Age-related asymmetry on a cued-listening task.

We report results on a cued-listening task designed to simulate the listening problems commonly described by individuals with sensorineural hearing loss, especially those experienced by elderly persons. Against a background of multitalker babble, the subject detected targets embedded in continuous discourse. Noncoherent segments of this discourse were presented simultaneously from loudspeakers on the right and left sides. A signal light cued the side to be monitored during a listening trial. The overall difficulty of the task was manipulated by variation of the message to competition intensity ratio. A sequence of listening trials, half-cued to the right side, half cued to the left side, was executed at each of four message to competition intensity ratios. Nineteen young adults with normal hearing and 28 elderly persons with presbyacusic hearing loss were evaluated. All subjects, young and elderly, were able to complete the cued-listening task successfully. Results showed a small but significant right-side advantage in the young group and a substantial right-side advantage in the elderly group. The application of the testing technique to the evaluation of hearing aid performance is illustrated in two elderly persons.


Central auditory processing disorders in the elderly: the effects of pure tone average and maximum word recognition.

We previously examined central auditory processing disorders and the effect of age in 1026 64- to 93-yr-olds. Here, we correlated three indices of central auditory processing disorders with age, pure tone averages (PTA) and maximum word recognition scores. With one exception, correlations of indices with PTA equaled or exceeded those with age. With one exception, correlations with word recognition scores were insignificant or smaller than those with age. Although statistically significant, the magnitudes of most effects were small (0.003 less than r2 less than 0.146). However, PTA accounted for approximately 30% of the variability in corrected Staggered Spondaic Word test error scores.


Comparison of continuous and pulsed stimuli in contralateral acoustic reflex threshold measurements.

Continuous pure-tone stimuli are traditionally used for contralateral acoustic reflex threshold (ART) testing. The GSI-33 middle ear analyzer provides an option of pulsed stimuli for contralateral ART testing. This study compared ARTs for the steady and the pulsed stimuli for 100 ears. Lower ARTs were consistently obtained with the continuous rather than the pulsed stimulus for more than 90% of the thresholds.


Addendum to "transfer functions and correction factors used in hearing aid evaluation and research".

In an earlier publication, various transformations used in hearing aid research and its application were summarized. As a result of continued interest and requests, additional transfer functions are provided in this addendum.


Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: causes, consequences, and prevention.

Diabetic nephropathy is caused primarily by advanced glomerulopathy, the renal expression of diabetic microangiopathy. With stereological methods a quantitative description of the structural changes is achieved. The glomerulopathy is characterized by an increase in basement membrane material: thickening of the capillary wall and an increase in mesangial volume relative to glomerular volume, comprising increase in matrix. Among groups of patients conformity between renal function stage and structure exists. The parameters measuring glomerulopathy are normal at the onset of diabetes; patients with normoalbuminuria may show slight basement membrane thickening, or normal parameters; the microalbuminuric group shows a measurable, but moderate glomerulopathy; patients with overt nephropathy have advanced lesions; at this stage heterogeneity among glomeruli makes the estimates weaker. Recent data indicate that the changes in peripheral basement membrane and in mesangial matrix develop in concert and both contribute to the early stage of glomerulopathy in patients with microalbuminuria. As to the consequences of the structural changes the mechanism of albuminuria is not clear. It is suggested that the early glomerulopathy entails other structural modifications, including formation of new vessels which may be the site of leakage. The marked deviations in glomerular filtration rate correspond well with estimates of filtration surface area: in the early hyperfunction state it is increased; in advanced nephropathy it is decreased, due to advanced glomerulopathy in conjunction with glomerular occlusion. The diabetic state is the necessary condition for the glomerulopathy. In relating structural changes to presumed contributing causes no supporting evidence of a relationship with glomerular hyperfunction or hypertrophy was observed. The structural parameters may be useful tools in clinical trials aiming at arresting the development of glomerulopathy, and thereby providing a prevention of diabetic nephropathy.


Potential use of glutathione for the prevention and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat.

It has been shown that parameters of oxidative stress are increased in experimental diabetic neuropathy. The glutathione redox system is one of the intracellular scavenger systems for neutralizing free oxygen radicals. In this investigation we studied the effect of glutathione-treatment on the development of diabetic neuropathy in streptozotocin-induced diabetic rats by measuring sensory and motor nerve conduction velocities. The total study period was 10 weeks. Four groups of rats were studied: Group 1 consisted of non-diabetic, age-matched control rats; Group 2, of diabetic rats treated with placebo from week 0 to 10; Group 3, of diabetic rats treated with 200 mg glutathione/kg body weight i.v. two times per week from weeks 0 to 10; and Group 4, of diabetic rats treated with placebo from weeks 0 to 4 and as Group 3 from weeks 4 to 10. The sensory and motor nerve conduction velocity of rats treated prophylactically with glutathione (Group 3) were significantly different from those of rats treated with placebo (Group 2) or with glutathione administered at a later time point (Group 4). Complete restoration of sensory and motor nerve conduction velocity was not reached. There was a significant improvement in motor nerve conduction velocity from weeks 4 to 6 (p less than 0.005), but not in sensory nerve conduction velocity in the delayed treatment group (Group 4). In conclusion, treatment with glutathione, a free radical scavenger, is partially effective in the prevention of diabetic neuropathy in streptozotocin-induced diabetic rats, but is of limited value when the neuropathy is already present.


Differential growth of brain and retinal bovine pericytes.

Within the central nervous system, pericyte degeneration in diabetes mellitus occurs only in the retinal microcirculation and is not seen in the brain. This study sought to elucidate differences between bovine retinal and brain pericytes. When pairs of retinal and brain pericytes from individual calves were cultured in vitro, the morphological organisation of early post-confluent retinal pericyte cultures was consistently different from that of brain pericyte cultures. When retinal and brain pericyte cultures were grown to second passage in high or normal glucose medium supplemented with fetal calf serum, brain pericyte cultures grew significantly faster than retinal pericytes in either medium (p less than 0.0001). Brain pericytes thus appeared to grow intrinsically faster than retinal pericytes and this effect was largely independent of glucose concentration. Brain pericytes also grew faster than retinal pericytes in high glucose medium containing human diabetic or control serum (p less than 0.002). The proliferative effect of serum from diabetic patients with non-proliferative diabetic retinopathy on pericytes grown in high glucose medium was not significantly different from that of control serum. Both brain and retinal pericytes showed variation in their ability to replicate in high concentrations of glucose. The selectivity of pericyte degeneration to the retinal circulation does not appear to be due to changes in the mitogenic activity of diabetic serum for retinal pericytes, but may relate to the intrinsic relative inability of the retinal pericyte to reproliferate in response to the metabolic injury of diabetes mellitus.


Effects of previous glycaemic control on the onset and magnitude of cognitive dysfunction during hypoglycaemia in type 1 (insulin-dependent) diabetic patients.

To determine whether the degree of previous glycaemic control may modify cognitive responses to hypoglycaemia, the glycaemic thresholds for, and magnitude of cognitive dysfunction as assessed by P300 event-related potentials as well as subjective and hormonal responses during hypoglycaemia were evaluated. Hypoglycaemia was induced by intravenous insulin infusion in 18 Type 1 (insulin-dependent) diabetic patients, 7 of whom were strictly controlled (HbA1c: 6.3 +/- 0.3%; mean +/- SEM; Group 1) and 11 of whom were poorly controlled (HbA1c: 9.1 +/- 0.4%; Group 2). Within 60 min, mean blood glucose declined from 5.6 and 5.7 mmol/l (baseline) to a nadir of 1.6 and 1.8 mmol/l followed by an increase to 5.6 and 4.3 mmol/l after 120 min in Group 1 and 2, respectively. There was no significant difference between the groups in regard to P300 latency at baseline, but between 50 and 70 min a significant prolongation of this component was noted in Group 2 as compared with Group 1 at blood glucose levels between 1.6 and 2.3 mmol/l (p less than 0.05). The glycaemic thresholds at which a significant increase of P300 latency over baseline was first noted were 1.6 +/- 0.2 mmol/l in Group 1 and 3.5 +/- 0.2 mmol/l in Group 2 (p less than 0.05). The glucose thresholds at which this prolongation was no longer demonstrable were 1.9 +/- 0.1 mmol/l in Group 1 and 3.8 +/- 1.4 mmol/l in Group 2, respectively (p less than 0.05). The glycaemic threshold at which the P300 amplitude was first significantly reduced was 2.2 mmol/l in Group 2, whereas no such reduction was observed in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)


The effects of sympathetic nervous system activation and psychological stress on glucose metabolism and blood pressure in subjects with type 2 (non-insulin-dependent) diabetes mellitus.

The sympathetic nervous system may contribute to excessive hepatic glucose output in Type 2 (non-insulin dependent) diabetes mellitus and could be implicated in the interrelated problem of hypertension. The aim of these studies was to determine whether subjects with Type 2 diabetes had normal sensitivity (compared with age- and weight-matched non-diabetic subjects) to noradrenaline infusion (60 ng.kg-1.min-1 for 60 min) and to compare the responses with oral tyramine administration (800 mg), and psychological stress (using competitive computer games). Noradrenaline infusion caused significantly greater plasma glucose (mean increment 2.1 +/- 0.4 vs 0.6 +/- 0.1 mmol/l, p less than 0.005) and pressor responses (mean systolic increment 21 +/- 3 vs 11 +/- 1 mmHg, p less than 0.02) in the diabetic subjects. The excessive glycaemia was due to increased hepatic glucose output rather than reduced glucose disposal. Tyramine administration caused significantly increased hepatic glucose output and plasma glucose levels, but with similar responses in the diabetic and non-diabetic subjects; the pulse and pressor responses were also similar between the groups. The psychological stressor induced significant increases in pulse, blood pressure and non-esterified fatty acid levels in the combined group of subjects (p less than 0.01) but did not influence plasma glucose levels in either diabetic or non-diabetic subjects. We conclude that pharmacologically-induced sympathetic nervous stimulation can induce hyperglycaemia. Subjects with uncomplicated Type 2 diabetes have increased sensitivity to exogenous noradrenaline but may not hyperrespond to endogenous sympathetic activation.


The number of glomeruli in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients.

The number of glomeruli per kidney in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients was estimated by an unbiased stereological method: the fractionator. No significant differences were observed between Type 1 and Type 2 diabetic patients without severe diabetic glomerulopathy and non-diabetic patients. Diabetic patients with proteinuria who were in the early stages of diabetic nephropathy also had a normal number of glomeruli. On the other hand, a subgroup classified as Type 1 diabetic patients with severe diabetic glomerulopathy had significantly less glomeruli compared with Type 1 diabetic patients with mild or no glomerulopathy. A probable explanation is that Type 1 diabetic patients lose glomeruli in relation to the progression of diabetic glomerulopathy. A more theoretical alternative is, however, that development of diabetic glomerulopathy is facilitated by a low number of glomeruli.


A population-based prevalence survey of known diabetes mellitus in northern Italy based upon multiple independent sources of ascertainment.

The aims of this survey were (1) to estimate the prevalence of known diabetes mellitus in 1988 in Casale Monferrato (Northern Italy); (2) to validate different data sources available in Italy; (3) to identify a population-based cohort of diabetic patients. Multiple independent data sources were used and the capture-recapture method was applied to estimate the completeness of ascertainment of the survey. The primary data source was the list of all patients attending the diabetic clinic or those referred by family physicians and paediatricians of the area. The secondary data sources were the list of hospital discharges, the prescriptions data source and the list of all people using reagent strips and insulin syringes. On 1 October 1988 (the cut-off date) 2,069 cases of known diabetes were identified. The estimated completeness of ascertainment of the survey was 91%. Prevalence of known diabetes, Type 1 (insulin-dependent), Type 2 (non-insulin-dependent) and insulin-treated diabetes were, respectively, 2.21% (95% CI 2.13-2.29), 0.80/1,000 (0.62-0.98) and 2.10% (2.01-2.19), 2.92/1,000 (2.57-3.27). A higher prevalence of Type 2 diabetes was observed in women (2.30%, 2.18-2.42) than in men (1.88%, 1.76-2.00). Age-specific prevalence of Type 2 diabetes increased with age. Computerized data sources routinely available in the Piedmont Region (hospital discharges and prescriptions data sources) showed a low completeness of ascertainment when considered together (65%, 1,338 of 2,069), indicating the need to involve the diabetic clinic and family physicians in the ascertainment of known diabetes. In conclusion, the prevalence of known diabetes in Italy was lower than in Northern Europe and the United States.


Renal excretion of kallikrein and eicosanoids in patients with type 1 (insulin-dependent) diabetes mellitus. Relationship to glomerular and tubular function.

Glomerular filtration rate, renal plasma flow, renal tubular sodium reabsorption (derived from lithium clearance) and renal excretion rates of kallikrein, prostaglandin E2 and systemic and renally-derived metabolites of prostacyclin and thromboxane A2 were measured in patients with Type 1 (insulin-dependent) diabetes mellitus and in normal subjects. Diabetic patients with glomerular hyperfiltration had greater active kallikrein and prostaglandin E2 excretion than patients with normal glomerular filtration rate or than normal control subjects. Both active kallikrein and prostaglandin E2 excretion correlated directly with glomerular filtration rate. Active kallikrein excretion correlated directly with the reabsorption of sodium in the distal tubule. The excretion rates of 6-keto prostaglandin F1 alpha, 2,3 dinor 6-keto prostaglandin F1 alpha, thromboxane B2, 2,3 dinor thromboxane B2 and 11-dehydro thromboxane B2 excretion were not different between the groups. This study confirms in man our previous finding of increased renal kallikrein production in the hyperfiltering streptozotocin-diabetic rat model. Given that kinins generated by kallikrein are extremely potent vasodilators and stimulate the renal production of eicosanoids that also regulate glomerular function, our findings suggest that increased kallikrein activity and prostaglandin E2 production may contribute to renal vasodilatation and hyperfiltration in human diabetes. The localization of kallikrein in the distal connecting tubule makes it plausible that altered sodium transport in the distal tubule may be a signal to increase generation of kallikrein.


Generation of thrombin activity in relation to factor VIII:C concentrations and vascular complications in type 1 (insulin-dependent) diabetes mellitus.

A possible association between plasma coagulant activity and the presence of vascular complications in patients with diabetes mellitus was studied by measuring the generation of thrombin in plasma of 20 control subjects and 50 diabetic patients classified according to the presence or absence of microvascular complications. Thrombin production was determined in defibrinated plasma using a semi-automated technique with measurement of thrombin activity using chromogenic peptide S2238. Values determined were the lag time to appearance of thrombin activity and time taken to generate 50% maximal thrombin activity. Thrombin activity was related to concentrations of coagulant factor VIII activity and fibrinopeptide A and these were correlated with HbA1C levels. The median time to generate 50% maximal thrombin activity was not significantly reduced in diabetic patients compared with control subjects (53 vs 54 s, p = 0.076) and there were no significant differences between patients with and without microvascular complications. There were no differences in median fibrinopeptide A concentrations between the diabetic and control subjects (1.5 vs 2.2 nmol/l, p = 0.169). Time to 50% maximal thrombin activity correlated inversely with factor VIII:C concentrations in diabetic patients (r = -0.344, p = 0.015, n = 50) and both this and lag time correlated with factor VIII:C in diabetic patients and control subjects combined (r = -0.395, p less than 0.01; r = -0.327, p = 0.006, n = 70). Factor VIII:C concentrations increased with age of the subject and with HbA1C concentrations. The results failed to show enhancement of coagulation in contact-activated diabetic plasma compared with control plasma and suggest that a relationship between high levels of factor VIII:C in diabetes and the development of mcirovascular complications is unlikely to be mediated through procoagulant activity in plasma.


The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects.

Sympathetic nervous system activation by insulin has been suggested as a mechanism explaining the association between insulin resistance and hypertension. We further examined the effect of insulin by direct microneurographic muscle and skin nerve sympathetic activity recordings during euglycaemic insulin clamps in healthy subjects. The mean plasma insulin level was elevated from 5.3 +/- 0.7 to 92.2 +/- 2.2 mU/l in seven subjects during a 90-min one-step clamp. In six other subjects plasma insulin was further raised from 85.7 +/- 4.0 mU/l to 747 +/- 53 mU/l between 45-90 min (two-step clamp). Four of the latter subjects received a sham clamp with NaCl infusions only on a second recording session. At the low dose of insulin muscle nerve sympathetic activity increased from a resting level of 22.7 +/- 5.0 bursts per min to 27.7 +/- 5.0 bursts per min at 15 min (p less than 0.05). The increases in muscle nerve sympathetic activity were significant (p less than 0.001; ANOVA) throughout insulin infusion, with a slight further increase (from 29.2 +/- 1.6 to 32.3 +/- 1.9 bursts per min) at the supraphysiological insulin concentration. During sham clamps muscle nerve sympathetic activity did not increase. Both insulin clamps induced minor, but significant, increases in forearm venous plasma noradrenaline concentrations. Skin nerve sympathetic activity (n = 3) did not change during insulin infusions. Heart rate increased slightly but significantly (p less than 0.005), during the insulin clamps. Blood pressure was not notably affected. In conclusion, hyperinsulinaemia was associated with increased vasoconstrictor nerve activity to skeletal muscle and with no change of sympathetic outflow to skin.


Incidence and prevalence of type 1 (insulin-dependent) diabetes mellitus in Icelandic children 1970-1989.

Through use of primary and secondary data sources for registration and validation, the incidence and prevalence of Type 1 (insulin-dependent) diabetes mellitus in children aged 0-14 years in Iceland has been completely ascertained for the years 1970-1989. The age-adjusted mean annual incidence per 100,000 for the 20-year period was 9.4 (95% confidence interval 7.8-11.3); similar for boys (9.9; 7.7-12.7) and girls (8.8; 6.7-11.5). Between 1970-1979 the incidence was 8.0 (6.0-10.6) and between 1980-1989 it was comparable at 10.8 (8.4-13.8) (p greater than 0.10). By Poisson regression analysis the variation in incidence was related to age at diagnosis (p less than 0.001), while a linear trend for calendar year at diagnosis did not reach statistical significance (p = 0.07). A quadratic curve, however, better described the temporal variation in incidence (p less than 0.05). The total prevalence per 1,000 by the end of 1979 and 1989 was similar, 0.45 (0.30-0.65) and 0.57 (0.40-0.79), respectively. In conclusion, this study confirms that both the incidence and prevalence of childhood Type 1 diabetes in Iceland are low compared to the other Nordic countries. The findings may suggest a causative role for environmental factors that are not related to latitude or ambient temperature.


Cyclosporin A treatment of young children with newly-diagnosed type 1 (insulin-dependent) diabetes mellitus. London Diabetes Study Group.

Several studies have demonstrated the efficacy of cyclosporin A in modifying the initial course of Type 1 (insulin-dependent) diabetes mellitus in older children and adults but none have reported the effects in very young children. We treated 14 newly-diagnosed Type 1 diabetic patients aged 22 months to 95 months with cyclosporin A. Mean insulin dose at entry was 0.7 +/- 0.07 IU.kg-1.day-1. Initial cyclosporin A dose was 10 mg.kg-1.day-1. Insulin dose reached a nadir of 0.13 IU.kg-1.day-1 by 180 days. Mean glucagon-stimulated connecting peptide levels were maximal at 6 months (0.75 nmol/l) and were maintained while on cyclosporin A. Insulin was discontinued in four patients for 4, 12, 15 and 30 months respectively. In five other patients the insulin dose was less than 0.15 IU.kg-1.day-1 for at least 3 months. Glycated haemoglobin levels for all patients were within the normal range. Side effects included anorexia, stomach pains, poor weight gain, hypertrichosis, gum hyperplasia, mild anaemia and elevated creatinine. All patients have now discontinued cyclosporin A and all but one have been followed for 5 years after discontinuation. Reasons for discontinuing cyclosporin A included exposure to chicken pox (varicella), non-resolving otitis media, incomplete or no response and relapse. All side effects have resolved since the treatment was discontinued. Following discontinuation of cyclosporin A insulin requirements and glycated hemoglobin levels increased while glucagon-stimulated connecting peptide levels declined dramatically.(ABSTRACT TRUNCATED AT 250 WORDS)


Immunohistochemical measurements of nerves and neuropeptides in diabetic skin: relationship to tests of neurological function.

Image-analysis was used to measure nerves immunoreactive to the general neuronal marker protein gene product 9.5 (PGP 9.5-IR) and the neuropeptides calcitonin gene-related peptide and vasoactive intestinal polypeptide in standardised leg skin biopsies of three age-matched groups of young subjects: non-diabetic (n = 14), diabetic patients with normal small fibre function ("non-neuropathic", (n = 11) and diabetic patients with abnormal small fibre function ("neuropathic", n = 11). Depletion of nerves and neuropeptides was most marked in the epidermis, where calcitonin gene-related peptide-immunoreactivity was more frequently absent than PGP 9.5-IR in diabetic patients. Epidermal PGP 9.5-IR nerve area and counts were reduced in neuropathic compared with normal subjects (p less than 0.001), as were epidermal calcitonin gene-related peptide nerve counts (p = 0.003). Sweat gland PGP 9.5 and vasoactive intestinal polypeptide, which may be involved in sweat production, showed no diminution in diabetic patients (area: p = 0.160, p = 0.372 by ANOVA). Two diabetic patients showed elevated sweat gland PGP 9.5-IR and three had increased sweat gland vasoactive intestinal polypeptide; this may represent nerve proliferation. In local sweat tests, acetylcholine-stimulated sweat output was associated with increased immunoreactivity, while the sympathetic skin response showed inverse correlations with immunoreactivity. There were no consistent changes with other commonly-used neurophysiological tests. HbA1 correlated negatively with immunohistochemical measurements. Neuropeptide changes were seen in the absence of macro- and microvascular disease, and epidermal nerve depletion occurred in patients with normal thermal thresholds and cardiac autonomic function.(ABSTRACT TRUNCATED AT 250 WORDS)


Cognitive function in type 1 (insulin-dependent) diabetic patients after nocturnal hypoglycaemia.

Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied on two consecutive and one subsequent overnight occasions. The aim was to evaluate the influence of nocturnal hypoglycaemia on neuropsychological and reaction time tests the following morning. Hypoglycaemia was induced by i.v. insulin infusion, blood glucose nadir was 1.5 +/- 0.3 mmol/l. Duration of hypoglycaemia (blood glucose less than 3 mmol/l) was 101 +/- 38 min. Whole night sleep statistics for all patients showed no statistical differences between the normoglycaemic and hypoglycaemic nights, however, there was a tendency of prolongation of the second sleep cycle in the nights with hypoglycaemia. Each patient was used as his own control and periods with blood glucose concentration less than 3 mmol/l were compared to exactly the same periods in nights with blood glucose level over 5 mmol/l. During hypoglycaemia the amount of deep sleep was reduced and replaced by superficial sleep and arousals of short duration. Further, the reduction in deep sleep was replaced later at night. Neuropsychological test scores and reaction time measurements in the morning showed no differences between the normoglycaemic and hypoglycaemic nights. despite sleep disturbances, nocturnal hypoglycaemia did not impair cognitive function the following morning in Type 1 (insulin-dependent) diabetic patients.


In vitro percutaneous absorption of cadmium from water and soil into human skin.

The objective was to determine percutaneous absorption of cadmium as the chloride salt from water and soil into and through human skin. Soil (Yolo County 65-California-57-8) was passed through 10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixed with radioactive cadmium-109 at 13 ppb. Water solutions of cadmium-109 at 116 ppb were prepared for comparative analysis. Human cadaver skin was dermatomed to 500-microns, and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 16-hr skin application time. Cadmium in water (5 microliters/cm2) penetrated skin to concentrations of 8.8 +/- 0.6 and 12.7 +/- 11.7% of the applied dose from two human skin sources. Percentage doses absorbed into plasma were 0.5 +/- 0.2 and 0.6 +/- 0.6%, respectively. Cadmium from soil (0.04 g soil/cm2) penetrated skin at concentrations of 0.06 +/- 0.02 and 0.13 +/- 0.05% for the two human skin sources. Amounts absorbed into plasma were 0.01 +/- 0.01 and 0.07 +/- 0.03%. Most of the nonabsorbed cadmium was recovered in the soap and water skin surface wash. Binding of cadmium from water to soil was greater than binding from water to powdered human stratum corneum, supporting the lower absorption from soil than from water. Short-term exposure of cadmium in water to human skin for 30 min (bath or swim) resulted in skin uptake, which upon further perfusion (48 hr), absorbed into the plasma receptor fluid (systemic). Cadmium in soil was increased from 6.5 to 65 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of a GnRH agonist on fertility following administration to prepubertal male and female rats.

Leuprolide, a GnRH agonist, was administered daily to male and female rats for 90 days. Animals were sexually immature (25 days old) at the outset. Dosages were 20 and 200 micrograms/kg/day. Five males and five females were euthanized on Day 91. Sex organs were weighed and evaluated for histopathologic changes. These procedures were repeated 140 days later. Following a recovery period lasting 45 days (onset of normal-appearing estrous cycles) in females and 140 days (two spermatogenic cycles) in males, the fertility of these rats was assessed by mating with untreated animals. Treated males gained less weight while treated females gained more weight than controls. Weights of primary and secondary sex organs were reduced below control, but returned to normal following 140 days of recovery. Treated males were fertile and produced normal litters. Reproductive performance of low-dosage (20 micrograms/kg/day) females was normal 45 days after treatment cessation, but half of the high-dosage (200 micrograms/kg/day) females failed to become pregnant. However, reproductive performance of this group compared well with control performance after an additional 6 weeks of recovery. Atrophic changes were noted in male and female sex organs. Following 140 days of recovery, ovaries, uterus, vagina, prostate, and seminal vesicle were normal. Although testes and epididymides showed partial recovery at this time, multifocal or segmental atrophy and mineralization were noted in portions of some seminiferous tubules.


Quantitative plasma disposition of retinol and retinyl esters after high-dose oral vitamin A administration in the cynomolgus monkey.

A solid-phase extraction technique followed by automated high-performance liquid chromatography sample elution was successfully used to evaluate the effect of three pharmaceutical parameters on the plasma profile of various forms of vitamin A after an oral dose to cynomolgus monkeys. The three parameters evaluated were the chemical form of vitamin A (retinol versus retinyl acetate), the vehicle (acetone/Tween 20/water versus acetone/soybean oil), and the retinol dose (2, 10, and 50 x 10(3) retinol equivalents/kg). The form of the administered compound, retinol or retinyl acetate, appeared to have no major effect on the formation of nonpolar retinoids. The ester profile in plasma differed depending on whether the dose was administered in the water-based or the oil-based vehicle. Irrespective of the vehicle type the predominant retinoid formed was retinyl palmitate/oleate. However, retinol doses in the water-based vehicle formed relatively high concentrations of retinyl laurate and retinyl myristate but no retinyl linolenate. The retinol dose in the oil-based vehicle formed consistent, but relatively minor, concentrations of retinyl linolenate, higher relative concentrations of retinyl linoleate, and no retinyl laurate or myristate. The dose of retinol administered had an impact on the diversity of the nonpolar retinoid profile. The low dose led to the presence of almost exclusively retinyl palmitate/oleate and retinyl stearate, whereas at higher doses the other retinyl esters became major retinol constituents.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute respiratory effects of endotoxin-contaminated machining fluid aerosols in guinea pigs.

Exposure to machining fluid aerosols in the automotive industry is associated with a variety of respiratory symptoms including cross-shift changes in pulmonary function, cough, asthma, and phlegm. Lubricating and cooling fluids used in machining operations are predominantly water and thus are susceptible to microbial growth. In the present study, the role of endotoxin in the acute pulmonary injury produced by machining fluid aerosols was examined in guinea pigs. Animals were exposed to nebulized water, unused machining fluid, or used machining fluid. At the end of a 3-hr exposure, specific airway conductance (SGaw) was not affected by exposure to the vehicle water, but was decreased in a dose-dependent manner by exposure to aerosols of the used machining fluid. SGaw decreased from preexposure baseline values by 0, 7, and 40% in animals exposed to 1, 10, and 100 mg/m3 used machining fluid, respectively. These exposure levels also produced acute lung injury as evidenced by changes in cellular and biochemical indices in lavage fluid. These adverse respiratory effects may have been due to microbial contamination of the used machining fluid as the aerosol exposures were associated with airborne endotoxin concentrations of 0.3, 1.9, and 5.3 micrograms/m3, respectively. Animals exposed to aerosols of the endotoxin-free unused machining fluid had no statistically significant adverse functional, cellular, or biochemical effects except for a fourfold increase in neutrophils at 100 mg/m3. These results suggest that contamination of machining fluid during use or storage may lead to the adverse respiratory effects of aerosolized machining fluids.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of dose on the disposition of methoxyethanol, ethoxyethanol, and butoxyethanol administered dermally to male F344/N rats.

The glycol ethers methoxyethanol (ME), ethoxyethanol (EE), and butoxyethanol (BE) are widely used in industrial and household products. Rodent studies indicate the ME and EE are potentially toxic compounds causing teratogenic, fetotoxic, hematotoxic, and testicular effects. Exposure of rodents to high concentrations of BE resulted in anemia due to hemolysis of blood cells, leukopenia, hemoglobinuria, and liver and kidney damage. The purpose of this study was to determine the uptake, metabolism, and excretion of dermally administered glycol ethers as a function of the externally applied dose. Three different amounts of the 14C-labeled glycol ethers (450-4000 mumole/kg) were applied to same-sized areas on the clipped backs of F344/N rats, and nonoccluded percutaneous absorption was measured. The rates of excretion of the 14C-labeled parent compound and metabolites by different routes were measured, as well as the amount of 14C remaining in the carcass. Within the dose range studied, the absorption and metabolism of these three glycol ethers by F344/N rats was linearly related to the dermally applied dose. The absorption of all three glycol ethers was approximately 20-25%, regardless of the chain length of the alkyl group or the dose administered. The majority of the absorbed dose was excreted in the urine. Feces and exhaled CO2 represented minor routes of excretion. The alkoxyacetic acid was a major metabolite for all three glycol ethers. The formation of small amounts of ethylene glycol indicated cleavage of the ether bond.(ABSTRACT TRUNCATED AT 250 WORDS)


Fourteen-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette. I. Inhalation toxicology and histopathology.

Sprague-Dawley rats were exposed 6 hr per day for 14 consecutive days to aged and diluted sidestream smoke (ADSS), used as a surrogate for Environmental Tobacco Smoke (ETS), at concentrations of 0.1 (typical), 1 (extreme), or 10 (exaggerated) mg of particulates per cubic meter. Animals were exposed nose-only, inside whole-body chambers, to ADSS from the 1R4F reference cigarette. End-points included histopathology, CO-oximetry, plasma nicotine and cotinine, clinical pathology, and organ and body weights. The only pathological response observed was slight to mild epithelial hyperplasia and inflammation in the most rostral part of the nasal cavity, in the high-exposure group only. No effects were noted at medium or low exposures. The minimal changes noted were reversible, using a subgroup of animals kept without further treatment for an additional 14 days. Overall, the end-points used in the study demonstrated that there was no detectable biological activity of ADSS at typical or even 10-fold ETS concentrations and that the activity was only minimal at very exaggerated concentrations (particle concentrations 100 times higher than typical real-world concentrations).


Fourteen-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette. II. DNA adducts and alveolar macrophage cytogenetics.

The chemical constituents of cigarette smoke are greatly diluted in environmental tobacco smoke (ETS). In the typical indoor environment where cigarettes are smoked, the mean value of respirable suspended particles is approximately 0.1 mg/m3. In this study, we used aged and diluted sidestream smoke (ADSS) of 1R4F University of Kentucky research cigarettes as a surrogate for ETS and exposed Sprague-Dawley rats nose-only to 0, 0.1, 1.0, and 10 mg wet total particulate matter (WTPM)/m3 for 6 hr per day for 14 consecutive days. DNA from lung, heart, larynx, and liver was tested for adduct formation after 7 and 14 days of exposure and after 14 days of recovery. In addition, alveolar macrophages from animals exposed for 7 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any of the animals at 0.1 or 1.0 mg WTPM/m3, which represent ambient and 10-fold exaggerated ETS concentrations, respectively. Slight diagonal radioactive zones, characteristic of adducts observed in human smokers and in animals exposed to mainstream smoke, were observed, but only in lung and heart DNA of animals exposed to the highest concentration of ADSS (10 mg WTPM/m3), a 100-fold exaggeration of typical field measurements of ETS. The mean relative adduct labeling values (+/- SE) were 8.7 (+/- 0.2) adducts per 10(9) nucleotides for lung DNA and 5.7 (+/- 0.7) adducts per 10(9) nucleotides for heart DNA after 14 days of exposure. No elevation in chromosomal aberrations was observed in alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)


Sequential study in rats of nasal and hepatic lesions induced by N-nitrosodimethylamine and N-nitrosopyrrolidine.

Female Sprague-Dawley rats were given an ip dose of N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR), singly or in combination, and the sequential development of lesions in the liver and nasal cavity was characterized. Liver and nasal tissues were collected from rats given either NDMA or NPYR and killed at 6 or 12 hr and 1, 3, 10, or 30 days. After combination exposure, rats were killed at 3 or 30 days. Olfactory epithelium and adjacent Bowman's glands were specifically targeted by each chemical. Lesions were seen as early as 6 hr and were most severe by 3 days. At the high doses (60 mg/kg NDMA or 100 mg/kg NPYR) regeneration was not complete by 30 days. Hepatic necrosis was seen at 1 and 3 days with NDMA but was not seen with NPYR. Combination exposure appeared to cause additive effects in both the liver and the nasal cavity. Results indicate that a single ip administration of NDMA or NPYR can induce severe and prolonged toxic effects on nasal tissues in rats.


The developmental toxicity of ethylene glycol diethyl ether in mice and rabbits.

Timed-pregnant CD-1 outbred Albino Swiss mice and New Zealand White rabbits were dosed by gavage with ethylene glycol diethyl ether (EGdiEE) in distilled water during major organogenesis. Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50, 150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19 (0, 25, 50, or 100 mg/kg/day). Maternal clinical status was monitored daily during treatment. At termination (gd 17, mice; gd 30, rabbits), confirmed-pregnant females (22-24 per group, mice; 26-32 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed, but maternal body weight gain during gestation and treatment, and at termination was reduced at 1000 mg/kg/day. The reduction of maternal body weight gain during gestation was secondary to embryo/fetal toxicity, i.e., reduced gravid uterine weight as a consequence of decreased litter size and fetal weight. The no-observed adverse effect level (NOAEL) for developmental toxicity was 50 mg/kg/day. At greater than or equal to 150 mg/kg/day the number of litters of mice with malformed fetuses was increased. At greater than or equal to 500 mg/kg/day fetal body weight was reduced, and malformation incidence was significantly increased. Exencephaly and fused ribs were observed most often. In rabbits, maternal body weight was unaffected by treatment even though 6% maternal mortality was observed at 100 mg/kg/day. The developmental NOAEL was 25 mg/kg/day. Malformations were increased at greater than or equal to 50 mg/kg/day; short tail, small spleen, fused sternebrae, and fused rib cartilage were observed most often. In summary, oral administration of EGdiEE to mice and rabbits during organogenesis produced profound adverse developmental effects even in the absence of significant maternal toxicity. Developmental effects in rabbits were more varied.


Reproductive and developmental toxicity of N,N-diethyl-m-toluamide in rats.

N,N-Diethyl-m-toluamide (mDET, DEET) is widely used as a topical insect repellent. It is the active ingredient in many consumer formulations, which usually contain 10-25% mDET in an alcohol base. More concentrated consumer products are also available, including some that are pure technical grade mDET. Persons living or employed in mosquito-infested areas may have very high seasonal exposures to mDET. Because contradictory reports had been published on the reproductive and developmental toxicity of mDET, a series of studies was conducted in male and female Sprague-Dawley rats. All treatments were administered by daily subcutaneous injections of undiluted mDET. A dose finding study was done using 12 time-mated females per group treated on Gestational Days (GD) 6-15 with 0.50, 0.62, 0.78, 0.92, or 1.2 ml mDET/kg/day. No females survived 10 days of mDET dosing with 1.2 ml/kg/day. Deaths occurred in all other groups except the low dose (0.50 ml/kg/day). Pregnant females treated on GD 6-15 with 0 or 0.30 ml/kg/day were used for the teratology study. Half of each group was euthanized on GD 20: the second half was singly housed in nesting boxes and allowed to deliver litters. Live pups were counted and weighed soon after birth on Postnatal Day (PD) 0 and again on PD 3, 9, and 14. Proven fertile males were treated 5 days/week for 9 weeks with 0, 0.30, 0.73, 1.15, or 1.80 ml mDET/kg/day for a male dose-finding study. Each group consisted of 20 males. No males survived the 1.80 ml/kg/day. Deaths occurred in all remaining dose groups except the 0.30 ml/kg/day and control group. Immediately following the final treatment of the male dose study, 11 males were randomly selected from the 0.30 and 0.73 ml/kg/day groups. They were cohabited for 7 days with 4 females per male during post-treatment Weeks 1 and 2. Half of the females were euthanized 12-14 days after the last day of cohabitation for a dominant lethal study; the remaining females were singly housed in nesting boxes and allowed to deliver litters. Live pups were counted and weighted on PD 0 and 3. There was no evidence of reproductive or developmental toxicity in any of these assays, but there were signs of neurotoxicity in treated adult male and female rats, which may relate to reports of neurotoxicity in humans heavily exposed to mDET-containing insect repellents.


1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats.

1-Aminobenzotriazole (ABT) is a suicide substrate of both hepatic and pulmonary cytochromes P450. The present studies were designed to compare the effects of ABT on hepatic and renal metabolism. Hepatic and renal microsomes and cytosol were prepared from male Sprague-Dawley rats following ABT pretreatment (0-100 mg/kg ip) for various times. Administration of 100 mg ABT/kg produced profound reductions in P450 content in both liver and kidney within 2 hr; loss of P450 in both tissues persisted for at least 48 hours. ABT-induced destruction of P450 was dose-dependent. Maximal destruction of about 80% of total hepatic P450 occurred at dosages of ABT equal to or greater than 10 mg/kg. Maximal destruction of about 80% of total renal P450 occurred at dosages of ABT equal to or greater than 50 mg/kg. In vitro, ABT rapidly and efficiently destroyed P450 in both hepatic and renal microsomes prepared from naive male Sprague-Dawley rats. Incubation of hepatic or renal microsomes in vitro with ABT produced detectable destruction of P450 within 5 min. Maximal destruction of P450 occurred within 10 min in both hepatic and renal microsomes during in vitro incubation with ABT. ABT-induced destruction of P450 in vitro was concentration-dependent. For hepatic microsomes, maximal destruction of about 70% of P450 required concentrations of ABT equal to or greater than 10 mM. For renal microsomes, maximal destruction of about 80% of P450 required concentrations of ABT equal to or greater than 10 mM. In both liver and kidney, only P450 content and P450-dependent activities were significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of p-xylene inhalation on the bioactivation of bromobenzene in rat lung and liver.

It is unclear whether the pneumotoxicity observed with bromobenzene (BB) in phenobarbital-induced rats is related to BB bioactivation in lung, liver or both. To help differentiate pulmonary from hepatic bioactivation, BB was administered alone and in combination with p-xylene, which inhibits pulmonary but induces hepatic cytochromes P450. Exposure to p-xylene alone (3400 ppm for 4 hr) produced no changes in bronchoalveolar lavage fluid (BALF) measurements (gamma-glutamyl transpeptidase, lactate dehydrogenase, protein, white blood cell count) or serum sorbitol dehydrogenase. p-Xylene increased hepatic microsomal benzyloxy- (BROD), pentoxy- (PROD), and ethoxy- (EROD) resorfuin O-dealkylase activities but decreased pulmonary microsomal BROD and PROD. Immunoblot analysis revealed an induction of hepatic but not pulmonary microsomal P450IIB apoprotein. When rats were exposed to p-xylene (2800 ppm) or room air for 4 hr, treated 12 hr later with BB (0.5 ml/kg, ip) or corn oil, and killed after 12 hr, p-xylene increased hepatic P450IIB (27-fold) concomittant with a similar increase in BROD activity. p-Xylene also increased hepatic P450IA apoprotein (3.4-fold) with a complimentary increase in EROD activity. p-Xylene potentiated BB-induced hepatotoxicity. In pulmonary microsomes p-xylene and BB each produced similar decreases in both EROD and BROD activities. The combination of p-xylene and BB had an additive effect on pulmonary P450IA1 reduction. BALF analysis and histopathology revealed no pneumotoxicity with any treatment. p-Xylene potentiation of BB-induced hepatotoxicity without pneumotoxicity suggests that the liver does not produce metabolites of BB which are directly involved in pulmonary damage.


Adverse male reproductive effects following subchronic exposure of rats to sodium dichloroacetate.

Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex enhancing carbohydrate and lactate utilization in animals. As a result it is used clinically in the treatment of acute lactic acidosis and has therapeutic potential in the treatment of stroke. Adverse effects of chronic DCA treatment include polyneuropathy and testicular degeneration. Since DCA is a principal product of the aqueous chlorination of fulvic acids concern has arisen regarding the agent's impact on environmental health. We treated male Long-Evans rats with 0, 31.25, 62.5, or 125 mg DCA/kg/day by oral gavage for 10 weeks. Compared to controls, preputial gland and epididymis weights were reduced at 31.25 mg/kg, body and liver weights at 62.5 mg/kg, and accessory organ weights at 125 mg/kg. Epididymal sperm counts were reduced and sperm morphology was impacted at the 62.5 and 125 mg/kg doses levels. Histologic examination of the testis and epididymis revealed inhibited spermiation in testes at the 125 mg/kg dose level. Computer-assisted sperm motion analysis revealed reductions in percentage motile sperm, curvilinear and straight-line velocity, linearity, and amplitude of lateral head displacement at both the 62.5 and the 125 mg/kg dose levels. In the assessment of fertility after an overnight mating, the number of viable implants on Day 14 of gestation was decreased only in the highest dose group. These studies demonstrate adverse effects of NaDCA treatment on the rat male reproductive system, primarily on the accessory organs and sperm within them at lower doses (31.25 and 62.5 mg/kg), and on the testis at the highest dose (125 mg/kg).


Chronic toxicity of the anticancer agent trimetrexate in rats.

Trimetrexate was administered to rats in an interrupted treatment regimen comparable to proposed human clinical treatment. Forty-five rats of each sex were dosed intravenously with trimetrexate at 0, 1, 10, or 30 mg/kg (0, 6, 60, or 180 mg/m2), once daily for 5 consecutive days, followed by a 23-day recovery period. This cycle of dosing and recovery was repeated for a total of six cycles. Hematology, urinalysis, clinical chemistry, and gross and microscopic pathology examinations were conducted for animals euthanatized 3 and 21 days after dosing cycles 1, 3, and 6. Additional rats in each group were maintained without dosing for an additional 56 days (77 days after the last trimetrexate dose) to assess the long-term reversibility of pathologic changes. Target organs were typical for an antifolate and included gastrointestinal tract, lymphoid tissues, and the hematopoietic and male reproductive systems. No toxicity was observed at 1 mg/kg. Treatment-related changes in hematology parameters following 10 and 30 mg/kg were fully reversible within 3 weeks of each dosing cycle. Except for testis and cecum, histopathological changes were also reversible within 21 days of dosing. Trimetrexate-induced testicular changes persisting during the course of multiple cycles of dosing were not reversible within 21 days, but required an additional 56 days for essentially complete recovery.


Noninvasive measurement of blood pressure in conscious cynomolgus monkeys.

Systolic (SP), diastolic (DP), and mean arterial blood pressures (MAP) and pulse rate (PR) were recorded on treated and untreated conscious cynomolgus monkeys by the oscillometric method (Dinamap 1846SX/P). Each monkey was placed in a restraining tube with the cuff placed on the base on the shaved tail. Measurements were taken on untreated animals once or twice a day for 4 weeks. The mean and standard deviations for SP, DP, MAP, and PR were approximately 121 +/- 17, 60 +/- 14, and 84 +/- 17 mm Hg and 193 +/- 18 pulses/min, respectively. One male and one female cynomolgus monkey were treated with isoproterenol, norepinephrine, and nitroprusside. Blood pressure was measured indirectly with the cuff on the tail and directly with an indwelling catheter in the descending thoracic aorta. Although the oscillometric method was not as sensitive as the catheter, the oscillometric method detected a change in the same direction of SP, DP, MAP, and PR compared with the direct method for all drugs administered. The monitor was reliable and sufficiently accurate to conclude that it may be useful in toxicology studies for evaluation of blood pressure parameters in conscious cynomolgus monkeys.


Toxicity of calcium sodium metaphosphate fiber. I. In vitro and in vivo degradation and clearance studies.

In an experiment to ascertain the degradability of calcium sodium metaphosphate (CSM) fiber in vitro, 32P-labeled CSM fiber was incubated in media with or without rat lung epithelial cells (LEC) or rat alveolar macrophages (RAM). The amount of radioactivity appearing in the filtrate of the media in the presence of cells minus the radioactivity in the media in the absence of cells was considered to reflect cell-aided dissolution of the fiber. LEC and RAM cells increased the degree of dissolution two- and sevenfold, respectively, compared to their respective media controls in a 7-day time period. In a separate experiment, male Fischer rats were given 32P-labeled CSM fiber either by intraperitoneal injection or by intratracheal instillation and the amount of radioactivity appearing in the urine and feces was measured over a period of 60 days. Selected animals from this experiment were also subjected to whole-body autoradiography 0, 1, 5, 15, 30, and 60 days postexposure. After intraperitoneal injection, approximately 0.9% of the administered dose appeared in the urine. A similar percentage of the dose was eliminated in the urine when the fibers were administered by intratracheal instillation; however, the amount of radioactivity in the feces after intratracheal instillation, i.e., 11.6% of the administered dose, was much higher than that after intraperitoneal dose, i.e., 0.24% of the administered dose. Whole-body autoradiographs showed a time-related increase in radioactivity at a site other than the site of administration, and the location of this radioactivity appeared to be exclusively associated with mineralized tissue. The clearance of nonradiolabeled CSM fiber (approximately 200,000 fibers) from rat lung after intratracheal inhalation (IH) and intratracheal instillation (IT) was monitored. Approximately 93% of the initial fiber load after IH and approximately 84% of the initial fiber load after IT was cleared from the lung in 6 months. Histological and biochemical evaluation of the rat lungs did not reveal any indication of fibrosis up to a period of 6 months. All the studies discussed indicate that CSM is degradable in biological systems and is cleared from the lung after IT and IH administration. These attributes of CSM fiber should reduce the potential for chronic adverse effects in the lung after inhalation.


Toxicity of calcium sodium metaphosphate fiber. II. Chronic inhalation and oncogenicity study.

Male and female Fischer 344 rats (80/sex/group) were exposed to CSM fiber 6 hr/day, 5 days/week at target-exposure levels of 0, 1, 5, or 25 mg/m3 for 24 months, corresponding to 0, 27, 80, and 513 fibers/cc, respectively. Number and size of the airborne fibers were determined during the course of the study. At 3 and 12 months, 10 rats/sex/group were euthanized and at 18 and 24 months 5 rats/sex/group were euthanized. In addition, 5 rats/sex/group were removed from exposure at 18 months and maintained for a 6-month recovery period. All animals surviving at the completion of the exposure period were maintained in a clean environment for up to 5 additional months. Clinical laboratory examinations were performed on 10 animals/sex/group at 3, 12, and 24 months. The number of fibers in the lung were also determined at 3, 12, 18, and 24 months. Body weight and survival did not appear to be affected by treatment. There were no biologically significant effects on clinical parameters. There was a dose-related increase in lung weight during the exposure period which was generally reversible during the recovery periods. There also was a dose-related increase in the number of fibers/milligram of lung, but no increase in lung fiber burden after the first 3 months. The number of fibers in the lungs of animals exposed to CSM fiber for 18 months and allowed 6-month recovery period showed a decrease especially at the high dose. No increase in tumors (benign or malignant) was observed in this study. Microscopic changes considered reflective of an irritant response were observed in the nasal turbinates notably at the 5 and 25 mg/m3 levels. Histological changes were also observed in the lungs at the 5 and 25 mg/m3 levels. The incidence and/or severity of histopathological changes in the 1 mg/m3 group was considered to be essentially comparable to controls.


Subchronic toxicity studies of t-butyl alcohol in rats and mice.

The purpose of this study was to evaluate the toxicity of t-butyl alcohol, an important commodity chemical, an additive to unleaded gasoline, and a contaminant of drinking water. Ninety-day toxicity studies were conducted in B6C3F1 mice and Fischer 344 (F344) rats of both sexes using dosed water. Dose levels of t-butyl alcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v). Lethality was observed at the 4% level of both sexes and species. Weight-gain depression was present in all dose levels of male rats; 4% female rats; 1, 2, and 4% male mice; and 2 and 4% female mice. Water consumption was increased at lower dose levels in male rats and decreased in the higher dose levels of both sexes of rats and female mice. Clinical signs in rats were ataxia in both sexes and hypoactivity in males. Clinical signs in mice were ataxia, abnormal posture, and hypoactivity. In rats, urine volumes were reduced, in association with crystalluria. Gross lesions at necropsy were urinary tract calculi, renal pelvic and ureteral dilatation, and thickening of the urinary bladder mucosa. Microscopic lesions were hyperplasia of transitional epithelia and inflammation of the urinary bladder. In male rats treated with t-butyl alcohol, microscopic renal changes were suggestive of alpha-2 mu-globulin nephropathy. No-effect levels for the urinary tract lesions were 1% in male rats and mice (803.7 mg/kg/day for the male rats and 1565.8 mg/kg/day for the male mice) and 2% in female rats and mice (1451.5 mg/kg/day for the female rats and 4362.9 mg/kg/day for the female mice). The results indicate that in rodents the urinary tract is the target organ for t-butyl alcohol toxicity, and males are more sensitive to t-butyl alcohol toxicity than females.


A survey of formal training in the care of children in family practice residency programs.

Declining hospitalization rates for children and an increased emphasis on ambulatory care may be affecting the way family practice residency programs train their residents in the care of children. We surveyed all US family practice residency program directors to determine the nature of the child care training that programs currently provide to residents. Responses were received from 78% of the programs. Residencies required a mean of 5.2 months of formal pediatric training (range: 1 to 11 months). Thirty percent of programs noted a declining inpatient census on inpatient pediatric teaching services, but since 1978, the mean duration of inpatient pediatric training increased by 0.4 months to a required mean of 2.7 months of general pediatric inpatient training (range: 0 to 6 months). The mean time devoted to structured outpatient pediatric training was only 1.6 months (range: 0 to 6 months). Nine percent of responding programs required no formal pediatric outpatient training other than family health center experience. Despite declining inpatient census and increased emphasis on comprehensive ambulatory care, family practice residencies require more formal inpatient pediatric training than formal outpatient training.


Policy recommendations for pharmaceutical representative-resident interactions.

Based on our review of existing written policies regarding pharmaceutical representative-resident interactions, we believe that residencies should develop more comprehensive policies. We present six topic areas that programs should address in formulating policies: 1) policy tone, 2) traffic control, 3) samples, 4) gifts, 5) screening of educational and promotional materials and events, and 6) honoraria, research funding, and other monetary exchanges.


A survey method for investigating ethical decision making in family practice.

The tension between respect for patient autonomy versus concern for patient welfare is a challenging ethical issue for physicians. The purpose of this research was to describe a method for analyzing ethical decisions and to report the results of a survey of ethical decision making among family physicians. We developed a survey instrument that used simulated case scenarios, each of which posed an ethical dilemma. The ethical problems on the survey included the extent to which diagnostic information should be revealed to patients, the extent to which physicians should become involved in patients' life-style issues, and how to deal with patients' family problems. We mailed the questionnaire to 1,300 US family physicians. Six hundred seventy-four physicians responded. Respondents did not deal with the simulated ethical problems in a uniform manner and often tended to respond more to specific details of a case rather than the overall ethical dilemma posed. Physicians who chose a course of action giving patients more control were motivated by factors that showed respect for patient autonomy. On the other hand, physicians who chose a course of action giving patients less control were not motivated by factors suggesting a concern for patient welfare. Based on responses to simulated case scenarios, family physicians did not demonstrate a uniform approach but rather a more contextual one. Respect for patient autonomy was linked to family physicians' reported courses of action.


A clinical trial to reduce the rate of low birth weight in an inner-city black population.

The goal of our study was to measure the effectiveness of a home-based intervention for prevention of low birth weight with 154 high-risk, low-income black women attending a prenatal clinic in Cleveland. Based on previous research, risk was defined by clinic registration between the 17th and 28th weeks of gestation, low family functioning score, and experience of at least one stressful life event prior to registration. Optional factors included being a smoker, a low maternal weight-height ratio, being age 27 or older, and a previous premature birth. A 21-item family function screen previously validated in a similar population was the primary determinant of psychosocial risk. Low birth weight was defined as weight less than 2,500 g regardless of gestational age. There was no decrease in the rate of low birth weight for women who received four home visits focusing on smoking, drug and nutrition education, support, and links with community services, compared to women who received no visits. The number of prenatal visits was significantly higher in the intervention group, but an increased number of prenatal visits did not correlate with a reduced rate of low birth weight. Despite previous research, the family function screen was not an effective predictor of low birth weight in our study. A revised equation involving a history of previous premature birth, smoking, and a low maternal weight-height ratio did predict low birth weight. These findings question the utility of short-term psychosocial interventions for influencing low birth-weight rates in low-income black clinic populations. The family function screen was not cross validated. Integration of any psychosocial intervention with the routine prenatal care occurring in the obstetrical clinic is suggested for future research.


Inflammation on the cervical Papanicolaou smear: the predictive value for infection in asymptomatic women.

The clinical significance of inflammation on the cervical Papanicolaou (Pap) smear of asymptomatic women is unknown. This study assessed the possible association between inflammation on Pap smears with the presence of cervical/vaginal pathogens. A questionnaire was given to 290 asymptomatic women seen for routine gynecologic examination, including Pap smear, in a primary care setting. The women were tested for the presence of Candida species, Trichomonas vaginalis, Gardnerella vaginalis, Neisseria gonnorrhoeae, and Chlamydia trachomatis. Recovery of Chlamydia and Trichomonas was more frequent in women with inflammation on Pap smear than in women without inflammation, but the positive predictive value of inflammation was only 7% for Chlamydia and 14% for Trichomonas. Seventy-one percent of the women with inflammation had no evidence of any of the organisms. After a 6-month follow-up period, women with inflammation on Pap smear were no more likely than their matched counterparts without inflammation to return for a clinic visit with symptoms of vaginitis. In this study, inflammation on Pap smear had a relatively low predictive value for the presence of vaginal pathogens in asymptomatic women.


Use of comprehensive geriatric assessment techniques by community physicians.

Research has shown that comprehensive assessment techniques have several clinical benefits for geriatric patients. The purpose of this study was to determine how frequently community practitioners used comprehensive geriatric assessment techniques to identify factors related to use of those techniques. The study group included 54% of the 100 community-based family physician preceptors who participate in the University of Mississippi's family medicine training programs. On-site interviews were conducted in each physician's office to measure the percentage of physicians who performed comprehensive geriatric assessment. The majority of physicians employed some selected age-related assessment techniques, but less than 25% performed functional assessment techniques considered unique to the geriatric patient, such as mental status assessment and evaluation of activities of daily living. Most physicians' personal and practice characteristics were unrelated to the use of assessment techniques. Although many physicians use some techniques of geriatric assessment, most practicing physicians do not perform comprehensive assessment of geriatric patients.


From hospital to home: elderly patients' discharge experiences.

Little is known about the effect on elderly patients of the transition that occurs upon discharge from the hospital to the patients' homes. This report describes hospital discharge as experienced by a group of elderly patients. Qualitative research techniques were used to study the effect of hospital discharge on 12 patients, 12 caregivers, and 62 health professionals involved in the process. Research methods included interviews, observation of participants, and review of pertinent documents. Findings indicate that the patients' mindsets and family relationships contribute to the discharge experience. Problems with communication among members of the health care team created problems in the discharge process. The opinions of health professionals and patients' family members sometimes differed regarding appropriateness of various facets of the discharge process. The findings suggest that there is a need to better facilitate communication and coordination of the hospital discharge process for elderly patients.


Voices from family medicine: Theodore Phillips. Interview by William B. Ventres and John J. Frey.

Ted Phillips has had a remarkable career in medicine. He practiced in a rural Alaskan town, helped build the University of Washington's Department of Family Medicine as its founding chair, labored as an associate and acting dean at the university, and, more recently, returned to clinical practice part time on a small island in Washington state and travels to the University of Washington to direct the course on introduction to clinical medicine. Dr. Phillips was president of the Society of Teachers of Family Medicine in 1978-1979 and received the Society's Certificate of Excellence in 1981. He currently serves as the only community-based physician on the National Advisory Council of the Agency for Health Care Policy and Research. This transcript is an abridged version of interviews conducted in April and June 1992.


Entry of US medical school graduates into family practice residencies: 1991-1992 and 11-year summary.

This is the 11th report prepared by the American Academy of Family Physicians on the percentage of each medical school's graduates entering family practice residency programs. Approximately 10.3% of the 15,499 graduates of US medical schools between July 1990 and June 1991 were first-year residents in family practice in October 1991. This compares to 10.7% the previous year. The West North Central region reported the highest percentage of medical school graduates who were first-year residents in family practice programs in October 1991 at 15.3%; the Middle Atlantic and New England regions continued with the lowest percentages. Graduates from publicly funded medical schools were more than twice as likely as those from privately funded schools to be first-year residents in family practice in October 1991, 12.9% compared to 6.2%. Approximately half of medical school graduates entering their first year of family practice residency training in October 1991 selected a program in the same state as their medical schools. This report includes the average percentage for each medical school for the last 11 years, as well as the number and percentage of graduates from osteopathic schools who entered ACGME-accredited family practice residency programs.


Results of the 1992 National Resident Matching Program.

After 4 years of declining fill rates through the National Resident Matching Program (NRMP), 74 more positions in family practice residencies were filled in 1992 than in 1991, including 24 more filled with US seniors. The March fill rate (67.5%) increased for the first time since 1987, while the July fill rate (90.7%) increased for the first time since 1984. The Mountain and Pacific regions had the highest fill rates (89.1% and 88.5%, respectively) through the NRMP. Community-based, unaffiliated and university-affiliated programs filled 71.0% and 70.3% of positions offered through the NRMP. University-based and community-based, university administered programs filled 63.8% and 61.0% of positions offered through the NRMP. The other commonly defined primary care specialties of internal medicine and pediatrics also filled increased numbers of positions offered through the NRMP. This is the first year since 1984 in which all three primary care specialties matched more positions than in the previous year. The demand for family physicians in the United States is increasing. Evidence presented here suggests that 1992 may mark the beginning of a new trend toward increased interest in careers in family practice.


Upper respiratory infection: stress, support, and the medical encounter.

The purpose of this study was to examine the relationship between stress and social support to behaviors of patients and physicians during an episode of upper respiratory infection (URI). This was a cross-sectional study of 104 patients older than age 14 from three family practice sites; all of the patients had experienced a URI during an 8-week period. Stress scores were calculated for each patient's family using several standard instruments. Clinical and medical care utilization data were also reviewed. Data were analyzed to determine if there were relationships among stress and support scores and measures of patient and physician behaviors. Measures of stress and support were related to the use of medical services, seeking additional medical care, extra phone calls, and longer perceived duration of illness. Physicians prescribed more medications, ordered more laboratory tests, and scheduled more return visits for patients with high stress or low support scores. Stress and support are related to patient utilization of health services and perception of illness severity. Physicians respond to patients with high stress and low support by offering more medical services.


Short-term training in geriatrics: an alternative for family medicine?

Family medicine has responded to the need for training in geriatrics by creating geriatric fellowships and by including geriatric education in residency and medical school curricula. Fellowships, in particular, require extensive time commitment by participating physicians. We developed a 1-month geriatric training experience for academic family physicians. We surveyed previous participants in this short course to determine their subsequent level of activity in geriatrics, whether they had become certified in geriatrics, and other information about their academic experience in geriatrics. Eighty-one percent of graduates of this 1-month course had passed the geriatrics certification examination, compared to only 56% nationally. Graduates of the program were active as geriatric program directors and teachers of geriatrics, but there was limited activity in research or other scholarly activities related to geriatrics. Intensive short-term training in geriatrics meets some but not all of the needs for academic competency and productivity in geriatrics.


The effect of a medical journal club on residents' knowledge of clinical epidemiology and biostatistics.

We performed a prospective controlled trial of a monthly journal club to determine if it would increase pediatric residents' knowledge of clinical epidemiology and biostatistics. Intervention residents received two didactic sessions before the journal club started. Eight monthly journal club sessions followed. Pediatric residents at another institution served as controls. Intervention and control residents completed a pre- and post-test on clinical epidemiology and biostatistics. Neither the intervention nor the control group showed a significant change in test scores over the 9-month period. A more intensive and more structured approach is needed to effectively teach clinical epidemiology and biostatistics to residents.


Prescribing behaviors of family physicians in the treatment of osteoarthritis.

Patients with osteoarthritis are frequently managed by family physicians. New evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) are no more effective than simple analgesics for treating osteoarthritis. The purpose of this study was to characterize the pharmacologic prescribing practices of family physicians for treatment of osteoarthritis. One hundred eleven Indian family physicians were asked to provide their initial treatment recommendations for a hypothetical patient who had uncomplicated osteoarthritis. Responses were analyzed and subsequently validated by an audit of actual cases managed by family physicians. The response rate was 78%. Of those responding, 97% chose NSAIDs as their first line of therapy. Physicians were more than twice as likely to use anti-inflammatory doses of these agents as they were to use analgesic doses. There were no significant differences between the results of the written simulation and the actual case audit (P = .4216). Family physicians generally treat osteoarthritis with NSAIDs, and they prescribe anti-inflammatory doses more than twice as often as analgesic doses. An audit of the actual practice behaviors of family physicians corroborated this prescribing pattern. This prescribing behavior may be inappropriate given evidence that simple analgesics are as effective as NSAIDs.


Voices from family medicine: Thomas Leaman. Interview by William B. Ventres and John J. Frey.

Thomas Leaman's relationship with the community of Hershey, Pa., extends over a period of 42 years. He began his commitment to that small central Pennsylvania community as one of its doctors; later he served as the first chair of the Department of Community and Family Medicine at the Pennsylvania State University School of Medicine in Hershey. He chaired the department from 1967 to 1987 and has been professor emeritus since that time. Dr. Leaman was president of the Society of Teachers of Family Medicine in 1982 and has continued to have an active role in many aspects of the Society, including the Long Range Planning and Medical Records Committees. He also served as a founding member of the Association of Departments of Family Medicine. This article is edited from interviews that occurred in May 1991 and July 1992.


Gene expression: nutrient control of pre- and posttranscriptional events.

Regulation of gene expression by specific nutrients has become a major frontier for the next generation of nutrition scientists. The techniques of molecular biology allow us to define nutrient needs, as well as the outcomes of nutrient excesses, in terms of events that govern gene transcription, mRNA processing, mRNA stability, and mRNA translation. Evidence is presented showing that dietary constituents specifically modulate the nuclear events governing gene transcription and transcript processing. For example, fatty acid synthase gene transcription is inhibited by specific polyunsaturated fatty acids; S14 and pyruvate kinase genes contain a specific carbohydrate response element; and editing of apo B-100 to apo B-48 is enhanced by dietary carbohydrate. Nutrients such as iron and glucose are shown to control mRNA stability and translational rates of certain transcripts by regulating the interaction of cytosolic proteins with specific nucleotide sequences. The data of this review clearly demonstrate that nutrients play an active and specific role in governing the expression of select genes.


Aerobic fermentation of glucose by trypanosomatids.

The consumption of glucose by trypanosomatid protozoa such as Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., and Crithidia spp. is characterized by the excretion of reduced products such as succinate, pyruvate, ethanol, L-alanine, or lactate (depending on the species) not only in anaerobiosis, but also under aerobic conditions. The "aerobic fermentation" of glucose is accompanied by a complete lack, or even a reversal, of the Pasteur effect. This peculiar catabolism is mediated by a so-far unique compartmentation of the glycolytic enzymes, most of which are placed in an organelle called the glycosome; by an almost complete lack of inhibitory controls at the level of hexokinase and phosphofructokinase; and by a central role of CO2 fixation through the reaction catalyzed by phosphoenolpyruvate carboxykinase. The production of fermentative products seems to be due to a relative inefficiency of the respiratory chain, which lacks NADH dehydrogenase and the first phosphorylation site and preferentially uses succinate as substrate.


Health promotion/disease prevention in family practice residency training: results of a national survey.

Patient screening criteria for health promotion/disease prevention have become widely available in recent years, but their effect on day-to-day practice has been somewhat limited, highlighting the importance of emphasizing health promotion in family practice residency training. To determine the extent and content of health promotion education in residency curricula and perceived shortcomings in this area, we conducted a survey of all 386 accredited family practice residency programs in the United States and Puerto Rico in February and April 1991, with a response rate of 80%. Program directors completed a two-page questionnaire on curriculum coverage of health promotion, subject areas included, and resources used. The survey found that 88% of residencies had a formal health promotion curriculum, with the most common topics being immunization protocols and hyperlipidemia and the least common topics being behavior change and compliance. American Academy of Family Physicians materials are the most common resources available in residencies, but the most frequently used is the US Preventive Services Task Force Report. Use of the latter resource varies by geographic location. Our study demonstrates that health promotion education is part of virtually all family practice residency training programs but also shows that use of available resources varies and that program directors find it difficult to help residents incorporate health promotion into day-to-day medical practice.


Toward a good death: an interpretive investigation of family practice residents' practices with dying patients.

Physicians' encounters with dying patients are often problematic. This study was designed to facilitate understanding of what happens when residents encounter dying patients. The research involved observing and interviewing 28 family practice residents as they worked with dying patients. The primary research technique was that of a grounded interpretive investigation. We found that working toward a "good death" was a central theme of the residents' everyday actions. At critical points, however, two important forces steered residents away from this central theme: biomedical technology and anxiety. Residents reacted to these forces by distancing, moving back toward a good death, or moving further from a good death. Understanding the oscillating course toward a good death will help residents, medical educators, and other physicians deal with dying patients and their families in more meaningful and satisfying ways.


p53: the ultimate tumor suppressor gene?

Alterations in the gene encoding the cellular p53 protein are perhaps the most frequent type of genetic lesions in human cancer. At the heart of these alterations is the abrogation of the tumor suppressor activity of the normal p53. In many cases this is achieved through point mutations in p53, which often result in pronounced conformational changes. Such mutant polypeptides, which tend to accumulate to high levels in cancer cells, are believed to exert a dominant negative effect over coexpressed normal p53. Extensive research on p53, especially in the course of the last 3 years, has already provided much insight into the biological and biochemical mechanisms that underlie its capacity to act as a potent tumor suppressor. There are now many indications that p53 may play a central role in the control of cell proliferation, cell survival, and differentiation. Nevertheless, despite the purported importance of p53 for such crucial processes, mice can develop apparently without any defect in the total absence of p53. This raises the possibility that p53 may become critically limiting only when normal growth control is lost.


Electromagnetic field effects on cells of the immune system: the role of calcium signaling.

During the past decade considerable evidence has accumulated demonstrating that nonthermal exposures of cells of the immune system to extremely low-frequency (ELF) electromagnetic fields (< 300 Hz) can elicit cellular changes that might be relevant to in vivo immune activity. A similar responsiveness to nonionizing electromagnetic energy in this frequency range has also been documented for tissues of the neuroendocrine and musculoskeletal system. However, knowledge about the underlying biological mechanisms by which such fields can induce cellular changes is still very limited. It is generally believed that the cell membrane and Ca(2+)-regulated activity is involved in bioactive ELF field coupling to living systems. This article begins with a short review of the current state of knowledge concerning the effects of nonthermal levels of ELF electromagnetic fields on the biochemistry and activity of immune cells and then closely examines new results that suggest a role for Ca2+ in the induction of these cellular field effects. Based on these findings it is proposed that membrane-mediated Ca2+ signaling processes are involved in the mediation of field effects on the immune system.


mRNA degradation in procaryotes.

The fast turnover of mRNA permits rapid changes in the pattern of gene expression. In procaryotes, many enzymes involved in mRNA degradation have been identified and some of these endo- and exo-ribonucleases are now being intensively studied. Some of the structural features of mRNA that influence decay rates have also recently been defined. Although important components of the decay pathway are still elusive, a coherent and simple model for mRNA decay has emerged in the last few years.


Biochemistry of carbohydrate-protein interaction.

Recognition of glycoconjugates is an important event in biological systems, and is frequently in the form of carbohydrate-protein interactions. To thoroughly understand these interactions, well-defined carbohydrate ligands must be available. Naturally derived glycoconjugates can be highly purified, and their structures (including conformational structures) can be elucidated to provide such ligands. This requires highly effective methods of separation, such as various forms of high-performance liquid chromatography. Alternatively, structurally well-defined glycoconjugates can be synthesized for this purpose. These include conjugates of carbohydrate derivatives to proteins, lipids, and nonbiological carriers and polymers. The efficacy of these conjugates is amply demonstrated in the studies of carbohydrate-binding proteins from animals. Hepatic carbohydrate receptors, requiring calcium for binding, recognize only the terminal sugar residues. Although different sugar specificities are manifested by different species, there is some commonality in the requirement of the substituents of the sugar rings. Clustering of the target sugars in proper geometric arrangement greatly enhances the binding by these proteins. Some other animal carbohydrate-binding proteins, however, may require penultimate sugars for optimal binding.


Mechanisms of lead neurotoxicity, or looking beyond the lamppost.

Despite several decades of research on the neurotoxicology of lead and its continued prominence as a major environmental and occupational health hazard, the mechanisms of its toxic action in the nervous system are still unknown. The differential effects of lead exposure in young children and adults, as well as inconsistencies between in vivo and in vitro studies, suggest that lead toxicity may have multiple mechanisms in the central nervous system (CNS). Two are: neurodevelopmental toxicity, possibly involving interference with cell adhesion molecules, resulting in miswiring of the CNS during early development and possibly permanent dysfunction; and neuropharmacological toxicity, which might involve interactions between lead and calcium and lead and zinc, resulting in interference with neurotransmission at the synapse. This may be reversible.


Membrane immunoglobulin and its accomplices: new lessons from an old receptor.

B lymphocytes express multisubunit receptors for antigen that play multiple roles in generation of the immune response. These receptors act as transmembrane signal transducers but also act to capture, concentrate, and internalize antigen for subsequent proteolytic processing and presentation to T cells. During the past decade great progress has been made in our understanding of the extended structure of the receptor and the molecular basis by which it transduces signals. It is now clear that the B cell antigen receptor is a complex structure composed of antigen binding and transducer/transporter substructures. The antigen binding substructure is composed of disulfide-linked immunoglobulin H and L chains, and is noncovalently associated with transducer/transporter substructures composed of disulfide-linked heterodimers of alpha, beta, and gamma chain products of the mb-1 (alpha) and B29 (beta and gamma) genes. The cytoplasmic tails of these chains associate with src-family tyrosine kinases including fyn, lyn, blk, and lck and other SH2-containing molecules such as phosphatidylinositol 3-kinase. Available evidence indicates that these interactions are mediated via an amino acid sequence motif of approximately 22 amino acids that is found in both alpha and beta chains. Receptor ligation triggers the activation of multiple receptor-associated src-family kinases leading to phosphorylation and activation of PLC gamma 1 and PLC gamma 2. Subsequent phosphoinositide hydrolysis and calcium mobilization, presumably acting in concert with other tyrosine kinase-activated mechanisms, leads to transcriptional activation of a number of immediate early genes and, ultimately, to B cell proliferation.


[The estrogen-androgen profile is unchanged in men with cholelithiasis].

It is well established that cholelithiasis is more frequent in women than in men. This difference is usually explained by the effects of estrogens and progesterone on the metabolism of bile acids, biliary cholesterol secretion and saturation, and gallbladder motility. Another explanation could be a protective effect of androgens against cholelithiasis in men. To test this hypothesis, we determined the hormonal, androgenic and estrogenic, status of 15 male patients with asymptomatic gallstone disease and in 15 control patients with normal gallbladder matched for age and body weight. No significant difference in the plasma concentrations and the urinary excretion rate of sex hormones (testosterone, dihydrotestosterone, androstenedione, testosterone and androstanediol glucuronides, estradiol, estrone, total estrogens), as well as in the plasma sex hormone binding globulin, was found between the 2 groups of patients. The development of cholelithiasis in men, therefore, does not appear to be related to modification of sex steroids.


[Celioscopic cholecystectomy. A survey of the French Society of Endoscopic Surgery and Operative Radiology. Apropos of 937 cases].

Twenty-eight surgeons, members of the Société Française de Chirurgie Endoscopique et de Radiologie Opératoire, took part in this multicenter study, carried out between March 1989 and January 1991. Nine hundred and thirty-seven patients were entered into the study, 934 of whom presented with biliary lithiasis and 3 with gallbladder polyps. Biliary colic was found in 918 (98 percent) of patients. One hundred and twenty-five patients (13.3 percent) presented with acute cholecystitis. Laparoscopic cholecystectomy had to be converted to traditional laparotomy in 50 cases (5.3 percent). The most frequent causes of conversion were the presence of cholecystitis (34 percent) and the occurrence of hemorrhage which could not be controlled laparoscopically (18 percent). There was one death (mortality rate: 0.1 percent) and there were 37 postoperative complications (morbidity rate: 3.9 percent) which required reoperation in 11 instances: 4 laparatomies, 5 laparoscopies and 2 ultrasonography guided drainages. The mean duration of postoperative hospital stay for patients without complications or conversion was 3.8 days. These results show both the limits and the advantages of laparoscopic cholecystectomy. This new technique is now well established and should be added to other therapies used in the treatment of patients with biliary lithiasis.


[Effect of the severity of liver disease on renal hemodynamics and renal oxygen consumption in patients with cirrhosis].

In patients with cirrhosis, it has been shown that abnormal systemic and splanchnic hemodynamics and systemic oxygen (O2) consumption are related to the severity of liver disease. Little is known on the relationship between the severity of cirrhosis, on one hand, and renal hemodynamics and O2 consumption, on the other. We measured renal hemodynamics and renal O2 consumption in 31 patients Pugh's grade A and B and in 13 patients grade C. Systemic and splanchnic hemodynamics as well as systemic O2 consumption were studied. Renal blood flow, glomerular filtration rate, and renal O2 consumption were not significantly different between grades A and B and grade C patients. The renal fraction of systemic O2 consumption was higher (11.4 +/- 5.9 vs 7.9 +/- 4.1 percent respectively; P less than 0.05) and the systemic O2 consumption (111 +/- 23 vs 128 +/- 26 ml.min-1.m-2 respectively; P less than 0.05) lower in patients with grade C than in grades A and B patients. The degree of systemic hyperkineticism and portal hypertension was related to the severity of cirrhosis. In our patients, renal hemodynamics and renal O2 consumption were not related to the severity of cirrhosis. However, liver failure was associated with an increased renal fraction of systemic O2 consumption due to unchanged renal O2 consumption and decreased systemic O2 consumption.


[Surgery of the esophagus under thoracoscopy. Study of feasibility].

An experimental study of thoracoscopic surgery on the esophagus was conducted in 11 animals. Complete dissection of the esophagus was carried out in the ten last cases. Other procedures performed included mode picking, truncal vagotomies, and myotomies. The thoracoscopic esophageal surgery might allow to decrease the morbidity of thoracotomy. Its interest, compared with other methods of dissection without thoracotomy, has to be evaluated.


A prospective study on duodenogastric reflux and on histological changes in gastric mucosa after cholecystectomy.

The authors carried out a prospective study to evaluate variations with time in postcholecystectomy duodenogastric reflux (expressed as "fasting bile reflux" in mumol/h) and in gastric mucosal damage. Ten patients underwent (before cholecystectomy, 6 months after surgery and after a median period of 4 years from surgery) a gastric drainage to assess total (enzymatic method) and single (high performance liquid chromatography) intragastric bile acids, and a gastroscopy with biopsies of the antrum and gastric body to assess histological damage to the mucosa. The results showed that there was a progressive increase in the fasting bile reflux of total bile acids with time (precholecystectomy median value 0.295 mumol/h; 6 months control median value 12.045 mumol/h; late control medial value 19.9 mumol/h; Friedman test, P = 0.0022). Examination of the gastric mucosa at the three moments of the study showed that histological damage worsened progressively. In fact chronic atrophic gastritis of the antrum was present in 10 percent of cases before surgery and in 50 percent 4 years after, and the prevalence of chronic superficial gastritis of the body progressed from 0 to 40 percent. Studies on larger groups of patients are necessary to evaluate whether these two phenomena are correlated.


Effects of alverine on the spontaneous electrical activity and nervous control of the proximal colon of the rabbit.

To analyse the mechanisms of the antispasmodic action of alverine, the effects of this drug on the spontaneous motility and nervous control of the proximal colon of the rabbit were studied in vivo. The electrical activity of the colonic smooth muscle was recorded using extracellular electrodes. The parasympathetic efferents were activated by electrical stimulation of distal ends of the vagus nerves. Alverine given intravenously inhibits spike potentials without modifying the slow waves. Excitatory and inhibitory responses induced by parasympathetic efferent stimulations, as well as the hyperpolarization due to intraluminal distension, were also blocked after drug injection. Our results show that alverine is able to block the spontaneous contractions and the nervous control of rabbit proximal colon, indicating that this drug has powerful antispasmodic effects.


[Assessment of the practice of adjuvant radiotherapy in cancer of the rectum in the department of Calvados].

The effectiveness of adjuvant radiotherapy (ART) in the treatment of rectal cancer (RC) is established for the local control of the tumor, but doubt remains as concerns improvement in survival. The aim of this work was to assess the present techniques and trends of ART in a French department based on a population-based study. From 1978 to 1986, 616 cases of RC were diagnosed in the department of Calvados (France). Tumor was removed in 346 patients (56 percent). Of these 346 cases, 29 percent were irradiated, 3/4 postoperatively and one forth preoperatively. Besides sex and age, the type of surgery (anal sphincter saving or not) and Dukes' tumor stade had an influence on the performance of ART. Thirty-one percent Dukes B tumors and 42.1 percent of Dukes C tumors were irradiated. The practice of ART for these tumors increased significantly from 1978 (18.5 percent) to 1986 (60 percent) (P less than 10(-4)). However, the practice and the distribution of centers performing ART were heterogenous within the department of Calvados. This heterogeneity was neither due to the environment (urban/rural) of the patient nor to the distance between the place of residence and the radiation therapy center. Such an heterogeneity could be explained only by the lack of consensus concerning the practice of ART. Such a consensus could be found considering the results of the latest controlled clinical trials, but definitive conclusions are needed about the effectiveness of ART on the improvement of survival.


[Prevalence of anal incontinence in adults].

Inquiries were conducted to determine the prevalence of anal incontinence in a) the general population over 45 by a gallup poll studying 1,100 persons (A); b) 3,914 patients seen by their general practitioner or their gastroenterologist during the same week (B); c) 500 patients consulting for urinary stress incontinence (C1); d) 1,136 neurological patients suffering from micturation disorders (C2); and e) 10,157 elderly persons living in retirement homes or in hospital (D). In the general community (A), the prevalence of anal incontinence, including gas and stool incontinence, was 11 percent, the prevalence of fecal incontinence, 6 percent, the prevalence of daily or weekly fecal incontinence, 2 percent; prevalences were respectively 15.5 percent, 7.9 percent, and 3.2 percent in group B, and 27 percent, 9 percent and 3.8 percent in group C1. The prevalence of fecal incontinence was 18 percent in group C2 and 33 percent in group D. Prevalence did not depend on age in group A and C1, but was twofold higher in group C1 than in group A. The prevalence increased with age in groups B and D.


[Severe hepatitis with encephalopathy induced by acetylsalicylic acid in a case of lupus erythematosus disseminatus].

The observation of a 62 year-old woman who had been suffering from arthritis for several years and in whom treatment with high doses of acetylsalicylic acid resulted in severe acute hepatitis is reported. Clinical and serological findings led to the diagnosis of systemic lupus erythematosus complicated by acute drug induced hepatitis.


[Rupture of the distal thoracic esophagus by closed trauma].

Closed traumatic rupture of the esophagus is uncommon, usually located in the upper third of the esophagus. We report a case occurring in the lower third. This diagnosis must be envisaged when faced with delayed clinical and radiological signs. The prognosis is severe and the therapeutic decisions are controversial.