RIPK1 inhibition contributes to lysosomal membrane stabilization in ischemic astrocytes via a lysosomal Hsp70.1B-dependent mechanism.

Receptor-interacting protein kinase 1 (RIPK1) contributes to necroptosis. Our previous study showed that pharmacological or genetic inhibition of RIPK1 protects against ischemic stroke-induced astrocyte injury. In this study, we investigated the molecular mechanisms underlying RIPK1-mediated astrocyte injury in vitro and in vivo. Primary cultured astrocytes were transfected with lentiviruses and then subjected to oxygen and glucose deprivation (OGD). In a rat model of permanent middle cerebral artery occlusion (pMCAO), lentiviruses carrying shRNA targeting RIPK1 or shRNA targeting heat shock protein 70.1B (Hsp70.1B) were injected into the lateral ventricles 5 days before pMCAO was established. We showed that RIPK1 knockdown protected against OGD-induced astrocyte damage, blocked the OGD-mediated increase in lysosomal membrane permeability in astrocytes, and inhibited the pMCAO-induced increase in astrocyte lysosome numbers in the ischemic cerebral cortex; these results suggested that RIPK1 contributed to the lysosomal injury in ischemic astrocytes. We revealed that RIPK1 knockdown upregulated the protein levels of Hsp70.1B and increased the colocalization of Lamp1 and Hsp70.1B in ischemic astrocytes. Hsp70.1B knockdown exacerbated pMCAO-induced brain injury, decreased lysosomal membrane integrity and blocked the protective effects of the RIPK1-specific inhibitor necrostatin-1 on lysosomal membranes. On the other hand, RIPK1 knockdown further exacerbated the pMCAO- or OGD-induced decreases in the levels of Hsp90 and the binding of Hsp90 to heat shock transcription factor-1 (Hsf1) in the cytoplasm, and RIPK1 knockdown promoted the nuclear translocation of Hsf1 in ischemic astrocytes, resulting in increased Hsp70.1B mRNA expression. These results suggest that inhibition of RIPK1 protects ischemic astrocytes by stabilizing lysosomal membranes via the upregulation of lysosomal Hsp70.1B; the mechanism underlying these effects involves decreased Hsp90 protein levels, increased Hsf1 nuclear translocation and increased Hsp70.1B mRNA expression.

Evaluation of knowledge, experiences, and fear toward prescribing and dispensing corticosteroids among Egyptian healthcare professionals: A cross-sectional study.

Background: Corticosteroids (CS) are essential drugs in the treatment of several medical conditions. Assuming different roles, physicians and pharmacists play a primary role in prescribing and dispensing these medications to optimize patients' clinical management. The data on assessing knowledge and experience of healthcare professionals toward CS is scarce. Therefore, this study aimed to assess and compare knowledge, experience, and fears towards CS among Egyptian physicians and pharmacists. Methods: A cross-sectional, self-administrated, validated online questionnaire was used to collect the data from Egyptian healthcare professionals. The questionnaire consisted of four sections with multiple choice questions: sociodemographic (7 questions), knowledge about CS (13 questions), experience with CS prescription/dispensing (5 questions), and fears and preferences toward CS prescription/dispensing (13 questions). Descriptive and inferential statistics were used to analyze the data. Results: A total of 600 responses were analyzed in this study. The study sample was almost two-half of healthcare providers: 303 (50.5%) pharmacists and 297 (49.5%) physicians. Pharmacists had marginally higher knowledge scores as compared to those recorded for physicians (11.29 versus 10.16, respectively; P = 0.047). Physicians had more experience choosing corticosteroids in treatment plans based on their experience (51.8% vs 38.5%) and guideline recommendations (72.8% vs 50.9%) than pharmacists. However, pharmacists had more experience dealing with corticosteroid use based on patients' preferences (19.5% vs 4.9%) and showed a broader scope of experiencing side effects of corticosteroids with their patients. The two professions demonstrated high levels of fear, with pharmacists acknowledging significantly lower concerns about CS than physicians (3.72 versus 4.0, respectively; P = 0.003). Conclusion: Discrepancies exist among healthcare professionals in knowledge and experience, favoring better scientific knowledge of pharmacists related to corticosteroids. Based on these findings, the interprofessional collaborative efforts would provide comprehensive, patient-centered care that maximizes the benefits of CS while minimizing their risks.

Geochemical, Mineralogical, and Geomorphological Characterization of Ash Materials as a Tracer for the Origin of Shifting Sands near Oldupai Gorge, Ngorongoro, Tanzania.

Shifting sand (SS) is a single dune-shaped mass of black ash material moving across western Ngorongoro in northern Tanzania. The moving sand has become an important tourist destination for several decades. Despite being part of the important geosites at the Ngorongoro Conservation Area, the nature, origin, and behaviors demonstrated by SS remain poorly understood. This work contributes toward understanding the nature and identification of the possible origin of the SS through the correlation of geochemical, mineralogical, and geomorphological data of ash material from four selected locations in the study area. To achieve this goal, elemental, mineralogical, and morphological characterization of ash samples was performed by energy-dispersive X-ray fluorescence, polarized petrographic microscopy, automated sieve shaker, and binocular microscopy techniques, respectively. Correlation studies were based on magnesian-ferriferous associations, similarities in mineralogy, particle size, shape, and distribution patterns of ash materials, and weather data. There are close similarities in the chemical compositions among ash samples of SS, Ootun area, and Oldoinyo Lengai. Augite and magnetite minerals appear only in samples of SS, Ootun area, and Oldoinyo Lengai, while hornblende appears only in the samples from the Ngorongoro crater. Oldoinyo Lengai rock petrography revealed significant amounts of augite minerals. Blocky and elongated-shaped ash particles dominate the samples from SS, Ootun area, and Oldoinyo Lengai. The particle size of ash materials decreases westwards across the study site. The distribution patterns of ash material align with the west-south-west wind direction. Based on these findings, the study concludes that SS and Ootun ash could be tephra depositions resulting from past volcanic eruptions of Oldoinyo Lengai.

Incidence of Plasmodium falciparum malaria infection in 6-month to 45-year-olds on selected areas of Bioko Island, Equatorial Guinea.

BACKGROUND: Extensive malaria control measures have been implemented on Bioko Island, Equatorial Guinea over the past 16 years, reducing parasite prevalence and malaria-related morbidity and mortality, but without achieving elimination. Malaria vaccines offer hope for reducing the burden to zero. Three phase 1/2 studies have been conducted successfully on Bioko Island to evaluate the safety and efficacy of whole Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccines. A large, pivotal trial of the safety and efficacy of the radiation-attenuated Sanaria® PfSPZ Vaccine against P. falciparum is planned for 2022. This study assessed the incidence of malaria at the phase 3 study site and characterized the influence of socio-demographic factors on the burden of malaria to guide trial design. METHODS: A cohort of 240 randomly selected individuals aged 6 months to 45 years from selected areas of North Bioko Province, Bioko Island, was followed for 24 weeks after clearance of parasitaemia. Assessment of clinical presentation consistent with malaria and thick blood smears were performed every 2 weeks. Incidence of first and multiple malaria infections per person-time of follow-up was estimated, compared between age groups, and examined for associated socio-demographic risk factors. RESULTS: There were 58 malaria infection episodes observed during the follow up period, including 47 first and 11 repeat infections. The incidence of malaria was 0.25 [95% CI (0.19, 0.32)] and of first malaria was 0.23 [95% CI (0.17, 0.30)] per person per 24 weeks (0.22 in 6-59-month-olds, 0.26 in 5-17-year-olds, 0.20 in 18-45-year-olds). Incidence of first malaria with symptoms was 0.13 [95% CI (0.09, 0.19)] per person per 24 weeks (0.16 in 6-59-month-olds, 0.10 in 5-17-year-olds, 0.11 in 18-45-year-olds). Multivariate assessment showed that study area, gender, malaria positivity at screening, and household socioeconomic status independently predicted the observed incidence of malaria. CONCLUSION: Despite intensive malaria control efforts on Bioko Island, local transmission remains and is spread evenly throughout age groups. These incidence rates indicate moderate malaria transmission which may be sufficient to support future larger trials of PfSPZ Vaccine. The long-term goal is to conduct mass vaccination programmes to halt transmission and eliminate P. falciparum malaria.

Maternal death surveillance and response in Tanzania: comprehensiveness of narrative summaries and action points from maternal death reviews.

BACKGROUND: Maternal deaths reviews are proposed as one strategy to address high maternal mortality in low and middle-income countries, including Tanzania. Review of maternal deaths relies on comprehensive documentation of medical records that can reveal the sequence of events leading to death. The World Health Organization's and the Tanzanian Maternal Death and Surveillance (MDSR) system propose the use of narrative summaries during maternal death reviews for discussing the case to categorize causes of death, identify gaps in care and recommend action plans to prevent deaths. Suggested action plans are recommended to be Specific, Measurable, Attainable, Relevant and Time bound (SMART). To identify gaps in documenting information and developing recommendations, comprehensiveness of written narrative summaries and action plans were assessed. METHODS: A total of 76 facility maternal deaths that occurred in two regions in Southern Tanzania in 2018 were included for analysis. Using a prepared checklist from Tanzania 2015 MDSR guideline, we assessed comprehensiveness by presence or absence of items in four domains, each with several attributes. These were socio-demographic characteristics, antenatal care, referral information and events that occurred after admission. Less than 75% completeness of attributes in all domains was considered poor while 95% and above were good/comprehensive. Action plans were assessed by application of SMART criteria and according to the place of planned implementation (community, facility or higher level of health system). RESULTS: Almost half of narrative summaries (49%) scored poor, and only1% scored good/comprehensive. Summaries missed key information such as demographic characteristics, time between diagnosis of complication and commencing treatment (65%), investigation results (47%), summary of case evolution (51%) and referral information (47%). A total of 285 action points were analysed. Most action points, 242(85%), recommended strategies to be implemented at health facilities and were mostly about service delivery, 120(42%). Only 42% (32/76) of the action points were deemed to be SMART. CONCLUSIONS: Abstraction of information to prepare narrative summaries used in the MDSR system is inadequately done. Most recommendations were unspecific with a focus on improving quality of care in health facilities.

Maternal near miss and mortality attributable to hypertensive disorders in a tertiary hospital, Tanzania; a cross-sectional study.

BACKGROUND: Hypertensive disorders in pregnancy is the second most common direct cause of maternal deaths accounting for 14% of maternal deaths worldwide. Severe pre-eclampsia and eclampsia are among the hypertensive disorders in pregnancy causing significant morbidity and mortality, hence categorized as Maternal Near Miss. At Muhimbili National Hospital these are the leading causes of maternal deaths accounting for 19.9% of maternal death. This study aimed to determine the proportion of severe maternal outcomes and maternal near-miss indices among patients with severe pre-eclampsia and eclampsia at Muhimbili National Hospital in Tanzania. METHODS: A descriptive cross-sectional study was conducted between September 2017 to January 2018 at Muhimbili National Hospital. Women with severe pre-eclampsia and eclampsia were recruited. Data were extracted from patient files after admission, and followed up until discharge or death; after discharge was categorized as maternal near miss or death as maternal death. The outcome indicators were calculated using the total number of live births during the study period, the number of maternal deaths and maternal near-miss due to severe pre-eclampsia/ eclampsia in the same period. RESULTS: Nearly two-thirds of women recruited, 199 (62.2%) had severe preeclampsia while 121 (37.8%) had eclampsia, 71 (22.1%) had severe maternal outcome whereby 63 had maternal near-miss with organ dysfunction and 8 maternal deaths. The overall maternal near-miss ratio was 87.4 while that for severe pre-eclampsia was 54, and 33 per 1000 live births for eclampsia. Overall severe maternal outcome ratio was 19.4 while that for severe pre-eclampsia was 12 and that for eclampsia was 9.5 per 1000 live births. Mortality index was 11% and the Case fatality rate was 2.5%. CONCLUSION: There is a high proportion of women with severe maternal outcome attributable to severe pre-eclampsia and eclampsia, with a reduced proportion of maternal deaths. This signifies improvement of performance in our facility in dealing with patients with severe morbidities due to severe pre-eclampsia and eclampsia, however, more effort should be put to further reduce maternal mortality.

Causes of maternal deaths and delays in care: comparison between routine maternal death surveillance and response system and an obstetrician expert panel in Tanzania.

BACKGROUND: To reduce maternal mortality Tanzania introduced Maternal Death Surveillance and Response (MDSR) system in 2015 as recommended by World Health Organization (WHO). All health facilities are to notify and review all maternal deaths inorder to recommend quality improvement actions to reduce deaths in future. The system relies on consistent and correct categorization of causes of maternal deaths and three phases of delays. To assess its adequacy we compared the routine MDSR categorization of causes of death and three phases of delays to those assigned by an independent expert panel with additional information from Verbal Autopsy (VA). METHODS: Our cross-sectional study included 109 reviewed maternal deaths from two regions in Tanzania for the year 2018. We abstracted the underlying medical causes of death and the three phases of delays from MDSR system records. We interviewed bereaved families using the standard WHO VA questionnaire. The obstetrician expert panel assigned underlying causes of death based on information from medical files and VA according to International Classification of Disease to Death in Pregnancy Childbirth and Puerperium (ICD-MM). They assigned causes to nine ICD-MM groups and identified the three phases of delays. We used Cohen's K statistic to compare causes of deaths and delays categorization. RESULTS: Comparison of underlying causes was done for 99 deaths. While 109 and 84 deaths for expert panel and MDSR respectively were analyzed for delays because of missing data in MDSR system. Expert panel and MDSR system assigned the same underlying causes in 64(64.6%) deaths (K statistic 0.60). Agreement increased in 80 (80.8%) when causes were assigned by ICD-MM groups (K statistic 0.76). The obstetrician expert panel identified phase one delays in 74 (67.9%), phase two in 24 (22.0%) and phase three delays in all 101 (100%) deaths that were assessed for this delay while MDSR system identified delays in 42 (50.0%), 10 (11.9%) and 78 (92.9%).The expert panel found human errors in management in 94 (93.1%) while MDSR system reported in 53 (67.9%) deaths. CONCLUSIONS: MDSR committees performed reasonably well in assigning underlying causes of death. The obstetrician expert panel found more delays than reported in MDSR system indicating difficulties within MDSR teams to critically review deaths.

Plexin-B2 in psoriasis; a clinical and immunohistochemical study.

Psoriasis is an inflammatory, immune-mediated disease. Plexins are transmembrane proteins that are involved in immune system regulation and inflammation. This work aimed to investigate the immunohistochemical expression of Plexin-B2 in plaque psoriasis in both lesional and perilesional skin. This case-control study included 30 patients with psoriasis vulgaris in comparison with 20 age- and sex-matched apparently healthy persons. We used the Psoriasis Area and Severity Index (PASI) score to evaluate psoriasis severity. Biopsies from 30 lesional, 30 perilesional, and 20 control-skin patients were subjected to histopathological and immunohistochemical evaluations of Plexin-B2. There was significant stepwise overexpression of Plexin-B2 in proliferating keratinocytes from controls (66 ± 31.02) to perilesional (116 ± 41.95) and lesional (159.7 ± 63.05) skin (P < .001). Also, Plexin-B2 showed significant overexpression in dermal inflammatory cells of lesional psoriatic skin (153.67 ± 72.71) when compared to controls skin (25.71 ± 11.34) (P < .001). There was a significant positive correlation between Plexin-B2 expression and psoriasis severity (r = 0.557; P < .001). Plexin-B2 could promote skin inflammation, as well as keratinocyte proliferation in psoriasis vulgaris; therefore, it may be used as a targeted therapy for psoriasis treatment.

Identification of Novel Molecular Network Expression in Acute Myocardial Infarction.

BACKGROUND: In the current study, we aimed to analyze the hypothesis that human myocardial-specific extracellular RNAs expression could be used for acute myocardial injury(AMI) diagnosis. METHODOLOGY: We used bioinformatics' analysis to identify RNAs linked to ubiquitin system and specific to AMI, named, (lncRNA-RP11-175K6.1), (LOC101927740), microRNA-106b-5p (miR-106b-5p) and Anaphase, promoting complex 11 (ANapc11mRNA). We measured the serum expression of the chosen RNAs in 69 individuals with acute coronary syndromes, 31 individuals with angina pectoris without MI and non-cardiac chest pain and 31 healthy control individuals by real-time reverse-transcription PCR. RESULTS: Our study revealed a significant decrease in both lncRNA-RP11-175K6.1 and ANapc11mRNA expression of in the sera samples of AMI patients compared to that of the two control groups alongside with significant upregulation of miR-106b-5p. CONCLUSION: Of note, the investigated serum RNAs decrease the false discovery rate of AMI to 3.2%.

Genetic and morphological diversity of mouse lemurs (Microcebus spp.) in northern Madagascar: The discovery of a putative new species?

Tropical forests harbor extremely high levels of biological diversity and are quickly disappearing. Despite the increasingly recognized high rate of habitat loss, it is expected that new species will be discovered as more effort is put to document tropical biodiversity. Exploring under-studied regions is particularly urgent if we consider the rapid changes in habitat due to anthropogenic activities. Madagascar is known for its extraordinary biological diversity and endemicity. It is also threatened by habitat loss and fragmentation. It holds more than 100 endemic primate species (lemurs). Among these, Microcebus (mouse lemurs) is one of the more diverse genera. We sampled mouse lemurs from several sites across northern Madagascar, including forests never sampled before. We obtained morphological data from 99 Microcebus individuals; we extracted DNA from tissue samples of 42 individuals and amplified two mitochondrial loci (cytb and cox2) commonly used for species identification. Our findings update the distribution of three species (Microcebus tavaratra, Microcebus arnholdi, and Microcebus mamiratra), including a major increase in the distribution area of M. arnholdi. We also report the discovery of a new Microcebus lineage genetically related to M. arnholdi. Several complementary approaches suggest that the newly identified Microcebus lineage might correspond to a new putative species, to be confirmed or rejected with additional data. In addition, morphological analyses showed (a) clear phenotypic differences between M. tavaratra and M. arnholdi, but no clear differences between the new Microcebus lineage and the sister species M. arnholdi; and (b) a significant correlation between climatic variables and morphology, suggesting a possible relationship between species identity, morphology, and environment. By integrating morphological, climatic, genetic, and spatial data of two northern Microcebus species, we show that the spatial distribution of forest-dwelling species may be used as a proxy to reconstruct the past spatial changes in forest cover and vegetation type.

Performance of Low-Cost Agar from Gracilaria salicornia on Tissue Culture of Pleurotus HK-37.

Currently, the demand of Pleurotus HK-37 (oyster mushroom) in Tanzania is growing rapidly due to the increasing of awareness on its nutrition, health, and economic benefits. Despite the increasing demand, the availability of strains of Pleurotus HK-37 species is still a challenge due to high cost of tissue culture technology. The high cost of importing agar seems to be among the factors for this failure. This study aimed at investigating the performance of low-cost agar from local Gracilaria salicornia on tissue culture of Pleurotus HK-37. Local extracted agars with different gel strengths ranging between 100, 200, 300, 400, and 500 g/cm2 were used to make PDA media. The average mycelia growth rate (mm/day) ranged between 9.87 ± 1.44 and 14.9 ± 0.85 mm/day. Low-cost agar shows quite similar performance as that of standard agar on active growth of Pleurotus HK-37 mycelia. All PDA plates appeared white and feathery and showed to grow in a circular mode (radial extension). Mycelia growth on standard agar PDA took 5 days while on extracted local agar PDA took 5 to 7 days to fully colonize the plate at 27 ± 2°C. The present study shows that the production cost can be reduced by ∼35-78% by using local agar.

Sauromatum guttatum extract promotes wound healing and tissue regeneration in a burn mouse model via up-regulation of growth factors.

Contexts: Sauromatum guttatum (Wall.) Schott (Araceae) has been traditionally used for the treatment of wounds. Objectives: This study evaluates the healing and tissue regeneration potential of S. guttatum extract in burn wounds. Materials and methods: S. guttatum extract was analysed using various chemical tests, thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Moreover, the extract was tested against burn associated bacteria and minimum inhibitory concentration (MIC) was also calculated. Wound healing and tissue regeneration potential was assessed using a thermally induced burn BALBc mouse model. S. guttatum extract (2% w/w) prepared in petroleum jelly, vehicle and positive control [silver sulfadiazine (SD)] groups was applied three times a day. The treatment was continued for 15 d and wound closure was measured and photographed on day 5, 10 and 15. The burnt tissues excised from wounds were subjected to histological and comparative gene expression analysis. Results: The results of the chemical tests indicated the presence of alkaloids, saponins, phenols, phytosterols, tannins, and flavonoids, while TLC and HPLC analysis indicated the presence of various compounds. The extract showed excellent activity against the tested pathogens. The lowest MIC (125 µg/mL) was observed against Staphylococcus aureus. A considerable decrease in wound area (72%) was observed in extract-treated group. Histological examination of extract-treated group showed good signs of wound healing with complete re-epithelialization and better tissue regeneration. Comparative gene expression analysis revealed the up-regulation of wound healing related PDGF, EGF and FGF genes. Conclusions: S. guttatum extract may be used to isolate bioactive constituents for the treatment of burn wounds.

Control of malaria in the Comoro Islands over the past century.

BACKGROUND: The Comoros are an archipelago located in the Indian Ocean between the eastern coasts of Africa and north of Madagascar. Malaria transmission appeared late in the 19th century due to the intensification of human migration. The story of malaria transmission for the past century is depicted to provide useful lessons for the future. Currently, malaria transmission occurs differently on each island; thus, control strategies must be adapted for each particular island. Tentative malaria control in Comoros has a long history of success and failure. This study reviews the data available as a basis for recommendations for the future. RESULTS: There has been much effort to reach a pre-eradication state in Anjouan and Moheli, but only control steps have been taken in the Great Comoro. To date, the primary strategy used is mass treatment of the population using artemisinin-based combination therapy (ACT), which is similar to the strategy deployed during the 1950s in other countries. ACT appears efficient in two of the three islands; however, the sustainability of the strategy is unknown. This sustainability is compromised by (i) the huge level of uncontrolled exchange between the Comoro Islands and their neighbours, increasing the risk of introducing ACT-resistant strains, (ii) the use of large quantities of pesticides for agriculture usually associated with the resistance of mosquitoes, and (iii) the cost of the actions themselves. CONCLUSIONS: In view of the history of malaria in this area, the first recommendation is to enhance the training of health workers and the population. The second step is to establish a national strategy to assess malaria and related factors, which is currently lacking. A survey to assess the drug sensitivity of the parasites is particularly important in a context of low transmission associated with mass treatment of the population. The last point should be to secure financial support, which is not obvious in a context of pre-elimination. The Comoro Islands are thus a living laboratory to experiments with strategies for elimination, but the future is complex.

CAUSES OF FEVER IN ADULTS IN THALL AND SURROUNDING AREAS.

BACKGROUND: The most common symptom for which the patients are admitted in our hospitals is fever. This study was carried out to know the causes of fever based on clinical and laboratory findings. METHODS: In this cross sectional study, 865 consecutive male patients with fever of 100 F and above were included in the study conducted from January 2010 to April 2012. RESULTS: All the patients were male having age between 17 years and 45 years. Out of the 865 patients, 507 (58.61%) came out to be malarial parasite slide positive, 186 (21.50%) patients were malarial parasite slide negative but were having clinical picture of malaria and*responded to anti-malarial treatment, 73 (8.44%) patients were of respiratory tract infections, 21 (2.43%) patients were having gastro enteritis, 20 (2.31%) were diagnosed as cases of typhoid fever, 17 (1.97%) were having urinary tract infections, 24 (2.77%) patients were referred to medical specialist and the rest 1-7 (1.97%) were grouped as others. CONCLUSION: The most common cause of fever in our study was malaria. Respiratory tract infections are the second most common cause.

Molecular modelling and synthesis of quinazoline-based compounds as potential antiproliferative agents.

In this study, four series of 4-anilinoquinazoline derivatives were designed and synthesized as potential anti-proliferative agents. Mechanism of anticancer activity was explained through molecular docking of the target compounds into epidermal growth factor receptor tyrosine kinase (EGFR-TK) active site which displayed comparable binding mode of certain compounds to that of lapatinib. Moreover, the newly synthesized compounds were tested for their anti-proliferative activity on breast carcinoma cell line (MCF-7). 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-(4-bromoanilino)quinazoline (14g) exhibited the most potent inhibitory activity (IC50=5.52 µM).

Study of the genomics and transcriptomics profiles of male-infertility genes in human prostate cancer: an in silico analysis.

The World Health Organization has considered the infertility as an international public health problem. Infertility affect nearly 1 in 7 couples and male component contributes to 50% of infertility cases. There is a clear link between male infertility and some cancers such as testicular germ cell, prostate and colon cancers. Two possibilities support this finding: 1) Cancer treatments can affect the fertility factors 2) Genetic profile of infertility genes have been altered in cancer patients. Although the previously published researches have mostly focused on the first factor, no article has yet confirmed the role of genetic factors. In this in silico study, we collected the large number of genes (n = 17703) involved in infertility. These genes were collected from NGS panel tests of male infertility and comprehensive literature review or online data base. The Prostate Adenocarcinoma genomic and transcriptomics raw data were downloaded from the cBioPortal Cancer dataset. This included with 494 patients of Prostate Cancer with 494 mutation data, 489 with CNA and 493 with RNA seqV2 data. TCGA RNA-Seq raw data was extracted in R using the cgdsr extension package with a threshold of ±2 relative to normal samples. The observed data showed that male infertility genes have been distributed through the human genome. Among the 17703 analyzed genes of this study, the genomic profile of three genes including OR9Q1, H4C6 and PSG7 were changed approximately in 100% of (n = 493) patients. In most of patients (>98%), genetic alteration was related to change in gene expression. In conclusion, this study showed that the genomic and transcriptomics patterns of some male-infertility genes are notably altered in patients of prostate cancer and suggested a possible role of genetic factors in occurrence of infertility in cancer patients. Our information can be used as a source for the design of genetic database of male-infertility.

Detecting nested clusters of human alveolar echinococcosis.

Recent changes in the epidemiology of alveolar echinococcosis (AE) in Eurasia have led to increasing concerns about the risk of human AE and the need for a thorough evaluation of the epidemiological situation. The aim of this study was to explore the use of a National Register to detect complex distribution patterns on several scales. The data were human AE cases from the FrancEchino register, diagnosed in France from 1982 to 2011. We used the Kulldorff spatial scan analysis to detect non-random locations of cases. We proposed an exploratory method that was based on the successive detection of nested clusters inside each of the statistically significant larger clusters. This method revealed at least 4 levels of disease clusters during the study period. The spatial variations of cluster location over time were also shown. We conclude that National Human AE registers, although not exempted from epidemiological biases, are currently the best way to achieve an accurate representation of human AE distribution on various scales. Finally, we confirm the multi-scale clustered distribution of human AE, and we hypothesize that our study may be a reasonable starting point from which to conduct additional research and explore the processes that underlie such distributions.

Transglutaminase-1 mutations in Omani families with lamellar ichthyosis.

OBJECTIVE: To determine the molecular basis of familial ichthyosis in three Omani families. SUBJECTS AND METHODS: Nine patients from three consanguineous families, A, B, and C, were born with typical features of lamellar ichthyosis subtype including collodion membrane and maintained ectropion, and epidermal scaling through their childhood. The 4 patients from family B had more severe symptoms requiring neonatal critical care and subsequent regular treatment with emollients, eye lubricants, and low-dose acitretin. DNA was extracted from peripheral blood by standard methods. The samples were initially genotyped to screen known loci linked to recessive ichthyosis on chromosomes 2q33-32 (ABCA12), 14q11 (TGM1), and 19p12-q12 using commercially supplied polymorphic fluorescent microsatellite markers. TGM1 was analyzed by direct sequencing for disease-associated mutations. RESULTS: Two known pathogenic mutations in TGM1 were detected: p.Gly278Arg in families A and B and p.Arg396His in family C. These two mutations were segregating in an autosomal recessive mode of inheritance. CONCLUSION: Two known pathogenic TGM1 mutations were detected in three large consanguineous Omani families with lamellar ichthyosis. This study confirmed the geographic distribution of known mutations to an apparently unrelated population.

Community perceptions and experiences on the events leading to facility maternal death; a verbal autopsy qualitative study.

BACKGROUND: Tanzania Maternal Death Surveillance and Response (MDSR) system introduced in 2015 emphasizes review of facility maternal deaths with little community involvement. Involving the community in deaths enquiry can help to make better strategies to prevent future deaths. We aimed to explore family members (caregivers) perceptions and experiences on the events leading to facility maternal deaths to inform future community involvement in MDSR. METHODS: Narrative interviews were conducted with 20 caregivers who cared for women who died in childbirth to investigate into delays and health care seeking experience. The unstructured questions on perceptions and experiences of events leading to death were administered together with standard verbal autopsy questionnaire. Two regions, Lindi and Mtwara of Southern Tanzania were selected for the study in 2018. Narrative thematic analysis was used for data analysis. RESULTS: Three main themes evolved: 'Prepared for birth but not ready for complications', 'Disconnect between caregivers and providers' and 'The bitter impact of maternal deaths. Caregivers made efforts to prepare for birth but their preparation were severely inadequate when complications that necessitated referral occurred. Decision to seek care was made jointly between the pregnant woman, husband and other family members. Caregivers tried with little success in communicating with heathcare providers regarding their admitted patients. They also experienced emotions of grief such as denial, anger, depression, bargaining and acceptance once maternal deaths occurred. Caregivers (mostly old women) were left with the burden of caring for the newborns and other children left by the deceased mother. CONCLUSION: Caregivers' perceptions and experiences of maternal deaths events provide valuable information for community interventions on birth preparedness, decision making, communication and providers' accountability. Maternal deaths bring far reaching mental, social and economic consequences to the family and society.

The brain protection of MLKL inhibitor necrosulfonamide against focal ischemia/reperfusion injury associating with blocking the nucleus and nuclear envelope translocation of MLKL and RIP3K.

Mixed lineage kinase like protein (MLKL) is a key mediator of necroptosis. While previous studies highlighted the important role of MLKL as one of the central regulators of brain damage against acute ischemic neuronal injury, how the activation of MLKL mediates brain injuries and cell death remains unclear, especially in astrocytes. In a transient middle cerebral artery occlusion (tMCAO) rat model in vivo, and an oxygen-glucose deprivation and reoxygenation (OGD/Re) injury model in both primary cultured astrocytes and human astrocytes, we show that necrosulfonamide (NSA), a MLKL specific inhibitor, reduces infarction volume and improves neurological deficits in tMCAO-treated rats. In addition, NSA treatment, as well as RIP1K inhibitor Nec-1 or RIP3K inhibitor GSK-872 treatment, decreases the OGD/Re-induced leakage of LDH in both primary cultured astrocytes and human astrocytes. NSA treatment also reduces the number of propidium iodide (PI)-positive cells, and prevents the upregulation of necroptotic biomarkers such as MLKL/p-MLKL, RIP3K/p-RIP3K, and RIP1K/p-RIP1K in ischemic penumbra of cerebral cortex in tMCAO-treated rats or in OGD/Re-treated human astrocytes. Importantly, NSA treatment blocks both the nucleus and nuclear envelope localization of MLKL/p-MLKL and RIP3K/p-RIP3K in ischemic cerebral cortex induced by tMCAO. Similarly, Co-immunoprecipitation assay shows that NSA treatment decreases tMCAO- or OGD/Re- induced increased combination of MLKL and RIP3K in nuclear envelope of ischemic penumbra of cerebral cortex or of primary cultured astrocytes, respectively. RIP3K inhibitor GSK-872 also reduces tMCAO-induced increased combination of MLKL and RIP3K in nuclear envelope of ischemic penumbra of cerebral cortex. These data suggest NSA exerts protective effects against focal ischemia/reperfusion injury via inhibiting astrocytic necroptosis through preventing the upregulation of necroptotic kinases as well as blocking both the nucleus and nuclear envelope co-localization of p-MLKL and p-RIP3K. The translocation of p-MLKL, along with p-RIP3K, to the nuclear envelope and the nucleus may play a crucial role in MLKL-mediated necroptosis under ischemic conditions.