Effect of inhaled methanol on pituitary and testicular hormones in chamber acclimated and non-acclimated rats.

Two experiments were conducted in which the acute effects of inhaled methanol on serum hormones associated with reproductive function in the male rat were evaluated. In the first experiment, rats exposed to methanol (0, 200, 5000 and 10,000 ppm) for 6 h were killed at the end of the exposure period (6 h) or the following morning (24 h). Also, because the process of exposure itself could modify neuroendocrine function, the effect of the handling associated with placing the rat in the exposure chamber was evaluated further by dividing the exposed animals into acclimated (2 weeks of prior handling) and non-acclimated groups. At 6 h, an effect of prior handling was noted in the sham-exposed rats, with serum luteinizing hormone (LH) of the non-acclimated group being greater than that of the acclimated group. Serum LH concentrations were altered by methanol exposure, but the direction of change and the exposure level at which an effect was noted differed between the acclimated and non-acclimated rats. Methanol (5000 ppm) reduced serum LH in the non-acclimated animals, while 10,000 ppm increased LH in the acclimated rats. Follicle stimulating hormone (FSH) and testosterone were unchanged by methanol in rats killed at 6 h. Thus, this experiment did not confirm earlier reports that exposure to 200 ppm for 6 h reduced serum testosterone. At 24 h, an effect of prior handling was still present in the hormonal measures, with serum and interstitial fluid testosterone concentrations being greater in the non-acclimated rats. Also, there was a dose x handling interaction with methanol exposure inducing an increase in serum testosterone in the non-acclimated rats (up to 5000 ppm) and a decrease in the acclimated rats (up to 10,000 ppm). In the second experiment, groups of acclimated and non-acclimated rats were exposed to 0 or 5000 ppm methanol for 1, 2 and 6 h and killed immediately after removal from the chamber. Serum LH, testosterone and FSH values were not different in sham- vs methanol-exposed rats at any time point. As in experiment 1, an effect of prior handling was noted. In general, the concentrations of these hormones and serum prolactin in the non-acclimated rats were greater than those observed for acclimated rats. Methanol exposure resulted in increased prolactin concentrations under both handling conditions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Limb lengthening by callus distraction: Complications in 53 cases operated 1980-1991

We reviewed our first 53 lengthenings performed in 45 patients with an average age of 19 years at the time of lengthening. The shortening was congenital in 16 patients, post-traumatic in 15 and had various causes in the 14 remaining. 31 femurs and 22 tibias with an average shortening of 6 and 5 cm, respectively, were lengthened 6 (2-14) cm. The aim was achieved in all but 4 patients, where lengthening had to be discontinued due to complications.

Potential complications of lengthening can be numerous but, if recognized, can in most cases be dealt with during the extended lengthening procedure. 38 cases of pin-tract infections healed with antibiotics. Restricted motion in one or more joints was registered in 49 cases during lengthening; minor restriction of joint motion persisted in 14 patients. 28 cases had angular deviations during lengthening. After additional surgery all but 10 could be corrected. 4 fractures occurred after removal of the external fixator. The total number of complications was 146, and of these 76 were minor, 42 moderate and 28 severe. 36 of the 42 patients available to follow-up were satisfied with the results of the lengthening procedure.     

Incidence of Perthes' disease in Uppsala, Sweden.

The annual incidence of Perthes' disease in Uppsala County, Sweden, was computed for the years 1978-1989 and further analyzed as regards age and sex distribution. The annual incidence was 8.5 per 100,000 in children 0-14 years of age.     

Serum and testicular testosterone and androgen binding protein profiles following subchronic treatment with carbendazim

While the general toxicity of the benzimidazole pesticides for mammals is low, one of these compounds, carbendazim (MBC), causes degeneration of testicular tissue and decreases spermatogenic activity at doses well below the LD50 value. A study conducted by S. D. Carter, R. A. Hess, and J. W. Laskey (1987, Biol. Reprod. 37, 709-717) showed that treatment with 400 mg/kg/day MBC resulted in severe seminiferous tubular atrophy and infertility. Since spermatogenesis is an androgen-dependent process, we characterized the effects of MBC (0-400 mg/kg/day) on the endocrine function of the rat testes. Following subchronic (85 day) exposure, serum hormones (TSH, LH, FSH, and Prl) were measured as were androgen binding protein (ABP) and testosterone in testicular fluids (interstitial fluid and seminiferous tubule fluid). In addition, the functional capacity of the Leydig cell to secrete testosterone was assessed in vitro following an hCG challenge. Subchronic treatment with MBC at doses of 50-100 mg/kg/day had no effect on pituitary or testicular hormone concentrations: 200 mg/kg/day elevated the testosterone concentration in the seminiferous tubule fluid and the ABP concentration in both the interstitial fluid and the seminiferous tubule fluid without affecting serum testosterone or ABP concentrations. The 400 mg/kg/day dose resulted in increased concentration of both testosterone and ABP in the interstitial fluid and seminiferous tubule fluid and elevated serum ABP, with no change in serum testosterone. This endocrine profile is consistent with the testicular atrophy and "Sertoli cell-only" syndrome seen in these animals as reported by Gray et al. (1987, Toxicologist 7, 717). We conclude that seminiferous tubule fluid testosterone may be a result of two factors: (1) increased interstitial fluid testosterone concentrations and (2) decreased testosterone outflow from the testis to the general circulation. Also, increased ABP in the interstitial fluid may reflect a change in the relative secretion of ABP into the interstitial fluid and the seminiferous tubules.     

Solid-phase radioimmunoassay of serum IgG, IgM, and IgA antibodies to cytomegalovirus

A radioimmunoassay (RIA) using polystyrene beads as the solid phase for cytomegalovirus (CMV) antigen and iodinated immunosorbent purified anti-human IgG, IgM, and IgA as indicator antibodies was developed for the detection of immunoglobulin class-specific antibodies to CMV. An antigen prepared from extracellular virus was essential for reliable results, and a preparation ultracentrifuged and sonicated twice was better than a crude antigen. The optimal antigen gave low cpm values with a negative reference serum, resulting in cpm ratios of 10 or higher between early convalescent phase serum and negative reference serum. Of six patients with an increase in CMV CF titres, all six had an increase in RIA IgG titres, four had an increase in IgA titres, and all had IgM antibodies. The IgG titres were high, up to 1/64,000. In a group of 17 infants negative in CMV CF test, 14 had CMV IgG antibodies in RIA test, indicating mainly low levels of maternal antibodies. In six of seven patients with CMV isolations from urine specimens, an increase in IgG or IgA titres or the presence of IgM antibodies was found, and only one of these patients had an increase in CMV CF titre. The specificity of the developed CMV RIA test was further demonstrated by detecting no significant increase in RIA titres in serum specimens of patients with primary herpes simplex infection, chickenpox, herpes zoster, or infectious mononucleosis.     

Methods for non-invasive detection of ventricular late potentials--a comparative multicenter study

To evaluate the methodological problems of the non-invasive registration of late potentials the results obtained with four different averaging devices in the same 109 patients were compared. The high-resolution ECG was obtained from the body surface, high-gain amplified and filtered. With the averaging technique, the improved signal-to-noise ratio was able to detect low-amplitude cardiac activity. The incidence of late potentials detected with the four averaging systems, whose characteristics are described, ranged between 12% and 21%. Corresponding positive results were obtained in 5.5%, corresponding negative results in 68.8%. The reasons for differing results were mainly due to differences in visual or automatic interpretation of the registered fractionated electrical cardiac activity. Additionally, the determination of the end of QRS using the QRS width, obtained from reference leads, may influence the specificity of the methods.     

Drug policy in China: pharmaceutical distribution in rural areas

In 1978, China decided to reform its economy and since then has gradually opened up to the world. The economy has grown rapidly at an average of 9.8% per year from 1978 to 1994. Medical expenditure, especially for drugs, has grown even more rapidly. The increase in medical expenditure can be attributed to changing disease patterns, a higher proportion of older people in the population and fee-for-service incentives for hospitals. Due to the changing economic system and higher cost of health care, the Chinese government has reformed its health care system, including its health and drug policy. The drug policy reform has led to more comprehensive policy elements, including registration, production, distribution, utilization and administration. As a part of drug policy reform, the drug distribution network has also been changed, from a centrally controlled supply system (push system) to a market-oriented demand system (pull system). Hospitals can now purchase drugs directly from drug companies, factories and retailers, leading to increased price competition. Patients have easier access to drugs as more drugs are available on the market. At the same time, this has also entailed negative effects. The old drug administrative system is not suitable for the new drug distribution network. It is easy for people to get drugs on the market and this can lead to overuse and misuse. Marketing factors have influenced drug distribution so strongly that there is a risk of fake or low quality drugs being distributed. The government has taken some measures to fight these negative effects. This paper describes the drug policy reform in China, particularly the distribution of drugs to health care facilities.     

Oxidative bioactivation of the lactol prodrug of a lactone cyclooxygenase-2 inhibitor.

The lactol derivative of a lactone cyclooxygenase-2 inhibitor (DFU) was evaluated in vivo and in vitro for its potential suitability as a prodrug. DFU-lactol was found to be 10 to 20 times more soluble than DFU in a variety of aqueous vehicles. After administration of DFU-lactol at 20 mg kg-1 p.o. in rats, a Cmax of 7.5 microM DFU was reached in the plasma. After oral administration, the ED50s of DFU-lactol in the carrageenan-induced paw edema and lipopolysaccharide-induced pyresis assays in rats are comparable with the ED50s observed when dosing with DFU. Incubations of DFU-lactol with rat and human hepatocytes demonstrated that the oxidation of DFU-lactol can be mediated by liver enzymes and that a competing pathway is direct glucuronidation of the DFU-lactol hydroxyl group. Assays with subcellular fractions from rat liver indicated that most of the oxidation of DFU-lactol occurs in the cytosolic fraction and requires NAD(P)+. Human liver cytosol can also support the oxidation of DFU-lactol to DFU when NAD(P)+ is added to the incubations. Fractionation of human liver cytosolic proteins showed that at least three enzymes are capable of efficiently effecting the oxidation of DFU-lactol to DFU. Incubations with commercially available dehydrogenases suggest that alcohol and hydroxysteroid dehydrogenases are involved in this oxidative process. These data together suggest that lactols may represent useful prodrugs for lactone-containing drugs.     

Toxicity of mercuric chloride to the developing rat kidney. III. Distribution and elimination of mercury during postnatal maturation

Mercuric chloride is a potent nephrotoxicant in the adult rat, but has little effect on newborns. Nephrotoxicity increases with postnatal maturation. This study assesses the changes in tissue distribution and excretion of Hg during postnatal development. Sprague-Dawley rats were injected sc with 5 mg/kg 203HgCl2 on postnatal Day 1, 8, 15, 22, or 29. Hg concentration was measured in the whole body, renal cortex, medulla and papilla, liver, and subcellular fractions of liver and kidney. Binding to cytosolic metallothionein was assessed. Whole-body elimination of Hg was slow at the three younger age groups, as only 20% of the initial load was eliminated by 5 days after injection. Excretion was much more rapid in the two older groups, which eliminated about half of the initial load within 5 days. Concentration of Hg was highest in renal cortex (the principal site of Hg toxicity), and there was an age-related increase in cortical Hg concentration. This may explain the increased toxicity of Hg with age. There was an age-related decrease in hepatic Hg concentration. The high levels of metallothionein present in perinatal rat liver may protect the renal cortex from receiving a toxic dose of Hg; however, the increased concentration of hepatic Hg in newborns is insufficient to account for all of the cortical decrease. It is probable that Hg was distributed to other tissues. In liver and kidney cells of neonates, Hg concentration was highest in the cytosol, decreasing in an age-related manner. This was accompanied by an age-related increase of Hg in the nuclear/mitochondrial fraction. Hg in the cytosol was largely bound to metallothionein, although there were substantial amounts associated with very low-molecular-weight molecules and high-molecular-weight proteins. There are significant maturational changes in the organ, cellular and subcellular distribution of Hg in the rat during the first 4 weeks after birth. These probably explain the increasing sensitivity with maturity to Hg nephrotoxicity.     

Hantavirus protein interactions regulate cellular functions and signaling responses

Rodent-borne pathogenic hantaviruses cause two severe and often lethal zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Currently, no US FDA-approved therapeutics or vaccines are available for HFRS/HCPS. Infections with hantaviruses are not lytic, and it is currently not known exactly why infections in humans cause disease. A better understanding of how hantaviruses interfere with normal cell functions and activation of innate and adaptive immune responses might provide clues to future development of specific treatment and/or vaccines against hantavirus infection. In this article, the current knowledge regarding immune responses observed in patients, hantavirus interference with cellular proteins and signaling pathways, and possible approaches in the development of therapeutics are discussed.