Identification and characterization of an alternative cancer-derived PD-L1 splice variant

Abstract

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544–15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.

https://ift.tt/2S8pHy6

A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Abstract

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect.

https://ift.tt/2A2Iu74

The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology

Abstract

The ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment sequences. Along these lines, the clinical translation of pre-clinical evidence generated by non-profit research entities is likely to provide a significant contribution to gaining new insights that will further boost the field of cancer immunotherapy. To pursue this goal, and to provide comprehensive educational programs in immune-oncology (I-O), several national and global networks have been revitalized or newly established in recent years. This rapidly evolving scenario led the Board of Directors of the Italian Network of Tumor Bio-Immunotherapy (NIBIT) to establish the NIBIT Foundation. This Focused Research Review summarizes the main ongoing and prospective I-O activities of the NIBIT Foundation.

https://ift.tt/2SUUOx8

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy

Abstract

A collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution in systems biology provides a deeper understanding of tumor and tumor microenvironment heterogeneity, there remains the need to identify and define genuinely predictive biomarkers to guide treatment and patient selection. Cross-specialty and cross-sector collaboration, along with a broader collective data-sharing approach are key to optimizing immuno-oncology therapy in clinical practice. Continued support of younger research-clinicians is essential for future success in clinical, translational and basic science investigations.

https://ift.tt/2CjW5Zl

Function: An Essential Postoperative Outcome for Older Adults

No abstract available

https://ift.tt/2QxzPjn

Proteomic Profile of Carbonylated Proteins Screen Regulation of Apoptosis via CaMK Signaling in Response to Regular Aerobic Exercise

To research carbonylated proteins and screen molecular targets in the rat striatum on regular aerobic exercise, male Sprague-Dawley rats (13 months old, n = 24) were randomly divided into middle-aged sedentary control (M-SED) and aerobic exercise (M-EX) groups (n = 12 each). Maximum oxygen consumption () gradually increased from 50%–55% to 65%–70% for a total of 10 weeks. A total of 36 carbonylated proteins with modified oxidative sites were identified by Electrospray Ionization-Quadrupole-Time of Flight-Mass Spectrometer (ESI-Q-TOF-MS), including 17 carbonylated proteins unique to the M-SED group, calcium/calmodulin-dependent protein kinase type II subunit beta (CaMKIIβ), and heterogeneous nuclear ribonucleoprotein A2/B1 (Hnrnpa2b1), among others, and 19 specific to the M-EX group, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), and malic enzyme, among others. Regular aerobic exercise improved behavioral and stereological indicators, promoted normal apoptosis (P

https://ift.tt/2Ev2MJH

Complex Clonal Diversity of Staphylococcus aureus Nasal Colonization among Community Personnel, Healthcare Workers, and Clinical Students in the Eastern Province, Saudi Arabia

Here, 210 healthy participants including community personnel (70), clinical students (68), and healthcare workers (HCWs) (72) from the eastern region of Saudi Arabia were studied. Sixty-three Staphylococcus aureus isolates were obtained from the nares of 37% of the community personnel and 26% of the clinical students and HCWs. Methicillin-resistant S. aureus (MRSA) was found in 16% (10 isolates) of the 63 isolates; six were from HCWs. Molecular characterization revealed high clonal diversity among the isolates, with 19 different spa types, 12 clonal complexes (CCs), and seven sequence types (STs) detected. The most common strain type was USA900, CC15, and t084, seen in 11 methicillin-susceptible S. aureus (MSSA) isolates. Moreover, three novel spa types in six isolates and one novel ST in two isolates were identified, most from HCWs. Interestingly, 29 isolates were mecA positive by PCR, whereas only 10 isolates were MRSA by disk diffusion (cefoxitin resistant). Of the 19 MSSA mecA-positive isolates, 16 were PBP2a negative, leaving three unique isolates from HCWs that were mecA and PBP2a positive yet cefoxitin susceptible. Our findings highlight the importance of phenotypically and genotypically characterizing S. aureus strains isolated from healthy communities to monitor the risk of possible cross-transmission to hospitalized patients. The identified strains showed a clonal lineage relationship with previously reported S. aureus and MRSA strains acquired from hospital settings.

https://ift.tt/2Es4D1J

Cancers, Vol. 10, Pages 522: NK Cell-Based Glioblastoma Immunotherapy

Cancers, Vol. 10, Pages 522: NK Cell-Based Glioblastoma Immunotherapy

Cancers doi: 10.3390/cancers10120522

Authors: Irene Golán Laura Rodríguez de la Fuente Jose A. Costoya

Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor mass and its high capacity for invading healthy tissues. Moreover, the glioblastoma microenvironment is capable of suppressing the action of the immune system through several mechanisms such as recruitment of cell modulators. Development of new therapies that avoid this immune evasion could improve the response to the current treatments for this pathology. Natural Killer (NK) cells are cellular components of the immune system more difficult to deceive by tumor cells and with greater cytotoxic activity. Their use in immunotherapy gains strength because they are a less toxic alternative to existing therapy, but the current research focuses on mimicking the NK attack strategy. Here, we summarize the most recent studies regarding molecular mechanisms involved in the GB and immune cells interaction and highlight the relevance of NK cells in the new therapeutic challenges.

https://ift.tt/2EA2NN7

Panafrican Medical Journal

PAMJ, 3 - 7 Dec 2018

RESEARCH Menstrual hygiene management practices among primary school girls from a pastoralist community in Kenya: a cross sectional survey Eleen Korir et al. Pubescent girls from developing countries are confronted with diverse menstrual hygiene management (MHM) challenges, especially at school. Girls from rural pastoralist communities experience insurmountable MHM barriers. Inadequate coping strategies adopted result in sub-optimal school performance, absenteeism and physical problems. Outcomes of tunneled internal jugular venous catheters for chronic haemodialysis at the University College Hospital, Ibadan, Nigeria Yemi Raheem Raji et al.  Vascular access is an important aspect of haemodialysis treatments and determinant of patient outcomes. Arteriovenous (AV) fistula has been described as the preferred haemodialysis vascular access for patients on chronic dialysis. IMAGES IN CLINICAL MEDICINE Une cataracte inhabituelle: régressive à noyau pétaloïde Ahmed Bennis et al. Nous rapportons le cas d'une patiente de 38 ans, sans antécédents médico-chirurgicaux, victime d'un traumatisme contusif de l'œil droit par coup de pierre il y a 20 ans, avec baisse de l'acuité visuelle progressive depuis 10 ans. Formes évolutives postérieures de la persistance de la vascularisation fœtale bilatérale à l'hôpital régional de Gao Ibrahima Conaré et al.  La persistance de la vascularisation fœtale (PVF) est une anomalie de la résorption du système vasculaire hyaloïdien. Formes évolutives postérieures bilatérales de la persistance chez un garçon âgé de 2 ans qui a consulté pour une leucocorie de l'œil droit.  CASE REPORTS Perforation cæcale néonatale inaugurale du diagnostic d'un mégacôlon congénital Abdoulaye Diallo Harouna et al. Les perforations intestinales spontanées sont rares chez un nouveau-né à terme. Nous rapportons le cas d'un nouveau-né issu d'une grossesse de 41 semaines d'aménorrhée, qui avait présenté à trois jours de vie, un pneumopéritoine inaugural d'un mégacôlon congénital. Corps étranger intra urétral inhabituel chez un adolescent schizophrène: à propos d'un cas Mustapha Ahsaini et al.  L'auto insertion d'un corps étranger s'observe généralement chez les patients ayant une psychose chronique dans le but d'automutilation ou érotique. Le diagnostic est parfois difficile s'il est rapporté tardivement ou si le patient est non coopérant, d'où l'intérêt d'un bilan d'imagerie complémentaire.

Indian Journal of Occupational and Environmental Medicine (Indian J Occup Environ Med) 2018 | September-December | Volume 22 | Issue 3

Occupational health surveillance Damodar Vishnu Lele Indian Journal of Occupational and Environmental Medicine 2018 22(3):117-120, Occupational health surveillance Damodar Vishnu Lele Indian Journal of Occupational and Environmental Medicine 2018 22(3):117-120 The untold story of fluoridation: Revisiting the changing perspectives Maitreyee P Unde, Raju Umaji Patil, Persis P Dastoor Indian Journal of Occupational and Environmental Medicine 2018 22(3):121-127 The discovery of fluoride in dentistry has revolutionized treatment modalities with a new aspect of prevention and conservation of tooth structure coming into foreplay. Since then, there has been a lot of research on both topical and systemic fluoridation in an overzealous attempt to control the most debilitating dental problem of caries. Although topical fluoride is still being widely used as a preventive measure for dental caries, systemic administration of the same has gained major criticism worldwide due to the low margin of safety of fluoride and no control over the amount of individual intake when administered on a community level. This problem is more prevalent in countries with presence of natural fluoride belts that extend from Turkey to China and Japan through Iraq, Iran, and Afghanistan increasing the chances of both dental and skeletal fluorosis and hence increasing the focus toward defluoridation. This historical review highlights the distribution of fluoride worldwide and in India and also discusses about the various claims of the antifluoride lobby.  Occupational and environmental exposure to lead and reproductive health impairment: An overview Sunil Kumar Indian Journal of Occupational and Environmental Medicine 2018 22(3):128-137 Lead is a heavy metal. It is used in lead-acid battery, as a coloring agent, paints, and metal alloyed as shielding materials, smelters, printing press, and so on. It is a toxic metal affecting various organs, and developing fetus and young children are more vulnerable to toxicity of lead. This overview is based on the information of toxic potential of lead to human reproduction and reproductive outcome. Exposure to lead may affect libido, semen quality by declining sperm count, motility, viability, integrity, elevation in morphological abnormalities, and sperm DNA integrity. These alterations led to reducing fertility potential and chances of miscarriages, preterm birth, and so on in a partner. Lead exposure impairs hormonal synthesis and regulations in both sexes. Lead exposure also affects female reproduction by impairing menstruations, reducing fertility potential, delaying conception time, altering the hormonal production, circulation, affecting pregnancy and its outcome, and so on. At present, the safe dose of lead cannot be advocated as more and more data are generated in recent years which indicate the toxic potential of lead to human reproduction at a low level that was previously thought not to have such effect. Hence, use of lead should be stopped/avoided or restricted to safeguard human reproduction.  Upper extremity muscular strength in push–pull tasks: Model approach towards task design Joydeep Majumder, Sanjay M Kotadiya, Lokesh Kumar Sharma, Sunil Kumar Indian Journal of Occupational and Environmental Medicine 2018 22(3):138-143 Background: Pushing and pulling in workplaces are common actions. Repetitive forceful exertions in long-duration works lead to increased risk of musculoskeletal disorders and injuries. Aim: To investigate the upper extremity strength in generic push–pull modes while using hand tools and forecasting the limits of the workers while frequent or continuous operation. Settings and Design: The study was conducted among men workers in Ahmedabad city, India, and the design was cross-sectional study. Materials and Methods: In all, 100 men were recruited (Group 1: 18–39 years and Group 2: 40–60 years). Upper extremity muscular strength (isometric mode) testing of the preferred hand during push–pull type of manual hand-tool operations was carried out for 60 s. Forecasting of strength to generate predictions for future events (120 s) based on known past events (measured 60 s) was carried out using Holt–Winters time-series model. Statistical Analysis: Descriptive statistics was used for analysis. For prediction model evaluation, WEKA 3.8.2 was used. Results: Anthropometric parameters of both groups were similar, having no effect on generated strength. Largely, pull strength was recorded to be higher than push strength, wherein Group 2 men generated slightly higher strength. Seated strength was also higher than standing exertion. Forecasting reveals steady strength values for Group 1 men, whereas steep decline among Group 2 men with increasing duration of trial. Conclusion: The strength data generated would aid in work schedule design. Strength forecasting model would assist in developing engineering guidelines in the design of tools at workplace.  Effects of occupational heat exposure on traffic police workers in Ahmedabad, Gujarat Amee Raval, Priya Dutta, Abhiyant Tiwari, PS Ganguly, LM Sathish, Dileep Mavalankar, Jeremy Hess Indian Journal of Occupational and Environmental Medicine 2018 22(3):144-151 One of the most concerning environmental effects of climate change is rising levels of extreme heat, which already poses serious risks in many parts of the world. In June and July 2015, we collected weekly heat exposure data using area and personal temperature monitoring in Ahmedabad, Gujarat. The study was conducted at four different traffic junctions with a cohort of 16 traffic police. For information on health effects, we administered a baseline survey at the start of the study and prospectively followed up with the officers on prevalence of heat-related symptoms. Wet bulb globe temperature (WBGT) levels ranged from 28.2°C to 36.1°C during the study period. Traffic police workers who participated in this study were exposed to WBGT levels higher than the recommended threshold limit value as per American Conference of Governmental Industrial Hygienists guidelines even beyond the hottest months of the season. Our findings suggest that airport measurements by the Indian Meteorological Department may not accurately capture heat exposures among individuals who work in and alongside high-density traffic junctions. Based on our temperature estimates, traffic police are at risk for heat stress. India is likely to experience warmer temperatures and increased heat waves in the coming decades, fueled by climate change. Therefore, it is important to reduce current and future heat-related risks for traffic police workers and similar occupational risk groups by establishing protection strategies. The protocol established in this study for occupational heat exposure assessment could be applied to a larger cohort.  The exposure to pollutants of the auto repair workers: Monitoring their oxidative stress Roberto Menicagli, O Marotta, L Menicagli Indian Journal of Occupational and Environmental Medicine 2018 22(3):152-155 Background and Aim: Auto repair workers are exposed to multiple pollutants, each of them potentially risks, dangerous for several target organs. The aim of this study is to identify their possible overall effect, by monitoring the concentration of salivary malondialdehyde, index of oxidative stress. Materials and Methods: Malondialdehyde of 25 male workers, smokers and non-smokers, further divided into two subgroups relatively to the amplitude of their working place, was monitored, in the saliva, with the Thiobarbituric acid method. The control group consists of 12 and 13 male smokers, and 13 non-smokers. Univariate (UVA) and Multivariate (MVA) analysis methods were used to analyze the results. Results: No variable is significant (P ≥ 0.05) for the control group using UVA, while age and smoking significantly increase the levels of MDA (P ≤ 0.05) using MVA. For workers group, the age and the place of work increase the MDA (P ≤ 0.05) using UVA analysis, while only the place of work remains significant (≤0.05) using MVA analysis. MVA analysis reveals that, besides the type of work, also the age and smoking significantly increase the level of MDA, as a result of a higher exposure to pollutants. Conclusions: You can check the cumulative effect of pollutants on auto repair workers, by monitoring the salivary malondialdehyde.  Impact of school air quality on children's respiratory health Peter Fsadni, Frank Bezzina, Claudia Fsadni, Stephen Montefort Indian Journal of Occupational and Environmental Medicine 2018 22(3):156-162 Background: Asthma is common in children with indoor pollutants influencing the development of the disease. Since children spend most of their time outside their homes within the school environment, school indoor air quality can directly influence their respiratory health. Aims: This study aims to analyze the indoor and outdoor air quality of Maltese schools and if an association exists between indoor pollutants and respiratory health in children. Settings and Design: Five primary schools were selected with 9- to 11-year-old students participating. Materials and Methods: Standardized health questionnaires and lung function tests were utilized. Indoor and outdoor air sampling together with traffic counts were carried out. Statistical Analysis Used: SPSS version 21 was used and the Chi-squared, logistic regression, and Pearson's correlation were used. Results: The mean indoor PM 2.5 level of 17.78 μg/m3 and CO (9.11 ppm) exceeded World Health Organization thresholds. Indoor ozone levels exceeded the mean European school's indoor ozone concentration of 8 μg/m3. High exposure to formaldehyde, NO2, and ozone was associated with atopy in children. Heavy vehicles passing near the schools were associated with current wheezing (P < 0.001) but not nocturnal cough (P = 0.34). Conclusions: School indoor and outdoor environment has a direct impact on children's respiratory health. This study has identified significant associations between high exposures to indoor air pollutants, school characteristics, and upper and lower airway inflammation.  Work related musculoskeletal disorders and postural stress of the women cultivators engaged in uprooting job of rice cultivation Amitava Pal, Prakash C Dhara Indian Journal of Occupational and Environmental Medicine 2018 22(3):163-169 Aims: A large number of workers including women are involved in the informal sector in India. A majority of them are engaged in agricultural sectors. The agricultural workers have to perform their jobs by putting manual labor and are exposed to different occupational stresses. The present study was aimed to evaluate postural stress and prevalence of musculoskeletal disorder (MSD) of women cultivators engaged in uprooting job of rice cultivation. Settings and Design: This cross-sectional study was conducted on 166 women cultivators from different districts of West Bengal state, India. Materials and Methods: Prevalence and intensity of MSDs of the cultivators were evaluated by Nordic questionnaire and 10-point body part discomfort scale. Work rest pattern and postural pattern were studied by direct observation method. Postural stress was assessed by OVAKO Working Postures Analysis System (OWAS), Rapid Entire Body Assessment (REBA), Rapid Upper Limb Assessment (RULA), and Quick Exposure Checklist (QEC) methods and as well as by measuring center of gravity. Results and Conclusions: MSD was highly prevalent among the study participants. Lower back, hip, wrist, shoulder, and knee were highly affected. Higher prevalence of MSDs among the cultivators may be because of prolonged working hours and awkward postures. The women cultivators had to start their day before dawn to finish off their household chores such as cooking, cleaning, washing clothes and dishes, etc., before they moved off to the fields, which altogether impose them under additional stress. It may be suggested that ergonomic interventions such as modifying work-rest schedules, improving work postures, and introducing new design hand tools should be considered for improving work condition of the women cultivators.  A comparative study of byssinosis in jute industries Asim Saha, Anirban Das, Bhaskar Prasad Chattopadhyay, Jane Alam, Tilak Kanti Dasgupta Indian Journal of Occupational and Environmental Medicine 2018 22(3):170-176 Background: Byssinosis is an acute respiratory difficulty that is caused usually following exposure to cotton and hemp dust. Occurrence of such similar acute symptoms had been reported following exposure to jute dust/fiber also. With passage of time, Jute industries have modernized themselves for increased quality and productivity, which has lessened workforce and thereby provided more working space. However, occupational health benefit due to such changes has rarely been explored. This study was initiated to understand whether this modernization can protect the health of workers. Methodology: This study was carried out in two jute mills manufacturing jute clothes, jute bags, and so on. Interview of the workers for their occupational and morbidity details, medical examinations, as well as pre-shift and post-shift pulmonary function tests was carried out. Results: It was observed that chest tightness was significantly more in the industry with old technologies. Breathlessness was also more in this industry. As far as pulmonary function status is concerned, it was noted that greater than 5% cross-shift change in forced expiratory volume in one second was more common in the industry with old technology. Obstructive feature on lung function test was also observed in workers of both industries. Conclusion: The study concluded that exposure to jute dust has contributed to both acute and chronic respiratory health effects in the jute industry workers. Modernized industry showed lesser prevalence of acute symptoms and changes related to byssinosis. Modernization of processes in jute industries may prove fruitful in lowering the respiratory problems of workers.  Nipah virus: South India in panic mode Jasmine Shanthi Kamath, Shruthi Hegde, Vidya Ajila Indian Journal of Occupational and Environmental Medicine 2018 22(3):177-178

The untold story of fluoridation: Revisiting the changing perspectives Maitreyee P Unde, Raju Umaji Patil, Persis P Dastoor Indian Journal of Occupational and Environmental Medicine 2018 22(3):121-127 The discovery of fluoride in dentistry has revolutionized treatment modalities with a new aspect of prevention and conservation of tooth structure coming into foreplay. Since then, there has been a lot of research on both topical and systemic fluoridation in an overzealous attempt to control the most debilitating dental problem of caries. Although topical fluoride is still being widely used as a preventive measure for dental caries, systemic administration of the same has gained major criticism worldwide due to the low margin of safety of fluoride and no control over the amount of individual intake when administered on a community level. This problem is more prevalent in countries with presence of natural fluoride belts that extend from Turkey to China and Japan through Iraq, Iran, and Afghanistan increasing the chances of both dental and skeletal fluorosis and hence increasing the focus toward defluoridation. This historical review highlights the distribution of fluoride worldwide and in India and also discusses about the various claims of the antifluoride lobby.

Occupational and environmental exposure to lead and reproductive health impairment: An overview Sunil Kumar Indian Journal of Occupational and Environmental Medicine 2018 22(3):128-137 Lead is a heavy metal. It is used in lead-acid battery, as a coloring agent, paints, and metal alloyed as shielding materials, smelters, printing press, and so on. It is a toxic metal affecting various organs, and developing fetus and young children are more vulnerable to toxicity of lead. This overview is based on the information of toxic potential of lead to human reproduction and reproductive outcome. Exposure to lead may affect libido, semen quality by declining sperm count, motility, viability, integrity, elevation in morphological abnormalities, and sperm DNA integrity. These alterations led to reducing fertility potential and chances of miscarriages, preterm birth, and so on in a partner. Lead exposure impairs hormonal synthesis and regulations in both sexes. Lead exposure also affects female reproduction by impairing menstruations, reducing fertility potential, delaying conception time, altering the hormonal production, circulation, affecting pregnancy and its outcome, and so on. At present, the safe dose of lead cannot be advocated as more and more data are generated in recent years which indicate the toxic potential of lead to human reproduction at a low level that was previously thought not to have such effect. Hence, use of lead should be stopped/avoided or restricted to safeguard human reproduction.

Upper extremity muscular strength in push–pull tasks: Model approach towards task design Joydeep Majumder, Sanjay M Kotadiya, Lokesh Kumar Sharma, Sunil Kumar Indian Journal of Occupational and Environmental Medicine 2018 22(3):138-143 Background: Pushing and pulling in workplaces are common actions. Repetitive forceful exertions in long-duration works lead to increased risk of musculoskeletal disorders and injuries. Aim: To investigate the upper extremity strength in generic push–pull modes while using hand tools and forecasting the limits of the workers while frequent or continuous operation. Settings and Design: The study was conducted among men workers in Ahmedabad city, India, and the design was cross-sectional study. Materials and Methods: In all, 100 men were recruited (Group 1: 18–39 years and Group 2: 40–60 years). Upper extremity muscular strength (isometric mode) testing of the preferred hand during push–pull type of manual hand-tool operations was carried out for 60 s. Forecasting of strength to generate predictions for future events (120 s) based on known past events (measured 60 s) was carried out using Holt–Winters time-series model. Statistical Analysis: Descriptive statistics was used for analysis. For prediction model evaluation, WEKA 3.8.2 was used. Results: Anthropometric parameters of both groups were similar, having no effect on generated strength. Largely, pull strength was recorded to be higher than push strength, wherein Group 2 men generated slightly higher strength. Seated strength was also higher than standing exertion. Forecasting reveals steady strength values for Group 1 men, whereas steep decline among Group 2 men with increasing duration of trial. Conclusion: The strength data generated would aid in work schedule design. Strength forecasting model would assist in developing engineering guidelines in the design of tools at workplace.

Effects of occupational heat exposure on traffic police workers in Ahmedabad, Gujarat Amee Raval, Priya Dutta, Abhiyant Tiwari, PS Ganguly, LM Sathish, Dileep Mavalankar, Jeremy Hess Indian Journal of Occupational and Environmental Medicine 2018 22(3):144-151 One of the most concerning environmental effects of climate change is rising levels of extreme heat, which already poses serious risks in many parts of the world. In June and July 2015, we collected weekly heat exposure data using area and personal temperature monitoring in Ahmedabad, Gujarat. The study was conducted at four different traffic junctions with a cohort of 16 traffic police. For information on health effects, we administered a baseline survey at the start of the study and prospectively followed up with the officers on prevalence of heat-related symptoms. Wet bulb globe temperature (WBGT) levels ranged from 28.2°C to 36.1°C during the study period. Traffic police workers who participated in this study were exposed to WBGT levels higher than the recommended threshold limit value as per American Conference of Governmental Industrial Hygienists guidelines even beyond the hottest months of the season. Our findings suggest that airport measurements by the Indian Meteorological Department may not accurately capture heat exposures among individuals who work in and alongside high-density traffic junctions. Based on our temperature estimates, traffic police are at risk for heat stress. India is likely to experience warmer temperatures and increased heat waves in the coming decades, fueled by climate change. Therefore, it is important to reduce current and future heat-related risks for traffic police workers and similar occupational risk groups by establishing protection strategies. The protocol established in this study for occupational heat exposure assessment could be applied to a larger cohort.

The exposure to pollutants of the auto repair workers: Monitoring their oxidative stress Roberto Menicagli, O Marotta, L Menicagli Indian Journal of Occupational and Environmental Medicine 2018 22(3):152-155 Background and Aim: Auto repair workers are exposed to multiple pollutants, each of them potentially risks, dangerous for several target organs. The aim of this study is to identify their possible overall effect, by monitoring the concentration of salivary malondialdehyde, index of oxidative stress. Materials and Methods: Malondialdehyde of 25 male workers, smokers and non-smokers, further divided into two subgroups relatively to the amplitude of their working place, was monitored, in the saliva, with the Thiobarbituric acid method. The control group consists of 12 and 13 male smokers, and 13 non-smokers. Univariate (UVA) and Multivariate (MVA) analysis methods were used to analyze the results. Results: No variable is significant (P ≥ 0.05) for the control group using UVA, while age and smoking significantly increase the levels of MDA (P ≤ 0.05) using MVA. For workers group, the age and the place of work increase the MDA (P ≤ 0.05) using UVA analysis, while only the place of work remains significant (≤0.05) using MVA analysis. MVA analysis reveals that, besides the type of work, also the age and smoking significantly increase the level of MDA, as a result of a higher exposure to pollutants. Conclusions: You can check the cumulative effect of pollutants on auto repair workers, by monitoring the salivary malondialdehyde.

Impact of school air quality on children's respiratory health Peter Fsadni, Frank Bezzina, Claudia Fsadni, Stephen Montefort Indian Journal of Occupational and Environmental Medicine 2018 22(3):156-162 Background: Asthma is common in children with indoor pollutants influencing the development of the disease. Since children spend most of their time outside their homes within the school environment, school indoor air quality can directly influence their respiratory health. Aims: This study aims to analyze the indoor and outdoor air quality of Maltese schools and if an association exists between indoor pollutants and respiratory health in children. Settings and Design: Five primary schools were selected with 9- to 11-year-old students participating. Materials and Methods: Standardized health questionnaires and lung function tests were utilized. Indoor and outdoor air sampling together with traffic counts were carried out. Statistical Analysis Used: SPSS version 21 was used and the Chi-squared, logistic regression, and Pearson's correlation were used. Results: The mean indoor PM 2.5 level of 17.78 μg/m3 and CO (9.11 ppm) exceeded World Health Organization thresholds. Indoor ozone levels exceeded the mean European school's indoor ozone concentration of 8 μg/m3. High exposure to formaldehyde, NO2, and ozone was associated with atopy in children. Heavy vehicles passing near the schools were associated with current wheezing (P < 0.001) but not nocturnal cough (P = 0.34). Conclusions: School indoor and outdoor environment has a direct impact on children's respiratory health. This study has identified significant associations between high exposures to indoor air pollutants, school characteristics, and upper and lower airway inflammation.

Work related musculoskeletal disorders and postural stress of the women cultivators engaged in uprooting job of rice cultivation Amitava Pal, Prakash C Dhara Indian Journal of Occupational and Environmental Medicine 2018 22(3):163-169 Aims: A large number of workers including women are involved in the informal sector in India. A majority of them are engaged in agricultural sectors. The agricultural workers have to perform their jobs by putting manual labor and are exposed to different occupational stresses. The present study was aimed to evaluate postural stress and prevalence of musculoskeletal disorder (MSD) of women cultivators engaged in uprooting job of rice cultivation. Settings and Design: This cross-sectional study was conducted on 166 women cultivators from different districts of West Bengal state, India. Materials and Methods: Prevalence and intensity of MSDs of the cultivators were evaluated by Nordic questionnaire and 10-point body part discomfort scale. Work rest pattern and postural pattern were studied by direct observation method. Postural stress was assessed by OVAKO Working Postures Analysis System (OWAS), Rapid Entire Body Assessment (REBA), Rapid Upper Limb Assessment (RULA), and Quick Exposure Checklist (QEC) methods and as well as by measuring center of gravity. Results and Conclusions: MSD was highly prevalent among the study participants. Lower back, hip, wrist, shoulder, and knee were highly affected. Higher prevalence of MSDs among the cultivators may be because of prolonged working hours and awkward postures. The women cultivators had to start their day before dawn to finish off their household chores such as cooking, cleaning, washing clothes and dishes, etc., before they moved off to the fields, which altogether impose them under additional stress. It may be suggested that ergonomic interventions such as modifying work-rest schedules, improving work postures, and introducing new design hand tools should be considered for improving work condition of the women cultivators.

A comparative study of byssinosis in jute industries Asim Saha, Anirban Das, Bhaskar Prasad Chattopadhyay, Jane Alam, Tilak Kanti Dasgupta Indian Journal of Occupational and Environmental Medicine 2018 22(3):170-176 Background: Byssinosis is an acute respiratory difficulty that is caused usually following exposure to cotton and hemp dust. Occurrence of such similar acute symptoms had been reported following exposure to jute dust/fiber also. With passage of time, Jute industries have modernized themselves for increased quality and productivity, which has lessened workforce and thereby provided more working space. However, occupational health benefit due to such changes has rarely been explored. This study was initiated to understand whether this modernization can protect the health of workers. Methodology: This study was carried out in two jute mills manufacturing jute clothes, jute bags, and so on. Interview of the workers for their occupational and morbidity details, medical examinations, as well as pre-shift and post-shift pulmonary function tests was carried out. Results: It was observed that chest tightness was significantly more in the industry with old technologies. Breathlessness was also more in this industry. As far as pulmonary function status is concerned, it was noted that greater than 5% cross-shift change in forced expiratory volume in one second was more common in the industry with old technology. Obstructive feature on lung function test was also observed in workers of both industries. Conclusion: The study concluded that exposure to jute dust has contributed to both acute and chronic respiratory health effects in the jute industry workers. Modernized industry showed lesser prevalence of acute symptoms and changes related to byssinosis. Modernization of processes in jute industries may prove fruitful in lowering the respiratory problems of workers.

Nipah virus: South India in panic mode Jasmine Shanthi Kamath, Shruthi Hegde, Vidya Ajila Indian Journal of Occupational and Environmental Medicine 2018 22(3):177-178

Identification and characterization of an alternative cancer-derived PD-L1 splice variant

Abstract

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544–15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.

https://ift.tt/2S8pHy6

A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Abstract

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect.

https://ift.tt/2A2Iu74

The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology

Abstract

The ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment sequences. Along these lines, the clinical translation of pre-clinical evidence generated by non-profit research entities is likely to provide a significant contribution to gaining new insights that will further boost the field of cancer immunotherapy. To pursue this goal, and to provide comprehensive educational programs in immune-oncology (I-O), several national and global networks have been revitalized or newly established in recent years. This rapidly evolving scenario led the Board of Directors of the Italian Network of Tumor Bio-Immunotherapy (NIBIT) to establish the NIBIT Foundation. This Focused Research Review summarizes the main ongoing and prospective I-O activities of the NIBIT Foundation.

https://ift.tt/2SUUOx8

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy

Abstract

A collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution in systems biology provides a deeper understanding of tumor and tumor microenvironment heterogeneity, there remains the need to identify and define genuinely predictive biomarkers to guide treatment and patient selection. Cross-specialty and cross-sector collaboration, along with a broader collective data-sharing approach are key to optimizing immuno-oncology therapy in clinical practice. Continued support of younger research-clinicians is essential for future success in clinical, translational and basic science investigations.

https://ift.tt/2CjW5Zl

Culturally related risk factors of suicidal ideation, intent, and behavior among Asian American women.

To date, research on suicidality among Asian American women has focused on descriptive statistics and factors associated with suicidal ideation or attempts. As a field, we have little understanding of the precipitants to suicidal ideation, the specificity of intent, the methods contemplated, and the degree of lethality among these women. This mixed-methods study used the Columbia Suicide Severity Rating Scale to assess the suicidal ideation, the specificity of intent, the methods contemplated, and the degree of lethality among 173 Chinese, Korean, and Vietnamese American young women of age 18–35 years (M = 23.3, SD = 3.8) who completed clinical eligibility assessments for the Asian American Women's Action for Resilience and Empowerment intervention. Among the 173 women, quantitative results indicated that 110 participants (63.6%) of age 18–35 years (M = 23.8, SD = 3.9) experienced at least one occurrence of suicidal ideation in their lifetime, and 32 participants (18.5%) reported an intent to commit suicide. Almost half of those participants (43.7%) also described plans of moderate to extremely high lethality. Qualitative results demonstrated that precipitants for suicidal ideation may be culturally relevant and include a pressure to achieve and perform, restrictive and controlling parents, and loss of power in intimate relationships. These results suggest that there is a need to examine interventions that promote family support and provide education on ways to establish healthy romantic relationships as well as decrease the internalized need for perfection. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

https://ift.tt/2CkaBjU

Asian Pacific Islander Americans’ and White Americans’ suicide methods.

This study investigated Asian Pacific Islander Americans' (APIAs) and White Americans' use of three common suicide methods—firearm, poisoning, and hanging—using data from the National Violent Death Reporting System in the United States. Overall, hanging was the most common suicide method among APIAs, whereas firearm suicides were most prevalent among White Americans. APIA suicide decedents died by firearms and poisoning at lower rates, but by hanging at a higher rate than White Americans, after controlling for the effects of gender and age. Several gender by race moderation effects demonstrated that these racial differences in suicide methods were stronger among women than among men. In parallel with the findings on racial differences, APIA immigrants had a lower rate of firearm suicide but a higher rate of suicide by hanging than their U.S.-born counterparts. A gender by nativity moderation effect showed that among APIA men, immigrant decedents had a greater likelihood of using hanging as a suicide method than U.S.-born decedents, whereas among APIA women, there were no differences between immigrant and U.S.-born decedents in their likelihood of suicide by hanging. The researchers also uncovered several age by race and age by nativity moderation effects. These findings underscore the value of attending to within-group diversity in APIAs' suicide methods. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Guest editors’ introduction to special issue on advancing our understanding of suicide among Asian Americans.

The issue of suicide among Asian Americans has been understudied to date, largely because suicide rates for Asian Americans in the United States have been historically lower than Caucasians. The current special issue gathers studies that represent progress in the state of science, both advancing the current state of knowledge about suicide in Asian American communities and highlighting innovative approaches to suicide prevention and management. We discuss how the articles in the special issue address the nature and salience of suicide among Asian Americans, risk factors, culturally based expression of suicidal ideation and behaviors, and recommendations for suicide prevention and interventions. We conclude by noting directions for future research. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Hidden suicidal ideation or intent among Asian American Pacific Islanders: A cultural phenomenon associated with greater suicide severity.

"Hidden suicidal ideation" (HSI)—the concealment or nondisclosure of suicidal distress to others—is often cited in suicide and ethnic minority research as a phenomenon that occurs frequently among ethnic minorities. Yet, there has been limited research to further understanding of this phenomenon, particularly in a within-group investigation among Asian American Pacific Islanders (AAPI). The aims of the current study were to characterize HSI in a community sample of 73 actively suicidal AAPI adults. Results indicated that a majority of participants (N = 44, 60.30%) hid their desire to kill themselves from others. A logistic regression showed that AAPI respondents who endorsed HSI reported greater severity of suicidal distress than their non-HSI counterparts and that HSI among AAPIs was associated with culturally salient suicide risk. These results provide critical information that highlights HSI as a "cultural phenomenon" (defined as having a relationship with cultural risk factors) and potential indicator of suicide disparities and may have implications for culturally responsive detection and management of suicide risk for AAPI populations. The current study represents the first dedicated examination of the phenomenon of HSI among AAPI individuals. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

https://ift.tt/2Cj6mEZ

South Asians and suicide: Beliefs about suicide in a U.S. community sample.

Research from the United Kingdom has suggested differential risk factors for suicide among South Asians when compared with the general population. Studies in the United Kingdom have found higher risk related to gender, marital status, and religion. It has been unknown how such demographic variables, acculturative stress, and lower rates of help-seeking influence rates of suicide among South Asians in the United States. In this study, a community sample of South Asians in the United States (n = 524) were asked to complete a demographic questionnaire and validated measures for levels of acculturation, help-seeking, and beliefs about reasons for living via web-based survey. South Asians' scores on the Reasons for Living Inventory (RFL) were significantly higher than the normative population across all subscales except the Survival and Coping Beliefs subscales. Demographic variables significantly related to RFL scores included gender (men with higher RFL scores), age (younger individuals with lower RFL scores), country of origin (those from India with lower RFL scores), education level (lower RFL scores in those with higher education levels), and income (those with lower incomes having lower RFL scores). Help-seeking attitudes were also significantly related to RFL scores. As a whole, the findings are consistent with U.K.-based studies and provide valuable comparative data on a U.S.-based sample. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

https://ift.tt/2T0gdp1

Suicide and suicide-related behavior among Bhutanese refugees resettled in the United States.

Suicidal behavior and death by suicide are significant and pressing problems in the Bhutanese refugee community. Currently, Bhutanese refugees are dying by suicide at a rate nearly two times that of the general U.S. population. Proper identification of risk factors for suicide saves lives; however, if risk is underestimated due to culturally inflexible risk assessments, preventable deaths may continue to occur. In this review, we examine specific cultural factors related to psychopathology and suicide among Bhutanese refugees. To contextualize the current suicide crisis among Bhutanese refugees, we propose an integration of the interpersonal psychological theory of suicide (Joiner, 2005) and the cultural model of suicide (Chu, Goldblum, Floyd, & Bongar, 2010). We provide recommendations for preventing suicide from a systems framework and discuss practical lessons from a preliminary study designed to test a culturally responsive model of suicide in Bhutanese refugees. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

https://ift.tt/2CkaAMS

Disparities in follow-up care for Asian American youth assessed for suicide risk in schools.

Asian American (AA) students in academically high-performing schools are thought to represent a high-risk but underidentified group for mental health need and potential suicide risk. Previous data indicate that internalizing mental health needs among AA students are more likely to go unmet compared with other racial/ethnic groups. This is the first study to examine disparities in rates of follow-up mental health services (MHS) for AA students assessed for suicide risk in schools. We examined rates of parental consent for MHS and ultimate linkage to care following risk assessments for students in an ethnically diverse, high-performing school district. Findings indicated that AA students were underrepresented among suicide risk assessments compared with their district enrollment. Although female students were more often referred for suicide risk assessments, AA boys appeared at heightened risk compared with boys from other racial/ethnic groups at the elementary and middle school levels. In terms of rates of MHS receipt, 43.4% of AA students and 57.1% of Latino students received new or ongoing MHS following risk assessment. Multinomial logistic regressions revealed racial/ethnic disparities in parental consent and linkage to care, such that AA students were at significantly higher risk of having parents decline MHS (relative risk ratio = .26, p

https://ift.tt/2T0gd8v

Understanding the impact of community on the experience of suicide within the Lao community: An expansion of the cultural model of suicide.

There is a dearth in the scientific literature examining community factors of suicide in a theoretically grounded manner, in particular for Asian American groups. This study used the cultural model of suicide to examine the experience of suicide for a Lao group in California. Interviews were conducted with focus groups and community leaders pooled from the Center for Lao Studies, and then coded using a direct content analysis, in tandem with an inductive approach. The results revealed areas in which the community had a notable impact and shaped suicide risk within the Lao group. The findings also highlighted the need for additions to the current cultural model of suicide to reflect the impact of these community factors. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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The use of an educational video to increase suicide awareness and enrollment in parenting interventions among Filipinos.

Filipino American adolescents are at higher risk for suicidal ideation and attempts compared with other ethnic subgroups. Results of previous studies suggest the need to engage Filipino parents in the use of culturally tailored, best-practice child-rearing strategies. The Incredible Years is an evidence-based preventive parenting intervention for the school-age years that can reduce children's high-risk behaviors. Qualitative research methods and community advisory board meetings were primarily used during the formative research phases in producing a theory-based, culturally tailored video to increase awareness about adolescent suicide and promote enrollment in the Incredible Years among Filipino American parents. A 14-min video was created to increase knowledge about adolescent risky behaviors among Filipino American youth (i.e., suicidal behavior and drug use) and to motivate Filipino parents using constructs from the health belief model and theory of planned behavior. The video presented parent and grandparent testimonials with whom a target audience can identify and health and mental health providers who discussed behavioral health disparities. The content and format of the video included culturally tailored cues and modeling to influence Filipinos decision to enroll in a parenting intervention. Perceived susceptibility to future adolescent risky behaviors, perceived benefits and barriers to participate in parenting interventions, and knowledge of behavioral health disparities can be effectively targeted in a video format to promote enrollment of Filipino parents in evidence-based parenting interventions. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

https://ift.tt/2SXXydn

School climate and parental involvement buffer the risk of peer victimization on suicidal thoughts and behaviors among Asian American middle school students.

Suicide is the second leading cause of death among Asian American youth. Few studies have examined the risk and protective factors for suicidal thoughts and behaviors (STB) for Asian American middle school students. This study used data from the Georgia Student Health Survey 2.0 to examine the relationship between individual (gender, grade level, substance use, mental health difficulties, face-to-face victimization, and cyber victimization), school (school climate, racial diversity at school, school size, student–teacher ratio, and socioeconomic status), and familial (parental involvement) predictors of STB among 12,511 Asian American middle school students from 510 schools (50.1% girls). Results showed that both face-to-face and cyber victimization predicted higher levels of STB. Positive school climate at the individual level buffered the relationship between face-to-face victimization and STB, whereas positive school climate at the school level buffered the relationship between cyber victimization and STB. Gender was also a significant moderator of these relationships. Specifically, both types of peer victimization predicted more STB for girls than for boys. Parental involvement mitigated the relationship between face-to-face victimization and STB for girls. Positive school climate at the individual level buffered the relationship between cyber victimization and STB for boys. Findings highlight the importance of school climate, parental involvement, and gender differences in STB among Asian American students. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

https://ift.tt/2CihYZ0

Asian American college students, perceived burdensomeness, and willingness to seek help.

The present study examined the relationship between known risk factors for suicide and willingness to seek help among Asian American college students. The results revealed that Asian American students, relative to White American students, reported higher levels of two major contributors to suicidal risk: perceived burdensomeness on others and thwarted belongingness with others. Asian American students also reported less willingness to seek help from counselors and other mental health professionals than did White students. Furthermore, perceptions of burdensomeness (but not thwarted belongingness) mediated the link between students' race (Asian vs. White) and their reluctance to seek help. These data suggest that for Asian Americans, perceptions of burdensomeness may increase desire for suicide while simultaneously decreasing willingness to seek help with one's mental health issues. Additional results support the notion that Asian Americans perceive seeking mental health help as bringing yet further shame to one's family. Perceived burdensomeness is not only a major contributor to suicidal risk but may also serve as a major obstacle on the road to recovery. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Impaired forward model updating in young adults with Tourette syndrome

Abstract

Current theories of motor control emphasize how the brain may use internal models of the body to ensure accurate planning and control of movements. One such internal model—a forward model—is thought to generate an estimate of the next motor state and/or the sensory consequences of an upcoming movement, thereby allowing movement errors to be monitored. In addition, forward models may provide a means by which to determine a sense of agency, i.e. the (conscious) sense of authorship and control over our actions. Tourette syndrome is a developmental neurological condition characterized by the occurrence of motor and phonic tics. The involuntary (or voluntary) nature of tics has been the subject of considerable debate, and it was recently argued that the presence of tics in Tourette syndrome could result in a blurring of any subjective boundary between voluntary and involuntary movements. In particular, it was proposed that the level of sensorimotor noise that accompanies tics may be particularly high in Tourette syndrome, and this may contribute to less efficient forward models used to determine agency. We investigated whether the internal monitoring of movements is impaired in individuals with Tourette syndrome, relative to a matched group of typically developing individuals, using a task that involved executing double-step aiming movements using a hand-held robot manipulandum. Participants were required on each trial to execute two movements in turn, each directed to a remembered target location without visual feedback. Importantly, we assumed that to perform accurately on the second (return) movement it would be necessary to update any forward model to take into account errors made during the first (outward) movement. Here we demonstrate that while the Tourette syndrome group were equally accurate, and no more variable, than the matched control group in executing aiming movements to the first (outward) target location, they were significantly less accurate, and exhibited greater movement variability, than controls when executing the second (return) movement. Furthermore, we show that for the return movement only, movement accuracy and movement variability were significantly predicted by the Tourette syndrome group's clinical severity scores. We interpret these findings as consistent with the view that individuals with Tourette syndrome may experience a reduction in the precision of the forward model estimates thought necessary for the accurate planning and control of movements.

https://ift.tt/2URPFrD

Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis

Abstract

With the discovery that the highly effective anti-CD20 antibody therapies developed to deplete CD20⁺ B cells deplete CD20⁺ T cells equally well, a great interest in the biological properties of CD20⁺ T cells has emerged. In this study we show that CD20⁺ T cells have a proinflammatory Th1/Tc1 phenotype with a high proliferative capacity to CNS antigens. We also found that the percentage of CD20⁺ T cells is increased in the blood of patients with multiple sclerosis and are enriched in the CSF of the patients. Furthermore, we found a positive correlation between CD20⁺ T cells in the CSF and multiple sclerosis disease severity and see that regulation of CD20⁺ T cells likely contributes to the positive treatment effect of the multiple sclerosis treatment alemtuzumab. These data represent an important contribution to the understanding of the nature of CD20⁺ T cells and strongly suggests a role of CD20⁺ T cells in the pathogenesis of multiple sclerosis.

https://ift.tt/2PKgElh

Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions

Abstract

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer ¹¹C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on ¹¹C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with ¹¹C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim− lesions (−14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (−5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, ¹¹C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim− lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.

https://ift.tt/2PFg5sR

Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features

Abstract

Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12–51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.

https://ift.tt/2UU2MbC

Evaluation of Possible Human Health Risk of Heavy Metals from the Consumption of Two Marine Fish Species Tenualosa ilisha and Dorosoma cepedianum

Abstract

In order to study the effects of contaminants on human health, fish is considered as a powerful model among all available species for risk-benefit assessments. Tenualosa ilisha and Dorosoma cepedianum are two fish species of great economic importance as they are found in undeveloped, developing and developed countries. Concentrations of heavy metals lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As) and mercury (Hg) were determined using validated and accredited test methods in order to assess the potential human health risk from the dietary intake of these two selected fish species. The estimated daily intake (EDI) of all the five heavy metals was measured from the consumption of the two species considering the mean fish consumption of 61 g person⁻¹ day⁻¹ defined for European population. The EDI indicates that no risk to people's health with respect to the EDI of Pb, Cd, Cr, As and Hg through the consumption of the two fish species. The estimation of target hazard quotient (THQ) demonstrating the non-carcinogenic risk indicates that intake of Pb, Cd, Cr and Hg through the consumption of two fish species is safe for human health, whereas, consumption of As suggests potential risk to consumers. The estimation of carcinogenic risk of Cd, Cr and As due to the consumption of two selected fish species indicates that consumers remain at risk of cancer. Thus, these fish species should not be considered safe for human consumption.

https://ift.tt/2BBjrIv

Prediction of pathological stage at radical prostatectomy: do commonly used prostate cancer nomograms apply to men from Far North Queensland?

We aimed to assess whether common prostate cancer nomograms are valid for prostate cancer patients in Far North Queensland. Partin's tables accurately predicted organ‐confined disease, extra‐prostatic extension and seminal vesicle invasion, whilst more patients in our cohort had organ‐confined disease than was predicted by the MSKCC (Memorial Sloan Kettering Cancer Centre) tool. Both tests performed well on logistic regression modelling.

Background

Clinical nomograms are routinely used by urologists to predict pathological and clinical outcomes. Commonly used prostate cancer nomograms include Partin's tables and Memorial Sloan Kettering Cancer Centre (MSKCC) nomograms which were developed in high‐volume centres in the United States. We aimed to assess whether these tools are valid for prostate cancer patients in Far North Queensland.

Methods

All patients undergoing radical prostatectomy in Cairns between August 2014 and September 2017 were identified. Preoperative data were entered into the online nomogram tools. The predicted probability of organ‐confined (OC) disease, extra‐prostatic extension (EPE) and seminal vesical invasion was compared to the observed outcomes.

Results

Preoperative clinical information was available for 290 patients. Partin's tables accurately estimated OC disease, EPE and seminal vesical invasion with the observed outcome plot overlying the ideal correlation curve. More patients in our cohort had OC disease than was predicted by the MSKCC nomogram; fewer patients had EPE that was predicted by the MSKCC nomogram. On logistic regression modelling, the area under the curve for MSKCC and Partin's were 0.751 and 0.706, respectively, suggesting both tests have good performance in predicting final pathological outcome for our population of patients with no statistical difference between the two nomograms (P = 0.29).

Conclusion

The MSKCC preoperative nomogram and Partin's tables were both able to accurately predict pathological outcomes from preoperative clinical information in men from Far North Queensland, despite likely differences in population genetics and environmental exposures.

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Diffuse large B cell lymphoma: cutaneous presentation

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Exclusively plant, whole-food diet for polypharmacy due to persistent atrial fibrillation, ischaemic cardiomyopathy, hyperlipidaemia and hypertension in an octogenarian

Polypharmacy is common and associated with negative health outcomes in the elderly. We report the case of an 82-year-old man with a history of polypharmacy due to coronary artery disease, myocardial infarction, ischaemic cardiomyopathy, hyperlipidaemia, hypertension and persistent atrial fibrillation who presented with memory loss, cognitive impairment, fatigue and weakness. His treatment plan included an exclusively plant, whole-food diet and moderate physical activity which resulted in a rapid reduction of hyperlipidaemia and high blood pressure and the discontinuation of statin, antihypertensive and beta blocker drug therapy. The patient also reported reversal of impaired cognition and symptoms associated with atrial fibrillation and ischaemic cardiomyopathy, including light-headedness, fatigue and weakness. This case demonstrates that dietary and lifestyle modifications have the potential to improve symptoms of cardiovascular disease and reduce polypharmacy along with associated negative consequences in the elderly.

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Citrobacter freundii sepsis in an immunosuppressed patient with pemphigus vulgaris

Pemphigus vulgaris is an autoimmune bullous disease that involves the skin and mucous membranes. Current therapies aim to decrease antibody production by means of the use of systemic corticosteroids, immunosuppressive agents and, recently, rituximab, an anti-CD20 monoclonal antibody. However, the chronic immune suppression could entail complications, like infections and secondary malignancies. We describe a case of a patient with pemphigus who developed a sepsis due to Citrobacter freundii infection.

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Rare complication of central venous catheter placement: bilateral hydrothorax

Central venous catheters (CVCs) are very useful tools in clinical medicine. It is important not only for the administration of medications or fluids but also the measurement of haemodynamic variables, especially in intensive care patients. CVC placement is a relatively safe procedure but may occasionally be associated with complications, such as pneumothorax, haemothorax, cardiac tamponade, sepsis and thrombosis. We aim to report an extraordinary case of bilateral hydrothorax due to CVC placement.

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Levator palpebrae superioris nuclear palsy in a child with artery of Percheron infarction

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Fungal endocarditis of native valves

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Misconceptions surrounding pregnancy-associated breast cancer

This case report describes a 31-year-old woman who presented with a right painless breast lump. A mammogram and ultrasound scan showed the lump was suspicious of cancer. Core biopsy and immunohistochemistry of the lump confirmed a triple negative, poorly differentiated, invasive ductal carcinoma of the right breast. One week following her diagnosis, the patient found out she was pregnant. The patient was worried about what the implications this diagnosis would have on both her baby and her own cancer treatment.

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Tilting the balance: hemidiaphragm paralysis leading to right to left cardiac shunt

Patent foramen ovale (PFO) is a congenital abnormality present in 25%–30% of healthy adults and rarely leads to any sequelae.^{1 2} It is associated with a left-to-right shunt which usually does not lead to any haemodynamic compromise. Occasionally, the shunt can get reversed; that is, right-to-left shunt occurs due to worsening pulmonary hypertension and can lead to persistent hypoxia. It is rare for the shunt reversal to happen in the absence of pulmonary hypertension. Here, we present an exceedingly rare case in a 61-year-old man presenting with hypoxia, was found to have shunt reversal due to unilateral diaphragmatic paralysis. He was successfully treated with PFO closure. The purpose of this report is to consider rare possibilities of PFO shunt reversal when the right-sided heart pressure is normal and to highlight that a simple chest X-ray can be a clue to the diagnosis.

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Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism

Purpose: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anti-cancer small molecule in clinical trials for high grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that oppose DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. Experimental Design: The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. Immunohistochemistry staining of DRD2/DRD5 was performed in tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. Results: DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from recurrent glioblastoma patients treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. Conclusions: These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.

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Impact of breast cancer subtypes on prognosis of women with operable invasive breast cancer: a population-based study using SEER database

Purpose: To determine prognostic roles of breast cancer subtypes in females with operable invasive breast cancer. Experimental Design: Data of 321,958 patients from Surveillance, Epidemiology, and End Results database were analyzed. Breast cancer subtypes were classified into four categories according to the status of hormone receptor (HRc) and human epidermal growth factor receptor 2 (HER2): HRc(+)/HER2(-), HRc(+)/HER2(+), HRc(-)/HER2(+), and HRc(-)/HER2(-). Results: Proportions of HRc(+)/HER2(-), HRc(+)/HER2(+), HRc(-)/HER2(+), HRc(-)/HER2(-), and unknown subtype were 70.3%, 9.4%, 3.9%, 10.4%, and 6.0%, respectively. HRc(+)/HER2(-) showed the highest five-year breast cancer-specific survival (BCSS) rate (95.5%), followed by HRc(+)/HER2(+) (94.1%), HRc(-)/HER2(+) (89.3%), and HRc(-)/HER2(-) (83.1%). HRc(+)/HER2(-) and HRc(+)/HER2(+) showed higher five-year overall survival (OS) rates (88.4% and 88.2%, respectively) than HRc(-)/HER2(+) and HRc(-)/HER2(-) (83.9% and 76.5%, respectively). HRc(-)/HER2(-) showed the worst BCSS irrespective of race, age, or stage. While proportions of HRc(-)/HER2(-) in the subgroup with negative event regarding BCSS and OS were 10.4% and 10.2%, respectively, they were 34.2% and 22.7%, respectively, in the subgroup with positive event. Subtype was a significant factor in both univariable and multivariable analyses regarding both BCSS and OS (all P < .001). Conclusions: Breast cancer subtype was a significant independent prognostic factor regarding both BCSS and OS in multivariable analyses. HRc(+) subtypes showed better prognosis compared to HRc(-) subtypes regarding both BCSS and OS. HRc(-)/HER2(+) showed better prognosis than HRc(-)/HER2(-) but worse prognosis than HRc(+) subtypes regarding both BCSS and OS. The triple negative subtype showed the worst BCSS compared to the other subtypes irrespective of race, age, or stage.

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