Minimal Histological Changes Research Articles

Role of cyclosporine in glomerular diseases.

Clinical researchers are beginning to use the immunosuppressive agent cyclosporine to treat a variety of immunologically mediated diseases. To review the clinical experience with cyclosporine in the nephrotic syndrome and in lupus nephritis. Most studies to date have been small or uncontrolled, or both. Nevertheless, cyclosporine appears to produce remissions in adults and children with the nephrotic syndrome with minimal histologic changes ("minimal-change disease"). It also appears to produce remissions in children with focal and segmental glomerulosclerosis; it is less effective in adults and in individuals with focal and segmental glomerulosclerosis that is resistant to steroids. It appears to reduce proteinuria and to slow the progression of renal insufficiency in membranous glomerulonephritis but has little beneficial effect in IgA nephropathy. Anecdotal experience in patients with lupus nephritis suggests cyclosporine produces an improvement in symptoms, a decrease in protein excretion, and improvement in renal function when other treatments have failed. Cyclosporine's pharmacokinetic properties vary widely with the age of the patient and the presence of concomitant diseases and drugs. Relapses are common after the drug is stopped, and nephrotoxicity is a real risk with prolonged treatment. Cyclosporine shows promise in treating immunologically mediated glomerular diseases, but larger randomized studies will be needed to define its role in this setting. Physicians should become more familiar with this drug as its indications increase.

Effects of GaAs and Ga2O3 on magnetometric behavior of iron oxide particles in rabbit lungs

AbstractIntratracheal instillation of a GaAs suspension has been histopathologically shown to induce a diffuse pulmonary response. In the present study, magnetometry was used to evaluate the effects of intratracheally instilled GaAs and Ga2O3 on the behavior of externally magnetized iron oxide (Fe3O4) particles instilled in rabbit lung. Magnetometric evaluation of the effects of GaAs in rabbits dosed with 30 mg or 300 mg per animal showed a significantly decreased relaxation of iron oxide particles at 1, 3, 7, 14, 21 and 28 days following instillation compared with the controls. On the other hand, in the rabbits exposed to Ga2O3, significantly reduced decay constants were observed only on the first and third days following instillation.Relaxation indicates a rapid decrease of remanent magnetic field following magnetization of the lungs due to random rotation of phagocytosed iron oxide particles in macrophages.Clearance of the iron oxide particles was measured by serial determinations of the remanent magnetic field at the end of magnetization estimated from relaxation curves. Clearance was significantly impaired at 14, 21 and 28 days after instillation in rabbits exposed to both doses of GaAs. Slightly delayed clearance was also observed in rabbits exposed to Ga2O3.Histological examination of lungs instilled with GaAs indicated active phagocytosis of GaAs and iron oxide particles by pulmonary macrophages, as well as pneumonocytes hyperplasia with marked thickening of the alveolar walls. Minimal histological changes with retention of iron oxide particles were found in the lungs exposed to Ga2O3.

Lack of detectable enhanced pulmonary histopathology in cotton rats immunized with purified F glycoprotein of respiratory syncytial virus (RSV) when challenged at 3–6 months after immunization

The cotton rat model has been used to evaluate the potential for immunogens to induce respiratory syncytial virus (RSV)-enhanced pulmonary histopathology. A recent study evaluated purified F protein in this model when animals were challenged intranasally with RSV 3 or 6 months after immunization. The authors concluded that the purified F protein was associated with the same level of histopathological changes as observed with the positive control, a formalin-inactivated RSV immunogen. Three pathologists have independently evaluated the lung sections from the animals of this study and the results are reported in this article. In contrast to the previously published data, we have found that F protein was associated with a substantially milder and qualitatively different response to that observed with the formalin-inactivated RSV vaccine. We concluded that the minimal histological changes observed and lack of clinical disease make it very difficult to assess the issue of enhanced pulmonary RSV disease with the cotton rat model.

The role of Kupffer cells in complement activation in D-Galactosamine/lipopolysaccharide-induced hepatic injury of rats.

To investigate the role of Kupffer cells in complement activation, we used a rat model of acute hepatic injury induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). In in vivo study, minimal histological changes were observed after i.p. GalN (200 mg/kg) single administration. Complement hemolytic activity (CH 50) decreased to 70% of its initial value 2-3 h after i.p. LPS (1.5 mg/kg) single administration. Massive hepatic necrosis was induced by simultaneous administration of GalN and LPS. After 2-3 h, CH 50 decreased to 70% of its initial value, and deposition of C3 fluorescence (C3) was observed in Kupffer cells. After 4 h, GPT was greatly increased (1286 +/- 240 IU/l), CH 50 was further reduced, and C3 was observed on hepatocyte membranes and in the cytosol. In in vitro study, we used hepatocyte cultures and co-cultures of hepatocytes and Kupffer cells to investigate the participation of GalN, LPS, complement, and Kupffer cells in hepatic cell necrosis. We found no increase of LDH (% leakage) when LPS and complement were added to the medium (22.7 +/- 5.7%). A moderate increase was observed with the addition of GalN (33.2 +/- 2.6%). A remarkable increase was observed only with the addition of GalN, LPS, and complement to the co-culture (50.0 +/- 8.8%). These results suggest that Kupffer cells activated by LPS are very important in promoting acute hepatic injury by complement.

Cocaine-induced alterations in prostaglandin production in rabbit aorta

To determine if alterations in endothelial prostaglandin production occur after long-term cocaine use, 26 New Zealand White rabbits were randomized to a low fat diet with (n = 12) or without (n = 14) daily intravenous cocaine (2 mg/kg body weight). Rabbits were killed at 6 or 12 weeks. Segments of aorta were examined in blinded manner for histologic changes. Additional slices were incubated in oxygenated Krebs buffer and release of 6-keto-prostaglandin F1 alpha, thromboxane B2 and prostaglandin E2 was assayed by radioimmunoassay. Minimal intimal histologic changes were seen in the aorta of three cocaine-treated rabbits. At 12 weeks 6-keto-prostaglandin F1 alpha was increased in the cocaine group (p = 0.063) as compared with levels in the control group. When rabbits killed at 6 and 12 weeks were considered together, increases in thromboxane B2 (p = 0.044) and a trend to increased prostaglandin E2 (p = 0.083) were seen in the cocaine group. The ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was increased in the cocaine group compared with that in the control group (p less than 0.02). These data suggest that an increase in prostaglandin production occurs in the vascular endothelium of rabbits ingesting cocaine before gross histologic changes are evident. In addition, thromboxane B2 increases disproportionately with respect to 6-keto-prostaglandin F1 alpha, suggesting that a milieu for thrombosis may exist in users of cocaine.

Variation in hepatic estrogen receptor concentrations in patients with liver disease. A multivariate analysis.

Hepatic estrogen receptor concentrations were measured in liver biopsy specimens from 102 patients (58 women and 44 men) with liver disease and correlated to several clinical, biochemical, and histologic background variables by means of multiple regression analysis. Half of the tissue was processed for histologic evaluation with a semiquantitative registration of histologic characteristics, whereas the other part was used for receptor analysis by enzyme immunoassay. Fifteen patients with no or minimal histologic changes served as controls. The analysis shows that the reduced estrogen receptor concentrations observed in patients with chronic liver diseases reflect the degree of liver dysfunction and not the specific type of liver disease. Serum albumin, log serum bilirubin, log serum alkaline phosphatases, and the degree of parenchymal fibrosis were significantly related to hepatic estrogen receptor level in the final regression model, but only part of the variation can be explained by these variables, and other factors must be of importance.

Scintigraphic evaluation of myocardial uptake of thallium 201 and technetium 99m pyrophosphate utilizing a rat model of chronic doxorubicin cardiotoxicity

To evaluate the usefulness of myocardial scintigraphy as a monitoring tool for chronic doxorubicin (DXR) cardiotoxicity, a rat model was used to investigate the relationship between the myocardial uptake of thallium 201 (Tl) or rechnetium 99m pyrophosphate (99mTc-PPi) and histological changes of the heart. Although there was no significant difference in myocardial Tl uptake between control and DXR-treated rats at an early phase after Tl injection, late-phase Tl uptake was significantly higher in the DXR-treated rats than in the control rats, indicating a slow wash-out of Tl from the myocardium. The wash-out rate calculated from scintigraphic examination of DXR-treated rats was significantly decreased with increasing degree of cardiomyopathy. Since the Tl wash-out rate was sharply decreased even in animals with minimal histological changes, it may be a possible monitoring tool for the early detection of chronic DXR cardiotoxicity. On the other hand, myocardial 99mTc-PPi images could be obtained only in rats with severe myocardial changes and hence would not useful for early detection.

The mechanism of heart failure caused by cardiac allograft rejection

Rejection of the cardiac allograft is often associated with reversible myocardial failure, the mechanism of which is not understood. We have examined this phenomenon in a small animal model that provides the opportunity for multimodality study of the rejection process. Heterotopic cardiac transplantation was performed in the Lewis rat with Lewis X Brown-Norway (allografts) or Lewis (isografts) donors. Without immunosuppression, allografts are completely rejected in 6 to 8 days. At 3 days cardiac grafts were explanted and mounted on a modified Langendorff apparatus for functional measurements or submitted for pathologic examination and biochemical determination of high-energy phosphates. Three-day isografts (n = 9) had minimal histologic changes. Pathologic examination of 3-day allografts (n = 13) showed lymphocytic infiltrate and myocyte necrosis, histologic features for which antirejection treatment is usually given clinically. For grafts subjected to functional studies (n = 11), heart rate, cardiac output, coronary flow, and stroke work were determined at baseline and in response to isoproterenol (3 x 10(-8) mol/ml). Three-day allografts (n = 6) and isografts (n = 5) had similar baseline function. The chronotropic response to isoproterenol was similar in allografts and isografts, but allografts had diminished cardiac output and stroke work after isoproterenol. Adenosine triphosphate levels were normal (41.9 nmol/mg) in 3-day allografts (n = 4). We have evaluated functional, biochemical, and pathologic changes associated with myocardial dysfunction during heterotopic cardiac transplant rejection in a small animal. This model reproducibly demonstrates diminished contractile reserve in 3-day allografts with normal baseline function and high-energy stores but histologically significant rejection.

Hepatocyte expression of HBcAg and serum HBeAg in hepatitis B: comparison of polyclonal and monoclonal antibodies during a trial of interferon.

The distribution and quantitative expression of HBcAg in relation to serum HBeAg and liver histology before and after a trial of interferon in 50 patients with chronic type B hepatitis were evaluated using polyclonal and monoclonal antibodies. In general, both antisera showed a similar pattern in terms of the distribution of HBcAg, with predominant localisation of HBcAg in the cytoplasm in HBeAg positive patients with chronic active hepatitis. Semiquantitative analysis showed, however, that there was a higher degree of cytoplasmic expression of HBcAg with polyclonal than with monoclonal anti-HBc. Some of the HBeAg positive patients with only a focal expression of HBcAg in the cytoplasm by polyclonal anti-HBc showed no expression of HBcAg with monoclonal anti-HBc. The expression of HBcAg with polyclonal anti-HBc correlated better with the histological features of chronic active hepatitis or the persistence of serum HBeAg on follow up, suggesting that it did not result from non-specific or false positive staining. All of the HBeAg negative patients with minimal histological changes or inactive cirrhosis were HBcAg negative with both antisera. In conclusion, though both polyclonal and monoclonal antibodies produced a quite similar distribution of HBcAg in patients with chronic type B hepatitis, polyclonal antibody seemed to be more sensitive in detecting HBcAg in the cytoplasm than did monoclonal anti-HBc, and the expression of HBcAg with polyclonal anti-HBc correlated better with the clinical and histological outcome.

Hepatic Radiation Injury in the Rat

The whole livers of rats were exposed intraoperatively to graded doses (0 to 75 Gy) of 137Cs gamma radiation. At various times (0 to 155 days) after liver irradiation, minimally invasive, nondestructive tests (rose bengal retention and plasma alkaline phosphatase, glutamic-oxaloacetic acid transaminase, glutamic-pyruvic transaminase) were performed on at least half the surviving animals in each dose group to assess developing liver injury. Liver histology was done on animals sacrificed 96 to 100 days after irradiation. Radiation damage to the stomach killed approximately 50% of the animals 30 to 60 days after exposure to doses of 25 Gy or higher. These deaths were significantly reduced when care was taken to shield the stomach during irradiation. Stomach injury did not, however, appreciably affect liver function as measured by rose bengal retention. Whole-liver irradiation to 15 Gy resulted in reduced liver size and minimal histological changes, but did not result in increased rose bengal retention or plasma alkaline phosphatase concentration. The next highest dose group studied (25 Gy) showed significant histological abnormalities and liver injury as measured by increased rose bengal retention and liver enzymes. The latent period for development of hepatic injury, as measured by increased rose bengal retention, was 35 to 42 days and was relatively invariant over the 25- to 75-Gy dose range. Hepatic vein lesions and cellular necrosis were the most prominent histological lesions observed in 25-Gy-irradiated liver.

Asymptomatic Low Molecular Weight Proteinuria in Children

We reviewed the clinical features in 7 boys with asymptomatic low molecular weight proteinuria. The disease had first been reported by us in 1980. The distinctive features common to all patients were male dominance, asymptomatic proteinuria with a large amount of low molecular weight proteins, normal development and growth, normal renal function tests in childhood, and minimal histological changes in renal biopsy specimens. In 1990, 35 cases have been reported in Japan. Thus, asymptomatic low molecular weight proteinuria is not a rare disease and is one of the causes of isolated proteinuria. Furthermore, this condition is recognized as a new entity.

Learning impairment and microtubule-associated protein 2 decrease in gerbils under chronic cerebral hypoperfusion.

A coiled stainless steel wire clip was made that allowed us to chronically reduce cerebral blood flow in Mongolian gerbils. After 6 weeks of reduced cerebral blood flow in 15 experimental gerbils, we evaluated their learning ability and found it to be impaired relative to that in 15 control gerbils. Eight weeks after surgery, regional cerebral blood flow in the parietal cortex measured by the hydrogen clearance method in the experimental gerbils was 73-76% of that in the control gerbils. Light microscopy showed minimal histologic changes in the brains of the experimental gerbils. Concentrations of brain proteins analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that among water-soluble brain proteins, the concentrations of cytoskeletal proteins (microtubule-associated protein 2, calspectin, and clathrin) declined in the experimental gerbils. In particular, the concentration of microtubule-associated protein 2 declined significantly. Our findings show that the reduction of cerebral blood flow via carotid stenosis impairs the learning behavior in gerbils, with an associated decrease in the concentration of microtubule-associated protein 2. We believe that Mongolian gerbils with chronically reduced cerebral blood flow are a useful animal model of chronic brain hypoperfusion.

Clinical and Molecular Evaluation of Acetowhite Genital Lesions in Men

A total of 108 male partners of women with cervical condyloma and/or dysplasia underwent evaluation for gross and subclinical condyloma via acetic acid screening with a magnified examination. Biopsies of acetowhite genital skin were obtained for histological and deoxyribonucleic acid hybridization analysis. Of the men 52 (49%) had acetowhite lesions and underwent biopsies, 44 of which were evaluable by histological and deoxyribonucleic acid analyses. Of the lesions 12 had features of condyloma or penile intra-epithelial neoplasia, among which 7 (58%) contained human papillomavirus deoxyribonucleic acid. The remaining 32 lesions revealed minimal histological changes sometimes suggesting condyloma. However, only 5 of the 32 biopsies (16%) contained human papillomavirus deoxyribonucleic acid. A tendency to overdiagnose condyloma based on histological findings is suggested. Criteria by which to identify best human papillomavirus-related morphology are presented.Acetowhite genital epithelia with minor (nonspecific) histological changes correlate poorly with human papillomavirus nucleic acids and in most cases do not represent disease involving common viral types. The application of appropriate histological criteria appears to be particularly relevant to management strategies that avoid overtreatment of minor epithelial abnormalities. It remains unclear whether acetowhite genital epithelia positive for human papillomavirus require treatment given the high tendency for recurrence and lack of demonstrated effect on the natural history of cervical carcinoma. (J. Urol, 143: 920−923, 1990)

Radiologic and Histologic Investigation of Pulmonary Oxygen Toxicity in Newborn Guinea Pigs

The hypothesis that pulmonary oxygen toxicity is radiographically demonstrable was tested by serially radiographing 23 newborn guinea pigs maintained in a 96 to 100% oxygen environment at normal atmospheric pressure. All animals died in the increased-oxygen environment by six and one-half days. Nineteen showed characteristic radiologic progression of disease to death. Graded histologic changes in the lungs, particularly at the bronchiolar level, correlated strongly with the duration of 96 to 100% oxygen exposure (correlation coefficient, 0.90, P < 0.001). Duration of life in 96 to 100% oxygen was directly related to birth weight, but not to sex. Seventeen control newborn guinea pigs maintained in room air showed no radiologic evidence of disease and minimal histologic changes.

Lovastatin Ameliorates the Development of Glomerulosclerosis and Uremia in Experimental Nephrotic Syndrome

The nephrotic syndrome was induced in uninephrectomized Sprague-Dawley rats using repeated injections of puromycin and protamine sulfate. Preliminary studies demonstrated that the administration of lovastatin (4 mg/kg body weight [BW] subcutaneously [SC] daily) was effective at lowering plasma cholesterol over a 63-day period, although not to normal values. Subsequently, two groups of rats that had been made nephrotic were studied; one group (n = 8) received lovastatin, the other (n = 9) received the vehicle alone. Blood and urine collections were made at days 0, 23, and 60. Clearance studies and renal histology were obtained at day 60. Lovastatin-treated rats had significantly lower cholesterol at day 23 and 60 than vehicle-treated rats (270.5 +/- 39.7 v 501.7 +/- 81.9 and 148.2 +/- 10.7 v 268.2 +/- 40.8 mg/dL, P less than 0.05). Both groups of rats developed equivalent degrees of proteinuria and hypoalbuminemia. At day 60, the lovastatin-treated rats had a lower urea: 18.3 +/- 4.1 v 55.8 +/- 9.6 mmol/L (blood urea nitrogen [BUN] 51.2 +/- 111.5 v 156.2 +/- 27.0 mg/dL, P less than 0.02) and greater unulin clearance (1.83 +/- 0.42 v 0.82 +/- 0.41 mL/min/kg BW, P less than 0.05) than the vehicle-treated rats. Neither group was hypertensive and the blood pressure (BP) was similar in both groups. The percentage of glomeruli showing no changes or minimal histological changes was significantly greater in the lovastatin-treated group (26.5% +/- 5.7% v 8.33% +/- 3.33%, P less than 0.02), and there were more glomeruli with global sclerosis in the vehicle-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and Histologic Observations of Monoarthritis

Synovial biopsies were performed on 84 patients with monoarticular synovitis from 1960 to 1984. Twenty-seven (32%) of 84 patients were pathologically differentiated; however, the other patients remained classified as nonspecific monoarthritic. Follow-up studies of nonspecific monoarthritis ranging from five to 25 years (average, 15 years) were carried out in 34 patients. Five patients (15%) disclosed polyarticular involvement and were diagnosed as having classic rheumatoid arthritis (RA) within five years after initial biopsy (RA group). In the remainder (non-RA group), 19 patients recovered completely and nine of ten patients complained of a slight degree of joint involvement. A good prognosis was observed in younger patients and in those who showed minimal histologic changes in the synovium. Initial laboratory examinations, including a white cell count, erythrocyte sedimentation rate, C-reactive protein, and agglutination test, did not show any differences between the RA and the non-RA groups. To determine predicting factors for RA, a comparative histologic study of the initial specimens was performed. Specimens from the RA group showed a predominant appearance of lymphoid aggregates, high endothelial postcapillary venules, and proliferative plasma cell infiltration. These histologic features suggest the future appearance of RA; therefore, careful observation and early treatment should be considered for these patients.

Proteinuria selectivity index in Saudi children with nephrotic syndrome.

Proteinuria selectivity index (PSI) was determined in 54 Saudi children with nephrotic syndrome whose renal biopsy showed minimal change in 13 and non-minimal histologic changes in 41 patients. The selectivity was determined with two pairs of proteins, IgG/transferrin and IgG/albumin. There was considerable overlap in the values of PSI in patients with minimal and non-minimal histological changes. The clinical utility of PSI in differentiating minimal change nephrotic syndrome and non-minimal change nephrotic syndrome is low.

Serum levels of soluble tac peptide in acute and chronic hepatitis B virus infection

Serum-soluble Tac peptide was measured by an enzyme-linked immunosorbent assay in 12 patients with acute type B hepatitis, 33 patients with chronic type B hepatitis, and 15 age- and sex-matched controls. All 12 patients with acute type B hepatitis had elevated levels of soluble Tac peptide with a mean (±SD) of 1527 ± 432 U/ml, significantly higher than that of normal controls (264 ± 74 U/ml) or patients with chronic type B hepatitis (646 ± 399 U/ml). Serial follow-up showed that serum levels of soluble Tac peptide tended to return to normal 2–4 months after onset of acute hepatitis along with the normalization of alanine aminotransferase and seroconversion of hepatitis B surface antigen (HBsAg) to anti-HBs. Patients with chronic type B hepatitis also had significantly higher levels of soluble Tac peptide than normal controls, although only 63.6% ( 21 33 ) of them had a level greater than the upper limit of normal. Serum levels of soluble Tac peptide in patients with chronic type B hepatitis varied considerably with the inflammatity in liver. The hepatitis B e antigen (HBeAg)-positive patients with chronic active liver disease had significantly higher levels of soluble Tac peptide (928 ± 424 U/ml) than HBeAg-positive (412 ± 146 U/ml) or anti-HBe-positive (424 ± 175 U/ml) patients with chronic persistent hepatitis or minimal histological change. In addition, there was a significant positive correlation between serum levels of soluble Tac peptide and alanine aminotransferase. These findings suggested that activation of T cells might play an important role in the pathogenesis of acute and chronic type B hepatitis. Assay of serum-soluble Tac peptide might provide a simple and useful means to better understand the immune mechanisms of acute and chronic hepatitis B virus infection.

Local and Systemic Effects of Chronic Intracavernous Injection of Papaverine, Prostaglandin E1, and Saline in Primates

To compare the local and systemic effects of chronic intracavernous injection of papaverine, prostaglandin E1, and saline on erectile tissue, eight pigtail monkeys underwent 75 injections over a nine-month period. Monkeys were divided into three groups; each group received papaverine (10 mg.), prostaglandin E1 (20 μg.), or saline (one ml.). The erectile response was closely observed for two hours after each injection to monitor the onset, degree, and duration of erection. Liver function tests were performed every three months to detect early systemic metabolic changes. After sacrifice, the simian penises were perfused in situ and examined histologically with both light and electron microscopy.Papaverine resulted in an initially strong erectile response, but this was maintained throughout the length of the study in only two monkeys. In contrast, prostaglandin E1 resulted in tumescence that was maintained in all monkeys over the nine-month period. In addition, the papaverine group had elevated liver enzymes and significant histologic changes with loss of normal architecture on both light and electron microscopy. The other two groups showed only minimal histologic changes or none. (J. Urol., 142: 403–408, 1989)

Effect of metronidazole on fertility and testicular function in male rats

The reproductive toxicology of metronidazole was studied in rats. Male Charles River Crl:CD(S-D)BR rats (10/group) were treated with metronidazole as a dietary admixture at doses of 0 (control), 25, 100, and 400 mg/kg/day for 8 weeks. The reversibility of effects after a 3 1 2 - month recovery period was determined in separate groups of 10 control and 10 rats treated with 400 mg/kg/day of metronidazole. After 2 and 4 weeks of metronidazole treatment, mating performance and fertility in treated and control animals were comparable. After 6 weeks of treatment, all high-dose rats were infertile; however, fertility in low- and middose rats was not affected. High-dose male rats killed after 8 weeks of treatment showed markedly decreased testicular and epididymal weights, and markedly decreased testicular spermatid counts and epididymal sperm counts. Most of the few epididymal sperm present in high-dose rats were viable, but morphologically abnormal. Histologically, severe degeneration of the seminiferous epithelium was observed in the testes of high-dose rats; the tubules were generally devoid of primary or secondary spermatocytes and spermatids. Rats treated with the low and middle doses of metronidazole exhibited normal testicular and epididymal weights, and normal testicular spermatid counts and epididymal sperm reserves. Epididymal sperm viability and morphology of treated and control animals were comparable. Minimal histologic changes were observed in the testes of middose rats, including degenerative fragmentation of spermatozoa and spermatids. In high-dose recovery rats, fertility was restored in most rats by 8 weeks after the cessation of treatment; however, the testicular and epididymal weights and sperm counts of rats killed after 3 1 2 months of recovery had increased but were still significantly decreased in treated rats as compared with controls. Histologically, spermatogenesis was observed in most tubules; however, a portion of atrophic tubules persisted. It is concluded that high doses of metronidazole produce infertility in the male rat through inhibition of spermatogenesis as early as the stage of the primary spermatocyte. This effect is partially reversible.