Synthesis and antimelanoma activity of sterically congested tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol

Interference with the biosynthetic pathway to melanin may be a useful means for developing new chemotherapeutic drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of tyrosine that is involved in the pathway to melanin. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes, resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by independently varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We also made a series of tertiary amides that again showed higher cytotoxicity than 1. In this work three new acetamides and two new cyclohexanecarboxamides containing 4-S-cysteaminylphenol were prepared incorporating both substitution alpha to the nitrogen and different substituents on the nitrogen of the amide in each compound to increase lipophilicity and to reduce further the possibility of hydrolysis of the amides. Most of the new tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity against these five cell lines with IC50 values of 1-15 nicroM, comparable to cisplatin, was observed for N-[2[(4-hydroxyphenyl)thio]-1,1-dimethylethyl]-N-methylcyclohexanecarboxamide (8c). The IC50 values of 14.5 and 5.4 microM for this compound against SK-Mel-24 (not containing tyrosinase) and an ovarian cell line, respectively, suggest that interference with the melanin pathway may not be the only mode of action of this new compound. The cyclohexanecarboxamides were better substrates for mushroom tyrosinase (EC 1.14.18.1) than the acetamides.     

Self-administration of methohexital,midazolam and ethanol: effects on the pituitary–adrenal axis in rhesus monkeys

Rationale There is disagreement in the literature with respect to how drugs of abuse affect the functioning of the hypothalamic–pituitary–adrenal (HPA) axis, and whether these changes in endocrine function may be related to the rewarding effects of these drugs.Objectives To determine whether reinforcing drugs with different mechanisms of action affect HPA axis function at doses at which they serve as reinforcers.Methods Seven monkeys (6 male) were randomly assigned to self-administer methohexital—a barbiturate (n=4), midazolam—a benzodiazepine (n=3), or ethanol (n=5). Each monkey had a surgically implanted indwelling venous catheter, and was trained to respond on a fixed ratio of 30 lever presses to receive an injection of drug or saline. Blood samples were obtained before, during, and after the self-administration sessions for the measurement of ACTH and cortisol by radioimmunoassay.Results Although methohexital, midazolam, and ethanol all maintained self-administration behavior across a range of doses, they differed in their effects on ACTH and cortisol. Ethanol inhibited ACTH and cortisol secretion. Methohexital and midazolam both tended to decrease ACTH and cortisol at large doses, and increase these hormones at small doses, but the HPA effects of neither drug differed significantly from when saline was available.Conclusions The neutral overall effect of methohexital and midazolam on HPA activity is consistent with other monkey and human studies, whereas the inhibitory effect of self-administered ethanol in the monkey contrasts with both the rat and human literature. The data in this study suggest that a change in HPA axis activity is not a requirement for drug-reinforced behavior in monkeys.Results from this paper were first presented at the annual meeting of ISPNE, Quebec City, Canada, in August 2001.     

Mortality in relation to alcohol consumption: a prospective study among male British doctors

BACKGROUND: To relate alcohol consumption patterns to mortality in an elderly population. METHODS: We undertook a 23-year prospective study of 12 000 male British doctors aged 48-78 years in 1978, involving 7000 deaths. Questionnaires about drinking and smoking were completed in 1978 and once again in 1989-91. Mortality analyses are standardized for age, follow-up duration, and smoking, and (during the last decade of the study, 1991-2001) subdivide non-drinkers into never-drinkers and ex-drinkers. RESULTS: In this elderly population, with mean alcohol consumption per drinker of 2 to 3 units per day, the causes of death that are already known to be augmentable by alcohol accounted for only 5% of the deaths (1% liver disease, 2% cancer of the mouth, pharynx, larynx, or oesophagus, and 2% external causes of death) and were significantly elevated only among men consuming >2 units/day. Vascular disease and respiratory disease accounted for more than half of all the deaths and were both significantly less common among current than among non-drinkers; hence, overall mortality was also significantly lower (relative risk, RR 0.81, CI 0.76-0.87, P = 0.001). The non-drinkers, however, include the ex-drinkers, some of whom may have stopped recently because of illness, and during the last decade of the study (1991-2001) overall mortality was significantly higher in the few ex-drinkers who had been current drinkers in 1978 than in the never-drinkers or current drinkers. To avoid bias, these 239 ex-drinkers were considered together with the 6271 current drinkers and compared with the 750 men who had been non-drinkers in both questionnaires. Even so, ischaemic heart disease (RR 0.72, CI 0.58-0.88, P = 0.002), respiratory disease (RR 0.69, CI 0.52-0.92, P = 0.01), and all-cause (RR 0.88, CI 0.79-0.98, P = 0.02) mortality were significantly lower than in the non-drinkers. CONCLUSIONS: Although some of the apparently protective effect of alcohol against disease is artefactual, some of it is real.     

Intimate partner violence among military veterans and active duty servicemen

Intimate partner violence (IPV) is a serious public health problem that has received increased attention in the military. We review existing literature regarding prevalence, consequences, correlates, and treatment of IPV perpetration among military veterans and active duty servicemen. Rates of IPV across these military populations range from 13.5% to 58%, with considerably lower rates obtained among samples not selected on the basis of psychopathology. For both military veterans and active duty servicemen, IPV results in significant victim injury and negative child outcomes, and problematic substance use, depression, and antisocial characteristics represent psychiatric correlates of IPV perpetration. For veterans, posttraumatic stress disorder also is an important correlate that largely accounts for the relationship between combat exposure and IPV perpetration. Additional correlates include military service factors, relationship adjustment, childhood trauma, and demographic factors. The only experimentally controlled IPV treatment study indicates that standard treatments are ineffective for active duty servicemen. Further research is needed to advance the development of etiological models of IPV among military populations, to determine whether such models necessarily differ from those developed among civilians, and to rigorously test IPV interventions tailored to the specific characteristics of these individuals.     

Unrecognised Ovarian Pseudomucinous and Serous Cystadenomata in Late Pregnancy Associated with Procidentia

Ovarian tumours in pregnancy are rare, the incidence in several series being 1:1,000 to 1:8,000 (Gustafson et al., 1954). The commonest tumours are pseudomucinous cystadenomata, and benign cystic terato-mata the second commonest. These two tumours may coexist in the same patient (Novak and Novak, 1965). Coexistent bilateral serous cystadenocarcinoma and bilateral benign cystic teratoma in pregnancy was recorded by Gleichert (1964).     

Measuring hearing aid outcomes using the Satisfaction with Amplification in Daily Life (SADL) questionnaire: Australian data

The aims of this study were to investigate hearing aid satisfaction for a group of older Australians fitted with government-funded hearing aids using the Satisfaction with Amplification in Daily Life (SADL) questionnaire; to compare the Australian data gathered with the provisional normative data reported by Cox and Alexander (1999); and to investigate the relationship between SADL satisfaction and several participant variables, hearing aid variables, and other outcome measures. The SADL questionnaire and a Client Satisfaction Survey (CSS) were distributed by mail to 1284 adults fitted with government-funded hearing aids three to six months previously. 1014 surveys were returned. The mean age of participants was 75.32 years; 54.4% of participants were male, and 54.8% were fitted binaurally. Participants were fitted primarily with digitally programmable hearing aids of various styles (22.5% BTEs, 34.8% ITEs, 41.8% ITCs, 0.9% nonstandard [NS] devices). Overall, participants reported a considerable level of satisfaction with their devices. SADL Global and subscale scores were significantly higher for the Australian sample than the U.S. norms described by Cox and Alexander (1999).     

Pick bodies in a family with presenilin-1 Alzheimer's disease

Presenilin-1 (PS-1) mutations can cause Pick's disease without evidence of Alzheimer's disease (AD). We describe a family with a PS-1 M146L mutation and both Pick bodies and AD. Sarkosyl-insoluble hyperphosphorylated tau showed three bands consistent with AD, although dephosphorylation showed primarily three-repeat isoforms. M146L mutant PS-1 may predispose to both Pick's disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism.