Impact of Pdx1-associated chromatin modifiers on islet ß-cells.

Diabetes mellitus arises from insufficient insulin secretion from pancreatic islet ß-cells. In type 2 diabetes (T2D), ß-cell dysfunction is associated with inactivation and/or loss of transcription factor (TF) activity, including Pdx1. Notably, this particular TF is viewed as a master regulator of pancreas development and islet ß-cell formation, identity and function. TFs, like Pdx1, recruit coregulators to transduce activating and/or repressing signals to the general transcriptional machinery for controlling gene expression, including modifiers of DNA, histones and nucleosome architecture. These coregulators impart a secondary layer of control that can be exploited to modulate TF activity. In this review, we describe Pdx1-recruited coregulators that impact chromatin structure, consequently influencing normal ß-cell function and likely Pdx1 activity in pathophysiological settings.

Patient reported outcome of adult perioperative anaesthesia in the United Kingdom: a cross-sectional observational study.

BACKGROUND: Understanding the patient perspective on healthcare is central to the evaluation of quality. This study measured selected patient-reported outcomes after anaesthesia in order to identify targets for research and quality improvement. METHODS: This cross-sectional observational study in UK National Health Service hospitals, recruited adults undergoing non-obstetric surgery requiring anaesthesia care over a 48 h period. Within 24 h of surgery, patients completed the Bauer questionnaire (measuring postoperative discomfort and satisfaction with anaesthesia care), and a modified Brice questionnaire to elicit symptoms suggestive of accidental awareness during general anaesthesia (AAGA). Patient, procedural and pharmacological data were recorded to enable exploration of risk factors for these poor outcomes. RESULTS: 257 hospitals in 171 NHS Trusts participated (97% of eligible organisations). Baseline characteristics were collected on 16,222 patients; 15,040 (93%) completed postoperative questionnaires. Anxiety was most frequently cited as the worst aspect of the perioperative experience. Thirty-five per cent of patients reported severe discomfort in at least one domain: thirst (18.5%; 95% CI 17.8-19.1), surgical pain (11.0%; 10.5-11.5) and drowsiness (10.1%; 9.6-10.5) were most common. Despite this, only 5% reported dissatisfaction with any aspect of anaesthesia-related care. Regional anaesthesia was associated with a reduced burden of side-effects. The incidence of reported AAGA was one in 800 general anaesthetics (0.12%) CONCLUSIONS: Anxiety and discomfort after surgery are common; despite this, satisfaction with anaesthesia care in the UK is high. The inconsistent relationship between patient-reported outcome, patient experience and patient satisfaction supports using all three of these domains to provide a comprehensive assessment of the quality of anaesthesia care.

Measuring quality of recovery-15 after day case surgery.

BACKGROUND: 'Quality of recovery' scores are patient-reported outcome measures evaluating recovery after surgery and anaesthesia. However, they are not widely used in the clinical or research setting. The Quality of Recovery-15 (QoR-15) is a recently developed, psychometrically tested and validated questionnaire. METHODS: We conducted a prospective study of all adult patients undergoing orthopaedic day case surgery over a period of six months (June 2013-November 2013). Patients completed the QoR-15 score preoperatively, and then were asked to repeat the score by telephone at 24 h, 48 h and seven days after surgery. RESULTS: 633 patients from a possible 714 (89%) completed the preoperative questionnaire and data from 437 patients who completed scores at all four time points were analysed. Most patients returned to their preoperative score by 48 h, and had exceeded it by seven days. Construct validity was supported by a negative correlation with duration of surgery and total inpatient opioid use. There was also excellent internal consistency (Cronbach's alpha 0.80-0.83). CONCLUSION: The QoR-15 is a clinically acceptable and feasible patient-centred outcome measure after day case surgery. The score demonstrated good validity, reliability and responsiveness. However, measurement of the QoR-15 score on the day of surgery may not provide a true baseline value. We suggest one follow-up call at 48 h would enable an adequate patient-centred assessment of postoperative recovery after day case orthopaedic surgery.

Surgeons' views on multi-disciplinary breast meetings.

The aim of this study was to assess surgeons' views and their current commitments to multi-disciplinary breast meetings (MDMs). Two hundred and fifty questionnaires were sent out to registered members of the British Association of Surgical Oncology. Hundred and fifty-three were returned (reply rate 61.2%), of which 136 were suitable for analysis. All those who replied were involved in MDMs. 80.9% held MDMs once a week. Only 28% of MDMs were held during a protected session. Over 95% of surgeons and breast care nurses were present for the whole meeting. Radiologists and pathologists were present for the whole meeting in 90-95% of cases. In contrast, clinical oncologists were present for the whole MDM in 70% of cases and medical oncologists attended the whole meeting in only 44.1% of cases. There was variability in which patients were discussed in MDMs, and in many centres not all patients with cancer were discussed before surgery. Suggestions for improvement of MDMs included more time on protected sessions (72.8% in favour), time to prepare for meetings (29% in favour), allocation of a designated co-ordinator (30.9% in favour) and attendance of oncologists for the whole meeting (over 35% in favour). The majority of Breast MDMs were held at breakfast, lunch or the evening. There was variable attendance with a significant percentage of both clinical and medical oncologists not being present for the whole meeting. A quarter of units did not discuss patients with breast cancer before operation. This study shows that there is a need to improve provision for MDMs and to produce guidelines for these meetings.

Aging influences multiple incidices of oxidative stress in the aortic media of the Fischer 344/NNiaxBrown Norway/BiNia rat.

Here, we determine the influence of aging on multiple markers of oxidative stress in the aorta of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSdxBrown Norway/BiNia (F344/NxBN) rats. Compared to adults, increases in as determined by oxidation of hydroethidine (HE) to ethidium (Et) were increased 79.7+/-7.0% in 36-month aortae and this finding was highly correlated with increases in medal thickness (r=0.773, p<0.01) and total protein nitration (r=0.706, p<0.01) but not Ki67, a marker for cell proliferation. Regression analysis showed that increases in aortic superoxide anion (O.-2) with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in metabolic (AMPK-alpha), signaling (mitogen activated protein kinases (MAPKs) along with c-Src), apoptotic (Bax, Bcl-2, Traf-2) and transcriptional (NF-kappaB) activities. These results suggest that the aging F344/NxBN aorta may be highly suited for unraveling the molecular events that lead to age-associated alterations in aortic oxidative stress.

Combination chemotherapy of L1210 leukemia with platinum compounds and cyclophosphamide plus other selected antineoplastic agents.

Six antitumor platinum compounds were used in combination with cyclophosphamide plut 1 of 7 other antitumor drugs for treatment of L1210 leukemia in B6D2F [C57BL/6 X DMA/2) F] mice. Data obtained from each three-agent regimen were compared with those obtained after administration of each compound alone and each appropriate two-agent combination. No cure (greater than 60-day survival) was obtained with any compound used alone. Combination of cyclophosphamide with a platinum compound (Pt+CY) yielded a collective cure rate of 193/420, and the addition of a third cure rate to 290/420 (P less than 0.001). Certain regimens produced 100% cure rates. The most effective drugs when used in combination with PT+CY were cytosine arabinoside, 5-fluorouracil, hydroxyurea, and Yoshi-864. Adriamycin, methotrexate, and vincristine were less effective at the doses used. Toxicity, as evidenced by maximum weight loss, was slightly greater with the three-agent combinations than with the Pt+CY regimens.

Antileukemic properties of organoplatinum complexes.

The antitumor activity of 46 cis-amineplatinum congeners was evaluated against L1210 leukemia in (C57BL/L X DBA/2)F1 mice. Several compounds in this series significantly prolonged the life-spans of mice with the leukemia. During the selection of the compound that yielded optimal activity [dichloro(1,2-diaminocyclohexane)platinum], the chlorides were substituted with various organic and inorganic anions. The aqueous solubility was greatly increased with retention of significant antileukemic activity. Most of the active compounds were synergistic with cyclophosphamide, and cure rates up to 80% were obtained with certain combinations.

Mobilization of iron by chiral and achiral anionic 3-hydroxypyrid-4-ones.

In the search for 3-hydroxypyrid-4-ones with enhanced iron-mobilizing ability, seven chiral, anionic amino acid derivatives of maltol (3-hydroxy-2-methyl-4-pyrone) have been synthesized, utilizing L-methionine, L-serine, L-leucine, L-phenylalanine, L-glutamic acid, and the D- and L-isomers of alanine. Two achiral, aromatic compounds were also synthesized and compared with the phenylalanine derivative. The biliary iron excretion following iv injection and the urinary iron excretion following po administration were measured using female Sprague-Dawley rats and compared to that of the standard, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). While none of the compounds was as effective as L1 in enhancing the urinary excretion of iron, all monoanionic chelators increased excretion relative to the controls. All monoanionic compounds were at least equivalent to L1 in enhancing the biliary excretion of iron, with the methionine, leucine, and benzoate derivatives surpassing the standard and the other aromatic compounds also showing strong activity. The dianionic glutamate derivative showed low activity relative to the controls for both urinary and biliary iron excretion. No significant difference in iron excretion was observed due to variation in chirality; molecular weight and the number of negative charges appeared to have the greatest influence on the ability of the various derivatives to enhance iron excretion. In order to evaluate the relative purity of the stereoisomers, the alanine derivatives were analyzed by circular dichroism. Further characterization was provided by UV/vis spectroscopy for all compounds and X-ray crystallography for the novel dianionic derivative.

Nonselective effects of the putative phospholipase C inhibitor, U73122, on adenosine A1 receptor-mediated signal transduction events in Chinese hamster ovary cells.

Adenosine A1 receptors can signal, through Gi/o proteins, to inhibit adenylyl cyclase activity and also to stimulate phosphoinositide hydrolysis and the subsequent release of intracellular Ca2+ stores. The aminosteroid U73122 (1-[6-1[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione) has been widely used as an inhibitor of phospholipase C, the enzyme mediating phosphoinositide hydrolysis. Using U73122, we sought to selectively block signalling through the phospholipase C pathway, in Chinese hamster ovary (CHO-K1) cells heterologously expressing human adenosine A1 receptors. U73122 inhibited A1 receptor-mediated phosphoinositide hydrolysis, as measured by total inositol phosphate accumulation, over the concentration range 1-15 microM. However, over the same concentration range, it also appeared to inhibit A1 receptor-mediated inhibition of forskolin-stimulated cyclic AMP accumulation, A1 receptor agonist-promoted [35S]GTP-gammaS binding, and at the higher concentrations (10-15 microM) produced marked morphological changes, leading to cytolysis. The structural analogue of U73122, U73343 (1-[6-[[17beta-3-methoxyestra-1,3,5(10-trien-17-yl]amino]hexyl]-2, 5-pyrrolidone-dione), typically used as an inactive control compound, had little effect on these events. The data suggest that U73122 is not a selective inhibitor of phospholipase C activity, interfering with adenosine A1 receptor signalling generally, either at the pre-effector level involving Gi/o proteins, or as a consequence of the morphological changes it induces.

Genome structure of spirochetes.

The genome structures of several pathogenic spirochetes have recently been determined. The genomes of Borrelia species consist of a linear chromosome of approximately one million base pairs (Mb) and various linear and circular plasmids. Analysis of restriction fragment length polymorphisms and 16S ribosomal RNA sequence data indicate the division of Borrelia burgdorferi into at least three distinct genetic groups. Leptospira interrogans has a circular chromosome 5 Mb in size and a 0.35 Mb extrachromosomal element. Repetitive sequence elements similar to insertion sequences have been identified in the Leptospira interrogans genome. The chromosome of Treponema pallidum subsp. pallidum is circular and has a size of approximately one Mb. Genetic studies conducted to date indicate that B. burgdorferi and L. interrogans have a high degree of genetic diversity, whereas remarkably few genetic differences have been observed among the pathogenic Treponema. Knowledge of the genomic structure of these organisms will serve as a basis for future genetic studies.

Vitamin A status affects the development of diabetes and insulitis in BB rats.

BB/Wor rats develop autoimmune diabetes mellitus with many features in common with human insulin-dependent diabetes mellitus. Since retinoids are known to have effects on insulin secretion and immune function, these studies were designed to investigate the effects of retinoid deficiency on diabetes in BB/Wor rats and to identify a role for retinoid status in the pathogenesis of autoimmune diabetes mellitus. Litters of diabetes-prone (DP) and diabetes-resistant (DR) BB/Wor rats were divided at weaning and fed a diet either (1) devoid of retinoids and leading to clinical deficiency at approximately 60 days of age (A-def diet)-following 10 days of clinical deficiency, rats on the A-def diet were changed to a diet containing 2 microg/g retinoic (A-def/RA diet); (2) containing 2 microg/g retinoic acid but deficient in retinol (RA diet); or (3) replete in retinol with 4 microg/g retinyl palmitate (RP diet). Rats receiving RP or RA diets were pair-fed to rats on the A-def/RA diet. Diabetes by 120 days of age was greatly reduced (P < .01) in DP rats that received the A-def/RA diet (four of 27) or RA diet (four of 29) versus the RP diet (13 of 31). Insulitis progressed with age in nondiabetic DP rats receiving the RP diet (P < .02) or RA diet (P < .05), but not the A-def/RA diet (P > .22). Insulin secretion was measured in perfused pancreas of nondiabetic rats after age 120 days and correlated negatively with insulitis (P < .05). DP rats receiving the RP diet had reduced insulin secretion as compared with other DP and DR rats (P < .05). In DR rats, retinoid status had no effects on insulitis through 120 days of age or on insulin secretion after 120 days of age. In conclusion, retinol deficiency reduces diabetes and insulitis in DP BB/Wor rats, and retinoic acid can at least partly substitute for retinol in the development of insulitis.

A survey of knowledge, attitudes, and perceptions (KAPs) of lymphatic filariasis, elephantiasis, and hydrocele among residents in an endemic area in Haiti.

To assess knowledge, attitudes, and perceptions about bancroftian filariasis, 104 residents of an endemic area in Haiti were interviewed. Questions focused on 1) whether people understood the relationship between infection and disease, 2) recognition of the role that mosquitoes play in transmission, 3) perceived importance of hydrocele and elephantiasis in relation to other recognized diseases, and 4) the willingness of the community to participate in a control program. Fewer than 50% of residents had heard of filariasis and only 6% of those surveyed knew that it was transmitted by mosquitoes. In contrast, all persons knew of the clinical conditions of hydrocele and elephantiasis. Hydrocele was thought to be caused by trauma (60%) or trapped gas (30%); elephantiasis by walking bare foot on soil or water (37%) or by use of ceremonial powder that had been sprinkled on the ground (23%). Of 76 respondents, 53% and 38% thought that hydrocele could be treated through surgery or a drug, respectively, whereas 86 respondents, 85% and 15% believed that either surgery or a drug could be used to treat elephantiasis. In this context, persons were not referring to a specific drug; rather, they believed a drug existed (possibly in some other country) that could cure these conditions. Hydrocele and elephantiasis ranked second to acquired immunodeficiency syndrome as perceived health problems, most likely because residents believed treatment for conditions such as malaria, intestinal worms, anemia, and diarrhea was easily obtained. Responses were influenced by age, sex, and symptoms, but none of these effects were statistically significant except that persons with hydrocele or elephantiasis were more likely to have sought treatment than persons without these conditions (P = 0.0006). The survey results indicate that awareness of the causes of disease, the relationship between infection and disease, and goals of treatment must be heightened through community-based education campaigns to increase the possibility of acceptance and support of control programs.

Experimental Onchocerca volvulus infections in mangabey monkeys (Cercocebus atys) compared to infections in humans and chimpanzees (Pan troglodytes).

Three chimpanzees, three mangabey monkeys (Cercocebus atys), and 14 patas monkeys (Erythrocebus patas) were inoculated with L3 Onchocerca volvulus of Guatemalan origin. One chimpanzee and two mangabey monkeys developed antibody activity to at least three different antigens. Both mangabey monkeys recognized a 20 kDa antigen 3.5-5 months post-inoculation, and the monkeys and the chimpanzee developed antibody activity to 14 and 22 kDa antigens 7.5-13 months post-inoculation. One mangabey monkey and the chimpanzee became microfilaria-positive in skin snips at 16 and 21 months post-inoculation, respectively. Antibody activity to the 20 kDa antigen in the mangabey monkeys is noteworthy because of the prominence of this antigen among putatively immune persons living in onchocerciasis-endemic areas. The two mangabey monkeys responded parasitologically in a manner comparable to immune humans. No microfilariae were detected in one monkey and only scant numbers of microfilariae were observed in the second. The mangabey monkey may be a good animal model for the study of onchocerciasis.

An investigation into in vitro methods for the detection of chlorhexidine resistance.

During an outbreak of catheter-related urinary tract infection, due to Proteus mirabilis, it was suggested that the epidemic strain was resistant to chlorhexidine. In this study, the minimum inhibitory concentrations (MICs) of chlorhexidine to the epidemic Pr. mirabilis and other laboratory isolates were tested in different media. Results were compared with killing times using 1/4 strength Ringers solution, normal human urine and the in vivo killing times in two patients' catheter bags. It was found that the MIC test was unreliable in the assessment of chlorhexidine resistance as it was dependent on the medium used, the inoculum size, and the age of the culture. The test which gave results closest to the in vivo experiments was the killing curve in normal human urine. It is concluded that chlorhexidine resistance is a complex phenomenon which is difficult to evaluate. If in vitro tests are to be used to evaluate the clinical relevance of reduced sensitivity to chlorhexidine, they must mimic the in-use conditions as closely as possible.

Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.

The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.

Nephrotoxic and ototoxic agents.

It is well established that many drugs, such as the aminoglycoside antibiotics and the chemotherapeutic drug cisplatin, are capable of inducing both nephrotoxicity and ototoxicity. The factors that selectively predispose the kidney and inner ear to the toxic effects of these agents as well as the mechanism by which damage is produced are not well defined. The two organs differ greatly in their exposure to these toxic agents. The kidney has an abundant vascular supply and tends to selectively concentrate a number of drugs within the renal cortex or medulla, often to toxic levels. The vascular supply of the inner ear is not as extensive. In addition, the stria vascularis of the cochlea may act as a functional regulator of drug entry into inner ear fluids. The absorption of drugs into perilymph and endolymph is poorly understood. Selective accumulation theories of drug accumulation in the inner ear must be questioned because of the results of recent pharmacokinetic studies, which give contrary data. Drug-induced ototoxicity and nephrotoxicity can be explained on a cellular level. Studies using radiolabeled gentamicin suggest that binding mechanisms of the drug to the plasma membrane of the outer hair cells of the cochlea and vestibular apparatus and to the brush border receptors of the renal proximal convoluted tubules are similar. This suggests the same receptor sites for aminoglycosides occur in otic and renal organs. Calcium channels are implicated because of the reversibility of aminoglycoside-induced changes in the cochlear microphonic by calcium and other divalent cations. Calcium channel blockers, such as verapamil, reduce the nephrotoxicity of a number of drugs that are also ototoxic. Studies are needed to assess potential prevention of ototoxicity by use of these same calcium channel blocking agents. Aminoglycosides concentrate within the lysosomes of renal proximal tubular cells. Possibly, they also may concentrate in lysosomes within the cells of cochlear and vestibular structures. Nephrotoxic heavy metals concentrate within proximal tubular cells and, some, such as lead or bismuth, specifically concentrate within intracytoplasmic or intranuclear inclusion bodies. Studies are necessary to determine if the same metals accumulate within the cochlear and vestibular cells, inclusion bodies, or both. These questions and others must be answered before it can be determined why many nephrotoxic drugs and agents are also ototoxic.

Inhibition of cisplatin toxicity without decreasing antitumor efficacy. Use of a dithiocarbamate.

OBJECTIVE: To demonstrate whether a dithiocarbamate derivative, N-methyl-D-glucaminedithiocarbamate, could prevent anorexia and weight loss and enhance survival without decreasing the antitumor efficacy of high-dose cisplatin therapy. DESIGN: One hundred forty-two mice were randomized into groups receiving cisplatin, 5 mg/kg per day, 7.5 mg/kg per day, or 10 mg/kg per day for three days with or without N-methyl-D-glucaminedithiocarbamate, 1000 mg/kg per day. Weight loss and morbidity were examined between groups. Antitumor efficacy of cisplatin combined with N-methyl-D-glucaminedithiocarbamate was examined using a subcutaneous melanoma model. SETTING: Institutional laboratory. MAIN OUTCOME MEASURES: N-methyl-D-glucaminedithiocarbamate intervention would decrease morbidity, weight loss, and increase survival without decreasing the antitumor efficacy of cisplatin. RESULTS: Weight loss and morbidity were significantly reduced when N-methyl-D-glucaminedithiocarbamate was coadministered with cisplatin (P < .05) at all doses of cisplatin. The antitumor efficacy of high-dose cisplatin therapy (7.5 mg/kg per day and 10 mg/kg per day) was not significantly decreased (P > .05) at all doses of cisplatin. CONCLUSION: As N-methyl-D-glucaminedithiocarbamate seems to limit morbidity and mortality of high-dose cisplatin administration without decreasing its antitumor efficacy, this drug deserves further investigation in the treatment of cancer.

Methods of reduction of cisplatin nephrotoxicity.

Cisplatin, an agent widely used in the chemotherapy of a variety of human malignancies, is often dose-limited owing to its nephrotoxicity. Some of the approaches under consideration, regarding the reduction of cisplatin nephrotoxicity, include the use of hydration and osmotic diuresis, pharmacological diuretics, chelating agents or agents which otherwise react with cisplatin or reverse cisplatin-induced deoxyribonucleic acid cross-links, and antioxidants to destroy free radicals, especially superoxide radicals, produced by cisplatin. The effects of each of these and other interventions on cisplatin-induced nephrotoxicity are delineated, along with their proposed mechanisms and effects on therapeutic efficacy. The current status of development of organoplatinum analogs yielding congeners with less nephrotoxicity and greater efficacy is discussed briefly. Finally, a possible role of endogenous and/or exogenous prostaglandins in protecting against or reversing heavy metal nephrotoxicity is suggested.

Viruses and human cancer.

The cause of human cancer is probably multifactorial and the role of viruses is unclear. The study of retroviruses has led to the identification of oncogenes responsible for transformation and tumor induction. Human viruses associated with malignancies include the JC virus (associated with progressive multifocal leukoencephalopathy) and some adenoviruses. No human malignancies have been associated with the latter group. A number of herpes viruses of lower animals have been associated with malignancies and herpes simplex virus type 2 has been associated with carcinoma of the cervix and vulva. The Epstein-Barr virus has been associated with Burkitt's lymphoma and nasopharyngeal carcinoma. Some circumstantial evidence suggests that cytomegalovirus may be associated with Kaposi's sarcoma among homosexuals. The hepatitis B virus (HBV) has been associated with hepatocellular carcinoma. The fullfillment of Koch's postulates presents ethical problems regarding man and proving the viral etiology of human malignancy. Social experiments may elucidate some of these questions. An increase in venereal herpes should be associated with an increase in carcinoma of the cervix and use of the HBV vaccine in populations with high incidences of HBV carrier states should decrease the incidence of hepatocellular carcinoma. The investigation of the retroviruses though not establishing viruses as causing human malignancies at least will improve our understanding of the malignant process.

Effects of drugs on the male and female reproductive systems.

Infertility, permanent or temporary, resulting from drug-induced injury is an important clinical problem. Many common used drugs are potentially toxic to gonads. It is well-known that estrogens are toxic to the male genital system, but androgens may also produce infertility. Anovulation may also be a consequence of exposure to sex steroids. Cimetidine regularly produces hypospermia in men; phenytoin does so occasionally. Marijuana has been shown to be a gonadal toxin, while the effects of lysergic acid diethylamide (LSD) remain controversial. The most significant group of drugs that may injure the gonads is the cancer chemotherapeutic agents, of which the alkylating agents are the worst offenders. Prediction of infertility induced by these agents may be possible based on the duration of therapy and the patient's age and sex.