Evaluation of α-D-ribofuranose (D-ribose) toxicity after intravenous administration to rabbits.

Rapid intravenous administration of D-ribose may result in a significant reduction in cellular damage in patients with sudden ischemic insults. The development of an effective and clinically safe therapeutic regimen using the intravenous route in critically ill patients especially with cardiac diseases requires a comprehensive assessment of potential toxic effects of the drug in laboratory animals and in human beings. The potential clinical, behavioral, hematological, biochemical, gross pathological and histological toxic effects associated with the intravenous administration of D-ribose in rabbits for 28 days were evaluated in this study. Except for an increase in neutrophil percentage in male rabbits in the D-ribose-treated groups, there were no statistically significant toxic effects induced by daily intravenous administration of the drug in male and female rabbits. Results of this study suggest that D-ribose administered intravenously for 28 days in the rabbit exhibited no toxicity at 420 mg/kg.

Further investigation on meloxicam contraceptivity in female rabbits: luteinizing unruptured follicles, a microscopic evidence.

Meloxicam, a selective cyclooxygenase-2 inhibitor, was administered orally or intravaginally, to sperm-positive female rabbits to assess its effect on ovulation. A single oral dose (20 mg/kg), administered 5 h postcoitus resulted in 100% contraceptive rate. On the other hand, for females receiving meloxicam suppositories (14.9 mg/kg), 5 h postcoitus, the contraceptive rate was 62.5% compared to placebo. The decrease in the contraceptive effect of meloxicam suppository may be due to the rejection of the dose by some females. Corpora lutea, maternal plasma progesterone, ovary fresh weight and maternal body weight gain were not affected by meloxicam treatment compared to placebo. Histopathologically, the surface of the ovary of meloxicam-treated females appears irregular and dilated due to the presence of different-sized cysts. Some of the cystic follicles were retained ova. Further, immunohistochemical stains for estrogen and progesterone receptors showed positive staining in granulosa cells and the wall of the unruptured follicle. It is concluded that contraceptive effect of meloxicam in female rabbits resulted in a failure of follicular rupturing.

Histopathology of human intestinal anastomosis.

The faultless seal of the anastomosis is an important aspect of abdominal surgery but opportunities to make a histological evaluation of human intestinal anastomosis sites are rare. This retrospective study examined 30 anastomoses that had been resected following complications or postmortem; the aim was to describe the histological changes at various stages of healing ranging from 4 days to 3.5 years post-surgery. Anastomosis dehiscence showed features of extensive mucosal necrosis and bad submucosal apposition. Old healed anastomoses continued to have chronic inflammatory cells and muscular discontinuity with areas of intervening fibrosis. It would be useful to understand more about how the intraluminal contents are propelled through this scarred area.

Histopathology of human intestinal anastomosis

The faultless seal of the anastomosis is an important aspect of abdominal surgery but opportunities to make a histological evaluation of human intestinal anastomosis sites are rare. This retrospective study examined 30 anastomoses that had been resected following complications or postmortem; the aim was to describe the histological changes at various stages of healing ranging from 4 days to 3.5 years post-surgery. Anastomosis dehiscence showed features of extensive mucosal necrosis and bad submucosal apposition. Old healed anastomoses continued to have chronic inflammatory cells and muscular discontinuity with areas of intervening fibrosis. It would be useful to underst and more about how the intraluminal contents are propelled through this scarred area

Meloxicam inhibits rabbit ovulation.

The nonsteroidal antiinflammatory, selective cyclo-oxygenase-2 (COX-2) inhibitor, meloxicam, was tested to assess its effect on rabbit ovulation. Meloxicam in different doses was administered intraperitoneally (ip) to adult female Californian rabbits at 2, 5, 8, and 24 h postcoitus with sperm-positive rabbits. Rabbits were killed on Day 10 of gestation. Meloxicam produced significant inhibition of ovulation in rabbits. This inhibition of ovulation by meloxicam was dose- and time-dependent. Ovulation in rabbits was completely inhibited by a single ip administration of meloxicam (20 mg/kg) when the drug was administered at 2 and 5 h postcoitus, whereas neither ovulation nor implantation were inhibited (pregnancy rate 75%) by the same dose administered 24 h postcoitus (approximately 14 h post ovulation). Further, ovulation was completely inhibited by 10 mg/kg of meloxicam when the drug was administered at 5 or 8 h postcoitus, but there was less inhibition of ovulation when 10 mg/kg of the drug was administered at 2 or 24 h postcoitus (pregnancy rate 25 and 80%, respectively). Corpora lutea, maternal plasma progesterone, ovary fresh weight, and maternal body weight gain were affected by meloxicam treatment. Histopathological findings observed in the ovaries of treated rabbits included microscopic dilatation of graffian follicles, particularly mature follicles. Some of the follicles were cystically dilated in addition to severe hemorrhage within the follicles which lost ova. These results show that ovulation can be inhibited in rabbits by meloxicam. Further studies are needed to assess the value of selective COX-2 inhibitors as potential nonhormonal contraceptive agents.

Congenital nephrotic syndrome: a clinico-pathologic study of thirty children.

BACKGROUND: Congenital nephrotic syndrome is an uncommon disorder that may be caused by several diseases. These may be inherited, sporadic, acquired or part of a general malformation syndrome. METHODS: We reviewed the clinical characteristics, pathologic findings, and results of medical management in 30 infants who presented to Jordan University Hospital with congenital nephrotic syndrome in the years 1989 to 1999. RESULTS: Most patients (80%) had parents who were consanguineous. Most patients (80%) were born premature, with an average gestational age of 36 weeks. Most infants (77%) presented the nephrotic syndrome in the first three months of life and 26 (87%) had significant growth retardation. Twenty-five verified episodes of serious bacterial infections occurred in 18 patients. Antibiotic therapy however was successful in all these episodes. Light microscopy of the renal biopsies was consistent with the Finnish type of congenital nephrosis in most patients (83%). Chronic renal insufficiency developed in 17, and five of them needed chronic peritoneal dialysis. Most patients were given albumin transfusion and diuretic therapy especially during episodes of severe edema. Captopril alone or in combination with ibuprofen was given to eight patients, but without a response in any of them. All patients died before the age of 5 years. Most deaths occurred at an average age of 15 months (range 1-60). CONCLUSION: The Finnish type of congenital nephrosis was the most common type in our patients, most of whom died within a few months of the onset of disease. In the developing countries, the management of patients with congenital nephrosis may have to be different from that in the developed countries in view of the high cost of medical management, poor outcome, high risk of serious complications, and high mortality rate.

Aluminum phosphide fatalities, new local experience.

Aluminum phosphide (AlP) pesticide is a highly toxic, low cost, and easily accessible rodenticidal agent. Its toxicity results from the liberation of phosphine gas upon exposure to moisture, which leads to multisystem involvement, resulting in serious consequences. The highly toxic parathion insecticide was a common cause of mortality in pesticide fatalities, prior to its banning. Its toxicity was familiar to the public as well as to physicians. Recently, ten fatalities due to AlP were encountered within a three-month period during spring, when it was used as a rodenticide in the vicinity of grain stores. The victims' ages ranged from 1-34 years. The circumstances of death were accidental in six cases, suicidal in two and possibly homicidal in two cases. Retrospectively, the clinical manifestations, scene investigation, autopsy, histological and toxicological findings supported the diagnosis of AlP intoxication. Immediate recognition was difficult due to unfamiliarity of the agent to the physicians. The occurrence of these fatalities might suggest changes of pattern in pesticide poisoning. This should raise the attention of the physician to the problem of AlP poisoning and also necessitates the awareness of the public to the hazards of this poison. Education, proper handling, strict observation and abiding by the regulations controlling this material are good protective measures against AlP poisoning.

Effects of castor bean extract and ricin A-chain on ovulation and implantation in rabbits.

The anti-implantation and antiovulation effects of castor bean extract (CBE) and ricin A-chain (RAC) were evaluated in rabbits. Both CBE and RAC, administered intraperitoneally on days 5-9 of pregnancy, exhibited a pronounced decrease in maternal body weight gain and in death of all fetuses. A significant (p < 0.01) decrease of implantation sites resulted after rabbits were treated with RAC on the first 6 consecutive days of pregnancy. When female rabbits were treated with RAC for 10 consecutive days followed by human chorionic gonadotropin (hCG) (50 IU/kg intravenously), there was a 30% reduction in the number of corpora lutae. These data clearly indicate that CBE and RAC possess potent effects on implantation and ovulation in rabbits. The protein contents of castor bean extract, separated by polyacrylamide gel electrophoresis, revealed the presence of several protein bands, ricin toxin being a major constituent of the extract.

Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis.

BACKGROUND: Chronic liver disease is characterised by excessive deposition of collagen and other extracellular matrix proteins, produced mainly, but not exclusively, by activated hepatic stellate cells in the perisinusoidal space. In primary biliary cirrhosis (PBC) fibrosis is concentrated mainly around the portal tracts. AIMS: To examine the hypothesis that, in addition to hepatic stellate cells, portal tract fibroblasts might play a significant role in the deposition of collagen in PBC. METHODS: Fifty liver biopsy specimens from patients with PBC were studied. An in situ hybridisation technique was adapted to localise and measure semiquantitatively type I procollagen mRNA in formalin fixed, paraffin wax embedded sections, using an 35S labelled cRNA probe specific for the alpha 1 chain of rat type I procollagen. Hepatic fibrogenic activity was also assessed using serum type III procollagen peptide (PIIINP). RESULTS: In PBC, type I procollagen gene expression was significantly increased. Signal was localised mainly in and around inflamed portal tracts, to cells which had the appearances of portal fibroblasts. Signal activity in these cells correlated with the degree of portal fibrosis and inflammation and also with serum PIIINP concentrations. CONCLUSIONS: Results are consistent with the hypothesis that the excessive extracellular matrix, deposited within the liver in PBC, is synthesised not only by hepatic stellate cells but also by portal tract fibroblasts. The semiquantitative assessment of procollagen mRNA in liver biopsy specimens may provide a useful method of evaluating the rate of synthesis of collagen and therefore disease activity in patients with PBC.

Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients.

This study was designed to establish whether measurement of a serological marker of fibrosis might reduce the need for liver biopsy in psoriatic patients receiving methotrexate (MTX). Levels of type III procollagen aminopeptide (PIIINP-O and PIIINP-B) and laminin P1 (LamP1-B) were measured in 147 serum samples taken at the time of liver biopsy in 87 patients receiving long-term MTX treatment for severe psoriasis. Biopsies were classified as: (1) normal, (2) steatosis, (3) inflammation, (4) fibrosis, or (5) cirrhosis. Groups 3-5 were considered to show clinically relevant abnormality. Compared with controls, PIIINP-O was significantly raised in the group of MTX-treated psoriatics (P < 0.001). Within this group, levels were significantly higher in patients with inflammation, fibrosis or cirrhosis compared with those with normal histology or steatosis alone (P < 0.0001). In contrast, PIIINP-B and LamP1-B did not distinguish between controls and MTX-treated patients or between histological groups. Forty-two patients had two or more biopsies with simultaneous PIIINP-O measurement. PIIINP-O levels at the time of the first biopsy were normal in six of the seven patients whose histology was initially normal and subsequently became abnormal. A single measurement of PIIINP-O thus did not predict which patients might develop abnormal histology following further MTX. In a group of 17 patients, PIIINP-O was measured 3-monthly for up to 6 years during MTX treatment. PIIINP-O was elevated at some time during follow-up in all three patients who developed abnormal histology but was consistently normal in eight of the 11 patients whose histology remained or became normal. Our findings indicate that PIIINP-O is of value in detecting liver damage and, particularly if measured serially, may reduce the need for liver biopsy in MTX-treated patients. Although the test does not detect all patients with fibrosis, it would appear that the risk of missing significant liver damage in patients with persistently normal PIIINP-O is low.

Sequential liver biopsies during long-term methotrexate treatment for psoriasis: a reappraisal.

One hundred and eighty-two liver biopsies were performed over a 10-year period on patients receiving long-term, low-dose, once weekly oral methotrexate (MTX) for severe psoriasis. Forty-nine patients had two or more biopsies during continued treatment and formed the study population for our analysis. The first and last biopsies were compared to determine progression of any histological abnormalities. Liver biopsies were assessed without knowledge of the MTX dose and allocated to one of five groups according to the severity of the histological abnormalities. These were defined as: (1) normal; (2) steatosis alone; (3) inflammation without fibrosis; (4) fibrosis; and (5) cirrhosis. The mean cumulative dose of MTX at the time of the first biopsy was 2743 mg (range 315-10,024), given over 275 weeks (range 26-738). In the interval between the first and last biopsies, patients received, on average, a further 2362 mg (range 390-7155) over 225 weeks (range 60-460). There was improvement in the histological assessment in 12 patients, no change in 28 patients, and deterioration in nine patients. None developed cirrhosis. Liver biopsy findings prompted discontinuation of MTX in four of the 49 patients on long-term treatment. This has to be weighed against the cost and morbidity of the 124 biopsies performed in these patients. Our results suggest that, with careful follow-up, the risk of development or progression of liver disease in patients receiving long-term, low-dose, once weekly oral MTX for psoriasis is modest, and that the requirement for performing routine liver biopsies in these patients needs to be reconsidered.

Red cell aplasia resembling Diamond-Blackfan anemia in seven children in a family.

PATIENTS AND METHODS: Seven children of the same family with a possible variant of Diamond-Blackfan anemia (DBA) are reported. Five were male siblings, and the other two were their cousins, one male and one female. All were products of consanguineous marriages of healthy parents. All cases occurred within one generation. Anemia was present at birth or shortly after birth. Hepatosplenomegaly was present in all. Four had short stature. Hematological findings included normochromic, normocytic, or macrocytic anemia, marked reticulocytopenia, with initial normal white blood cell and platelet count, and absent or markedly decreased erythroid precursors on bone marrow examination. All were treated initially with prednisolone; in one patient oxymetholone was added. RESULTS: Three children failed to respond to the initial treatment, and also failed to respond to cyclosporin A and pulse doses of methylprednisolone. Myelofibrosis occurred in two siblings, 9 and 11 years from diagnosis. In two children the disease recurred 9 and 12 years after initial diagnosis. CONCLUSIONS: Our cases point to a possible variant of DBA characterized by the presence of normochromic normocytic anemia, hepatosplenomegaly, absent skeletal malformations, and unusual long- term complications.