The gut microbiota and metabolic disease: current understanding and future perspectives.

The human gut microbiota has been studied for more than a century. However, of nonculture-based techniques exploiting next-generation sequencing for analysing the microbiota, development has renewed research within the field during the past decade. The observation that the gut microbiota, as an environmental factor, contributes to adiposity has further increased interest in the field. The human microbiota is affected by the diet, and macronutrients serve as substrates for many microbially produced metabolites, such as short-chain fatty acids and bile acids, that may modulate host metabolism. Obesity predisposes towards type 2 diabetes and cardiovascular disease. Recently, it has been established that levels of butyrate-producing bacteria are reduced in patients with type 2 diabetes, whereas levels of Lactobacillus sp. are increased. Recent data suggest that the reduced levels of butyrate-producing bacteria might be causally linked to type 2 diabetes. Bariatric surgery, which promotes long-term weight loss and diabetes remission, alters the gut microbiota in both mice and humans. Furthermore, by transferring the microbiota from postbariatric surgery patients to mice, it has been demonstrated that an altered microbiota may contribute to the improved metabolic phenotype following this intervention. Thus, greater understanding of alterations of the gut microbiota, in combination with dietary patterns, may provide insights into how the gut microbiota contributes to disease progression and whether it can be exploited as a novel diagnostic, prognostic and therapeutic target.

Associations among late chronotype, body mass index and dietary behaviors in young adolescents.

BACKGROUND/OBJECTIVES: Levels of pediatric obesity continue to rise. Previous evidence has linked short sleep duration and/or poor sleep quality to obesity development, although objective data are limited. As adolescents transition through puberty, circadian shifts occur, resulting in sleep loss. However, little is known whether chronotype is associated with body mass index (BMI) or dietary behaviors in adolescents. We hypothesized late chronotype would be positively associated with BMI and poorer dietary behaviors. SUBJECTS/METHODS: A total of 511 UK young adolescents (11-13 years) from eight secondary schools across the Midlands region (UK) participated in the Midlands Adolescent Schools Sleep Education Study (MASSES), a cross-sectional study to assess potential relationships between chronotype and BMI z-score as well as dietary habits. Height (cm) and weight (kg) were objectively measured for BMI calculation and participants completed a questionnaire to assess dietary habits. A subsample of 236 adolescents wore wrist actigraphy for 7 days to estimate average sleep duration (weekday, weekend and combined) and sleep efficiency. RESULTS: Definitely evening chronotype was positively associated with BMI z-score compared to definitely morning chronotypes ß = 0.51, P < 0.01, after adjustment. Higher frequency of consuming unhealthy snacks, night-time caffeine consumption and inadequate daily intake of fruit/vegetables were also associated with later chronotype (all P ⩽ 0.01). Actigraphy estimated sleep duration was an independent predictor of BMI z-score ß = -0.36, P < 0.001. Sleep efficiency did not predict BMI z-score after adjustment, ß = -0.03, P = 0.07. CONCLUSIONS: Later chronotype young adolescents are at risk of increased BMI and poorer dietary behaviors. Although short sleep duration, but not sleep efficiency, was also an independent risk factor for increased BMI, different mechanisms may be driving the late chronotype and shorter sleep duration associations with BMI in this age group. Sleep hygiene education may help adolescents to better understand the impact of sleeping habits on physical health.

Exploring the complex pathways among specific types of technology, self-reported sleep duration and body mass index in UK adolescents.

OBJECTIVE: To examine the independent associations between sleep duration, four technology types (computer use, mobile telephones, TV viewing and video gaming) and body mass index (BMI) z-score. We propose a theoretical path model showing direct effects of four technology types on BMI z-score and sleep duration as well as the indirect effects of each technology on BMI z-score while considering sleep duration as a mediator. METHODS: Consenting adolescents (n=632; 63.9% girls, aged 11-18 years) were recruited to the Midlands Adolescent Schools sleep Education Study. The School Sleep Habits Survey (SSHS) and Technology Use Questionnaire (TUQ) were administered. Objective measures of height (cm) and weight (kg) were obtained for BMI z-score calculation. RESULTS: Weekday use of all technology types was significantly associated with reduced weekday sleep duration after adjustment (ß (computer use)=-0.38, P<0.01; ß (mobile telephone)=-0.27, P<0.01; ß (TV viewing)=-0.35, P<0.01; and ß (video gaming)=-0.39, P<0.01). Use of all technology types, with the exception of mobile telephones, was significantly associated with increased BMI z-score after adjustment (ß (computer use)=0.26, P<0.01; ß (TV viewing)=0.31, P<0.01; and ß (video gaming)=0.40, P<0.01). Our path model shows that weekday sleep duration was significantly and negatively associated with BMI z-score (ß=-0.40, P<0.01). CONCLUSION: Weekday sleep duration potentially mediates the effects of some technologies on BMI z-score. If confirmed, improving sleep through better management of technology use could be an achievable intervention for attenuating obesity.

Boosting Student Wellbeing Despite a Pandemic: Positive Psychology Interventions and the Impact of Sleep in the United Arab Emirates.

Positive psychology interventions hold great promise as schools around the world look to increase the wellbeing of young people. To reach this aim, a program was developed to generate positive emotions, as well as improve life satisfaction, mental toughness and perceptions of school kindness in 538 expatriate students in Dubai, United Arab Emirates. Starting in September 2019, the program included a range of positive psychology interventions such as gratitude, acts of kindness and mental contrasting as examples. Life satisfaction and mental toughness at mid-year were sustained or grew by the end of the year. Positive affect, emotional wellbeing and social wellbeing increased at post-intervention 1, compared to baseline. However, this improvement reverted to baseline levels at post-intervention 2, when data were collected during the COVID-19 pandemic. Only psychological wellbeing, negative affect, perceptions of control, and school kindness were increased at post-intervention 2. During the lockdown, students moved less, but slept and scrolled more. Those who extended their sleep duration reported greater wellbeing. Boosting wellbeing through the use of positive psychology interventions works - even in a pandemic - and extended sleep duration appears to be a driving factor for this observation.

Clinical and demographic factors associated with fractures among older Americans.

UNLABELLED: Medicare claims data were used to investigate associations between history of previous fractures, chronic conditions, and demographic characteristics and occurrence of fractures at six anatomic sites. The study confirmed previously established associations for hip and spine fractures and identified several new associations of interest for nonhip, nonspine fractures. INTRODUCTION: This study investigates the associations of a history of fracture, comorbid chronic conditions, and demographic characteristics with incident fractures among Medicare beneficiaries. The majority of fracture incidence studies have focused on the hip and on white females. This study examines a greater variety of fracture sites and more population subgroups than prior studies. METHODS: We used Medicare claims data to examine the incidence of fracture at six anatomic sites in a random 5% sample of Medicare beneficiaries during the time period 2000 through 2005. RESULTS: For each type of incident fracture, women had a higher rate than men, and there was a positive association with age and an inverse association with income. Whites had a higher rate than nonwhites. Rates were lowest among African-Americans for all sites except ankle and tibia/fibula, which were lowest among Asian-Americans. Rates of hip and spine fracture were highest in the South, and fractures of other sites were highest in the Northeast. Fall-related conditions and depressive illnesses were associated with each type of incident fracture, conditions treated with glucocorticoids with hip and spine fractures and diabetes with ankle and humerus fractures. Histories of hip and spine fractures were associated positively with each site of incident fracture except ankle; histories of nonhip, nonspine fractures were associated with most types of incident fracture. CONCLUSIONS: This study confirmed previously established associations for hip and spine fractures and identified several new associations of interest for nonhip, nonspine fractures.

Epidemiological trends of leprosy in an urban leprosy centre of Delhi: a retrospective study of 16 years.

This study was done by collecting the retrospective data from 1994 to 2009 of patients attending the urban leprosy centre attached to the department of dermatology, STD & leprosy of PGIMER & Dr. R M L Hospital, New Delhi. The data was analysed according to age, sex, type of leprosy, leprosy reactions, deformities and relapse and compared with the national figures by comparison of proportions after taking the national data per 10,000 population. A total of 3659 patients attended our ULC (Urban Leprosy Centre) among which 2741 were male and 945 females (M:F-3:1). 669 patients (18.2%) were children. The data analysed show a gradual decline in new case detection rate with a marginal rise in 2005 and 2008. Percentage of MB cases was falling consistently till 2005 after which it showed an abrupt rise. The incidence of type 1 reaction varied from 21% in 1994 to 10% in 2009 in PB patients and from 6% in 1994 to 8% in 2009 in MB patients. The trend of type 2 reactions in MB patients showed a slow declining trend. MDT completion rate showed an impressive improvement from 56% in 1994 to 90% in 2009. The number of patients revisiting the ULC with features of relapse also showed a decrease in number. The pattern of visible deformities showed an almost constant trend similar to national figures. Improved MDT completion rate helps in reducing the disease transmission, severity, reactions and disabilities.

Do physicians within the same practice setting manage osteoporosis patients similarly? Implications for implementation research.

UNLABELLED: Using data from long-term glucocorticoid users and long-term care residents, we evaluated osteoporosis prescribing patterns related to physician behavior and common practice settings. We found no significant clustering effect for common practice setting, suggesting that osteoporosis quality improvement (QI) efforts may be able to ignore this factor in designing QI interventions. INTRODUCTION: Patients' receipt of prescription therapies are significantly influenced by their physician's prescribing patterns. If physicians in the same practice setting influence one another's prescribing, evidence implementation interventions must consider targeting the practice as well as individual physicians to achieve maximal success. METHODS: We examined receipt of osteoporosis treatment (OP Rx) from two prior evidence implementation studies: long-term glucocorticoid (GC) users and nursing home (NH) residents with prior fracture or osteoporosis. Common practice setting was defined as doctors practicing at the same address or in the same nursing home. Alternating logistic regression evaluated the relationship between OP Rx, common practice setting, and individual physician treatment patterns. RESULTS: Among 6,281 GC users in 1,296 practices, the proportion receiving OP Rx in each practice was 6-100%. Among 779 NH residents in 66 nursing homes, the proportion in each NH receiving OP Rx was 0-100%. In both, there was no significant relationship between receipt of OP Rx and common practice setting after accounting for treatment pattern of individual physicians. CONCLUSION: Physicians practicing together were not more alike in prescribing osteoporosis medications than those in different practices. Osteoporosis quality improvement may be able to ignore common practice settings and maximize statistical power by targeting individual physicians.

Differential human multiple myeloma cell line responsiveness to interferon-alpha. Analysis of transcription factor activation and interleukin 6 receptor expression.

Although IFN-alpha is commonly used as maintenance treatment for multiple myeloma patients, its effectiveness is varied. In this study, we have used a panel of IL-6 responsive myeloma cell lines that vary remarkably in responsiveness to IFN-alpha. Three cell lines were growth arrested by IFN-alpha; however, IFN-alpha significantly stimulated growth of the fourth cell line, KAS-6/1. Our studies have focused on elucidating the mechanism of differential IFN-alpha responsiveness. First, we have shown that IFN-alpha-stimulated growth of the KAS-6/1 cells did not result from induction of autocrine IL-6 expression. Second, analysis of Stats 1, 2, and 3 and IFN regulatory factor-1 (IRF-1) and IRF-2 activation failed to reveal differences between the IFN-alpha growth-arrested or growth-stimulated cells. Third, although IFN-alpha treatment of the IFN-alpha growth-inhibited cell lines reduced IL-6 receptor (IL-6R) expression, IFN-alpha also reduced KAS-6/1 IL-6R expression. Finally, although IFN-alpha treatment reduced IL-6R numbers on each cell line, analysis of Stat protein activation revealed that the receptors were still functional. We conclude that myeloma cell responsiveness to IFN-alpha is heterogeneous and that mechanisms of IFN-alpha-mediated growth inhibition other than IL-6R downregulation must exist in myeloma. Identification of these mechanisms may allow development of agents that are more universally effective than IFN-alpha.

Non-intrusive characterization of the redox potential of landfill leachate plumes from self-potential data.

Contaminant plumes (e.g., associated with leakages from municipal landfills) provide a source of natural electrical potentials (or "self-potentials") recordable at the Earth's surface. One contribution to these self-potentials is associated with pore water flow (i.e., the "streaming potential"), and the other is related to redox conditions. A contaminant plume can be regarded as a "geobattery": the source current potentially results from the degradation of the organic matter by micro-organisms, which produces electrons. These electrons are then carried by nanowires that connect bacteria and thorough metallic particles that precipitate in areas of strong redox potential gradient. In the case of the Entressen landfill (South of France), reported here, the hydraulic head differences measured in piezometers outside the contaminant plume is strongly linked to the surface self-potential signals, with a correlation coefficient of -0.94. We used a Bayesian method that combines hydraulic head and self-potential data collected outside the contaminated area to estimate the streaming potential component of the collected self-potential data. Once the streaming potential contribution was removed from the measured self-potentials, the correlation coefficient between the residual self-potentials and the measured redox potentials in the aquifer was 0.92. The slope of this regression curve was close to 0.5, which was fairly consistent with both finite element modelling and the proposed geobattery model.

Long-term visual outcomes in intraocular retinoblastoma with eye preservation.

PURPOSE: Inconsistent data exist on long-term visual outcomes in survivors of retinoblastoma. No studies have been reported on role of ocular coherence tomography (OCT) in predicting visual acuity. We assessed visual acuity in patients with retinoblastoma treated at our center in whom affected eyes were preserved. METHODS: Patients who had completed a 2-year follow-up and were more than 5 years of age at assessment were included. Clinical data were obtained from database and factors predicting visual acuity were analyzed. OCT was performed in these patients to assess central macular thickness (CMT). RESULTS: Visual outcomes were assessed in 45 eyes of 43 patients, of which 38 (88 %) had bilateral retinoblastoma. The median age at diagnosis was 12 months. Sixty percent (27/45) had International classification of retinoblastoma group C or D disease with 40 % eyes showing macular lesions. The far visual acuity was better than 6/12 in 53 % (24/45), 6/12 to 6/60 in 40 % (18/45) and 6/60 in 7 % (6/60). Macular location and International classification of retinoblastoma predicted poor vision (p = 0.06 and 0.07, respectively). CMT was less than 200 µm in 3 of 36 eyes (8 %) and 1 eye showed epiretinal membrane. Radiotherapy was associated with foveal thinning (p = 0.003). Two of 3 eyes with foveal thinning had a vision of 6/60. CONCLUSIONS: Good visual outcomes were observed in half of retinoblastoma patients treated with eye preservation. Macular location and International classification of retinoblastoma group C and D predicted poor visual acuity, while previous radiotherapy predicted foveal thinning, which was associated with poor visual acuity.

Ocular surgery in patients with diabetic nephropathy.

Patients with severe diabetic nephropathy often have diabetic retinopathy requiring eye surgery. During the course of their nephropathy, which was treated medically (group A, N = 34), with dialysis (group B, N = 18), or with renal transplantation (group C, N = 2), 54 diabetic patients have had eye surgery. The ophthalmologic procedures included cataract extraction, vitrectomy, scleral buckling, and cyclocryosurgery. The complications included postoperative hemorrhagic glaucoma and persistent retinal detachment. These were encountered in two patients of group A and in two of group B. All other cases showed uneventful intra- and postoperative courses. Major eye surgery can be performed safely during therapy for diabetic nephropathy, including hemodialysis with anticoagulation and transplantation with immunosuppression.

Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone.

Polycystic ovarian syndrome (PCOS) is a complex disorder with multiple abnormalities, including hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. The majority of patients have elevated LH levels in plasma and a persistent rapid frequency of LH (GnRH) pulse secretion, the mechanisms of which are unclear. Earlier work has suggested that the sensitivity of the GnRH pulse generator to inhibition by ovarian steroids is impaired. We performed a study to determine whether antiandrogen therapy with flutamide could enhance feedback inhibition by estradiol (E2) and progesterone (P) in women with PCOS. Ten anovulatory women with PCOS and nine normal controls (days 8-10 of the cycle) were studied on three occasions. During each admission, LH and FSH were determined every 10 min and E2, P, and testosterone (T) every 2 h for 13 h. After 12 h, GnRH (25 ng/kg) was given iv. After the first admission, patients were started on flutamide (250 mg twice daily), which was continued for the entire study. The second admission occurred on days 8-10 of the next menstrual cycle for normal controls and on study day 28 for PCOS patients. Subjects were then given E2 transdermally (mean plasma E2, 106+/-18 pg/mL) and P by vaginal suppository to obtain varied plasma concentrations of P (mean P, 4.4+/-0.5 ng/mL; range, 0.6-9.0 ng/mL), and a third study was performed 7 days later. At baseline women with PCOS had higher LH pulse amplitude, response to GnRH, T, androstenedione, and insulin and lower sex hormone-binding globulin concentrations (P < 0.05). Most hormonal parameters were not altered by 4 weeks of flutamide, except T in controls and E2 and FSH in PCOS patients, which were lower. Of note, flutamide alone had no effect on LH pulse frequency or amplitude, mean plasma LH, or LH responsiveness to exogenous GnRH. After the addition of E2 and P for 7 days, both PCOS patients and normal controls had similar reductions in LH pulse frequency (4.0+/-0.7 and 5.8+/-0.7 pulses/12 h, respectively). This contrasts with our earlier results in the absence of flutamide, where a plasma P level of less than 10 ng/mL had minimal effects on LH pulse frequency in women with PCOS, but was effective in controls. These results suggest that although the elevated LH pulse frequency in PCOS may in part reflect impaired sensitivity to E2 and P, continuing actions of hyperandrogenemia are important for sustaining the abnormal hypothalamic sensitivity to feedback inhibition by ovarian steroids.

The effect of mechanoreceptor stimulation of the laryngopharynx on the oesophago-gastric junction.

Stimulation of the pharynx by injection of minute amounts of water induces prolonged period of lower oesophageal sphincter (LOS) relaxation and augmentation of the crural diaphragm (CD) contraction. The purpose of this study was to determine the effects of stimulating mechano-receptors at the laryngopharynx on the LOS and CD by using an air pulse stimulation device. Air pulses were delivered via the internal channel of a flexible endoscope. Oesophageal, LOS, and CD pressures; CD electromyogram; and oesophageal pH 5 cm above the LOS were recorded in nine healthy subjects. Stimulation of the laryngopharynx induced LOS relaxation in the absence of swallow and oesophageal peristalsis. The stimulation of epiglottis and arytenoid produced higher incidence of LOS relaxation compared to the base of tongue. The magnitude of LOS relaxation differed significantly between the three anatomical sites, with greater relaxation occurring at the epiglottis and arytenoid compared with the base of the tongue. None of the LOS relaxations induced by laryngeal stimulation resulted in inhibition of the CD or gastroesophageal reflux. We conclude that stimulation of the laryngopharyngeal mechanoreceptors induces LOS but not CD relaxation. The LOS relaxation induced by laryngopharyngeal stimulation is not accompanied by acid reflux in fasting state.

The complexity of obesity in U.K. adolescents: relationships with quantity and type of technology, sleep duration and quality, academic performance and aspiration.

BACKGROUND: Contemporary technology and multiple device use may link to increased body mass index (BMI). The sleep-obesity relationship is inconsistent in adolescents. Sleep duration and quality may have crucial connections to obesity development, particularly in adolescents where sleep alterations are common. Elevated BMI in adolescents may influence academic performance and aspiration, but data are limited. OBJECTIVES: The objectives of this study was to assess the linear associations between BMI z-score and (i) quantity/type of technology used; (ii) sleep quantity/quality and (iii) academic performance/aspiration. METHODS: Consenting adolescents (n = 624; 64.9% girls, aged 11-18 years) were recruited. The Schools Sleep Habits Survey and Technology Use Questionnaire were administered. Objective measures of height/weight were obtained. RESULTS: Quantity of technology was positively associated with BMI z-score ß = 0.10, P < 0.01. Those who always engaged in video gaming had significantly higher BMI z-score vs. never-users, ß = 1.00, P < 0.001. Weekday sleep duration and sleep onset latency were related to BMI z-score, ß = -0.24, P < 0.001 and ß = 0.01, P < 0.001, respectively. An inverse linear association was observed between BMI z-score and academic performance, ß = -0.68, P < 0.001. CONCLUSIONS: If confirmed prospectively, reducing bedtime use of technology and improving sleep hygiene in adolescents could be an achievable intervention for attenuating obesity with potentially positive effects on academic performance.

Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999-2006.

Information on the impact of bone metastasis and skeletal-related events (SREs) on mortality among prostate cancer patients is limited. Using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified men aged 65 years or older diagnosed with prostate cancer between July 1 1999 and December 31 2005 and followed to determine deaths through December 31 2006. We classified subjects as having bone metastasis and SREs as indicated by Medicare claims. Using Cox regression, we estimated mortality hazards ratios (HR) among men with bone metastasis with or without SRE, compared with men without bone metastasis. Among 126,978 men with prostate cancer (median follow-up, 3.3 years), 9746 (7.7%) had bone metastasis at prostate cancer diagnosis (1.7%) or during follow-up (5.9%). SREs occurred in 4296 (44%) men with bone metastasis. HRs for risk of death were 6.6 (95% CI=6.4-6.9) and 10.2 (95% CI=9.8-10.7), respectively, for men with bone metastasis but no SRE and for men with bone metastasis plus SRE, compared with men without bone metastasis. Bone metastasis was associated with mortality among prostate cancer patients. This association appeared to be stronger for bone metastasis plus SRE than for bone metastasis without SRE.

Substitute of Animals in Drug Research: An Approach Towards Fulfillment of 4R's.

The preclinical studies for drug screening involve the use of animals which is very time consuming and expensive and at times leads to suffering of the used organism. Animal right activists around the world are increasingly opposing the use of animals. This has forced the researchers to find ways to not only decrease the time involved in drug screening procedures but also decrease the number of animals used and also increase the humane care of animals. To fulfill this goal a number of new in vitro techniques have been devised which are called 'Alternatives' or 'Substitutes' for use of animals in research involving drugs. These 'Alternatives' are defined as the adjuncts which help to decrease the use as well as the number of animals in biomedical research. Russell and Burch have defined these alternatives by three R's - Reduction, Refinement and Replacement. These alternative strategies include physico-chemical methods and techniques utilizing tissue culture, microbiological system, stem cells, DNA chips, micro fluidics, computer analysis models, epidemiological surveys and plant-tissue based materials. The advantages of these alternatives include the decrease in the number of animals used, ability to obtain the results quickly, reduction in the costs and flexibility to control the variables of the experiment. However these techniques are not glittering gold and have their own shortcomings. The disadvantages include the lack of an appropriate alternative to study the whole animal's metabolic response, inability to study transplant models and idiosyncratic responses and inability to study the body's handling of drugs and its subsequent metabolites. None-the-less these aalternative methods to certain extent help to reduce the number of animals required for research. But such alternatives cannot eliminate the need for animals in research completely. Even though no animal model is a complete set of replica for a process within a human body, the intact animal does provide a better model of the complex interaction of the physiological processes.

Skeletal health among African Americans with recent-onset rheumatoid arthritis.

OBJECTIVE: African Americans with rheumatoid arthritis (RA) may be at increased fracture risk. We applied the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) and National Osteoporosis Foundation (NOF) guidelines to a cohort of African Americans with early RA to identify which patients were recommended for osteoporosis treatment. METHODS: Risk factors and bone mineral density (BMD) were assessed in a cohort of African Americans with RA. The WHO FRAX tool estimated 10-year fracture risk. Patients were risk stratified using FRAX without BMD to identify which individuals might be most efficiently targeted for BMD testing. RESULTS: Participants (n = 324) had a mean age of 51 years and included 81% women. There were no associations of RA disease characteristics with BMD. The proportion of patients recommended for osteoporosis treatment varied from 3-86%, depending on age and body mass index (BMI). Ten-year fracture risk calculated with BMI only was generally the same or higher than fracture risk calculated with BMD; adding BMD data provided the most incremental value to risk assessment in patients 55-69 years of age with low/normal BMI, and in those > or =70 years of age with BMI > or =30 kg/m2. CONCLUSION: A high proportion of African Americans with RA were recommended for treatment under the 2008 NOF guidelines. FRAX without BMD identified low-risk patients accurately. Systematic application of FRAX to screen high-risk groups such as patients with RA may be used to target individuals for BMD testing and reduce the use of unnecessary tests and treatments.

Differential myeloma cell responsiveness to interferon-alpha correlates with differential induction of p19(INK4d) and cyclin D2 expression.

Interferon-alpha (IFN-alpha) has been used as therapy for the treatment of a variety of viral diseases and malignancies including multiple myeloma. The effectiveness of interferon-alpha in treating multiple myeloma, however, has been somewhat variable, and the mechanism(s) accounting for this is not well understood. As a means to examine the basis for the differential effectiveness of this cytokine, we have analyzed IFN-alpha-mediated modulation of the cell cycle in two human myeloma cell lines. These two cell lines, ANBL-6 and KAS-6/1, display dramatically different outcomes in response to this cytokine. Although IFN-alpha inhibited the growth of ANBL-6 cells by blocking cell cycle progression from G0/G1 to S phase, IFN-alpha stimulated cell cycle progression in KAS-6/1 cells. Moreover, the effects of IFN-alpha on cell cycle progression correlated with the phosphorylation status of the retinoblastoma protein. Of interest, IFN-alpha increased cyclin D2 expression and cyclin-dependent kinase activity in the KAS-6/1 cells but not in the ANBL-6 cells. To determine whether the differential effects of IFN-alpha on myeloma cell cycle progression could also result from differences in the expression of cyclin-dependent kinase inhibitors, we examined the effects of IFN-alpha on the induction of cyclin-dependent kinase inhibitors with broad regulatory function (p21 and p27) and those with specificity for G1-associated cyclin-cyclin-dependent kinase complexes (p15, p16, p18, and p19). Although we failed to detect an effect of IFN-alpha on expression levels of p21, p15, p16, or p18, IFN-alpha treatment of the ANBL-6 cell line resulted in induction of p19 expression, whereas it was without effect on the KAS-6/1 cell line. These results suggest that heterogeneity in IFN-alpha-mediated growth effects in myeloma cells correlates with differential induction of cyclin D2 and p19(INK4d) expression.

Neonatal androgen affects copulatory behavior in the female musk shrew.

The role of neonatal testosterone in the development of copulatory behavior was examined in an insectivore, the musk shrew (Suncus murinus). Female musk shrews were treated with testosterone propionate (TP) for the first 5 days of life and then tested in adulthood for either female or male-like copulatory behavior. Early TP had a masculinizing effect; neonatally treated animals mounted a stimulus female more frequently, and with shorter latencies, in response to adult testosterone treatment than did control females. Neonatally androgenized females also showed deficits in female sexual behavior; few received ejaculations from stud males. This difference was likely caused by increased aggression exhibited by the neonatally TP-treated females toward males. In turn, female aggression decreased efficiency of male partners' intromission attempts. Early TP treatments also caused structural abnormalities in the ovaries, but did not effect their capacity to ovulate in response to either gonadotropin-releasing hormone or human chorionic gonadotropin injection. In sum, exposure to TP during development augmented display of male-like behavior in females and had subtle deleterious effects on expression of feminine behavior.