Tag: nevin manimala

BioDrugs. 2023 Apr 4. doi: 10.1007/s40259-023-00590-w. Online ahead of print.

ABSTRACT

BACKGROUND: Mucopolysaccharidosis type II is a severe lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase. The only medicinal product approved by the US Food and Drug Administration for enzyme replacement therapy, recombinant iduronate-2-sulfatase (idursulfase, Elaprase^®), is a large molecule that is not able to cross the blood-brain barrier and neutralize progressive damage of the central nervous system caused by the accumulation of glycosaminoglycans. Novel chimeric protein HIR-Fab-IDS is an anti-human insulin receptor Fab fragment fused to recombinant modified iduronate-2-sulfatase. This modification provides a highly selective interaction with the human insulin receptor, which leads to the HIR-Fab-IDS crossing the blood-brain barrier owing to internalization of the hybrid molecule by transcytosis into endothelial cells adjacent to the nervous system by the principle of a ‘molecular Trojan horse’.

OBJECTIVES: In this work, the physicochemical and biological characterization of a blood-brain barrier-penetrating fusion protein, HIR-Fab-IDS, is carried out. HIR-Fab-IDS consists of an anti-human insulin receptor Fab fragment fused to recombinant iduronate-2-sulfatase.

METHODS: Comprehensive analytical characterization utilizing modern techniques (including surface plasmon resonance and mass spectrometry) was performed using preclinical and clinical batches of HIR-Fab-IDS. Critical quality parameters that determine the therapeutic effect of iduronate-2-sulfatase, as well as IDS enzymatic activity and in vitro cell uptake activity were evaluated in comparison with the marketed IDS product Elaprase^® (IDS RP). In vivo efficiency of HIR-Fab-IDS in reversing mucopolysaccharidosis type II pathology in IDS-deficient mice was also investigated. The affinity of the chimeric molecule for the INSR was also determined by both an enzyme-linked immunosorbent assay and surface plasmon resonance. We also compared the distribution of ¹²⁵I-radiolabeled HIR-Fab-IDS and IDS RP in the tissues and brain of cynomolgus monkeys after intravenous administration.

RESULTS: The HIR-Fab-IDS primary structure investigation showed no significant post-translational modifications that could affect IDS activity, except for the formylglycine content, which was significantly higher for HIR-Fab-IDS compared with that for IDS RP (~ 76.5 vs ~ 67.7%). Because of this fact, the specific enzyme activity of HIR-Fab-IDS was slightly higher than that of IDS RP (~ 2.73 × 10⁶ U/μmol vs ~ 2.16 × 10⁶ U/μmol). However, differences were found in the glycosylation patterns of the compared IDS products, causing a minor reduced in vitro cellular uptake of HIR-Fab-IDS by mucopolysaccharidosis type II fibroblasts compared with IDS RP (half-maximal effective concentration ~ 26.0 vs ~ 23.0 nM). The efficacy of HIR-Fab-IDS in IDS-deficient mice has demonstrated a statistically significant reduction in the level of glycosaminoglycans in the urine and tissues of the main organs to the level of healthy animals. The HIR-Fab-IDS has revealed high in vitro affinity for human and monkey insulin receptors, and the radioactively labeled product has been shown to penetrate to all parts of the brain and peripheral tissues after intravenous administration to cynomolgus monkeys.

CONCLUSIONS: These findings indicate that HIR-Fab-IDS, a novel iduronate-2-sulfatase fusion protein, is a promising candidate for the treatment of central nervous system manifestations in neurological mucopolysaccharidosis type II.

PMID:37014547 | DOI:10.1007/s40259-023-00590-w

Obes Surg. 2023 Apr 4. doi: 10.1007/s11695-023-06575-6. Online ahead of print.

ABSTRACT

PURPOSE: Few studies examine whether maternal and neonatal outcomes differ by time from metabolic and bariatric surgery (MBS) to conception. We describe maternal and neonatal outcomes among women with pregnancy after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) overall and by whether conception occurred during the period when pregnancy is not recommended (< 18 months postoperative) versus later.

MATERIALS AND METHODS: A prospective cohort study enrolled 135 US adult women (median age, 30 years, body mass index [BMI], 47.2 kg/m²) who underwent RYGB or SG (2006-2009) and subsequently reported ≥ 1 pregnancy within 7 years. Participants self-reported pregnancy-related information annually. Differences in prevalence of maternal and neonatal outcomes by postoperative conception timeframe (< 18 versus ≥ 18 months) were assessed.

RESULTS: Thirty-one women reported ≥ 2 postoperative pregnancies. At time of postoperative conception (median 26 [IQR:22-52] months postoperative) median BMI was 31 (IQR:27-36) kg/m². Excessive gestational weight gain (55%), cesarean section (42%) and preterm labor or rupture of membranes (40%) were the most common maternal outcomes. Forty percent of neonates had a composite outcome of still birth (1%), preterm birth (26%), small for gestational age (11%), or neonatal intensive care unit admission (8%). Prevalence of outcomes did not statistically significantly differ by timeframe.

CONCLUSION: In US women who conceived ≤ 7 years following RYGB or SG, 40% of neonates had the composite neonatal outcome. The prevalence of maternal and neonatal outcomes post-MBS were not statistically significant by conception timeframe.

PMID:37014543 | DOI:10.1007/s11695-023-06575-6

Geroscience. 2023 Apr 4. doi: 10.1007/s11357-023-00781-x. Online ahead of print.

ABSTRACT

Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty construct, estimating its impact on the odds of all-cause dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and other dementias in 2838 older individuals from the population-based Italian PRoject on the Epidemiology of Alzheimer’s disease (IPREA). Biopsychosocial frailty operationalization was based on the results of a previous comprehensive geriatric assessment and the presence of physical frailty. In this cross-sectional study, participants with biopsychosocial frailty showed an increased odds ratio of all-cause dementia [odds ratio (OR): 5.55, 95% confidence interval (CI): 3.72-8.28, p < 0.001], in particular for probable AD (OR: 3.62, 95% CI: 1.55-8.45, p < 0.001), probable VaD (OR: 10.05, 95% CI: 5.05-19.97, p < 0.001), and possible VaD (OR: 17.61, 95% CI: 6.42-48.32, p < 0.001). No statistically significant association was found between this biopsychosocial frailty phenotype and possible AD (OR: 2.84, 95% CI: 0.81-9.97, p = 0.09) or other dementias (OR: 1.77, 95% CI: 0.75-0.21, p = 0.19). In conclusion, in a large cohort of Italian older individuals, a biopsychosocial frailty model was associated to all-cause dementia, probable AD, and probable and possible VaD. In the next future, other large and prospective population-based studies evaluating the association between the biopsychosocial frailty phenotype and incident all-cause dementia, AD, and VaD are needed, addressing also potential bias and confounding sources.

PMID:37014539 | DOI:10.1007/s11357-023-00781-x

Clin Transl Oncol. 2023 Apr 4. doi: 10.1007/s12094-023-03154-0. Online ahead of print.

ABSTRACT

Obesity is a relevant risk factor in breast cancer (BC), but little is known about the effects of overweight and obesity in surgical outcomes of BC patients. The aim of this study is to analyse surgical options and associated overall survival (OS) in overweight and obese women with BC. In this study, 2143 women diagnosed between 2012 and 2016 at the Portuguese Oncology Institute of Porto (IPO-Porto) were included, and the clinicopathological information was retrieved from the institutional database. Patients were stratified by body mass index (BMI). Statistical analysis included Pearson’s chi-squared test with statistical significance set at p < 0.05. Multinomial, binary logistic regression and cox proportional-hazards model were also performed to calculate odd ratios and hazard ratios with 95% confidence intervals for adjusted and non-adjusted models. The results revealed no statistical difference in histological type, topographic localization, tumour stage and receptor status and in the number of surgical interventions. Overweight women have increased probability to be subjected to sentinel node biopsy. Obese and overweight women are more likely to be submitted to conservative surgery and contrariwise, less likely to undergo total mastectomy. Patients submitted to conservative surgery and not submitted to total mastectomy had a favourable OS although without statistical significance. No significant differences were observed in OS when stratified by BMI. Our results revealed significant variations regarding the surgical options in overweight and obese patients, but these were not translated in OS difference. More research is recommended to better address treatment options in overweight and obese BC patients.

PMID:37014510 | DOI:10.1007/s12094-023-03154-0

Glob Chang Biol. 2023 Apr 4. doi: 10.1111/gcb.16682. Online ahead of print.

ABSTRACT

Forest carbon is a large and uncertain component of the global carbon cycle. An important source of complexity is the spatial heterogeneity of vegetation vertical structure and extent, which results from variations in climate, soils, and disturbances and influences both contemporary carbon stocks and fluxes. Recent advances in remote sensing and ecosystem modeling have the potential to significantly improve the characterization of vegetation structure and its resulting influence on carbon. Here, we used novel remote sensing observations of tree canopy height collected by two NASA spaceborne lidar missions, Global Ecosystem Dynamics Investigation and ICE, Cloud, and Land Elevation Satellite 2, together with a newly developed global Ecosystem Demography model (v3.0) to characterize the spatial heterogeneity of global forest structure and quantify the corresponding implications for forest carbon stocks and fluxes. Multiple-scale evaluations suggested favorable results relative to other estimates including field inventory, remote sensing-based products, and national statistics. However, this approach utilized several orders of magnitude more data (3.77 billion lidar samples) on vegetation structure than used previously and enabled a qualitative increase in the spatial resolution of model estimates achievable (0.25° to 0.01°). At this resolution, process-based models are now able to capture detailed spatial patterns of forest structure previously unattainable, including patterns of natural and anthropogenic disturbance and recovery. Through the novel integration of new remote sensing data and ecosystem modeling, this study bridges the gap between existing empirically based remote sensing approaches and process-based modeling approaches. This study more generally demonstrates the promising value of spaceborne lidar observations for advancing carbon modeling at a global scale.

PMID:37013906 | DOI:10.1111/gcb.16682

Rocz Panstw Zakl Hig. 2023;74(1):103-111. doi: 10.32394/rpzh.2023.0250.

ABSTRACT

BACKGROUND: Thailand is a tropical developing country which has a serious increase in health risk due to hot weather exposure among outdoor workers.

OBJECTIVES: The aims of this study were to compare the factors related to environmental heat exposure in three different seasons, and to assess the relationship between environmental heat and dehydration status in each season among farmworkers in Nakhon Ratchasima, Thailand.

METHODS: A semi-longitudinal study was carried out in 22 male farmworkers throughout a year of farming. The primary data were collected in farmworkers for socio-demographic information, clinical assessments, and heat-related illnesses.

RESULTS: Average of environmental heat index (Median, SD) were severe in summer (WBGT=38.1, 2.8°C), rainy season (WBGT=36.1, 2.1°C), and winter (WBGT=31.5, 2.7°C). Average urine Sp. Gr. in summer, rainy season, and winter were 1.022, 1.020, and 1.018 respectively. The third sentence should be corrected as follows: The Friedman analysis revealed a statistically significant difference between the three different seasons in WBGT (wet bulb globe temperature), body temperature, heart rate (P<0.01), and respiratory rate (P<0.05). There was a statistically significant difference between the three different seasons for skin rash/itching, dizziness, muscle cramp dyspnea (P<0.05), and weakness (P<0.01). Wilcoxon signed-ranks analysis found a significant difference in the medians of the paired sets of urine Sp. Gr. values between baseline and summer (P<0.05). Spearman’s rank correlation coefficient did not find a relationship between WBGT and urine Sp. Gr. in the three different seasons.

CONCLUSIONS: This study demonstrated that farmworkers had exposure to environmental heat stress which was expressed through physical changes. Therefore, there is a need for either interventions or guidelines to prevent dehydration for outdoor workers in this region.

PMID:37013902 | DOI:10.32394/rpzh.2023.0250

Genet Med. 2023 Mar 31:100836. doi: 10.1016/j.gim.2023.100836. Online ahead of print.

ABSTRACT

PURPOSE: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the two known disease genes associated with RTS in over 70% of cases. We describe RTS-like features in five individuals with biallelic variants in CRIPT (OMIM#615789).

METHODS: Two newly identified and four published individuals with CRIPT variants were systematically compared to RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.

RESULTS: All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with RTS individuals. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors, and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate.

CONCLUSION: CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.

PMID:37013901 | DOI:10.1016/j.gim.2023.100836

Rocz Panstw Zakl Hig. 2023;74(1):93-102. doi: 10.32394/rpzh.2023.0246.

ABSTRACT

BACKGROUND: Considered a modern phobia, Nomophobia (NO MObile PHOne PhoBIA) is a term describing irrational fear or anxiety of being unable to access one’s own mobile phone.

OBJECTIVES: To develop and validate the nomophobia questionnaire, administering it to a sample of adolescents representing undergraduate dental students. To assess the prevalence of Nomophobia, determine the usage pattern of mobile phones and evaluate the impact due to lack of access to mobile phones among undergraduate dental students.

MATERIAL AND METHOD: A cross-sectional study was conducted on 302 undergraduate students of Bhubaneswar through a self-administered questionnaire via Google Forms consisting of 19 items evaluating the pattern and anxiety related to usage of mobile phones. Responses were recorded on a 5-point Likert scale. Kruskal Wallis, Mann-Whitney U and Chisquare tests were used for statistical analysis.

RESULTS: Test-Retest reliability showed kappa of k=0.86 and Internal consistency Chronbach’s-Alpha to be α=0.82. Prevalence of nomophobia (score ≥ 58) was 32.1%, and students at risk of being nomophobic (score 39-57) was 61.9%. It was highest in males (32.6%) and amongst the interns (41.9%) and lowest (25.5%) amongst the second-year students. Participants felt nervous/insecure if their phones were away from them because of the fear that somebody might have accessed their data (3.07±1.93) and or tried to contact them (3.09±1.13) which were not statistically significant (p>0.05).

CONCLUSIONS: The present study confirms that nomophobia is an emerging behavioural addiction among dental students. Adequate prevention strategies would be helpful in reducing the impact of the chronic mobile usage. Effect of the mobile phone on dental students and the fear of not having it with them is increasing elaborately, that needs to be controlled. Otherwise, it would negatively affect their academic achievement and well-being.

PMID:37013899 | DOI:10.32394/rpzh.2023.0246

Rocz Panstw Zakl Hig. 2023;74(1):83-91. doi: 10.32394/rpzh.2023.0241.

ABSTRACT

BACKGROUND: Internet can act as an excellent resource for gaining valuable health related information. However, excessive online research and investigation about health-related issues may impose a negative impact. The term cyberchondria is used to describe a clinical condition in which frequent internet searches for health-related information leads to exaggerated anxieties about physical well-being.

OBJECTIVES: To determine the prevalence of cyberchondria and associated factors among the information technology professionals of Bhubaneswar in India.

MATERIALS AND METHODS: A cross-sectional study was carried out among 243 software professionals in Bhubaneswar using a previously validated Cyberchondria Severity Scale (CSS-15) questionnaire. Descriptive statistics in terms of number, percentage, mean and standard deviation were presented. Independent t-test and one-way analysis of variance was applied to compare the cyberchondria score between two and more than two independent variables respectively.

RESULTS: From 243 individuals 130 (53.5%) were males and 113 (46.5%) were females with mean age 29.82±6.67 years. The prevalence of cyberchondria severity was found to be 46.5%. The mean cyberchondria score of all study subjects was 43.80±10.62. It was significantly higher among those who spend more than 1 hour in the internet during night, feel fear and anxiety in visiting the doctor or dentist, interested in gaining the health-related information from other resources and agreed that gaining health related information has increased after COVID-19 pandemic (p˂0.05).

CONCLUSION: Cyberchondria is a growing issue with regard to mental health in developing countries and has the ability to cause anxiety and distress. Appropriate actions must be taken to prevent it on a societal level.

PMID:37013889 | DOI:10.32394/rpzh.2023.0241

Future Oncol. 2023 Apr 4. doi: 10.2217/fon-2023-0038. Online ahead of print.

NO ABSTRACT

PMID:37013832 | DOI:10.2217/fon-2023-0038