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While the ability to process fermented fruits and alcohols was once an adaptive trait that improved nutrition and quality of life, the availability and prevalence of high potency alcoholic drinks has contributed to alcohol abuse disorders in a vulnerable portion of the population. Although the neural reward systems take part in the initial response to alcohol, negative reinforcement and stress, which are normally adaptive responses, can intersect to promote continued alcohol use at all stages of the addiction cycle. Eventually a point is reached where these once adaptive responses become dysregulated resulting in uncontrolled intake that constitutes a clinically important condition termed alcohol use disorder (AUD). Current research is targeted at both the behavioral and molecular adaptations in AUDs in an effort to better develop novel approaches to intervention. In this review, historical context is provided demonstrating the societal burden of alcohol use and abuse disorders. The importance of gender in the mechanism of action of alcohol is discussed. Finally, the impact of alcohol on stress-related circuitry, uncovered by preclinical research, is outlined to provide insight into potential novel pharmacological approaches to the treatment of AUD.

This study empirically examined opinions of treatment providers regarding contingency management (CM) programs while controlling for experience with a specific efficacious CM program. In addition to empirically describing provider opinions, we examined whether the opinions of providers at the sites that implemented the CM program were more positive than those of matched providers at sites that did not implement it. Participants from 7 CM treatment sites (n = 76) and 7 matched nonparticipating sites (n = 69) within the same nodes of the National Institute of Drug Abuse Clinical Trials Network completed the Provider Survey of Incentives (PSI), which assesses positive and negative beliefs about incentive programs. An intent-to-treat analysis found no differences in the PSI summary scores of providers in CM program versus matched sites, but correcting for experience with tangible incentives showed significant differences, with providers from CM sites reporting more positive opinions than those from matched sites. Some differences were found in opinions regarding costs of incentives, and these generally indicated that participants from CM sites were more likely to see the costs as worthwhile. The results from the study suggest that exposing community treatment providers to incentive programs may itself be an effective strategy in prompting the dissemination of CM interventions.

The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pretreatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional four hours. At the end of the experiment, animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration.

The skin of the vulva constitutes a complex mixture of keratinized hairbearing skin of the labia majora and pubic area, the thinner rugeose but keratinized skin of the labia minora, and the adjacent vaginal introitus where the mucosal surface of the vagina begins. The surrounding buttock, natal cleft and inner thigh skin contribute to the relatively occluded microenvironment and high humidity. Skin disorders that can affect any part of the skin can appear slightly different in the vulval area; various disorders occur more frequently at ano-genital sites than elsewhere on the body.

Infections and infestations of the skin form a large proportion of skin diseases in children, especially in the tropics, but also in temperate areas. In many instances, superficial skin infections can be self-limiting as long as there is no impairment of the immune system, but some infections are chronic even when the immune responses are intact. In this review, we will concentrate on primary skin infections and infestations that are common in Europe, those potentially serious if not recognised and those in which recent advances have altered approach to management.

Accurate HPV typing is important for natural history and epidemiology studies. With the introduction of prophylactic multivalent HPV vaccines, there is also the need to determine the dominant genotypes in different populations and the effect of a vaccination programme on infection profiles. The interplay between multiple infection, viral persistence and implementation of interventions is a complicated one and therefore requires a reliable and accurate HPV detection and typing method. The Linear Array HPV genotyping test is a PCR-based HPV detection kit which can detect qualitatively Multiple HPV Infection in cervical cells collected in PreservCyt® Solution. The utility of this kit for multiple HPV typing of archival frozen tissue and cervical cells not collected in PreservCyt® are described.

Epidermodysplasia verruciformis (EV)-type human papillomavirus (HPV) DNA have been detected by PCR in squamous cell carcinomas (SCC) from both organ transplant recipients (OTR) and immunocompetent individuals. Their role in skin cancer remains unclear, and previous studies have not addressed whether the viruses are transcriptionally active. We have used in situ hybridization to investigate the transcriptional activity and DNA localization of HPV. EV-HPV gene transcripts were demonstrated in four of 11 (36%) OTR SCC, one of two (50%) IC SCC, and one of five (20%) OTR warts positive by PCR. Viral DNA co-localized with E2/E4 early region gene transcripts in the middle or upper epidermal layers. Non-EV cutaneous HPV gene transcripts were demonstrated in one of five (20%) OTR SCC and four of 10 (40%) OTR warts. In mixed infections transcripts for both types were detected in two of six (33%) cases. Our results provide evidence of EV-HPV gene expression in SCC; although only a proportion of tumors were positive, the similarly low transcriptional activity in warts suggests this is an underestimate. These observations, together with emerging epidemiological and functional data, provide further reason to focus on the contribution of EV-HPV types to the pathogenesis of cutaneous SCC.

Cutaneous epidermodysplasia verruciformis (EV)-associated human papillomaviruses (HPVs) are found frequently in skin cancers especially in immunosuppressed people. They are also detectable in the normal skin and hair follicles of a proportion of individuals who have no immune defect. The available evidence to link HPVs causally with skin carcinogenesis is not conclusive, but includes epidemiological, molecular and immunological studies.

Summary Background Neural stem cells are a potential source of cells for drug screening or cell-based treatments for neurodegenerative diseases. However, ethical and practical considerations limit the availability of neural stem cells derived from human embryonic tissue. An alternative source of human neural stem cells is needed; a source that is readily accessible, easily expanded, and reliably induced to a neural fate. Methods Dermis isolated from biopsy samples of adult human skin was cultured and expanded in the presence of the mitogens epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF 2), and then by serum. We used immunocytochemical techniques, clonal analysis, and physiological characterisation to assess neural differentiation after the treatment of expanded cells with novel induction media. Findings Initial characterisation of skin samples confirmed the absence of nestin, a neural precursor marker. Sequential culture in EGF and FGF 2 followed by adherent expansion in serum, and re-exposure to mitogens in substrate-free conditions resulted in large numbers of nestin-positive/musashi-positive neural precursors. Subsequent exposure of these precursors to hippocampal-astrocyte-derived signals resulted in cells of neuronal morphology that had stable expression of markers of neuronal differentiation (neurofilament, β tubulin). We also show the presence of voltage-dependent calcium transients, and demonstrate monoclonal neural potential. Interpretation We describe the isolation and characterisation of cells derived from adult human dermis that can be expanded for extended periods of time in vitro, while retaining inducible neural potential. The generation of almost limitless numbers of neural precursors from a readily accessible autologous adult human source provides a platform for further experimental studies and has potential therapeutic implications.

Gender differences have been shown to be related to the course of cocaine dependence and treatment. While previous research has shown cue exposure procedures to be somewhat effective at reducing reactivity of substance dependent individuals to drug related stimuli, the few studies that have examined gender differences in craving and cue-reactivity have yielded equivocal results. We have recently demonstrated that an active cue-exposure procedure that featured cocaine-dependent individuals receiving immediate feedback about their level of physiological arousal following videotaped exposure to cocaine-related stimuli was capable of positively influencing in-treatment (helplessness, abstinence efficacy) as well as 9-month followup outcome (i.e., urinalysis) indices (Sterling, R., Gottheil, E., Murphy, J., & Weinstein, S. (2001). Cue exposure and abstinence efficacy. College on Problems of Drug Dependence, Phoenix, AZ, June 17, 2001). The purpose of the present study was to determine whether differential in-treatment or 9-month followup outcomes were obtained for male and female study participants. Subjects in this study were 81 individuals (47 male/34 female) who met DSM-IV criteria for cocaine dependence and who had consented to be randomly assigned to either the active cue-exposure or control conditions. Participants were compared along a myriad of pre-treatment, in-treatment, and 9-month followup measures. Other than males reporting more recent employment, there was no obvious systematic pattern of differences on pre-treatment indices. No gender differences in treatment retention were observed. With respect to 9-month followup, no gender differences on measures of addiction severity, psychological functioning, or urinalyses were noted. However males were more “cue-reactive” and more successful at establishing control over their reactivity to the cocaine stimuli. Additional research is needed to determine whether these differences in reactivity can be more clearly defined and utilized positively in a treatment setting.

Objective.—To determine the physician gender preferences of children and the consequences of meeting/not meeting children's preferences, both in their liking and feeling comfortable in talking with the pediatrician. Methods.—A convenience sample of 125 parent-child pairs completed surveys when coming for an outpatient visit to a university-sponsored, urban pediatric practice. Results.—Both adolescents and preadolescents (especially females) as young as 9 years of age expressed a gender preference for their physician. Meeting those preferences significantly affected how much children both liked and felt comfortable in talking with their physician. In young teen females, gender-preferred physicians are synonymous with gender-congruent physicians; yet although their preference for gender-congruent physicians increased in early adolescence, data indicated that their preference was often not met for several years to come. Conclusions.—Liking and comfort with the pediatrician are not only desirable, but may also influence the doctor-patient relationship and young people's ability to develop health communication skills that they need as adults. These results, if validated, could also lead to a rethinking of parental dominance in the role of physician selection.

The effects of emulsified crude oil and salinity (15, 30 per thousand ) on the steady state aggregate volume distributions and fractal dimensions were determined for a range of mean velocity gradients, (G(m) =5-50 s(-1)). Aggregation was performed in a 40-L cylindrical tank with a 4-blade paddle mixer. Three-dimensional fractal dimensions (D3) and volume distributions were determined using a procedure integrating data from an electrozone and an in situ light scattering instrument. Two-dimensional fractal dimensions (D2) and derived volume distributions were determined using a recently developed submersible flow cytometer equipped with a digital camera and image analysis software. For latex beads or emulsified crude oil systems, the above listed instruments yielded consistent size distributions and fractal dimensions (D2=1.92 +/- 0.16, D3=2.94 +/- 0.12). Mean volume aggregate diameters determined using the FlowCAM were consistently larger that those determined using the LISST-100 or Coulter Multisizer due to aggregate orientations during measurements. With increasing G(m) values, all colloidal aggregates showed increasing D3 values due to reduced aggregate length. Because of the compactness of all the aggregates (D3 >2), D2 values remained constant at 2. Neither salinity nor sediment type significantly affected D2 values calculated for sediment-crude oil aggregates. However, clay-oil aggregates showed higher D3 values than clay aggregates. This suggests that colloidal oil and mixing shear are the more dominant factors influencing aggregate morphology in nearshore waters. Overall, the data suggests that the analysis methods provide consistent size distribution results. However, because of the shear and salinity of coastal waters, resulting aggregates are too compact to estimate their D3 values using image analysis alone.

Identifying Coronal Mass Ejection (CME) precursors in the solar corona would be an important step in space weather forecasting, as well as a vital key to understanding the physics of CMEs. Twisted magnetic field structures are suspected of being the source of at least some CMEs. These features can appear sigmoid (S or inverse-S) shaped in soft X-ray (SXR) images. We review recent observations of these structures and their relation to CMEs, using soft X-ray (SXR) data from the Soft X-ray Telescope (SXT) on the Yohkoh satellite, and EUV data from the EUV Imaging Telescope (EIT) on the SOHO satellite. These observations indicate that the pre-eruption sigmoid patterns are more prominent in SXRs than in EUV, and that sigmoid precursors are present in over 50% of CMEs. These findings are important for CME research, and may potentially be a major component to space weather forecasting. So far, however, the studies have been subject to restrictions that will have to be relaxed before sigmoid morphology can be used as a reliable predictive tool. Moreover, some CMEs do not display a SXR sigmoid structure prior to eruption, and some others show no prominent SXR signature of any kind before or during eruption.

The purpose of this study was to determine what proportion of individuals entering treatment for cocaine dependence admitted to battering an intimate partner and to compare the characteristics of those who were not identified as batterers. Of the 77 men in the sample, 38% were characterized as cocaine-dependent batterers. The batterers and nonbatterers were found to differ on a variety of background and assessment variables. Cocaine-dependent batterers more often reported a history of serious conflict with their sexual partner, trouble controlling violent behavior, greater psychiatric disturbance, difficulty relaxing, and being easily annoyed. A summary of the findings as well as implications for future research are discussed.

The institution of prospective payment systems, in which flat fees are paid per discharge, raised the concern that hospitals might preferentially admit patients expected to have a short length of stay (LOS). This concern presupposes that intake workers could accurately predict psychiatric hospitalization LOS, but this does not appear to have been empirically demonstrated. Accordingly, we examined the ability of two psychiatrists heading separate treatment teams on an inpatient, dual-diagnosis unit and a program coordinator who worked with both teams to predict LOS for 94 patients consecutively admitted to one or the other of these teams. Predictions were highly consistent across the raters and were significantly correlated with actual LOS (r = 0.25, 0.35, and 0.45 for the three raters). However, we found that the psychiatrists were accurate predictors only for patients for whom they were the attending psychiatrist. The program coordinator, who was involved in the treatment of all patients, was an accurate predictor for the patients of either psychiatrist. We concluded that the relationships found between predicted and actual LOS held true only when the rater also influenced treatment management and discharge. Our results do not support the proposition that specialized intake workers independent of those providing care would be able to predict LOS accurately.

Observations of two flares, an M 2.2 event on 16 December, 1991 and the precursor to an X1 flare on 15 November, 1991 are presented. Spectra obtained with the Bragg Crystal Spectrometer (BCS) are compared with data from the Hard and Soft X-ray Telescopes (HXT, SXT) and the Wide Band Spectrometer (WBS) on the satellite. For both events the creation of upflowing plasma is detected. While the first event seems to conform well to the chromospheric evaporation model for high temperature plasma production, the behaviour for the second event is more complex.

Using spectra from the Bragg Crystal Spectrometer on Yohkoh we have derived coronal abundances of sulphur, calcium and iron during several flares from the ratio of the flux in the resonance line to the nearby continuum. Multi-thermal effects have been taken into account using differential emission measure analysis. We have also determined the abundance of S in cool active regions during a period of very low solar activity. We compare the coronal abundances of S, Ca and Fe with their photospheric values.

After 27 years methadone maintenance remains perhaps the most controversial form of available opiate addiction treatment. Recognizing that many patients choose to remain in methadone treatment for extended periods of time the authors have wondered whether such patients might actually be harmed by long-term involvement. A review of the records of 3 patients who had been in continuous treatment for 15 years or more revealed that all of their lives had improved over the course of their treatment involvement. They varied in the length of time required before they showed improvement and all three indicated that they wished to remain on methadone because previously they had resumed drug use when they tried detoxing either alone or in treatment. There were periods during their treatment involvement when these patients were not doing well and could have been regarded as treatment failures. Continuing on in treatment, however, all three had made positive changes in their lives, changes which were of benefit to the society as well as the individual.

The human papillomavirus (HPV) causes warts, but is also associated with the development of squamous cell dysplasia and carcinoma. The virus is host and tissue specific and the numerous HPV types show predilection for different body sites. Experimental production of HPV 16 particles is at present only possible using in vivo culture of keratinocytes containing episomal viral DNA. Using immunoelectron microscopy, we have investigated the localization of HPV 16 E4 and L1 proteins in a keratinized epithelium formed by grafting HPV 16-containing cervical keratinocytes onto the athymic mouse. New viral progeny are produced in this system, as confirmed by labeling of intranuclear particles with a mouse monoclonal antibody against the HPV 16 major capsid (L1) protein. The role of the E4 protein is not yet clear, although it is believed to be important for the later stages of the virus life cycle. Here we confirm its cytoplasmic localization in the cells of the spinous and granular layers and demonstrate co-localization with keratin tonofilaments.

Sir—The report by Lois Conley and colleagues (Jan 12, p 108) confirms the challenge faced by clinicians looking after HIV-1-positive patients who have intraepithelial neoplasia of the lower genital tract. We agree that all such women should undergo clinical assessment of the vulva and perianal region as part of a gynaecological examination, but we caution against the investigators’ expectations of vulvar colposcopy and biopsy since it is currently not possible to rule out invasive disease with these procedures. Although vulvoscopy may allow detection of subtle changes in surface contour and superficial vasculature, the technique is not as sensitive or specific for dysplasia as colposcopy for cervical disease. Punch biopsy to assess suspicious lesions may provide false reassurance. In two studies of excisional treatment for vulvar intraepithelial neoplasia, high incidence (18–22%) of occult carcinoma has been reported. Conley and colleagues’ findings lend support to previous evidence that most dysplastic vulval lesions in younger women are multifocal and associated with human papillomavirus. The ruling out of invasive disease with full excision of such lesions would carry substantial morbidity without guarantee of cure, since multifocal lesions show a high recurrence rate. Immunosuppressed patients with lower-genital-tract neoplasia present an increasing difficulty to clinicians. We look forward to more effective diagnostic and therapeutic procedures to help in their management.

A multidisciplinary center for the ongoing care of hundreds of patients with amyotrophic lateral sclerosis reports its findings regarding the natural history of motor neuron disease. Median survival is longer than that generally quoted. Pure upper or lower motor neuron patients typically have still better survival. Progression tends to follow consistent regional patterns.

By the use of transmission and scanning electron microscopy and X-ray and electron diffraction techniques, evidence has been obtained of a new crystalline form of silver following its formation by the reduction of silver nitrate with sunlight in the presence of starch. Such crystals are hexagonal in form and have completely different reflections from that obtained by a projection along the [III] axis of the normal cubic silver. The X-ray diffraction data confirm that the new crystalline form is not due to the presence of the more likely impurities. Several other new forms of crystalline silver also appeared to be present although these have not been precisely characterized.