increased significantly from a mean baseline of 112 +/- 6 pg/ml to a mean peak of 158 +/- 19 pg/ml (P less than 0.005) at 20 min, although the magnitude of the response was substantially reduced (P = NS). These observations suggest that in the conscious dog, 2-DG stimulates SLI secretion in part via cholinergic mechanism.

Evidence for a role of free fatty acids in the regulation of somatostatin secretion in normal and alloxan diabetic dogs.

To investigate the effect of acute elevation of plasma free fatty acids (FFA) on the secretion of splanchnic somatostatin-like immunoreactivity (SLI), the peripheral venous, pancreatic, and gastric venous effluent levels of SLI were measured in normal and chronic alloxan diabetic dogs before and after the infusion of a fat emulsion supplemented with heparin. In normal conscious dogs heparin injected during the infusion of a fat emulsion elevated FFA levels from a mean (+/-SE) base-line level of 0.7+/-0.1 meq/liter to a peak value of 1.5+/-0.1 meq/liter (P < 0.001) and plasma SLI rose from a mean (+/-SE) base-line value of 145+/-7 pg/ml to a peak of 253+/-44 pg/ml (P < 0.05). Neither the infusion of glycerol, of fat emulsion without heparin, of heparin alone nor of saline itself had an effect on either the plasma level of FFA or SLI. In another group of anesthetized dogs with surgically implanted catheters the administration of fat emulsion plus heparin was accompanied by more than a two-fold rise in the concentration of SLI in the venous effluent of the pancreas and of the gastric fundus and antrum in association with an elevation of FFA levels. In a group of conscious diabetic dogs fat emulsion plus heparin raised FFA from a mean base-line level of 1.2+/-0.2 to 1.6+/-0.3 meq/liter (P < 0.05) and SLI rose from a mean base-line level of 185+/-9 pg/ml to a peak value of 310+/-44 pg/ml (P < 0.01). Although SLI levels were significantly greater than in normal dogs at several time points after the rise in FFA, the magnitude of the increment in diabetic dogs did not differ from normal. These results demonstrate that a rise in FFA levels is a potent stimulus for SLI secretion from the pancreas and stomach and raise the possibility that FFA is an important physiological regulator of SLI secretion.

Glucagon-like polypeptides in canine brain.

Glucagon-like material has been detected by radioimmunoassay in several areas of the canine brain. High concentrations of glucagon-like immunoreactivity (GLI), measured with antibodies directed against the N-terminal region of glucagon, have been found in the hypothalamus, amygdala, and mesencephalon, but a high concentration of immunoreactive glucagon (IRG), measured with antibodies directed against the C-terminal region of glucagon, has been found only in the hypothalamus. The predominant molecular forms of GLI isolated from brain extracts by affinity chromatography are the same as those isolated from gut extracts. The predominant form of IRG in brain extracts is of the same (approximate) molecular weight as pancreatic glucagon.

Somatostatin analogs inhibit somatostatin release.

To determine if, like insulin, somatostatin inhibits its own secretion from the pancreas, nonimmunoreactive analogs of somatostatin were perfused in an isolated dog pancreaticoduodenal preparation using a nonrecirculating system. [D-Trp8-D-Cys14]somatostatin, at a concentration of 200 ng/ml, blocked the response of somatostatin-like immunoreactivity (SLI) to cholecystokinin and arginine. When perfusion of the analog was discontinued, SLI release increased. At a concentration of 0.1 ng/ml, des Asn5-[D-Trp8]somatostatin lowered SLI levels significantly without significantly reducing glucagon levels. At a concentration of 1 ng/ml, des Asn5-[D-Trp8]somatostatin significantly inhibited SLI as well as insulin and glucagon release. Perfusion of glucagon at a concentration of 10 ng/ml failed to overcome the blockade of SLI and insulin release caused by 50 ng/ml des Asn5-[D-Trp8]somatostatin. The results are compatible with a direct inhibitory effect of somatostatin analogs upon SLI release and raise the possibility of a self-inhibiting action of the native hormone.

The role of glucagon deficiency in the Houssay phenomenon of dogs.

Plasma glucose, immunoreactive glucagon (IRG), and insulin were measured in hypophysectomized dogs receiving cortisol and thyroid replacement therapy. 4 wk after hypophysectomy mean fasting plasma glucose levels had declined from 90+/-2 mg/100 ml to 64+/-2; fasting and arginine-stimulated insulin and IRG levels were, respectively, approximately 50% lower and unchanged. 12 wk or more after hypophysectomy, despite lower plasma glucose levels, fasting and arginine-stimulated IRG levels were significantly below control dogs. Hypophysectomized and shamhypophysectomized dogs were subjected to total pancreatectomy. Postoperatively, in the sham-hypophysectomized, depancreatized dogs fasting glucose levels ranged from 300-500 mg/100 ml on 8-10 U/day of insulin; IRG levels averaged 215+/-29 pg/ml. The hypophysectomized, depancreatized dogs required 0-4 U/day and fasting glucose levels under 100 mg/100 ml were not uncommon, even without insulin; fasting IRG levels averaged 63+/-4 pg/ml (P < 0.001). During arginine infusion in sham-hypophysectomized, depancreatized dogs, IRG levels rose from 215+/-60 pg/ml to a peak of 404+/-112 pg/ml; in hypophysectomized, depancreatized dogs, the base line IRG averaged 44+/-8 and the peak 110+/-25 pg/ml (P < 0.05). IRG levels in the venous effluent of the gastric fundus, the major source of nonpancreatic glucagon, reached a peak of 4,898+/-959 pg/ml in the sham-hypophysectomized, depancreatized group during arginine infusion and only 219+/-128 pg/ml in the hypophysectomized, depancreatized group. In three hypophysectomized, depancreatized dogs, a replacement infusion with glucagon for 10 h promptly increased hyperglycemia by 80-180 mg/100 ml and worsened glycosuria, evidence of a hepatic response to glucagon replacement. It is concluded that hypophysectomy somehow decreased both the hypersecretion of gastric IRG and the severe hyperglycemia that otherwise follows pancreatectomy. The hypophysectomized, depancreatized animal, therefore, has combined insulin and glucagon deficiency, and the latter may contribute to reduced severity of its hyperglycemia.

The effects of gastrin, gastric inhibitory polypeptide, secretin, and the octapeptide of cholecystokinin upon immunoreactive somatostatin release by the perfused canine pancreas.

The effects of gastrin, gastric inhibitory polypeptide, secretin, and the octapeptide of pancreozymin-cholecystokinin on immunoreactive somatostatin release were studied in the isolated perfused dog pancreas. Gastrin at a concentration of 65 ng/ml and the octapeptide of pancreozymin-cholecystokinin at a concentration of 25 ng/ml produced a prompt, but transient statistically significant, twofold rise in mean somatostatin concentration. Secretion at a concentration of 0.3 U/ml and gastric inhibitory polypeptide concentration of 58 ng/ml produced a prompt two- to threefold rise in mean somatostatin release, which persisted throughout the perfusion period. With all four polypeptides the pattern of the somatostatin response resembled that of insulin. It appears that pancreatic somatostatin release is stimulated by gastrointestinal hormones that influence the secretion of insulin and glucagon.

Release of immunoreactive somatostatin from the pancreas in response to glucose, amino acids, pancreozymin-cholecystokinin, and tolbutamide.

The effects of glucose, amino acids, pancreozymin-cholecystokinin, and tolbutamide upon the release of immunoreactive somatostatin (IRS) from the isolated perfused pancreas were studied. In seven experiments in which glucose was perfused either at a concentration of 100 or 350 mg/dl or at 25 mg/dl, IRS levels were significantly greater at the higher glucose concentrations. In three dose-response experiments in which the perfusing glucose concentration was increased at 30-min intervals from an initial concentration of 25 mg/dl to a final concentration of 300 mg/dl, progressive increases in IRS release were noted at glucose concentrations of 100 mg/dl and above. Perfusion of a 20 mM mixture of 10 amino acids also elicited a prompt and significant biphasic IRS rise in each of six experiments. In five experiments, 20 mM leucine evoked a similar response in mean IRS. Perfusion with 0.075 Ivy U/ml of pancreozymin-cholecystokinin, with or without the presence of a 1 mM 10-amino acid mixture, elicited a prompt rise in IRS with a pattern resembling that of insulin in a total of six experiments. Tolbutamide (0.75 mg/min) also stimulated IRS release in five of six challenges. The IRS responses to nutrients and to pancreozymin and their similarity to the insulin responses raise the possibility that, like insulin, pancreatic somatostatin may have an endocrine role related to nutrient homeostasis.

Effects of hypothalamic factors on insulin and glucagon release from the islets of Langerhans.

Isolated pancreatic islets were used to determine whether substances of hypothalamic origin could directly influence the release of insulin and glucagon. Media in which various regions of the brain had been incubated were tested in the islet system, as were the synthetic peptides neurotensin and substance P, and the catecholamines, dopamine and norepinephrine. Substance(s) released from the ventromedial hypothalamic (VMH) segments in vitro inhibited insulin release and stimulated glucagon release from the islets. Incubates of ventrolateral hypothalamic (VLH) or cortex tissue failed to alter insulin or glucagon levels. The VMH medium retained these activities even after oxidation with K3Fe (CN)6, whereas the ability of the catecholamines to inhibit insulin release and stimulate glucagon release was eliminated by this treatment. Neurotensin and substance P (0.1 and 1.0 nmol/ml) inhibited insulin release while glucagon release was increased; however, radioimmunoassay indicated that these peptides were virtually absent from the VMH incubate. These results show that incubates of VMH contain substances which can inhibit insulin and stimulate glucagon release in vitro. They may influence the endocrine pancreas by way of the peripheral circulation although the possibility of their occurrence in or near the pancreas itself has not been excluded.