Apparent prevalence of Mycoplasma wenyonii, Candidatus Mycoplasma haemobos, and bovine leukemia virus in Wisconsin and Michigan dairy cattle herds.

Mycoplasma wenyonii (formerly Eperythrozoon wenyonii) is a hemotrophic, epicellular bacterial parasite of cattle that has been associated with clinical disorders, including hemolytic anemia, decreased milk yield, and peripheral edema. Mycoplasma wenyonii and a related organism, Candidatus Mycoplasma haemobos, have been detected in both ill and apparently healthy cattle, but little is known about their prevalence in US dairy cattle. The objective of this prospective, cross-sectional study was to determine herd-level apparent prevalence of M. wenyonii and C. M. haemobos in dairy cattle located in Wisconsin and Michigan compared with seroprevalence of bovine leukemia virus (BLV) in the same herds. In summer 2018, researchers collected blood samples from 30 lactating cows per herd from randomly recruited farms in selected dairy-intensive counties in each state. During the farm visit, a brief survey was used to collect herd management information. Detection of M. wenyonii and C. M. haemobos were based on PCR testing, and ELISA was used to test for antibodies to BLV. Blood samples were collected from lactating cows located in 64 Wisconsin herds (n = 1,930 samples) and 18 Michigan herds (n = 591 samples). Herd-level apparent prevalence was 100% for both M. wenyonii and C. M. haemobos. Herd-level seroprevalence for BLV was 83 and 100% for Wisconsin and Michigan herds, respectively. Estimated within-herd apparent prevalence of M. wenyonii was 71.7% ± 1.0% (ranging from 23.3 to 93.5%) and for C. M. haemobos was 77.3% ± 1.0% (ranging from 16.7 to 100%). Within-herd prevalence of BLV positive samples was 39.8% ± 1.0% and ranged from 0 to 86.7%. About 22% of cows were concurrently positive for all 3 organisms. Parity and stage of lactation were recorded for 2,317 cows. Prevalence of positive cows for parity groups 1, 2, and ≥3 were 72.0, 73.8, and 67.7% for M. wenyonii; 80.9, 76.8, and 74.9% for C. M. haemobos; and 25.3, 39.7, and 55.5% for BLV, respectively. None or only minor differences in apparent prevalence were observed based on stage of lactation. This is the first report of the prevalence of hemotrophic mycoplasmas in Wisconsin and Michigan dairy herds and indicates that infection with these organisms is endemic. The impact of infection on cattle health and productivity remains unknown, and risk factors associated with infection warrant further study.

Macrocyclic proteasome inhibitors.

Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors.

Long-term follow-up of patients' status after gastric bypass.

BACKGROUND: We report a long-term (13-15 year) follow-up of a cohort of 100 patients who underwent gastric bypass for morbid obesity. METHODS: Sources of information include baseline data collected before surgery and information obtained at follow-up interview including data on weight history, psychosocial functioning, and medical complications. RESULTS: Mean age at follow-up was 56.8 years. The mean weight loss at long-term follow-up was 29.5 kg (range -13.6 to 93.6 kg). Three subjects weighed more at long-term follow-up than before the operation. Overall, 74% of those interviewed indicated that the gastric bypass had benefited them in terms of their physical health. However, 68.8% reported continued problems with vomiting and 42.7% with "plugging". Eight had died. CONCLUSION: The findings in this study suggest that at long-term follow-up the majority of individuals who have undergone gastric bypass feel that the procedure benefited them, although some complications including difficulties with "plugging" and vomiting were present at long-term follow-up.

The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats.

Efavirenz, a potent nonnucleoside reverse transcriptase inhibitor widely prescribed for the treatment of HIV infection, produces renal tubular epithelial cell necrosis in rats but not in cynomolgus monkeys or humans. This species selectivity in nephrotoxicity could result from differences in the production or processing of reactive metabolites, or both. A detailed comparison of the metabolites produced by rats, monkeys, and humans revealed that rats produce a unique glutathione adduct. The mechanism of formation and role of this glutathione adduct in the renal toxicity were investigated using both chemical and biochemical probes. Efavirenz was labeled at the methine position on the cyclopropyl ring with the stable isotope deuterium, effectively reducing the formation of the cyclopropanol metabolite, an obligate precursor to the glutathione adduct. This substitution markedly reduced both the incidence and severity of nephrotoxicity as measured histologically. Further processing of this glutathione adduct was also important in producing the lesion and was demonstrated by inhibiting gamma-glutamyltranspeptidase with acivicin pretreatment (10 mg/kg, IV) prior to dosing with efavirenz. Again, both the incidence and severity of the nephrotoxicity were reduced, such that four of nine rats given acivicin were without detectable lesions. These studies provide compelling evidence that a species-specific formation of glutathione conjugate(s) from efavirenz is involved in producing nephrotoxicity in rats. Mechanisms are proposed for the formation of reactive metabolites that could be responsible for the renal toxicity observed in rats.

Using interactive voice response technology and timeline follow-back methodology in studying binge eating and drinking behavior: different answers to different forms of the same question?

As part of a study of the relationship of binge eating, alcohol use, mood, and stressors, we compared the results of two forms of reporting on binge eating and drinking behavior. Forty-three first-year college women participated in an interactive voice response (IVR) study for 12 weeks. Participants answered computer-administered questions daily via IVR technology on number of eating binges and number of alcoholic drinks consumed. After 12 weeks, participants completed a Timeline Follow-back (TLFB) interview retrospectively for number of binges and drinks in the past 12 weeks. Results of this distally retrospective methodology (commonly used in drinking research and applied here also to binge eating) were compared to the results of daily IVR reporting. There was convergence across measures for drinking behavior, but divergence between IVR and TLFB for binge eating reports. TLFB reports underrepresented actual binge eating frequency, which calls into question the validity of applying this methodology to the assessment of binge eating.

Metabolic rate in the right amygdala predicts negative affect in depressed patients.

The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.

The relationship between intravenous cocaine self-administration and avidity for saccharin.

Two experiments were conducted to determine whether measures of saccharin intake could be used as a predictor of intravenous cocaine self-administration. Saccharin avidity, defined as the ratio of total daily fluid intake when saccharin and water were available to total intake when only water was available, was measured in male rats. Cocaine self-administration (0.4 mg/kg/infusion) was subsequently measured in an initial 18-h session, followed by daily 1-h sessions in which the infusion dose and the reinforcement schedule were varied. In the initial overnight session, some rats obtained the maximum or near-maximum number of infusions; this high level of cocaine intake was unrelated to saccharin avidity. In the remaining rats, there was a pattern somewhat resembling an "inverted-U," in which rats with low or high avidity self-administered less cocaine than those with intermediate avidity. This pattern reemerged later in the experiment when rats were tested at a low cocaine infusion dose combined with a FR-6 reinforcement schedule. In a second experiment, no significant relationship was observed between the self-administration of a lower cocaine dose (0.125 mg/kg/infusion) and avidity for either saccharin or the artificial sweetener SC-45647. Although these results are consistent with a previous report indicating no simple relationship between saccharin preference and the acquisition of cocaine self-administration, they do suggest that a more complex relationship may be observed under some conditions. Additional research with other drugs, as well as with caloric and noncaloric sweeteners, will be needed to determine the usefulness of taste measures in identifying or treating substance abuse.

Pharmaceutical development and specification of stereoisomers.

The pharmaceutical development of chiral drugs requires the activities of many different research and development groups. Guidelines which help to coordinate the activities of these groups and assist in the successful development of compounds with either single or multiple chiral centers are outlined and discussed.

Evaluation of hexamethylphosphoramide for gene mutations in Salmonella typhimurium using plate incorporation, preincubation, and suspension assays.

Hexamethylphosphoramide (HMPA), a potent rat nasal carcinogen by inhalation, and three of its metabolites, pentamethylphosphoramide (PMPA), trimethylphosphoramide (TriMPA), and formaldehyde (HCHO), were assessed in Salmonella typhimurium gene mutation assays using various protocols, including plate incorporation, preincubation and suspension assays. HMPA (tested up to 15,000 micrograms/plate) was not mutagenic in plate incorporation or preincubation assays with or without metabolic activation. HCHO was mutagenic in the plate incorporation and preincubation assays (tested up to 150 micrograms/plate). In suspension assays, however, HMPA (tested up to 40 mg/ml), PMPA (up to 44 mg/ml) and HCHO (up to 45 micrograms/ml), but not TriMPA (up to 29 mg/ml), were mutagenic. HMPA and PMPA were positive only with activation. HMPA's mutagenicity was optimized using a relatively high level of rat liver S9 protein (3.5 mg/plate) in the metabolic activation mixture. Semicarbazide, an HCHO trapping agent, added at concentrations up to 167 micrograms/ml, markedly inhibited the mutagenic activities of HMPA and PMPA suggesting that HCHO generation may play a role in their mutagenicity. These studies show that HMPA is mutagenic in a modified Salmonella typhimurium reverse mutation assay with metabolic activation. Successive N-demethylation of HMPA eventually eliminates the mutagenic activity which further suggests that HMPA's mutagenic activity is related to the release of HCHO.

Sleep-onset rapid eye movement after electroconvulsive therapy is more frequent in patients who respond less well to electroconvulsive therapy.

The response to electroconvulsive therapy (ECT) was monitored with sleep polysomnography studies (SPS) performed pre- and post-ECT, in 25 patients with major depressive disorder (MDD). Patients included in this study met research diagnostic criteria for MDD and had been free of psychotropic medication for at least 10 days before SPS were performed. We compared ECT responders and nonresponders on SPS, demographic, and clinical parameters. Many SPS parameters, regardless of the clinical response, changed significantly with ECT. The presence of delusions was significantly associated with SOREM post-ECT. The presence of sleep-onset REM periods post-ECT was associated with poor response to ECT. SPS performed during a course of ECT may help identify patients at risk of responding less well to this modality of treatment.

Dieting severity and gastrointestinal symptoms in college women.

Young women report symptoms associated with irritable bowel syndrome (IBS), such as pain, bloating, and changes in bowel movements, more often than young men. Young women with eating disorders also report these gastrointestinal symptoms frequently. We hypothesized that if dieting behaviors were associated with these symptoms, the prevalence and frequency of the symptoms would be positively related to dieting severity in young women. We interviewed 301 1st-year college women representing the continuum of dieting severity. We found that severity of dieting was positively related to frequency of abdominal pain, bloating, diarrhea, and constipation, and that the women who reported 3 or more symptoms regularly scored higher on a scale for dieting severity. Although this study did not examine the relationship between dieting severity and clinical IBS, the findings suggested that dieting is associated with gastrointestinal symptoms in young women.

Dieting in sixth grade predicts alcohol use in ninth grade.

Recent studies of community-based populations have shown that the comorbidity seen in clinical studies of individuals with eating disorders and substance abuse extends in a graded manner to subclinical levels of each dysfunction as well as to adolescent populations. We hypothesized that frequency of dieting in the sixth grade would predict later alcohol use in middle school students. Data from 1,905 participants in a middle school health promotion project were analyzed. We found a positive, graded relationship between the frequency of dieting in the sixth grade and the frequency of alcohol intake in the ninth grade. We also found that frequency of dieting in sixth grade was a more powerful predictor of future drinking than such parameters as others' approval of alcohol use, perceptions of peer use of alcohol, and personal feelings of shyness and self-satisfaction. Implications of these findings are discussed.

Obsessionality in eating-disorder patients: relationship to clinical presentation and two-year outcome.

Obsessionality and obsessive-compulsive symptoms have been regarded as important characteristics in the clinical presentation of the eating disorders. In this report, we examined the relation between obsessionality and the clinical presentation and outcome of a sample of eating-disordered patients. Self-rated obsessional symptoms, defined by the obsessive-compulsive subscale of the Symptom Checklist 90 (revised version), were compared with presenting clinical symptomatology, and scores on the Eating Disorder Inventory (EDI) and Beck Depression Inventory (BDI) in a sample of 110 consecutively evaluated women who met DSM-IIIR criteria for eating disorders. Forty patients were contacted for a follow-up investigation, 2 years after the initial evaluation. Higher obsessive-compulsive subscale scores at presentation were associated with more severe dieting, a greater number of psychiatric hospitalizations, and higher EDI, SCL-90R and BDI scores. Initial obsessive-compulsive scores did not predict the subsequent outcome of a sample of these patients in the community. However, elevated obsessive-compulsive scores obtained at follow-up were associated with the presence of lower body weight and more severe eating-disorder symptoms at that time. These results support the hypothesis that elevated obsessionality is associated with more severe eating disorder symptomatology. In addition, obsessional symptoms change along with those of the eating disorder, and their persistence may be associated with a poorer outcome.

Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters.

To test the hypothesis that endogenous opiate peptides selectively influence hedonic response to sweet and high-fat foods, the opiate antagonist naloxone, opiate agonist butorphanol, and a saline placebo were administered by intravenous infusion to 16 obese and 25 normal-weight women. Twenty of the women (10 obese, 10 lean) fulfilled DSM-III-R diagnostic criteria for bulimia nervosa, as determined by psychiatric interview. During drug infusion the women tasted and rated 20 sweetened dairy products and were presented with eight snack foods of varying sugar and fat content. Naloxone suppressed hedonic responses in all subject groups and suppressed the consumption of sweet and high-fat foods in binge eaters, but not in nonbingers. Food intakes of obese women were not affected by naloxone. Butorphanol had no effect on either hedonic response or on food consumption in any group. Although opiate blockade is not a viable strategy for weight reduction in the treatment of obesity, it may be useful in the clinical management of the binge-eating disorder.

Development and initial validation of a measure of drinking urges in abstinent alcoholics.

Although drinking urges and cravings are commonly reported by alcoholics, prospective studies have found inconsistent associations between such urges and drinking relapses. Previous studies have measured drinking urges by use of single-item ratings of alcohol craving or other measures of unknown reliability and validity. To permit improved evaluation of hypotheses regarding alcohol craving, a 49-item questionnaire that reflects several urge-related domains was developed and pretested. Items assessed subjects' desire for a drink, expectations of positive effects following drinking, relief of withdrawal and negative affect following drinking, and intention to drink. Exploratory and confirmatory factor analyses of the responses of 351 abstinent, treatment-seeking alcoholics indicated that alcohol urges are best described by a single factor. Based on these analyses, an internally consistent, reliable, and psychometrically valid 8-item scale, the Alcohol Urge Questionnaire (AUQ), was developed. Data indicated that AUQ scores were strongly related to alcohol dependence severity and to cognitive preoccupation with alcohol, and that they declined with prolonged abstinence. The AUQ may be useful in alcoholism treatment research and in laboratory studies of reactivity to alcohol or other manipulations.

Effects of body image on dieting, exercise, and anabolic steroid use in adolescent males.

This cross-sectional survey study examined body image, dieting and exercise variables, and steroid use in 2,088 high-school graduates aged 18 years. In contrast to women, more men wished to gain (46%) rather than loose weight (32%). Men who wished to gain weight were more satisfied with their body shape, showed no fear of fatness, and dieted and exercised less frequently than did men who wished to lose weight. The prevalence of dieting was low (4%), even among men who wished to lose weight (9%), and physical exercise was more likely to be used for both weight loss and weight gain. Contrary to expectations, anabolic steroid use was rare (0.6%) and was not associated with a desire for weight gain. Steroid users were more likely to engage in running and swimming than football. The data did not support the notion that anabolic steroid use is widespread among high-school males.

The severity of dieting and bingeing behaviors in college women: interview validation of survey data.

A combined survey and interview study was conducted to validate a categorical Dieting and Bingeing Severity Scale (DBSS), and to estimate the prevalence of eating disorders in young women. We hypothesized that assignment to the DBSS categories would be confirmed by clinical interviews such that interview-diagnosed eating disorders would be found with increasing frequency and severity at the upper end of the DBSS. Freshmen college women (n = 1367) completed a survey instrument addressing the frequency and severity of dieting, binge-eating, and other behaviors and attitudes related to weight control. Random stratified sampling procedures were used to select a subset of women (n = 306) from each DBSS category for structured clinical interviews for DSM-III-R (SCID). Survey respondents were assigned to one of six mutually exclusive DBSS categories: non-dieters (9% of sample), casual dieters (26%), moderate dieters (23%), intense dieters (21%), dieters at-risk (19%), and probable bulimia nervosa (2%). The DBSS effectively rank-ordered subjects according to the risk of having interview-diagnosed eating disorders. Women in the three most severe DBSS categories were significantly more likely to have current subthreshold and threshold level eating disorders, in particular bulimia nervosa and eating disorder not otherwise specified (EDNOS). The estimated prevalence of current bulimia nervosa was approximately 2% by both survey and interview methods. The prevalence of current EDNOS was 13%, more than six times greater than the prevalence of bulimia nervosa. The DBSS was found to be a reliable and valid measure of dieting and bingeing severity. The survey instrument may be useful in measuring the extent of, and changes in, pathological dieting in community-based samples of young women, and in studying comorbidity of dieting and bingeing severity with other psychiatric conditions including depression and substance use. The DBSS may also be useful in identifying risk factors associated with the onset of eating disorders.

Intravenous morphine self-administration by rats with low versus high saccharin preferences.

An experiment was performed to determine the relationship between saccharin preference and the self-administration of morphine via the oral and intravenous routes. On the basis of voluntary intake of a saccharin solution by male rats, low and high preference groups were formed. Rats selected for high saccharin preference self-administered more morphine intravenously than rats selected for low preference. The two groups did not differ in oral morphine intake. The positive relationship between the intake of saccharin and intravenous morphine self-administration may be due to their mediation by a common mechanism. Measures of taste sensitivity or preference may be useful in identifying individuals at risk for drug abuse.