Comprehensive Lifestyle Improvement Program for Prostate Cancer (CLIPP) is associated with improvement in weight and components of metabolic syndrome in men exposed to androgen deprivation therapy for prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer is associated with adverse effects, such as obesity and metabolic syndrome, which increase cardiovascular risk, the most common cause of non-cancer mortality in men diagnosed with prostate cancer. The Comprehensive Lifestyle Improvement Program for Prostate Cancer (CLIPP) was created to determine the feasibility of conducing a comprehensive lifestyle modification intervention in men on ADT for prostate cancer and determine its early efficacy in reducing obesity and metabolic syndrome. METHODS: A single-arm, open-label clinical trial was conducted by recruiting 31 men diagnosed with prostate cancer and exposed to ADT within the last 5 years. A multicomponent lifestyle modification program was delivered weekly for 16 weeks by a trained health coach. This was followed by 8 weeks of passive follow-up resulting in a total trial duration of 24 weeks. Feasibility was determined by calculating study recruitment, retention, and adherence rates. Weight and components of metabolic syndrome (waist circumference, triglycerides (TG), high-density lipoprotein (HDL), serum glucose, and blood pressure (BP)) were measured at baseline, 12, and 24 weeks. RESULTS: Recruitment, retention, and adherence rates were 47.1%, 90.3%, and 100%, respectively. Statistically significant improvements were noted between baseline and end of study measurements for weight (206.3 vs. 191.3 lbs, p < 0.001), waist (41.3 vs. 38.8 inches, p < 0.001), systolic BP (144.1 vs. 133.4 mm of Hg, p = 0.014), diastolic BP (83.3 vs. 76.2 mm of Hg, p = 0.0056), TG (146.0 vs. 113.8 mg/dl, p = 0.022), HDL (51.1 vs. 55.0 mg/dl, p = 0.012), and serum glucose (114.0 vs. 103.2 mg/dl, p = 0.013). CONCLUSION: CLIPP demonstrates feasibility and early efficacy of a multicomponent lifestyle modification intervention toward addressing obesity as well as components of metabolic syndrome in men on ADT for prostate cancer. This study provides strong preliminary data to develop future clinical trials in this population.

Protocol for a feasibility and early efficacy study of the Comprehensive Lifestyle Improvement Program for Prostate Cancer-2 (CLIPP2).

BACKGROUND: Although androgen deprivation therapy (ADT) for prostate cancer demonstrates improved overall and disease-free survival, it is associated with adverse effects such as obesity and metabolic syndrome that increase risk of cardiometabolic disease and diabetes type 2. ADT also leads to fatigue, depression and erectile dysfunction, which reduce quality of life (QoL). Lifestyle modification has shown promise in reducing obesity, metabolic syndrome and diabetes type 2 in other disease types. However, there is a paucity of data regarding the utility of lifestyle modification in men receiving ADT for prostate cancer. METHODS: The primary aim of the Comprehensive Lifestyle Improvement Program for Prostate Cancer-2 (CLIPP2) is to test the feasibility of conducting a 24-week lifestyle modification intervention in men on ADT for prostate cancer. Additionally, it will also determine the effect of this intervention on weight loss, cardiometabolic markers (secondary aim and markers of interest: serum glucose, insulin resistance, hemoglobin A1C and lipid panel), and QoL (tertiary aim). The intervention will be delivered weekly via telephone for the first 10 weeks and bi-weekly for the remaining 14 weeks. Questionnaires and serum samples will be collected at baseline, week 12, and week 24. Anthropometric measurements will be collected at baseline, week 6, week 12, week 18 and week 24. RESULTS: We hypothesize that the CLIPP2 intervention will produce a 7% weight loss that will result in improved markers associated with cardiometabolic disease and type 2 diabetes in the study population. CONCLUSION: Results will provide insight into the role of lifestyle modification in addressing ADT adverse effects as well as provide preliminary data to inform the development of future lifestyle interventions in this area. TRIAL REGISTRATION: NCT04228055 Clinicaltrials. gov.

Fine Particle Emissions From Tropical Peat Fires Decrease Rapidly With Time Since Ignition.

Southeast Asia experiences frequent fires in fuel-rich tropical peatlands, leading to extreme episodes of regional haze with high concentrations of fine particulate matter (PM2.5) impacting human health. In a study published recently, the first field measurements of PM2.5 emission factors for tropical peat fires showed larger emissions than from other fuel types. Here we report even higher PM2.5 emission factors, measured at newly ignited peat fires in Malaysia, suggesting that current estimates of fine particulate emissions from peat fires may be underestimated by a factor of 3 or more. In addition, we use both field and laboratory measurements of burning peat to provide the first mechanistic explanation for the high variability in PM2.5 emission factors, demonstrating that buildup of a surface ash layer causes the emissions of PM2.5 to decrease as the peat fire progresses. This finding implies that peat fires are more hazardous (in terms of aerosol emissions) when first ignited than when still burning many days later. Varying emission factors for PM2.5 also have implications for our ability to correctly model the climate and air quality impacts downwind of the peat fires. For modelers able to implement a time-varying emission factor, we recommend an emission factor for PM2.5 from newly ignited tropical peat fires of 58 g of PM2.5 per kilogram of dry fuel consumed (g/kg), reducing exponentially at a rate of 9%/day. If the age of the fire is unknown or only a single value may be used, we recommend an average value of 24 g/kg.

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles.

Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with 'paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

Strain differences in the effects of chronic corticosterone exposure in the hippocampus.

Stress hormones are thought to be involved in the etiology of depression, in part, because animal models show they cause morphological damage to the brain, an effect that can be reversed by chronic antidepressant treatment. The current study examined two mouse strains selected for naturalistic variation of tissue regeneration after injury for resistance to the effects of chronic corticosterone (CORT) exposure on cell proliferation and neurotrophin mobilization. The wound healer MRL/MpJ and control C57BL/6J mice were implanted subcutaneously with pellets that released CORT for 7 days. MRL/MpJ mice were resistant to reductions of hippocampal cell proliferation by chronic exposure to CORT when compared to vulnerable C57BL/6J mice. Chronic CORT exposure also reduced protein levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of C57BL/6J but not MRL/MpJ mice. CORT pellet exposure increased circulating levels of CORT in the plasma of both strains in a dose-dependent manner although MRL/MpJ mice may have larger changes from baseline. The strains did not differ in circulating levels of corticosterone binding globulin (CBG). There were also no strain differences in CORT levels in the hippocampus, nor did CORT exposure alter glucocorticoid receptor or mineralocorticoid receptor expression in a strain-dependent manner. Strain differences were found in the N-methyl-D-aspartate (NMDA) receptor, and BDNF I and IV promoters. Strain and CORT exposure interacted to alter tropomyosine-receptor-kinase B (TrkB) expression and this may be a potential mechanism protecting MRL/MpJ mice. In addition, differences in the inflammatory response of matrix metalloproteinases (MMPs) may also contribute to these strain differences in resistance to the deleterious effects of CORT to the brain.

Casos clínicos -reversión del déficit sensorial asociadoal alivio del dolor después de un tratamiento congabapentina / Case reports -reversal of sensory deficit associated with pain relief after treatment with gabapentin

Muchos pacientes con dolor neuropático presentan también déficits sensoriales. El dolor neuropático puede aliviarse con una serie de medicamentos, pero se supone que los déficits sensoriales son permanentes. En un estudio de los efectos de la gabapentina en pacientes con dolor neuropático, se realizaron exploraciones sensoriales minuciosas todos los meses durante los primeros tres meses de tratamiento. De cinco pacientes con déficits sensoriales que toleraron el tratamiento con gabapentina, tres mostraron una marcada mejoría de los déficits sensoriales asociados al alivio del dolor. Se presentan estos casos y se comentan las posibles explicaciones de las mejoras sensoriales observadas. Estos hallazgos plantean interesantes preguntas neurofisiológicas, aparte de su posible relevancia para el problema clínico de las lesiones de los tejidos neuropáticos (AU)

Benign multicystic mesothelioma: a case report.

Benign multicystic mesothelioma (also known as multilocular peritoneal inclusion cyst) is a rare lesion found on any abdominal peritoneal surface that occurs most frequently in premenopausal women. We report the case of a 36-year- old woman, who presented with a history of generalized abdominal pain, intermittent abdominal bloating, and episodes of loose stools. A pelvic ultrasound revealed a complex cystic mass with fine internal septations. The patient was managed by laparotomy with removal of mass, total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and multiple peritoneal biopsies. Final pathology revealed benign multicystic mesothelioma. Although mesothelioma is a rare tumour, it is important for all gynaecologists to recognize its existence, the appearance of this lesion, and its generally benign course. This is especially important as it occurs in young women where fertility considerations must be part of the discussion of any pelvic surgery.

Case reports - reversal of sensory deficit associated with pain relief after treatment with gabapentin.

Many patients with neuropathic pain have coexistent sensory deficits. Neuropathic pain may be alleviated by a variety of drugs but sensory deficits are assumed to be permanent. In an audit of the effects of gabapentin therapy on patients with neuropathic pain, monthly detailed sensory examinations were performed during the first three months of treatment. Of five patients with sensory deficits who tolerated gabapentin therapy, three showed marked improvement of their sensory deficits associated with pain alleviation. The cases are presented and possible explanations for the observed sensory improvements are discussed. These findings raised exciting neurophysiological questions in addition to being of potential importance to the clinical problem of neurotrophic tissue injury.

A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity.

Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide (the 42-residue isoform of the amyloid-beta peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant beta-amyloid precursor protein (APP) lowered their brain levels of Abeta42. In cultured cells, the decrease in Abeta42 secretion was accompanied by an increase in the Abeta(1-38) isoform, indicating that NSAIDs subtly alter gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Abeta42 peptide levels independently of COX activity and that this Abeta42-lowering activity could be optimized to selectively target the pathogenic Abeta42 species.

Longitudinal analysis of subjective quality of life in schizophrenia: anxiety as the best symptom predictor.

We examined the relationships among changes in anxiety, depression, core symptoms of schizophrenia, and subjective quality of life (QL) longitudinally. Fifty-three stabilized outpatients diagnosed with schizophrenia or schizoaffective disorder were assessed for QL and symptoms every 3 months for a period of 1 year. Using mixed effects models, we found that changes in anxiety, as rated on the Brief Psychiatric Rating Scale, were inversely associated with general life satisfaction and satisfaction with many specific domains. These relationships were stronger than the relationships of QL and any other core symptoms of schizophrenia, including depression. Anxiety was also related to some positive and negative symptoms. These findings support the notion that more precise analysis of general psychopathology, and anxiety in particular, is important in clarifying the factors involved in QL in schizophrenia. We explain our findings in the context of current theories of affect and suggest implications for the treatment of schizophrenia.

Quality of life in schizophrenia: contributions of anxiety and depression.

A number of studies have demonstrated a strong relationship between quality of life in schizophrenia and general psychopathology measures, and moreover, that the positive, negative, and disorganized symptoms are less related to quality of life. The current investigation examined the relationship between quality of life and symptomatology in 63 stabilized outpatients diagnosed with schizophrenia or schizoaffective disorder. Consistent with other findings, more severe depression, as rated on the Brief Psychiatric Rating Scale (BPRS) was associated with lower general life satisfaction and lower satisfaction with daily living, finances, health, and social life. In addition, higher anxiety ratings on the BPRS were associated with less satisfaction with global quality of life, daily activities, family, health and social relationship, even when controlling for positive symptoms, negative symptoms, or depression. No other symptoms of schizophrenia were as strongly associated with subjective quality of life. Anxiety was also significantly correlated with a number of positive and negative symptoms while depression was substantially less related. These findings, suggest that more precise analyses of general psychopathology, and anxiety in particular, may be necessary to further clarify the factors involved in quality of life in schizophrenia. In addition, these findings suggest future directions for theories of affect and treatment in schizophrenia.

Photoproduction of hydrated electron from constituents of natural waters.

The wavelength dependence for the photoproduction of the hydrated electron (e-(aq)) from various humic and fulvic acids and from natural waters was determined, employing a method that converts e-(aq) to a methyl radical that is detected fluorimetrically as the O-methylhydroxylamine of a stable nitroxide. Quantum yields for e-(aq) production from potassium ferrocyanide and N,N-dimethylaniline are in agreement with previously reported values. The quantum yields for production of e-(aq) from colored dissolved organic matter (CDOM) decrease precipitously with increasing wavelength with the rate of decline increasing in the order: humic acid < fulvic acid < natural water in the UV-B region. For Suwannee River fulvic acid, quantum yields ranged from 7.9 x 10(-6) at 366 nm to 1.9 x 10(-4) at 296 nm indicating that previously reported values for e-(aq) production from CDOM involving laser sources of irradiation are high due to experimental artifact. Apparent natural water quantum yields at 296 nm are higher than those for humic substances, ranging from 9.4 x 10(-5) to 3.7 x 10(-3) depending on location. The highly absorbing waters of the Delaware and Chesapeake Bays show insignificant production of e-(aq). These results indicate that the hydrated electron, through its reaction with dioxygen, is not a significant source of hydrogen peroxide in many natural waters and that humic substances may not be the principal source of e-(aq) production.

Female marmoset monkeys (Callithrix jacchus) can be identified from the chemical composition of their scent marks.

The present study analyzed 42 organic solvent extracts of scent mark pools from five dominant female common marmosets by gas chromatography (GC) and combined GC and mass spectrometry. We determined whether there were qualitative or quantitative differences between the chemical composition of scent marks from individual females. Gas chromatography and mass spectral analysis detected the same 162 chemicals in 86% (36/42) of scent mark pools from five dominant females. This near identical chemical composition of scent marks suggested there were few, if any, qualitative differences between the chemical composition of scent marks from individual females. Instead, quantitative differences in scent may provide the key factor distinguishing individual females. Using the relative concentration of highly volatile chemicals detected by GC in scent marks, linear discriminant analysis classified scent mark pools to their correct donor approximately 91% of the time. Such highly reliable statistical matching of scent to donor suggested that each individual female common marmoset has a unique ratio of highly volatile chemicals in their scent marks which may permit individual identification of females from odors in their scent alone.

Oxytocin responsivity in mothers of infants: a preliminary study of relationships with blood pressure during laboratory stress and normal ambulatory activity.

The neuropeptide oxytocin (OT) enhances maternal behavior and decreases blood pressure (BP) and stress responses in animals. Thus, the relationship of OT responsivity to BP in 14 breast- and 11 bottle-feeding mothers of infants was examined. Laboratory BP was assessed during baseline, speech preparation, active speech, and recovery on 2 days, 1 in which baseline and speech were separated by 10 min of baby holding and the other by no baby contact. Systolic BP reactivity to speech was lower after baby contact. Plasma OT change from baseline to speech after baby contact defined OT increase, minimal OT change, and OT decrease groups. OT increase mothers were primarily breast-feeders, and they had lower BP throughout both stress sessions and after baby feeding at home than OT decrease mothers, who also had greater BP reactivity to preparation and recovery. These results suggest that oxytocin has antistress and BP-lowering effects in humans.

Adolescents' knowledge and beliefs about pregnancy: the impact of "ENABL".

Finding effective ways to prevent adolescent pregnancy is a concern of public health officials, educators, social workers, parents, and legislators. Numerous programs exist, but there is debate as to whether it is the specific program itself or other factors that are responsible for participants' successful outcomes. Using a quasi-experimental design, this study sought to determine which factors predicted changes in knowledge and beliefs among middle school students (N = 1,450) after exposure to Postponing Sexual Involvement (PSI), the curricular component of Education Now and Babies Later (ENABL), a pregnancy prevention program. It was found that the single most important predictor of improvement in knowledge and beliefs about pregnancy prevention was PSI itself, not background variables. The findings contradict some of the previous studies on factors impacting teenage pregnancy and lend support for the continued examination of ENABL as a promising component of pregnancy prevention efforts.

True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management.

PURPOSE: The purpose of this study was to classify all ipsilateral breast tumor relapses (IBTR) in patients treated with conservative surgery and radiation therapy (CS+RT) as either new primary tumors (NP) or true local recurrences (TR) and to assess the prognostic and therapeutic implications of this classification. METHODS AND MATERIALS: Of the 1152 patients who have been treated at Yale-New Haven Hospital before 1990, 136 patients have experienced IBTR as their primary site of failure. These relapses were classified as either NP or TR. Specifically, patients were classified as NP if the recurrence was distinctly different from the primary tumor with respect to the histologic subtype, the recurrence location was in a different location, or if the flow cytometry changed from aneuploid to diploid. This information was determined by a detailed review of each patient's hospital and/or radiotherapy record, mammograms, and pathologic reports. RESULTS: As of 2/99, with a mean follow-up of 14. 2 years, the overall ipsilateral breast relapse-free rate for all 1152 patients was 86% at 10 years. Using the classification scheme outlined above, 60 patient relapses were classified as TR, 70 were classified as NP and 6 were unable to be classified. NP patients had a longer mean time to breast relapse than TR patients (7.3 years vs. 3.7 years, p < 0.0001) and were significantly younger than TR patients (48.9 years vs. 54.5 years, p < 0.01). Patients developed both TR and NP at similar rates until approximately 8 years, when TR rates stabilized but NP rates continued to rise. By 15 years following original diagnosis, the TR rate was 6.8% compared to 13.1% for NP. Of the patients who had been previously tested for BRCA1/2 mutations, 17% (8/52) had deleterious mutations. It is noteworthy that all patients with deleterious mutations had new primary IBTR, while patients without deleterious mutations had both TR and NP (p = 0.06). Ploidy was evenly distributed between TR and NP but NP had a significantly lower S phase fraction (NP 13.1 vs. TR 22.0, p < 0.05). The overall survival following breast relapse was 64% at 10 years and 49% at 15 years. With a mean follow-up of 10.4 years following breast relapse, patients with NP had better 10-year overall survival (TR 55% vs. NP 75%, p < 0.0001), distant disease-free survival (TR 41% vs. NP 85%, p < 0.0001), and cause-specific survival (TR 55% vs. NP 90%, p < 0.0001). CONCLUSION: It appears that a significant portion of patients who experience ipsilateral breast tumor relapse following conservative surgery and radiation therapy have new primary tumors as opposed to true local recurrences. True recurrence and new primary tumor ipsilateral breast tumor relapses have different natural histories, different prognoses, and, in turn, different implications for therapeutic management.

Multiregion contact systems for modelling STD epidemics.

This paper elicits properties of some multiregional contact systems for STD infections that are intended to assist the understanding of disease control strategies. To this end, a space-time SIS model is described that maintains the symmetry of contact that is inherent in the formation of sexual partnerships. It is demonstrated how the characteristic stability conditions of this model provide a framework for understanding the potential for sustained transmission after the introduction of the agent into a given region. Then, more complex SI specifications are derived that are particularly relevant to the transmission of HIV. These extensions include the introduction of alternative modes of travel and behavioural adaptations made in response to the circulation of HIV and the incidence of AIDS. The discussion suggests some additions to the systems that might enhance their applicability in practice.

Ethical decision making among family therapists and individual therapists.

In this study, we investigated the ethical decision making of 30 individual and 30 family therapists in order to detect the types of decision making used by practicing therapists. Informants responded to three ethical dilemmas. Two of the situations were hypothetical. The third dilemma was a situation the informant had experienced in practice. Each interview was assessed for decision-making style, using content analysis. Kohlberg's justice reasoning and Gilligan's care reasoning provided the conceptual foundations for this analysis. The results suggest that both family and individual therapists prefer care reasoning on all dilemma types. There was significantly more care reasoning demonstrated on the personal dilemma than on the hypothetical dilemmas. Characteristics of informants did not provide clear explanations for the differences found in reasoning.

Presenilin 1 regulates pharmacologically distinct gamma -secretase activities. Implications for the role of presenilin in gamma -secretase cleavage.

Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the gamma-secretase cleavage that generates the amyloid beta protein (Abeta). It is not clear how PSs regulate gamma-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the gamma-secretase cleavage, gamma-secretase themselves, or regulators of intracellular trafficking that indirectly influence gamma-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit Abeta production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct gamma-secretases, we show that PS1 regulates multiple pharmacologically distinct gamma-secretase activities as well as inducible alpha-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be gamma-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.