Secondary immune defects in non-Hodgkin's lymphoma. Changes in the humoral, cellular and phagocytic components of the immune system were investigated in 44 biopsy proven, untreated patients of non-Hodgkin's lymphoma (NHL). There was significant decrease in the total lymphocyte number, their subsets (T and B) and the T helper (T mu) population. Impaired leukocyte migration inhibition response and DNA synthesis following stimulation by phytohaemagglutinin were noted. Significant reduction of serum IgA was found in patients of both diffuse and nodular NHL. Phagocytic activity and nitroblue tetrazolium (NBT) reduction were unaltered, but chemotaxis was significantly reduced and bactericidal activity showed variable results.


Characterization of G6PD Rohini--a new class III Indian variant. A new Indian G6PD variant was detected in a 15 yr old Maratha male during a population screening programme in high school children in Bombay (India). The propositus and two family members having the same variant were apparently healthy. This enzyme variant has a mild erythrocyte G6PD deficiency and a slow electrophoretic mobility. It is characterized by a high Michaelis-Menton constant for G6P, a bimodal curve for pH optima and a slight decrease in the thermostability. The rate of utilization of substrate analogue is similar to that of normal. These observations suggest identification of a new class III variant, designated as G6PD Rohini.


Treatment of intractable spasticity in spinal cord injured patients. Spasticity and flexor spasms can be most incapacitating in SCI victims. Muscle relaxants, physiotherapy and elimination of triggering factors must be tried before opting for peripheral surgery or alcohol block. The choice of alcohol block or peripheral surgery depends in whether damage to the spinal cord is complete or incomplete. Results of both the procedures are satisfactory in rightly chosen patients. Alcohol block is a simple, safe and effective method of treating spasticity in the patients of complete paraplegia. The effect is immediate and almost permanent. However, alcohol block is contra-indicated in the patients of incomplete paraplegia where peripheral surgery is a better choice.


Diabetes mellitus in Libya: a retrospective study. The records of the Diabetes Hospital, Tripoli, Libya for the years 1961-1983 were examined and the available particulars relating to 24,962 diabetic patients (12,486 males + 12,476 females) registered during this period were obtained. The highest number of male and female diabetic patients were in the age group 40-50 years and the highest number of obese diabetic patients also belong to this age group. There was a gradual increase in the number of diabetic patients visiting the Diabetes Hospital with the highest number in 1983. The increase has been both in the type I and type II patients. In 1983, 15% of the diabetic patients belong to type I diabetes. Family history of diabetes appears to be an important factor in the onset and manifestation of type II diabetes. Patients with diabetes in the family have a lower mean body mass index and fasting blood glucose level as compared with those of patients without known case of diabetes in the family. This may be due to greater alertness, early diagnosis of the disease and steps taken to control blood glucose levels and body weight in the case of patients with family history of diabetes.


Unusual manifestations of myxoedema.

Unusual manifestations of myxoedema. The lesser known manifestations of myxoedema encompass a wide spectrum of neurologic, psychiatric, endocrinologic and autoimmune pathology that mask obvious clinical diagnosis. Interesting head and neck presentations are discussed. The relationships with the Pendred and Down syndromes raise hereditary and genetic considerations.


Mechanisms of action of known human carcinogens. Mutational mechanisms can be proposed for most, if not all, known human carcinogens. Many of these are electrophilic or metabolically activated to reactive molecules which can alter DNA, causing genetic damage and different types of mutations. Even some human carcinogens previously proposed to be nongenotoxic (e.g., hormones and asbestos) exhibit mutational activity in assays for chromosomal mutations. Since such chemicals are usually inactive in the Salmonella assay and other assays for gene mutation, more emphasis has been placed on their nonmutational mechanisms. Clear evidence exists that these carcinogens can alter gene expression and stimulate cell proliferation by epigenetic mechanisms. Such properties are undoubtedly important in their carcinogenic activity. Although they are less well studied, DNA reactive, genotoxic carcinogens also alter gene expression and increase cell turnover by epigenetic mechanisms. These findings are consistent with the current understanding of the molecular basis of multistep carcinogenesis. Most common human cancers evolve as the result of multiple mutational events. The molecular basis of these mutations is varied, and they include point mutations, deletion mutations, chromosomal rearrangements, gene amplification and chromosomal losses and gains. Therefore, different mutational activities of carcinogens can influence the carcinogenic process at different steps. Influences on gene expression and cell proliferation are also important in allowing clonal expansion of preneoplastic cells and in disrupting the suppressive effects of surrounding normal cells on preneoplastic cells (Dotto et al., 1988). The mechanisms of action of human carcinogens, and very probably many rodent carcinogens, include both genetic and epigenetic processes. Carcinogenesis is a multistep, multigenic, multicausal process (Barrett, 1987b), so both epigenetic and genetic factors are probably important.(ABSTRACT TRUNCATED AT 250 WORDS)


Use of short-term tests in determining the genotoxicity or nongenotoxicity of chemicals. This article brings together the several current approaches to the use of short-term tests for identifying carcinogens and the several meanings of the term 'genotoxic'. Examples of genotoxic and nongenotoxic carcinogens and of genotoxic and nongenotoxic mechanisms of carcinogenesis are discussed. Emphasis is placed on the determination of genotoxicity as it affects evaluation of the mechanism of action of a new rodent carcinogen.


Sex hormones and cancer.

Sex hormones and cancer. There are few instances in which a clear effect of hormones on cancer risk is known and in which the effects of those hormones on the cells concerned are also known. The best examples are the relationships between sex hormones and cancer in women. The effects of sex hormones both on the risk for endometrial cancer and on the cells of the endometrium are well understood, and the evidence strongly suggests that hormones act by altering the rate of cell division. The same mechanism may explain the relationships between sex hormones and the risk for breast cancer, but our understanding of cancers at this site is incomplete. Less still is known about the mechanisms of the effects of sex hormones on other hormone-related cancers, such as those of the ovary and cervix. Most sex hormones are not genotoxic.


Structure-activity relationships for carcinogens with different modes of action. The application of structure-activity concepts to the elucidation of the action of chemical carcinogens may proceed by two approaches: the hypothesis and the knowledge-based approaches. The former, exemplified by the 'structural alerts' devised by Ashby and associates, derives from the recognition of the electrophilic nature of carcinogens that damage DNA. The latter approach does not assume an a priori mechanism of action but derives information from the establishment of relationships between structural features and carcinogenicity. Indeed, the 'structural alerts' of Ashby et al. are recognized by such an approach; however, if structural features are associated with the activity of 'nongenotoxic' carcinogens, they would also be recognized by the knowledge-based approach. Obviously, the recognition of new (nonelectrophilic) structural features associated with carcinogenicity will lead to testable hypotheses.


Chemically induced cell proliferation in carcinogenesis. Carcinogenesis can proceed by a variety of pathways involving the sequential mutation of normal cellular growth control genes and the clonal expansion of the resulting precancerous or cancerous cells. Chemical carcinogens may act by inducing mutations and/or altering cellular growth control. One class of chemical carcinogens are the genotoxicants. These compounds or their metabolites are DNA reactive and directly induce mutations or clastogenic changes. The observation that most mutagens are also carcinogenic is the basis for many current predictive assays and risk assessment models; however, there are different classes of nongenotoxic carcinogens that do not interact with DNA. Mitogens directly induce cell proliferation in the target tissue; cytotoxicants produce cell death followed by regenerative cell proliferation. Differential toxicity and/or growth stimulation induced by mitogens and cytotoxicants may provide a preferential growth advantage to spontaneous or chemically induced precancerous or cancerous cells. Mutagens are much more effective carcinogens at doses that also induce cell proliferation, and mutational activity may occur as an event secondary to cell proliferation. Thus, chemically induced cell proliferation is an important mechanistic consideration for both genotoxic and nongenotoxic carcinogens. The complex quantitative relationships between chemically induced cell proliferation and carcinogenic activity are under study in many laboratories. Such information should be considered in setting doses for cancer bioassays, for classifying chemical carcinogens and in providing more realistic approaches to risk assessment. Of particular concern in extrapolating cancer risk from rodent models to humans are those nongenotoxic agents that exhibit carcinogenic activity only at doses that also produce cytolethality and regenerative cell proliferation in the target organ.


Chemicals classified by IARC: their potency in tests for carcinogenicity in rodents and their genotoxicity and acute toxicity. Chemicals classified by the IARC to its groups 1, 2A, 2B and 3 were examined in an attempt to identify characteristics of their behaviour in experimental studies of carcinogenicity, genotoxicity and acute mammalian toxicity that correlate with those categories. Only those agents for which information on carcinogenic potency was available were studied. In both mice and rats, more chemicals were potent carcinogens if they had been categorized in Group 1 (human carcinogens) than if they had been put into one of the other categories. Not surprisingly, there was a weak association between carcinogenic potency and acute toxicity. Mice were especially sensitive to tumour induction by halides; the lower sensitivity of rats to any carcinogenic effect of halides could be due in part to their higher systemic toxicity in this species: a reduced differential of toxic and carcinogenic doses decreases the dose window in which carcinogenic effects may be demonstrated. It was notable that the human carcinogens were active in those genotoxicity tests with higher specificity for identifying rodent carcinogens. Predictive assays for carcinogenicity that were considered to be highly specific were tests for cytogenetic effects in vivo, unscheduled DNA synthesis in hepatocytes, mutation in any of the five commonly used strains of Salmonella typhimurium and mutation at the hprt locus in mammalian cells. None of the relationships was strong enough to form the basis of a simple categorization, but they could serve to alert investigators to chemicals of special toxicological interest and importance.


Medium-term bioassays for carcinogens.

Medium-term bioassays for carcinogens. Medium-term bioassay systems in rats have been developed for rapid detection of carcinogenic agents and have been introduced for practical use. There are two major systems: N-nitrosodiethylamine and partial hepatectomy in liver and multiorgan models. The first model takes eight weeks; it consists of an initial intraperitoneal injection of N-nitrosodiethylamine, six weeks' administration of test chemical(s) beginning two weeks later, partial hepatectomy at week 3, and analysis of immunohistochemically identified glutathione S-transferase placental form-positive liver-cell foci. Using this model, the potency of carcinogenic agents can be predicted satisfactorily, at least for those of which the liver is a target organ. The multi-organ models include wide-spectrum organ initiation by N-methyl-N-nitrosourea or combined, short treatment with several carcinogens sequentially and subsequent administration of test chemical(s) for 12-20 weeks. Although these systems require a longer time, their accuracy as organotropism-independent testing systems has been validated by whole-body histological examination. These approaches promise precise, rapid detection of carcinogenic agents and should bridge the gap between established methods for screening in vitro and long-term carcinogenicity testing, with their inherent disadvantages. Other medium-term bioassay methods are discussed in addition to our two systems.


Transgenic mice in carcinogenicity testing. The biological effects of the expression of single genes can be evaluated in transgenic animals. Transgenic techniques have been used to investigate a wide variety of biomedical topics, including the consequences of oncogene expression, but their use in carcinogenicity testing is just beginning. Probable future developments involving transgenic animals are new short-term assays for carcinogenicity in vivo and methods for detecting and characterizing the critical genotoxic events in carcinogenesis.


Chemical toxicity and chemical carcinogenesis. Is there a causal connection? A comparative morphological evaluation of 1500 experiments. Chemicals cause toxic and carcinogenic effects as well as beneficial and other adverse effects in animals and in humans. The purpose of this paper is to assess whether there is a direct, uniform causal relationship between toxicity and carcinogenicity. Within this context, specific issues receive attention: the influence of exposure concentrations on carcinogenesis; kidney cancer and alpha 2 mu-globulin; urinary calculi and tumours; and cell turnover or proliferation and cancer. The data used to evaluate histopathological site-specific correspondence between these two end-points comes from 130 studies of chemical carcinogenesis designed and conducted by the US National Toxicology Program (NTP). Nearly 1500 sex-species-exposure group experiments were evaluated for morphological evidence of toxicity and/or carcinogenicity, for dose-response relationships, and for site-specific correlations of toxicity and carcinogenicity. The major conclusions are that chemicals evaluated for long-term toxicity and carcinogenicity in experimental animals can be divided into three categories: (1) those that cause organ toxicity without cancer, (2) those that cause site-specific cancer with no associated toxicity and (3) those that cause toxicity and cancer in the same organ. Examples are given to illustrate each category. On the basis of this comparative analysis, in the great majority of cases the available data do not support a correlation between chemically induced toxicity and carcinogenicity. Moreover, until considerably more scientific knowledge about molecular mechanisms of carcinogenesis becomes available and accepted, attempts to use findings on toxicity to modify the risk assessment process will be fraught with uncertainty and might even have a negative impact on public health.


Species differences in carcinogen metabolism and interspecies extrapolation. Many carcinogens demonstrate both qualitative and quantitative species differences in activity. Since many carcinogens must be metabolized to reactive electrophiles to elicit their tumorigenic effects, the observed species differences may have a metabolic basis. A number of examples exist that support the concept that metabolic differences are the underlying cause of species variation in carcinogenicity. Such differences are most often of a quantitative nature, but qualitative differences in carcinogenicity may also be due to differences in rates and/or pathways between species. There are also many instances in which there is no clear evidence that metabolism explains species differences in carcinogenicity. Carcinogenicity studies are often performed at much higher doses than those encountered by humans. Since metabolic processes may become saturated at high tissue concentrations, the rates and pathways of metabolic activation and detoxication may be different at high doses from those at lower doses. Such metabolic variation can lead to differences in target tissue doses, resulting in altered tissue responses at high doses in relation to lower doses. In situations in which no saturation of the metabolic pathways occurs, tissue concentrations are proportional to the administered dose. Scaling of doses from those used in experimental animals to those experienced by humans has often involved simple conversion factors, such as body weight or surface area. Since the reactions involved in carcinogen metabolism may differ both for high and low doses and for various species, much more realistic extrapolations from animal to human can be obtained using physiologically based kinetic modelling. The metabolism of carcinogens in humans shows large interindividual variation, which in turn may be reflected in differences in individual risks. The occurrence of genetic polymorphisms in carcinogen metabolizing enzymes indicates that subgroups of the population may experience carcinogenic risks distinctly different from those of the rest of the population.


Human cytogenetic damage as a predictor of cancer risk. The human cytogenetic assays presently available for biomonitoring are still inadequate for use in routine surveillance procedures and they must be applied with care. Knowledge of the effects of the agents concerned in experimental systems is a prerequisite, and confounding factors should be assessed. Consequently, the methods are useful and informative under carefully selected conditions and can indicate agents and exposures that are capable of causing chromosomal damage in humans, hinting at possible human cancer risk. Established and potential human carcinogens have frequently been shown to induce chromosomal aberrations in humans in vivo. It is also well documented that chromosomal rearrangements play an important role in the development of neoplasia. These combined lines of evidence suggest that structural chromosomal aberration in vivo has advantages over other cytogenetic end-points in predicting potential human cancer risk. Preliminary findings in a prospective follow-up study suggest that subjects with a high percentage of structural chromosomal aberrations but not sister chromatid exchanges may be at elevated risk for cancer.


Genes and gene products that regulate proliferation and differentiation: critical targets in carcinogenesis. Our understanding of the mechanism of carcinogenesis is developing rapidly, owing to the discovery of genes and gene products involved in the regulation of cell proliferation and differentiation and the identification of genetic events implicated in tumour formation. Our current concept is that cancer is basically the result of accumulating genetic damage. This damage may range from single base-pair substitutions to gross chromosomal changes, leading to distortion of either the expression or the biochemical function of genes, particularly those involved in proliferation and differentiation (PDR genes). These PDR genes and gene products can now be envisioned as critical targets for interaction with carcinogens. This paper discusses only the evidence that PDR genes are critical targets for carcinogenic agents.


Dose-response relationships in carcinogenesis. Considerable information on the carcinogenic potential of chemical and radiological agents has accumulated from the epidemiological and toxicological studies conducted to date. In this article, we discuss dose-response relationships in carcinogenesis from both empirical and theoretical points of view. Emphasis is placed on the application of biologically based models to describe observed dose-response relationships for exposure to single and multiple agents known to increase cancer risk. The implications of these observations for inferences about possible mechanisms of carcinogenesis are explored.


The role of epidemiological observation in elucidating the mechanisms of carcinogenesis. Epidemiological observations concerning a number of carcinogenic agents have been used to make inferences about the biological mechanisms of carcinogenesis. These inferences have generally been based on comparisons of epidemiological data with the predictions of various mathematical models of the process of carcinogenesis. Particular interest has focused on the relationships between cancer occurrence and level of exposure, age at exposure and time since cessation of exposure, and the combined effect of two carcinogenic agents. Analyses of epidemiological data in relation to mathematical cancer models have led to conclusions about mechanisms of action, but the validity of these conclusions is necessarily limited by the nature of epidemiological data and the unverifiability of assumptions underlying the models. A more fruitful application of the epidemiological perspective in elucidating the mechanisms of carcinogenesis may be through collaborative studies involving the recently developed techniques of molecular biology and related areas.


Epidemiology of cervical cancer--overview. Numerous studies of the epidemiology of cervical cancer have shown strong associations with religious, marital and sexual patterns. Although it is well established that women with multiple partners and early ages at first intercourse are at high risk, less is known about how these factors interact or how risk is affected by specific sexual characteristics. Recent studies indicate that number of steady partners and frequent intercourse at early ages may further enhance risk, supporting hypotheses regarding a vulnerable period of the cervix and a need for repeated exposure to an infectious agent. It is now widely accepted that HPV is the major infectious etiological agent, but whether other infectious agents play supportive or interactive roles is unclear. Of specific interest is the independent effect of HSV 2 on risk, especially given some evidence that this viral agent may interact with HPV. Other speculative risk factors for cervical cancer include cigarette smoking, oral contraceptive usage and certain nutritional deficiencies, but again it is not clear whether these factors operate independently from HPV. Although cervical cancer incidence trends correlate with the population prevalence of various venereally transmitted agents, it is not certain how disease rates are affected by other potential risk factors which have changed during recent time (e.g., exposure to HPV, sexual behaviour, cigarette smoking). In addition, a number of recent studies highlight the need for considering not only female influences on risk of cervical cancer, but also male factors, since the sexual behaviour of the male consort appears to play an important role.


Reassessment of the morphological continuum of cervical intraepithelial lesions: does it reflect different stages in the progression to cervical carcinoma? Currently used histological and cytological classification systems for cervical lesions are reviewed. These suffer from poor inter- and intra-observer reproducibility, and do not allow accurate identification of which mild lesions will progress towards cancer. The Bethesda classification system is described and it is postulated that low-grade and high-grade squamous intraepithelial lesions might represent distinct entities with different potential for progression rather than necessary stages of a continuum leading to cervical cancer. Improved understanding of the etiological role of HPV types in cervical cancer and of the natural history of low- and high-grade intraepithelial lesions might result in more suitable clinical treatment of low-grade lesions.


Protein kinase C of smooth muscle.

Protein kinase C of smooth muscle. The primary mechanism of regulation of smooth muscle contraction involves the phosphorylation of myosin catalyzed by Ca2+/calmodulin-dependent myosin light chain kinase. However, additional mechanisms, both Ca(2+)-dependent and Ca(2+)-independent, can modulate the contractile state of smooth muscle. Protein kinase C was first implicated in the regulation of smooth muscle contraction with the observation that phorbol esters induce slowly developing, sustained contractions. Protein kinase C occurs in at least four Ca(2+)-dependent (alpha, beta I, beta II, and gamma) and four Ca(2+)-independent (delta, epsilon, zeta, and eta) isoenzymes. Only the alpha, beta, epsilon, and zeta isoenzymes have been identified in smooth muscle. Both classes of isoenzymes have been implicated in the regulation of smooth muscle contraction. However, the physiologically important protein substrates of protein kinase C have not yet been identified. Specific isoenzymes may be activated by different contractile agonists, and individual isoenzymes exhibit some degree of substrate specificity. Prolonged activation of protein kinase C can result in its proteolysis to the constitutively active catalytic fragment protein kinase M, which would dissociate from the sarcolemma and phosphorylate proteins such as myosin that are inaccessible to membrane-bound protein kinase C. Protein kinase M induces relaxation of demembranated smooth muscle fibers contracted at submaximal Ca2+ concentrations. We suggest that protein kinase C plays two distinct roles in regulating smooth muscle contractility. Stimuli triggering phosphoinositide turnover or phosphatidylcholine hydrolysis induce translocation of protein kinase C (probably specific isoenzymes) to the sarcolemma, phosphorylation of protein, and a slow contraction. Prolonged association of the kinase with the membrane may lead to proteolysis and release into the cytosol of protein kinase M, resulting in myosin phosphorylation and relaxation.


Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats. We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 0.3% NaCl diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137 +/- 3 mm Hg versus 119 +/- 3 mm Hg, p < 0.05; plasma norepinephrine, 0.40 +/- 0.02 ng/ml versus 0.27 +/- 0.01 ng/ml, p < 0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an alpha-blocker (bunazosin, 10 mg/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCl), insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model.


Relation between blood pressure and stroke mortality. The relation between stroke mortality and blood pressure was investigated in 10,186 hypertensive patients followed up in the Department of Health Hypertension Care Computing Project for an average of 9 years. An untreated blood pressure measurement was available in 3,472 men and 3,405 women. The age-adjusted risk of stroke death increased by 1% for every 1 mm Hg increase in untreated systolic blood pressure. The relative hazard rate was 1.014 (95% confidence interval [CI], 1.007, 1.021) in men and 1.009 (1.003, 1.016) in women. The corresponding increases for 1 mm Hg for untreated diastolic blood pressure were almost 3% in men and again 1% in women (relative hazard rate 1.026 [95% CI, 1.014, 1.038] in men and 1.010 [1.000, 1.021] in women). Treated blood pressure measurements were available in 3,073 men and 3,148 women. Stroke mortality increased by 2% for a 1 mm Hg increase in treated systolic pressure and 3% for the corresponding increase in diastolic blood pressure. The relation between stroke mortality and blood pressure was similar over and under the age of 65, although the increase in mortality with pressure was greater for treated diastolic blood pressure in women under the age of 65 than over this age. There was no evidence for a J-shaped relation between stroke mortality and either systolic or diastolic pressure in men. In women there was a suggestion of such a relation, but since this relation was also observed for untreated pressures, any increase in risk at lower pressures is unlikely to be a result of treatment.


Increased response to physical and mental stress in men with hypertensive parents. Blood pressure and heart rate responses to isometric handgrip exercise were studied at age 31 and after 5 years in young nonhypertensive men with positive family histories of hypertension (n = 13) and in those with negative family histories of hypertension (n = 13) for two generations to test whether subjects with positive family histories established a pattern of increased blood pressure and heart rate responses during the 5-year follow-up period. At follow-up the response to mental stress (Stroop's color word test) was also studied. Baseline blood pressure and heart rate at rest did not differ, initially or at follow-up, between the groups. At the initial examination, absolute blood pressure levels were significantly higher during isometric handgrip exercise just before exhaustion in subjects with positive family histories. At follow-up the absolute blood pressure level (p < 0.001) and the blood pressure responses (p < 0.01-0.001) were found to be significantly increased during handgrip exercise in subjects with positive family histories compared with subjects with negative family histories. In subjects with positive family histories the diastolic blood pressure response was significantly higher (p < 0.01) at follow-up than initially and was significantly related (r = 0.70, p < 0.01) to changes in baseline diastolic blood pressure during the follow-up period. In subjects with negative family histories the systolic blood pressure response was somewhat lower at follow-up than initially. During the mental stress test, the blood pressure response was significantly greater in subjects with positive than with negative family histories.(ABSTRACT TRUNCATED AT 250 WORDS)


Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. We have previously described a rat model that responds to repetitive episodic hypoxia (FiO2 nadir 3-5% for 12 seconds every 30 seconds for 7 hr/day for 35 days) with chronic increase in arterial blood pressure. The purpose of the current study was to determine if peripheral sympathetic nervous system denervation blocks this persistent blood pressure elevation. Chemical sympathetic denervation was achieved and maintained by three intraperitoneal injections (100 mg/kg 6-hydroxydopamine) on days 1, 3, and 27 of a 47-day experiment in two groups of rats. One denervated group was subjected to episodic hypoxia for 40 consecutive days beginning on day 7 and the other remained unhandled in their usual cages. A third group was injected with vehicle only and subjected to the same episodic hypoxia while a fourth group remained unhandled for 40 days. The vehicle-treated, episodic hypoxia-exposed group showed a 7.7 mm Hg increase in mean arterial blood pressure (conscious, unrestrained) over the 40-day period, whereas all other groups showed a decrease in mean arterial pressure. The left ventricle and septum/whole body weight ratio was higher in both episodic hypoxia-exposed groups at the end of the study. Plasma epinephrine in both groups administered 6-hydroxydopamine was higher on day 6 than in the vehicle-injected rats. Measurement of catecholamines in cardiac muscle homogenate confirmed denervation in 6-hydroxydopamine animals. These results indicate that the peripheral sympathetic nervous system is necessary for the persistent increase in blood pressure in response to repetitive episodic hypoxia.


Hypocalcemia and pregnancy-induced hypertension produced by maternal fasting. During pregnancy, maternal calcium needs increase as a result of increasing calcium requirements for fetal bone development. These needs have to be completely supplied by the mother via placental transfer. Several studies link low serum ionized calcium concentrations with the development of hypertension and pregnancy-induced hypertension. We hypothesized that maternal hypocalcemia would develop concomitantly with the development of hypertension in sheep that were fasted in late gestation. Sixteen instrumented ewes were used in the present study. After a 2-day baseline period, food was withdrawn from 10 animals in the experimental group (group 2) for 3 days, whereas the remaining six were allowed to eat and drink normally (group 1). Blood pressure, uteroplacental blood flow, and heart rate were monitored daily. Fasted animals were given deionized water (calcium free) to drink, whereas control animals were given tap water containing 32.9 mg/l calcium concentration. Based on the analysis of the ionized calcium concentration response to fasting, group 2 animals were placed in one of two groups: hypocalcemia did not develop in group 2a, whereas in group 2b the ionized calcium concentration decreased 27% (from 1.09 +/- 0.07 to 0.80 +/- 0.06 mM, p = 0.01) by the third day of fasting. Group 2b responded with a 16% elevation in maternal blood pressure (p = 0.01) and a 43% reduction in uteroplacental blood flow. Furthermore, a positive correlation was found between maternal and fetal blood ionized calcium concentrations (r = 0.860).(ABSTRACT TRUNCATED AT 250 WORDS)


Increased platelet angiotensin II receptor number in pregnancy-induced hypertension. Women with pregnancy-induced hypertension (PIH) are characterized by relatively greater blood pressure sensitivity to exogenous angiotensin II (Ang II) than normotensive pregnant women. Evidence suggests that this is due to an alteration in Ang II receptor sites. However, the question of whether this represents an increase in receptor number or affinity remains unanswered. To answer this question Ang II receptors on platelets from normotensive women during each trimester of pregnancy and the postpartum period were studied and compared with platelet Ang II binding in third trimester women with PIH and in postpartum women who had had a recent pregnancy complicated by PIH. We also measured plasma renin activity, Ang II, and aldosterone in blood samples from these women and sodium and creatinine in 24-hour urine collections. Normotensive pregnant women had significantly less platelet Ang II binding than nonpregnant, postpartum women (0.85 +/- 0.19 versus 2.87 +/- 0.83%, p = 0.003), reflecting a reduction in receptor number but not affinity. This probably reflects the significant increase in Ang II during pregnancy. Urinary sodium excretion was equivalent and could not explain these changes. Comparisons of third trimester women with PIH against those without PIH documented a significantly higher Ang II binding in the women with PIH (2.23 +/- 0.42 versus 0.85 +/- 0.19%) that was caused by an increase in receptor number (6.0 +/- 1.3 versus 3.0 +/- 0.8 fmol Ang II per 5.6 x 10(8) platelets, p = 0.047) but similar Ang II binding affinity. This reflected significantly lower Ang II levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Angiotensin II-induced protein phosphorylation in the hypertrophic heart of the Dahl rat. Angiotensin II-induced phosphorylation of proteins was examined in isolated myocytes from hearts of Dahl rats. A high salt diet induced cardiac hypertrophy in Dahl salt-sensitive rats. Angiotensin II-induced phosphorylation of a 42-kd protein (pp42) was detected by two-dimensional electrophoresis in hypertrophic but not normal ventricular myocytes. Angiotensin II stimulation was time-dependent, with a peak effect at 30 minutes. The half-maximal and maximal concentrations of angiotensin II that stimulated pp42 phosphorylation were 1 and 10 nM, respectively. Phosphorylation of pp42 was a function of cardiac hypertrophy. Phorbol 12-myristate 13-acetate-induced phosphorylation of pp42 indicates the possibility of an association between protein kinase C and the signal transduction pathway of angiotensin II-induced pp42 phosphorylation. Ionomycin and A23187 (both at 1 microM) did not stimulate phosphorylation of pp42. Angiotensin II produced a small increase in the synthesis of myocyte proteins in both normal and hypertrophic cells as shown by [35S]methionine incorporation. However, this increase could not account for the increase in the phosphate content of pp42. This protein was not an isoform of actin nor was it of platelet origin. These results raise the possibility that angiotensin II may play a role in the activation of factors in hypertrophic myocytes; however, further study is required to define a link between phosphorylation of pp42 and the hypertrophic process.


Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats. Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.


Alterations in renal endothelin-1 production in the spontaneously hypertensive rat. Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct. Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR.


Effects of antihypertensive agents on arterial baroreceptor reflexes in conscious rats. The effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor reflex control of renal sympathetic nerve activity and heart rate were investigated in 45 conscious spontaneously hypertensive rats and 37 age-matched Wistar-Kyoto rats. Antihypertensive agents were administered for 2 weeks beginning at 8 weeks of age to treat and prevent the development of hypertension. Blood pressure was reduced to a similar level (-13 +/- 3 mm Hg, p < 0.05) by each antihypertensive agent. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded in the conscious state during phenylephrine and nitroglycerin ramp infusion. The gain in the baroreceptor reflex was determined from the maximum slope of logistic function curves. Untreated spontaneously hypertensive rats exhibited decreased sensitivity of reflex control of renal sympathetic nerve activity and heart rate (-1.78 +/- 0.07% of control/mm Hg and -2.16 +/- 0.05 beats per minute/mm Hg, respectively) compared with untreated Wistar-Kyoto rats (-3.62 +/- 0.18% of control/mm Hg, p < 0.01, and -3.46 +/- 0.11 beats per minute/mm Hg, p < 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Enzymatic activity and immunoreactivity of extracellular phospholipase A2 in inflammatory synovial fluids. Synovial fluid PLA2 concentration was measured by an ELISA technique using monoclonal antibodies raised against human recombinant "synovial-type" group II phospholipase A2. This ELISA was specific for synovial-type PLA2 and did not detect pancreatic (group I) PLA2. In all synovial fluids examined, including rheumatoid, osteoarthritic, psoriatic, and gouty fluids, synovial fluid PLA2 enzyme activity significantly correlated with PLA2 immunoreactivity (P < 0.001). Within the limits of the ELISA technique, there was no evidence for the presence of specific or nonspecific modulation of PLA2 activity by either putative PLA2 activating or inhibitory proteins.


Concentration and turnover of intraperitoneal hyaluronan during inflammation. Aseptic peritonitis was induced in rabbits by intraperitoneal injection of irritating agents, mainly starch suspensions. The inflammatory response was followed in the peritoneal lavage fluid by cell counts (average increase about 800-fold the first day) and hyaluronan concentration (average increase about 200-fold on the second and third days). The turnover rate of hyaluronan was studied by injecting tritium-labeled hyaluronan intraperitoneally and by following the appearance of tritiated water in serum. In control animals given trace amounts of hyaluronan, half-lives of 1-14 h were recorded. When the labeled polysaccharide had been mixed with 10 mg/ml of unlabeled hyaluronan, the half-life was approximately one day. Rabbits with ongoing peritonitis exhibited half-lives between 1 and 16 h. It was concluded that there was a large individual variation in uptake kinetics, that the removal process could be receptor mediated, and that the increase in intraperitoneal hyaluronan in peritonitis mainly was due to an increased production of the polysaccharide rather than a decreased rate of removal.


Bone-resorbing activity is expressed by rat macrophages in response to arthropathic streptococcal cell wall polymers. Rat peritoneal macrophages stimulated in vivo by group A streptococcal peptidoglycan-polysaccharide (PG-APS) resorb bone as measured by solubilization of 45Ca from radiolabeled, devitalized bone chips. Activity was strain-dependent and correlated with the susceptibility of rat strains to PG-APS-induced arthritis. PG-APS-stimulated macrophages from the resistant Buf rat strain were not induced to resorb bone, but ingested equivalent concentrations of PG-APS compared to bone-resorbing macrophages from the arthritis-susceptible Lew strain. Resorptive activity peaked at three to five days and decreased to background levels by 10 days after injection. PG-APS-stimulated macrophages from congenitally athymic Lew rats were as effective as macrophages from heterozygous littermates at resorbing bone. Lew macrophages were also responsive to small, nonarthropathic PG-APS polymers generated by mutanolysin digestion. Resident peritoneal macrophages did not respond to stimulation by PG-APS in vitro. Indomethacin at a concentration of 10 micrograms/ml was an effective blockade against PG-APS-induced macrophage bone resorption in vitro, but catalase was ineffective. These results indicate that expression of rat macrophage bone-resorbing activity reflects genetic regulation of the response to PG-APS rather than a defect in ingestion of these polymers and imply that PG-APS-stimulated, bone-resorbing macrophages may contribute to early, initial bone destruction that occurs in inflammatory arthritis.


Inhibition of prekallikrein activation in human plasma by components of bovine plasma. Contact of plasma with a negatively charged surface activates prekallikrein and factor XII reciprocally. Activation of prekallikrein by several activators was impaired in bovine plasma when compared to that in human plasma. The activated partial thromboplastin time of bovine plasma, induced by several activators, was significantly longer than that of human plasma. Cleavage of [125I]factor XII was optimum at 10 min in human plasma but took up to 60 min in bovine plasma. Addition of bovine plasma to human plasma caused significant inhibition of dextran sulfate-induced prekallikrein activation, indicating that the impaired rate of contact activation in bovine plasma is due to the presence of inhibitors. The inhibitory effect was greater at lower concentrations of dextran sulfate but could not be abolished by increasing the concentration. The inhibitory activity eluted in two peaks at low and medium salt concentrations on carboxymethyl ion-exchange chromatography of bovine plasma.


Neuropeptides in pulmonary edema fluid of adult respiratory distress syndrome. A role for peptidergic nerves in the adult respiratory distress syndrome (ARDS) was examined by radioimmunochemically quantifying neuropeptides in pulmonary edema (PE) fluids from seven patients with ARDS and six patients with PE from congestive heart failure (CHF). The PE fluid mean concentrations of substance P (SP) and gastrin-releasing peptide (GRP) were significantly higher in ARDS (0.59 +/- 0.29 SD and 0.10 +/- 0.03 nM, respectively, P < 0.001 for both) than in CHF (0.19 +/- 0.08 and 0.04 +/- 0.01), whereas no difference was detected between the mean levels of vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) in the two forms of PE. Mean alveolar fluid concentration of SP was 8.7 nM (range 2.1-20.5 nM, N = 4) in sheep with acute lung injury from intravenous Pseudomonas aeruginosa, but was undetectable in sheep with balloon-induced high left atrial pressure simulating CHF (N = 2) or control sheep (N = 2). Pulmonary lymphatic clearance of SP, which reflected the rate of generation of SP in the lungs, attained a maximum of 25-95 pmol/h in sheep given P. aeruginosa intravenously, but was detected in only one of four control sheep at a lower level. Some pulmonary neuropeptides thus are released locally by acute lung injury and may contribute to endothelial and/or epithelial abnormalities underlying the altered capillary-alveolar permeability in ARDS.


Synergism among oxidants, proteinases, phospholipases, microbial hemolysins, cationic proteins, and cytokines. A striking similarity exists between the pathogenetic properties of group A streptococci and those of activated mammalian professional phagocytes (neutrophils, macrophages). Both types of cells are endowed by the ability to adhere to target cells; to elaborate oxidants, hydrolases, and membrane-active agents (hemolysins, phospholipases); and to freely invade tissues and destroy cells. From the evolutionary point of view, streptococci might justifiably be considered the forefathers of "modern" leukocytes. Our earlier findings that synergy between a streptococcal hemolysin (streptolysin S, SLS) and a streptococcal thiol-dependent proteinase and between cytotoxic antibodies+complement and streptokinase-activated plasmin readily killed tumor cells, led us to hypothesize that by analogy to the pathogenetic mechanisms of streptococci, the mechanisms of tissue destruction initiated by activated leukocytes in inflammatory sites, as well as in tissues undergoing episodes of ischemia and reperfusion, might also be the result of the synergistic effects among leukocyte-derived oxidants, phospholipases, proteinases, cytokines, and cationic proteins. The current report extends our previous synergy studies with endothelial cells to two additional cell types--monkey kidney epithelial cells and rat beating heart cells. Monolayers of 51Cr-labeled cells that had been treated by combinations of sublytic amounts of hydrogen peroxide (generated either by glucose oxidase, xanthine-xanthine oxidase, or by paraquat) and with sublytic amounts of a variety of membrane-active agents (streptolysin S, phospholipases A2 and C, lysophosphatides, histone, chlorhexidine) were killed in a synergistic manner (double synergy). Crystalline trypsin markedly enhanced cell killing by combinations of oxidant and the membrane-active agents (triple synergy). Injury to the cells was characterized by the appearance of large membrane blebs that detached from the cells and floated freely in the media, looking like lipid droplets. Cytotoxicity induced by the various combinations of agonists was depressed, to a large extent, by scavengers of hydrogen peroxide (catalase, dimethyl thiourea, and by Mn2+) but not by SOD or by deferoxamine. When cationic agents were employed together with hydrogen peroxide, polyanions (heparin, polyanethole sulfonate) were also found to inhibit cell killing. It is proposed that in order to effectively combat the deleterious toxic effects of leukocyte-derived agonists on cells and tissues, antagonistic "cocktails" comprised of cationized catalase, cationized SOD, dimethylthiourea, Mn(2+)+glycine, proteinase inhibitors, putative inhibitors of phospholipases, and polyanions might be concocted. The current literature on synergistic phenomena pertaining to mechanisms of cell and tissue injury in inflammation is selectively reviewed.


Hyperphospholipasemia A2 in human volunteers challenged with intravenous endotoxin. Phospholipase A2 (PLA2) activity was measured in the serum of 23 individuals infused intravenously with endotoxin (EN) at a dose of 4 ng/kg body weight. A marked increase in PLA2 was noted 3 h after EN challenge (mean 828 +/- 513 units/ml), reached its maximum at 24 h after the challenge (mean 2667 +/- 2442 units/ml), and was still evident at 48 h (mean 763 +/- 366 units/ml). In contrast, TNF levels were maximal (mean 712 +/- 375 pg/ml) 90 min after the EN challenge and subsided to very low values (5 +/- 5 pg/ml) 5 h after the challenge. There was a positive correlation between the maximum response of TNF and that of PLA2 (r = 0.82, P < 0.01). Administration of ibuprofen or pentoxifylline did not alter the PLA2 response. EN challenge did not affect serum pancreatic PLA2 concentration or that of the lysosomal cationic enzyme, lysozyme. Neutralizing antibody against human recombinant (synovial type) PLA2 completely abolished PLA2 activity in the sera tested. We conclude that EN infusions cause marked intravascular release of nonpancreatic secretory PLA2 and that the magnitude of this response seems to be related to the prior generation of TNF.


Congenital factor XIII deficiency.

Congenital factor XIII deficiency. Clinical and hematological data of 9 cases with factor XIII deficiency is highlighted. The age at first bleed ranged from 3 days of life to 1 year. Seven of these 9 cases had bleeding from the umbilicus, 3 had recurrent subcutaneous and muscle hematomas, while 4 cases had CNS bleeds of which 3 expired. Routine coagulogram was normal, while clot solubility in 5 molar urea solution was abnormal in all cases. Factor XIII assay was not done in any. Patients were treated with plasma transfusion during episodes of bleeding. No patient received plasma transfusion as prophylactic therapy. The cumulative Indian data so far documented, inclusive of this series, shows a very high incidence of CNS bleeds (33%) in patients with this inherited coagulation disorder.


Glanzmann's thrombasthenia.

Glanzmann's thrombasthenia. During January 1981 to June 1991, 20 patients from 16 unrelated families were detected to have Glanzmann's thrombasthenia (GT). Twelve families (75%) had history of consanguinity, with 6 first cousins and 3 uncle-niece marriages; of these 7 were Muslims, 6 Hindus and 3 Christians. There were 12 girls and 8 boys; the mean age at diagnosis was 7.05 +/- 6.03 yr (range 1 day-22 yr). All cases had initial bleeding prior to the age of 5 yr with the mean age at the initial episode of bleeding being 2.21 +/- 1.34 yr (range 1 day-5 yr). Common pattern of bleeding included epistaxis, gingival bleeding, post-traumatic bruises, menorrhagia, gastrointestinal (2 cases), post-operative (2 cases) and spontaneous bleeding (2 cases). No patient showed hemarthrosis, intracranial bleeding or hemoptysis. Menorrhagia was a serious problem necessitating repeated transfusions and hormonal therapy. Twelve cases (60%) required 1-120 units of blood transfusions while five received platelet concentrates.


Efficacy of intrathecal methotrexate with and without cranial radiotherapy in preventing central nervous system relapses in acute lymphocytic leukemia. Introduction of CNS chemoprophylaxis was a major milestone in the development of current therapy for acute lymphocytic leukemia. However, controversies are still existing for ideal form of CNS chemoprophylaxis. The present study was conducted to determine the efficacy of intrathecal methotrexate (IT-MTX) with and without cranial radiotherapy in preventing CNS relapses in Indian children. CNS chemoprophylaxis comprising of six injections of intrathecal methotrexate (12 mg/M2) was administered alone or along with cranial radiotherapy (2000 GY) in 76 children each after successful induction remission. Cranial radiotherapy (RT) with intrathecal methotrexate (IT-MTX) was observed to be more effective as CNS relapses were seen in 11.8% of children as compared to 16.8% of children receiving IT-MTX alone. IT-MTX along with cranial RT delayed the occurrence of CNS relapses and prolonged the event free survival periods.


Diagnostic and prognostic value of bromide partition test in tuberculous meningitis. Bromide partition ratio was determined in 32 cases of tuberculous meningitis, 6 pyogenic meningitis, 8 viral meningitis and 9 cases of febrile convulsions. Bromide partition ratio below the critical value of 1.6 was present in 30 out of 32 tuberculous meningitis patients (93.74%) whereas all the control children had a ratio above 1.6. Two children who were on regular chemotherapy showed progressively rising ratio. It is concluded that in doubtful cases with inconclusive CSF picture, a low bromide partition ratio is a strong reason for starting antituberculous treatment without any delay. A very low ratio also suggests poor prognosis.


Comparative study of oral versus injectable vitamin K in neonates. One hundred term exclusively breast fed babies weighing more than 2.5 kg were evaluated to determine the efficacy of various modes and doses of Vitamin K to prevent hemorrhagic disease of newborn (HDN). The babies were grouped into four categories of 25 each: Group A--1 mg Vitamin K intramuscular (Menadione sodium disulphite) at birth; Group B--0.5 mg Vitamin K intramuscular; Group C--1 mg Vitamin K orally, and group D--no Vitamin K. The prothrombin index was estimated in all babies between 36-72 hours of age. The results revealed a prothrombin index in Groups A, B, C and D as 94.98 +/- 7.64%, 95.08 +/- 9.91%, 92.51 +/- 10.10% and 80.39 +/- 15.90%, respectively. The differences between Groups A, B and C were insignificant. However, Group D, prothrombin index was significantly reduced as compared with the other three groups. It is, therefore, concluded that oral Vitamin K is as effective as injectable Vitamin K and its usage is recommended in our country to reduce complications and costs of parenteral therapy.


Bronchial challenge with purified protein derivative of Mycobacterium tuberculosis in asthma. Response to bronchial challenge (BC) with purified protein derivative of Mycobacterium tuberculosis (PPD), was studied in children with bronchial asthma and correlated with Mantoux test and serum immunoglobulin E (IgE) against PPD (PPD-Sp IgE). Nearly 59% patients with bronchial asthma and 12.2% patients with pulmonary tuberculosis gave positive BC. Children with extra-pulmonary tuberculosis and normal children did not show positive BC. In asthma, 25% gave early (EAR), 50% gave late (LAR) and 25% gave both early and late (DAR) asthmatic response. Forced expiratory flow volumes in 1 sec (FEV.1) of 13 age and sex matched asthmatic and normal children showed similar volumes before BC, however, the values were significantly lower in asthma at 20 min (p less than 0.005) and 24 h (p less than 0.005) after BC. There was no relationship between response to BC and the severity or chronicity of asthma. PPD-Sp IgE was estimated by the radioimmunoassay method (Pharmacia Diagnostics). It was detected in 75% with positive BC and none of the controls. The titre was of Phadebas RAST Class III in 66.7%, Class II in 22.2% and Class I in 11.1%. The presence of early Mantoux reactions, positive BC with PPD and serum PPD-Sp IgE suggest the existence of Type I or Arthus type of reactions to PPD, which could cause hyperreactive airways in some cases of asthma.


Chest radiographs in neonatal septicemia. Chest radiographs of 63 culture proven cases of neonatal septicemia were evaluated in this prospective study. Gram negative septicemia was responsible for 76.2% cases. Radiological abnormalities were observed in 27 cases (42.8%). Seven of these had no respiratory distress. The findings were right sided infiltrates (27%); hyperinflation (7.9%), bronchopneumonia (6.3%) and pneumothorax (1.6%). Increasing gestational age, late onset of illness (greater than 3 days) and presence of respiratory signs of distress had a positive correlation with presence of X-ray findings. Term newborns with respiratory distress of late onset sepsis (greater than 3 days) had significantly higher number (p less than 0.05) of abnormal radiographs. Presence of radiological abnormality neither influenced the clinical outcome nor was affected by the causative organisms. The practice of doing a chest radiograph routinely in cases of neonatal septicemia is justified irrespective of presence of respiratory signs of distress.


Participation of health workers, school teachers and pupils in the control of rheumatic fever: evaluation of a training programme. In a rural community block of north India we initiated a programme for control of rheumatic fever and rheumatic heart disease (RF/RHD). This included a training campaign for all 74 health workers, 773 school teachers and 12,500 older pupils (class V to X) to enable them to suspect and refer cases of RF/RHD and counsel them about secondary prophylaxis. Training material was used by project staff, medical officers and teachers to convey that this serious disease with onset between 5 and 15 years can be recognized by four simple criteria: fever with joint pain or swelling; breathlessness and fatigue; involuntary face and limb movements. One year later we evaluated awareness generated by training by administering a questionnaire to random samples in the intervention area and in a noncontiguous control area. Health workers, teachers and pupils of the intervention block were significantly better aware of the nature, severity and presentation of the disease and reported having recognized cases whom they had referred for diagnosis, prophylaxis and counselled for follow up. We conclude that a training protocol incorporating simple messages can effectively create practical awareness for RF/RHD control among teachers, health workers and pupils in a rural community.


Experience with a measles vaccine manufactured in India. Five hundred and twenty seven children between 7 months and 2 years of age were vaccinated with measles vaccine manufactured by the Serum Institute of India. The sero-conversion rate in children who had no antibodies previous to vaccination was 98.4% as tested in HI. Ninety per cent of children who had pre-vaccination measles antibodies showed a two-fold or more rise in HI antibodies. The side reactions of the vaccine were negligible.


Eight years' experience of clinical activity in an outpatient fracture clinic. Major changes to the method of planning and provision of health care in Britain have led to the introduction of contracts as the main means through which services are procured. Never before has the need for accurate and comprehensive clinical information been greater. Yet comprehensive outpatient information, though planned, is not yet available, and there is relatively little experience of such systems which have been introduced in individual localities. Fracture clinic patients are an important group of outpatient, not least because interventions are often undertaken as an integral part of the outpatient episode. This is relevant for estimating resource use and for pricing, but until now has been 'hidden' work as far as conventional information systems are concerned. This study describes the establishment and manifestation of a clinical information system based on a fracture clinic serving the majority of a population of 850,000. Information was gathered over 8 years on 61,635 patients, who had 72,984 diagnoses and received 93,878 treatments. An information system of the type described in this study can be of great value as part of the contracting process (for both purchasers and providers of orthopaedic services), as a basis for clinical audit and research, and to facilitate undergraduate and postgraduate teaching.


Iselin's operative technique for thumb proximal metacarpal fractures. Between 1980 and 1989, 33 patients were treated operatively according to Iselin for a proximal metacarpal thumb fracture. At follow-up all but one patient had a good functional result with no restrictions in work, sports, or delicate hand movements.


Primary external fixation and secondary intramedullary nailing in the treatment of tibial fractures. The results of primary external fixation and secondary intramedullary nailing of 21 tibial fractures are presented. It is shown that if secondary nailing is delayed until after granulation of the pin sites the technique is associated with a low infection rate. The union time for tibial fractures compares well with that of external fixation, although in closed and Gustilo type I open fractures primary intramedullary nailing gives superior results.


Role of prophylactic antibiotics in open and basilar fractures of the skull: a randomized study. The aim of this study was to investigate the controversial issue of the use of prophylactic antibiotics in open and basilar fractures of the skull. A series of 157 patients were randomized to receive no antibiotics (group A = 46 patients) or ceftriaxone for 3 days (group B = 50 patients), or the combination ampicillin/sulphadiazine for 3 days (group C = 61 patients). The incidence of meningitis was similar in both the antibiotic and non-antibiotic groups. However, the overall incidence of infectious complications in the non-antibiotic group was significantly higher than in the antibiotic group (8.7 per cent vs 0.9 per cent, P < 0.05). There was no significant difference between the ceftriaxone group and the ampicillin/sulphadiazine group. The results of the study suggest that antibiotic prophylaxis has a role in the management of open and basilar fractures.


Interlocking nailing for fractures of the femur and tibia. In 132 patients, fractures of the lower limb (71 femoral and 61 tibial fractures) were treated using interlocking nailing (ILN) according to Grosse and Kempf during the period 1986-1989. Of these, 118 were followed up for a median of 19 months (range 9-32 months). Inpatient stay averaged 9 days regardless of the fracture. Consolidation was achieved in approximately 3 or 4 months from the operation in tibial and femoral fractures, respectively. Tibial fractures were technically more demanding than femoral ones, and their average operating time was significantly longer (73 min versus 51 min). Only one patient had a malunion in malrotation. The most serious complication was in a closed upper tibial fracture with traumatic rupture of the popliteal artery. Although the nailing was technically successful, an above-knee amputation had to be carried out. In only one case did the nail fail, and tibial plating had to be performed. Given the present degree of expertise, ILN for fractures of the long bones of the lower limb is a safe and relatively easy procedure to perform.


Percutaneous screw fixation of tibial plateau fractures. A series of 13 patients with displaced fractures of the tibial plateau treated by closed reduction and percutaneous pinning have been reviewed 17 months after surgery. All the operations were performed using image intensification to aid reduction of the fracture by ligamentotaxis and to guide screw placement. In two cases, arthroscopy was used in addition to facilitate elevation of the articular surface using a probe inserted through a cortical window in the proximal tibial metaphysis. The postoperative rehabilitation programme consisted of early mobilization and non-weight bearing for at least 2 months. Of the patients, 11 had a satisfactory result, one patient had a fair result with persistent pain and the other had a poor result when the fixation failed in a comminuted bicondylar fracture in porotic bone. This technique is minimally invasive and avoids many of the complications of both conservative and operative treatment and will have an expanding role to play in the management of these fractures.


Post-traumatic abdominal mucormycosis.

Post-traumatic abdominal mucormycosis. Gastrointestinal mucormycosis, an opportunistic fungal infection, is a rare complication of trauma. We report on four patients who developed this frequently fatal condition after delayed treatment of intra-abdominal sepsis and discuss the aetiology, diagnosis and management of the disease.


Trauma deaths in the south west Thames region. This is an epidemiological study based on Coroners' records analysing mode of injury and place and cause of death. The aim of the study is to provide data on the incidence and patterns of death from trauma and to assess the need for changes in trauma management. All traumatic deaths occurring in the South West Thames Region during 1988 were studied. We analysed 434 of these deaths (mean age 52 years) in some detail. Of the deaths, 59 per cent occurred before arrival at hospital. Road traffic accidents are the commonest cause of death from trauma, being most prevalent in the areas containing major trunk roads. The majority of deaths due to chest injury (79 per cent) and multiple injuries (70 per cent) occurred before arrival at a hospital, whereas the majority of deaths due to head injury (63 per cent) occurred after admission. The majority of deaths from trauma occur before arrival at a hospital, particularly in the semi-rural areas. Improvements in hospital trauma care could have only a limited effect on the death rate in existing circumstances. If important reductions in deaths from severe injury are to be made then prevention and prehospital care need to be improved.


Injuries to the spinal cord in elderly patients. There are certain differences between the mechanism of injury and the course and results of treatment of post-traumatic spinal cord injuries in younger and older victims. Between 1965 and 1990 there were 564 patients over 60 years of age with spinal cord or cauda equina injuries treated at the Spinal Cord Centre in Konstancin, Poland. This article presents the level and degree of the nervous system injury, the methods of treatment and early mortality in the series. Of the patients, 43 per cent were aged between 60 and 65 years, but 31 per cent were patients over 70 years of age. More patients sustained injury to the cervical spine (72 per cent), and 42 per cent of lesions to the spinal cord were neurologically assessed as complete transverse cases. This paper stresses the high mortality rate, amounting to 26 per cent overall and 48 per cent in the groups with complete spinal cord lesions.


Surgery in Afghanistan: a light model for field surgery during war. Owing to a poor capability for evacuation, mobile medical teams were sent to the area of Gazni in Afghanistan to work with local paramedics as part of a medical programme for the area. The teams were equipped to perform major surgery. During 1 month a surgical team inside Afghanistan performed 53 operations. The operations were performed in the patients' homes at night. The team had to move frequently so as not to be spotted by the Soviet and government surveillance. Equipment equivalent to a light field hospital was stored in a safe place and the team carried supplies for 1 or 2 days on their bicycles. One postoperative death and one wound infection were recorded. It is concluded that adequate surgery can be performed inside territories where enemy forces have air control and under primitive conditions with an acceptable rate of complications. However, due to the nature of the guerrilla warfare with scattered military confrontations over vast areas, the average time between injury and treatment for war casualties was 36 h.


Surgery in a Palestinian refugee camp.

Surgery in a Palestinian refugee camp. From 1985 to 1987, three Palestinian refugee camps in Lebanon were attacked several times by a Lebanese militia. We present a review of 1276 casualties who were wounded in the refugee camp of Bourj al-Barajneh during two such attacks between December 1985 and April 1987. All were treated in Haifa Hospital (30-40 beds), which had limited equipment, was situated inside the refugee camp and was badly damaged by war. During both attacks, the refugee camp was surrounded and put under siege such that patients could not be evacuated and supplies were not allowed in. The second period lasted almost 6 months resulting in severe shortages of medicines, equipment and food, leading to a rationing of resources and modification of treatment. More than 300 operations were carried out under general anaesthesia, the remainder under local or without anaesthesia. The overall operative mortality was 3.2 per cent. Despite the deprivation, many patients survived severe and complicated wounds because they were quickly brought to the hospital, provided with adequate quantities of fresh blood for transfusion, and sound surgical principles were followed.


Magnetic resonance imaging of the knee: initial experience in a district general hospital. We present the results of a prospective study comparing the accuracy of magnetic resonance imaging with arthroscopy in the assessment of knee complaints. Using a low field strength magnet, MRI was able to achieve a high diagnostic accuracy within the setting of a district general hospital.


Gallbladder and extrahepatic biliary duct injury following abdominal trauma. Extrahepatic biliary tract and gallbladder injuries are rare, but many occur after both blunt and penetrating abdominal trauma. During a 5-year period, 24 patients requiring laparotomy for abdominal trauma were found to have an extrahepatic biliary tract injury, representing 13 per cent of all patients admitted with hepatic trauma during the same period. The majority of patients had injury to the gallbladder; only one case of common bile duct injury was identified. Of the patients, 50 per cent had an associated hepatic injury; 17 per cent had important pancreatic trauma. Isolated gallbladder injury occurred in only 8 per cent of patients. The overall mortality associated with gallbladder trauma was 16 per cent. This uncommon injury usually results from severe trauma and is associated with a high incidence of other major visceral injuries.


Effectiveness of the macrolide clarithromycin in the treatment of Mycobacterium avium complex infection in HIV-infected patients. In a randomized double-blind study, nine mycobacteremic patients with AIDS-related disseminated Mycobacterium avium complex (MAC) infection received clarithromycin or placebo in addition to a basic regimen that included isoniazid, ethambutol and clofazimine. All four patients receiving clarithromycin showed blood culture conversion and clinical response. Of the five patients treated without clarithromycin, two showed resolution of mycobacteremia and clinical response, while another two died without having shown response. The remaining patient deteriorated until a switch from placebo to clarithromycin led to blood culture conversion and rapid clinical improvement. After finishing six weeks of intensive treatment, clarithromycin was given in an open maintenance phase to all patients, initially in combination with rifabutin for 24 weeks and then alone. One patient had a relapse of MAC infection while receiving clarithromycin alone. The relapse was associated with acquired resistance to the drug. Clarithromycin appears to be a promising component of multi-drug therapy for patients with MAC infection. Monotherapy can lead to drug resistance.


Long-term persistence of anti-HBs after hepatitis B immunization in thalassaemic patients. An epidemiological study was carried out on 114 beta-thalassaemics in order to select those subjects susceptible to hepatitis B virus (HBV) infection for hepatitis B vaccination. The results confirmed the high risk of HBV infection in these patients: 9.6% were HBsAg positive, 29.8% were anti-HBs positive/anti-HBc positive, and 9% were anti-HBc positive. In 60 HBV-negative patients, 20 micrograms doses of hepatitis B vaccine were administered on a schedule of 0, 1 and 6 months. Sera were collected for six years to determine the seroconversion rate and the anti-HBs titre. Seroconversion reached a maximum rate of 93% 12 months after the first vaccination dose and was 80% at the final control (72 months). Highly protective anti-HBs titres were observed until the last control in a high percentage of subjects. The HBVax hepatitis B vaccine has been shown to be safe, immunogenic and effective in beta-thalassaemics.


Antibiotic resistance of Escherichia coli in fecal samples of healthy people in two different areas in an industrialized country. Fecal samples of 310 healthy persons, from two populations from different areas in the Netherlands, were examined for the presence of Escherichia coli resistant to ampicillin, tetracycline, sulfamethoxazole, trimethoprim and nitrofurantoin. High prevalences of resistance were found in both populations, ranging from 28% for trimethoprim to 89% for ampicillin. The percentages of the fecal samples with a dominantly resistant E. coli flora (> 50% resistance) were distinctly lower, ranging from 1% for nitrofurantoin to 21% for tetracycline. No significant differences in the level of resistance were observed between these two comparable populations in two different areas. The susceptibilities to 11 antimicrobial agents of 456 at random isolated E. coli were determined. The percentages of resistance varied widely: from 80% for chloramphenicol to 9% for nitrofurantoin. Only 19% of the isolates were susceptible to all antibiotics tested and 14% were resistant to more than four of the agents tested. Great differences in resistance rates between the two populations examined were seen for chloramphenicol (80% to 41%) and trimethoprim (16% to 36%). The results of this study underscore the presence of a human reservoir of antibiotic resistant microorganisms.


Silences: helping elderly Holocaust victims deal with the past. Persons who have faced severe crises such as the Holocaust in Nazi Germany confront painful memories, guilt, and the perceived irrationality of their own survival, which represses thoughts and memories. There is no language to share the dark and difficult years of the past. Silence is their only voice of expression. In later life, when friends are gone, the need to share with others becomes urgent; to bear witness is vital. Helping persons share these experiences is no easy task. To engage the elderly with reminiscences, memory, bereavement, and the working through of guilt provide unusual challenges for the helping professions. Significant family events are also important opportunities for sharing the past. It is the children and grandchildren's desire to know that also prompts the sharing of past horrors and future hopes. They often enable the deepest silences to be shared and it is the elderly that often welcome this opportunity. Being sensitive to these integenerational dynamics are important in helping elderly Holocaust victims deal with their past.


Importance of the environment and the faecal flora of infants, nursing staff and parents as sources of gram-negative bacteria colonizing newborns in three neonatal wards. Gram-negative bacteria are an important cause of invasive infection among neonates. In this study a novel fingerprinting method was used for the first time to assess the importance of various potential reservoirs of the major gram-negative enterobacteria that colonized 46 consecutive infants in three neonatal special care units during a three to four week period. Such bacteria were isolated from the oropharynx, umbilical cord and faeces in 24%, 33% and 100% of the infants, respectively. Klebsiella/Enterobacter spp. dominated over Escherichia coli and spreading (shared) over sporadic strains. Sixty-one percent of the neonates were colonized with at least one and up to six different strains shown to exist in the ward, mainly in other infants. Environmental reservoirs and the faecal flora of mothers and staff were of minor importance. Vertical transmission occurred in 12% of vaginally delivered infants and in 0% of those delivered by caesarean section.


Widowhood in elderly women: exploring its relationship to community integration, hassles, stress, social support, and social support seeking. This study examined the degree to which widows were integrated in their community, the daily hassles and stress they may have experienced, and their social networks and support-seeking behavior. A sample of 160 women, sixty years of age or older, eighty widows and eighty non-widows were interviewed. Half the sample participated in senior centers in Kansas City, Missouri, while the other half belonged to other organizations or were obtained through a truncated snowball technique. The findings indicated that widowhood in and of itself does not appear to be a predictor either of community integration or the lack of it or the experience of stress and hassles. Those who experienced hassles were not the same persons as those who experienced stress. It was surprising to find that those who sought social support did not seem most in need of it. Age and education, along with community integration, were better predictors of the variables studied than was widowhood.


The influence of physical fitness on automatic and effortful memory changes in aging. A cross-sectional study was carried out in order to determine the influence of cardiovascular fitness on age-related declines in cognitive performance. Forty-eight volunteers were divided into Young (n = 13, 18-27 years), Middle-Aged (n = 22, 60-65 years) and Old (n = 13, 65-88 years) groups and tested on a battery of cardiovascular, pulmonary, hemodynamic, and biochemical tests in order to assess physical fitness. Cognitive performance was evaluated by a variety of memory tasks distributed along an automatic-to-effortful processing continuum. Memory for location and frequency of occurrence were selected as representative of automatic processing, whereas, an auditory free-recall task was selected as representative of effortful processing. Age-related performance declines were observed for the free-recall task, but no such age-dependent association was observed for frequency and location memory. With regard to the influence of physical fitness; the Middle-Aged and Older participants were divided into High and Low Fitness groups and significant differences were observed between these groups for the effortful but not the automatic memory tasks. These data suggest that the relationship between physical fitness and cognitive performance in old age is task dependent. Furthermore, the apparent prophylactic effects of physical fitness on effortful memory, do not appear to extend to cognitive tasks requiring less effortful processing.


Predictors of self-reported problems of confusion among the aged. Responses to questions on the 1984 Supplement on Aging to the National Health Interview Survey (NHIS) about the experience of personal confusion revealed that two-thirds of those interviewed reported never having an episode of confusion during the preceding year. Of those who reported episodes, fewer than one in five said they were happening with increased frequency. The many meanings of confusion found in the literature prompted a modest local study of what respondents understood by the term when asked the NHIS questions. Of those who admitted occasional confusion, almost two-thirds gave definitions that included memory loss or forgetfulness. Consequently, increased frequency of memory problems and difficulty in remembering were included with other variables in the analyses to identify significant predictors. They emerged the single best predictors of how often a respondent reported getting confused. Others were change in health status, number of functional limitations, educational attainment, and vision problems.


Rapidly fatal Q-fever pneumonia in a patient with chronic granulomatous disease. Acute Q-fever is a systemic illness which rarely has a fatal outcome. Fatal cases do occur with the chronic form of the disease and associated with endocarditis. This report presents the case of a fatal, acute Q-fever pneumonia in an 11-year-old patient with chronic granulomatous disease. Complement fixation antibody titer rose to 1:1,024 with positive IgM in immunofluorescence. Giemsa stained lung sections and indirect immunofluorescence demonstrated the microorganisms in the tissues. The Coxiella burnetii infection was probably contracted during a holiday trip to rural France. Despite the fact that the patient received a variety of antimicrobial agents with broad spectrum activity against bacteria and fungi, coverage for Q-fever, i.e. chloramphenicol or tetracyclines, was not included.


Seniors' assessment of their health and life satisfaction: the case for contextual evaluation. Health care professionals have been puzzled by the highly positive statements on health and life satisfaction made by seniors, particularly when compared to professionally collected data. In 1987-1988, a stratified, random sample of 520 seniors living independently in the community (70-99 years) were interviewed in their own homes. The above response pattern again held. However, it was apparent that opinions on life satisfaction vary with type of health problem. Content analysis of the spontaneous remarks made by the participants indicates that the overall, current, and anticipated levels of satisfaction expressed were associated significantly with the historical perspective or lifeview of the participants, and with their state of health. Utilizing the theoretical concept "sense of coherence" gives direction to understanding these phenomena.


Loracarbef versus penicillin V in the treatment of streptococcal pharyngitis and tonsillitis. Ten-day, double-blind, randomized, parallel treatment regimens of loracarbef (200 mg capsule twice daily or 15 mg/kg/day oral suspension in two divided doses up to a maximum of 375 mg/day; n = 169) and penicillin V (250 mg capsule four times daily or 20 mg/kg/day suspension in four divided doses up to a maximum of 500 mg/day; n = 175) were compared in the treatment of group A beta-haemolytic streptococcal (GABHS) pharyngitis and tonsillitis. Post-therapy clinical responses were similar for evaluable patients in both treatment groups: 97.4% of the loracarbef group (101/115 patients cured and 11/115 improved) and 96.0% of the penicillin group (101/124 patients cured and 18/124 improved). A statistically significant difference in the pathogen elimination rate was noted between treatment groups: post-therapy throat cultures were negative for GABHS in 94.8% (109/115) of loracarbef-treated patients compared with 87.1% (108/124) of penicillin-treated patients (p = 0.040). Loracarbef and penicillin V were comparable in terms of safety. Headache and nausea/vomiting were the most common events reported during therapy (nausea/vomiting were slightly less common in the loracarbef group). Three patients in each group were discontinued from the study due to drug-related adverse events; one due to rash in the loracarbef group and one due to rash and one due to vomiting in the penicillin group. These data support the conclusion that loracarbef twice daily is more effective in eradicating GABHS than penicillin V four times daily, and the two drugs are comparable in safety and clinical efficacy in the treatment of GABHS pharyngitis and tonsillitis.


Pharmacokinetic and pharmacodynamic studies of the effect of ketoconazole on reproductive function in male rats. A single oral dose (300 mg kg-1) of ketoconazole induced reversible immobilization of rat epididymal spermatozoa at 8-24 h after dosing. This occurred when the drug concentrations in cauda epididymal fluid and seminal plasma were at their peak (18.0 +/- 7.3 and 13.5 +/- 3.0 micrograms ml-1, respectively), and which was preceded by a peak plasma concentration (Cmax) of 64.82 +/- 2.47 micrograms ml-1 at 5.15 +/- 0.68 h (Tmax). In contrast, rete testis fluid collected from the same animals contained only minute amounts of ketoconazole (0.47 +/- 0.34 micrograms ml-1). Plasma testosterone concentration showed a sharp decline within 4 h of dosing, followed by a recovery from suppression, even after administration of a low dose (100 mg kg-1) which did not affect sperm motility. These findings suggest that ketoconazole gains access to the post-testicular sex organs and affects the mature spermatozoa therein much more readily than it affects testicular spermatogenesis. Synthesis and screening of compounds with a related molecular structure but which exhibit more pronounced spermicidal and less pronounced anti-androgenic effects are thus suggested in the hope that rapidly acting and reversible male contraceptives might be identified and developed.


Testicular blood flow and vasomotion can be maintained by testosterone in Leydig cell-depleted rats. The effect of testosterone supplementation on testicular blood flow, testicular vasomotion, the number of polymorphonuclear leucocytes (PMN's) in testicular blood vessels and prostatic blood flow were studied in rats in which the Leydig cell had been destroyed specifically by a single injection of ethane dimethylsulfonate (EDS). Other rats were supplemented with testosterone by subcutaneous injection of 25 mg testosterone propionate on days 1, 3 and 6. In some experiments, the effect of a single injection of 25 or 125 mg testosterone was studied. Testicular and prostatic blood flow and the number of PMN's in testicular blood vessels decreased, and vasomotion disappeared in Leydig cell-depleted rats, but testosterone supplementation restored all parameters to normal values. Moreover, a single injection of testosterone was able to restore testicular and prostatic blood flow to normal levels but had an inconsistent effect on vasomotion. These results suggest that testosterone may play a role in the physiological control of the testicular microcirculation.


Purification and characterization of phospholipase A2 from bovine prostate. Phospholipase A2 (PLA2) was purified from bovine prostate by ammonium sulphate precipitation and fractionation by anion exchange chromatography, chromatofocusing and gel filtration. The purified enzyme was Ca(2+)-dependent and had a pH-optimum of 8.0. Ba2+, Fe2+, Hg2+, Mg2+, Pb2+, Sr2+ and Zn2+ as well as lysophosphatidylcholine, lysophosphatidylethanolamine and p-bromophenacyl bromide (p-BPB) inhibited the enzyme strongly. The enzyme had an estimated molecular weight of 12,000 +/- 1,000 daltons on SDS-PAGE. Isoelectric focusing showed one PLA2 activity-containing band at pl 5.3. The purified enzyme hydrolysed linoleic acid at the sn-2 position of phosphatidylcholine and phosphatidylethanolamine with high selectivity, compared to arachidonic acid.


Relationship between sperm quality and chromatin condensation measured by sperm DNA fluorescence using flow cytometry. DNA flow cytometry of sperm from 100 randomly chosen men undergoing fertility investigation revealed a general association between reduced sperm quality, as judged by conventional parameters, and the appearance of sperm with lower degrees of chromatin condensation in the ejaculate as measured by DNA fluorescence intensity. Chromatin hypocondensation, as measured by increased fluorescence, was manifested to different degrees in different samples. In many cases of more extreme sperm pathology, such as oligoasthenoteratozoospermia (OAT), the whole population of spermatozoa appeared to be affected. Significant numbers of hypercondensed spermatozoa were present in both normozoospermic men and men with different degrees of disturbance in sperm quality. All of the different parameters of sperm quality could be correlated significantly with certain of the flow parameters, although not one in particular could be used to predict deviations from the normal flow profile. In several asthenoteratozoospermic men and a small proportion of men with OAT, the DNA profiles were normal, implying that in these cases the disturbance may not be so fundamental. The presence of leucocytes in the ejaculate was associated with a general increase in the preponderance of hypocondensed subpopulations of spermatozoa in men with OAT as well as in normozoospermic subjects, emphasizing the effect of inflammatory conditions in the reproductive tract on sperm quality.


Residual sperm function in oligozoospermia induced by testosterone enanthate administered as a potential steroid male contraceptive. To investigate the fertility of men who remain oligozoospermic despite sex steroid suppression, the in-vitro fertilizing capacity of residual spermatozoa was assessed in 30 men receiving intramuscular testosterone enanthate (TE). Spermatozoa were prepared by either Percoll or repetitive centrifugation/washing. Although the mean (+/- SEM) pretreatment zona-free hamster oocyte penetration (HOP) rates were similar (59.4 +/- 10.1 and 63.8 +/- 10.8%), following the induction of oligozoospermia the Percoll-prepared spermatozoa exhibited a penetration rate (26.9 +/- 10.2%) which was markedly greater than that obtained for sperm prepared by repetitive washing (0 +/- 0%). In addition, the partners of two men exhibiting a HOP test with Percoll-prepared spermatozoa, conceived despite a sperm concentration of 3 x 10(6) ml-1 and a negative HOP test with spermatozoa prepared by repetitive washing. These results suggest that Percoll preparation optimizes the assessment of in-vitro sperm function and that the fertility of men with TE-induced severe oligozoospermia is suppressed but not abolished.


Castration-resistant secretion in the hamster seminal vesicle does not depend on androgens. The secretory activity of seminal vesicles (SV) in the castrated hamster was studied by stereological analysis and biochemical approaches following treatment with cyproterone acetate (CPA) and adrenalectomy in order to investigate whether extra-testicular androgens are responsible for castration-resistant protein secretion. Treatment of castrated animals with CPA decreased the size of secretory granules and increased the number of apical granules, though neither the absolute nor the relative volume of all the components analysed was changed. In addition, CPA-treatment increased the amount of protein exocytosed by SV in castrated animals, though total protein synthesis remained unchanged. Adrenalectomy neither suppressed secretion nor induced any further ultrastructural changes in the SV epithelium. Our results demonstrate that secretory activity of the hamster SV following castration is not controlled by extra-testicular androgens and suggest that SV secretory proteins, which are heterogeneous with regard to their sensitivity to androgen withdrawal, might be regulated differentially by androgens.


Immunohistochemical localization of calmodulin in the human testis [corrected]. The localization of calmodulin in the normal human testis was studied by the indirect immunoperoxidase method. Three different types of fixative were used: phosphate-buffered formalin, Bouin's solution or Carnoy's solution. Immunoreactivity specific for calmodulin was not detectable in the testis fixed in Carnoy's solution. The specimens fixed in phosphate-buffered formalin and in Bouin's solution were stained. The immunostaining for calmodulin was observed in pachytene spermatocytes, secondary spermatocytes and round spermatids but not in spermatogonia, or in pre-leptotene, leptotene and zygotene spermatocytes, elongated spermatids, spermatozoa or Leydig cells. Sertoli cells were not stained or were stained slightly. Among pachytene spermatocytes, the cells at the early stage were barely stained but those at the middle and late stages were slightly and intensely stained, respectively. The present report provides the first confirmation of the localization of calmodulin in the human testis.


Mechanical issues in vascular grafting: a review. Despite intensive research, the success of artificial small-diameter vascular grafts has yet to match that of natural grafts like the saphenous vein. One of the possible reasons is mechanical mismatch of the graft to the host vessel. The study of compliance (dilatability under pressure) has not been conclusive, especially after a series of recent investigations on vein graft evolution. Lately, the focus has been shifting towards more detailed characteristics, like anastomic behaviour, longitudinal elasticity, and flow-related variables. When the relevant property is identified, it should be included in the criteria for design and use of vascular prostheses.


Effect of recombinant human erythropoietin (r-HuEPO) therapy on plasma FT3, FT4, TSH, FSH, LH, free testosterone and prolactin levels in hemodialysis patients. The aim of this study was to evaluate the effect of r-HuEPO treatment on free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone and prolactin levels in uremic hemodialysis patients. Twenty-four uremic hemodialysis patients were given r-HuEPO with a dose 60 U/kg as intravenous bolus injection at the end of each dialysis session. Once the hematocrit value of the patient had reached a range of 30-35%, the dose was adjusted so as to keep the hematocrit levels constant. Twenty uremic dialysis patients were taken as control group. The above-mentioned hormone levels of patients and control group were determined before and 4 months after r-HuEPO treatment. After the treatment, serum prolactin levels significantly decreased in both sexes (36.8 +/- 7.8 vs 22.9 +/- 6.3 ng/ml and 78.3 +/- 13.3 vs 37.4 +/- 10.4 ng/ml male and female, respectively). FT3 and FT4 significantly increased (1.17 vs 1.67 pg/ml, p < 0.05, and 0.64 vs 0.084 ng/dl, p < 0.05, respectively). TSH levels increased but those changes were not significant. There was no change in the level of any hormone in the control group. Also, the sexual functions of eight male patients treated with r-HuEPO improved and menstruation started again in four female patients. We concluded that r-HuEPO treatment especially decreases prolactin level in uremic hemodialysis patients. It is conceivable that correction of elevated prolactin levels could improve sexual disorders in these patients.


Hemodialysis with defibrotide: effects on coagulation parameters. In a crossover study conducted with eight uremic patients maintained on hemodialysis, the Authors compared the effects of heparin (100 IU/kg at the start of dialysis) and defibrotide (400 mg at the start, repeated at 2 hours of ongoing dialysis) on the parameters of blood coagulation (VIII:C, AT III, TAT, PC antigen and activity, PS, and FPA), each being assessed before dialysis and at 2, 3 and 4 hours of the ongoing procedure. Heparin-assisted dialysis resulted in a significant rise of VIII:C and AT III; with defibrotide, instead, there was evidence of thrombin activation (increased FPA and TAT). PC levels were raised with both dialysis modalities; however, PC activity and PS levels were increased only in defibrotide-assisted dialysis. There were no adverse reactions or evidence of fibrin formation. These results confirm the antithrombotic activity of defibrotide in the course of dialysis and indicate that this action is independent of thrombin neutralization.