Beyond insulin: Unraveling the complex interplay of ER stress, oxidative damage, and CFTR modulation in CFRD

\ua9 2024 The Author(s)CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD\u27s molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease\u27s root causes and improve the quality of life for individuals with CF

Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast.

An association has been reported between consumption of a high soy diet and a low incidence of breast cancer within populations of Southeast Asia. Phytoestrogens present in soy act as partial estrogen agonists or antagonists and can inhibit breast cancer cell proliferation in vitro. The effect of 14-day dietary soy supplementation with 60 g (45 mg isoflavones) on the normal breast of 84 premenopausal patients was determined. Serum concentrations of the isoflavanoids, genistein, daidzein, and equol, were raised in patients after soy supplementation (P < or = 0.025). Nipple aspirate (NA) levels of genistein and daidzein were higher than paired serum levels, both before (P < 0.001 and P = 0.001, respectively) and after soy supplementation (P < 0.001 and P = 0.049, respectively); however, there was no significant increase in NA isoflavone levels in response to soy. NA levels of apolipoprotein D were significantly lowered and pS2 levels raised in response to soy supplementation (P < or = 0.002), indicative of an estrogenic stimulus. No effect of soy supplementation on breast epithelial cell proliferation, estrogen and progesterone receptor status, apoptosis, mitosis, or Bcl-2 expression was detected. In conclusion, short term dietary soy has a weak estrogenic response on the breast, as measured by nipple aspirate apolipoprotein D and pS2 expression. No antiestrogenic effect of soy on the breast was detected

Prevalence and Predictors of Vitamin D Insufficiency in Children: A Great Britain Population Based Study

Objectives To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children In Great Britain. Design A nationally representative cross-sectional study survey of children (1102) aged 4–18 years (999 white, 570 male) living in private households (January 1997–1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L). Results Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4–63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53–59 degrees latitude had lower levels (compared with 50–53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14–18 years old), odds ratio (OR) = 3.6 (95%CI 1.8–7.2) compared with younger children (4–8 years); non white children (OR = 37 [95%CI 15–90]); blood levels taken December-May (OR = 6.5 [95%CI 4.3–10.1]); on income support (OR = 2.2 [95%CI 1.3–3.9]); not taking vitamin D supplementation (OR = 3.7 [95%CI 1.4–9.8]); being overweight (OR 1.6 [95%CI 1.0–2.5]); <1/2 hour outdoor exercise/day/week (OR = 1.5 [95%CI 1.0–2.3]); watched >2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0–2.4]). Conclusion We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children

Nutritional status and the gonadotrophic response to a polar expedition.

Polar expeditions have been associated with changes in the hypothalamic-pituitary-testicular axis consistent with central hypogonadism (i.e., decreased testosterone, luteinising hormone (LH), and follicle stimulating hormone (FSH)). These changes are typically associated with body mass loss. Our aim was to evaluate whether maintenance of body mass during a polar expedition could mitigate against the development of central hypogonadism. Male participants (n = 22) from a 42-day expedition (British Services Antarctic Expedition 2012) volunteered to take part in the study. Body mass, body composition, and strength data were recorded pre- and postexpedition in addition to assessment of serum testosterone, LH, FSH, thyroid hormones, insulin-like growth factor 1 (IGF-1), and trace elements. Energy provision and energy expenditure were assessed at mid- and end-expedition. Daily energy provision was 6335 ± 149 kcal·day(-1). Estimated energy expenditure midexpedition was 5783 ± 1690 kcal·day(-1). Body mass and percentage body fat did not change between pre- and postexpedition. Total testosterone (nmol·L(-1)) (14.0 ± 4.9 vs. 17.3 ± 4.0, p = 0.006), calculated free testosterone (pmol·L(-1)) (288 ± 82 vs. 350 ± 70, p = 0.003), and sex hormone binding globulin (nmol·L(-1)) (33 ± 12 vs. 36 ± 11, p = 0.023) concentrations increased. LH and FSH remained unchanged. Thyroid stimulating hormone (TSH; IU·L(-1)) (2.1 ± 0.8 vs. 4.1 ± 2.1, p < 0.001) and free triiodothyronine (FT3; IU·L(-1)) (5.4 ± 0.4 vs. 6.1 ± 0.8, p < 0.001) increased while free thyroxine, IGF-1, and trace elements remained unchanged. Hand-grip strength was reduced postexpedition but static lift strength was maintained. Maintenance of body mass and nutritional status appeared to negate the central hypogonadism previously reported from polar expeditions. The elevated TSH and free FT3 were consistent with a previously reported "polar T3 syndrome"

Simplifying transformations for nonlinear systems: Part I, an optimisation-based variant of normal form analysis

This paper introduces the idea of a ‘simplifying transformation’ for nonlinear structural dynamic systems. The idea simply stated; is to bring under one heading, those transformations which ‘simplify’ structural dynamic systems or responses in some sense. The equations of motion may be cast in a simpler form or decoupled (and in this sense, nonlinear modal analysis is encompassed) or the responses may be modified in order to isolate and remove certain components. It is the latter sense of simplification which is considered in this paper. One can regard normal form analysis in a way as the removal of superharmonic content from nonlinear system response. In the current paper, this problem is cast in an optimisation form and the differential evolution algorithm is used

Fate and transport of volatile organic compounds in glacial till and groundwater at an industrial site in Northern Ireland

Volatile organic compound (VOC) contamination of subsurface geological material and groundwater was discovered on the Nortel Monkstown industrial site, Belfast, Northern Ireland. The objectives of this study were to (1) investigate the characteristics of the geological material and its influences on contaminated groundwater flow across the site using borehole logs and hydrological evaluations, and (2) identify the contaminants and examine their distribution in the subsurface geological material and groundwater using chemical analysis. This report focuses on the eastern car park (ECP) which was a former storage area associated with trichloroethene (TCE) degreasing operations. This is where the greatest amount of volatile organic compounds (VOCs), particularly TCE, were detected. The study site is on a complex deposit of clayey glacial till with discontinuous coarser grained lenses, mainly silts, sands and gravel, which occur at 0.45-7.82 m below ground level (bgl). The lenses overall form an elongated formation that acts as a small unconfined shallow aquifer. There is a continuous low permeable stiff clayey till layer beneath the lenses that performs as an aquitard to the groundwater. Highest concentrations of VOCs, mainly TCE, in the geological material and groundwater are in these coarser lenses at similar to 4.5-7 m bgl. Highest TCE measurements at 390,000 mu g L-1 for groundwater and at 39,000 mu g kg(-1) at 5.7 m for geological material were in borehole GA19 in the coarse lens zone. It is assumed that TCE gained entrance to the subsurface near this borehole where the clayey till was thin to absent above coarse lenses which provided little retardation to the vertical migration of this dense non-aqueous phase liquid (DNAPL) into the groundwater. However, TCE is present in low concentrations in the geological material overlying the coarse lens zone. Additionally, VOCs appear to be associated with poorly drained layers and in peat &lt; 3.0 m bgl in the ECP. Some indication of natural attenuation as VOCs degradation products vinyl chloride (VC) and dichloromethane (DCM) also occur on the site

A Network Approach to Neonatal Palliative Care Education: Impact on Knowledge, Efficacy, and Clinical Practice

More than 80 000 babies are admitted to specialist neonatal units in the United Kingdom every year, with approximately 2109 neonatal deaths a year; 98% in hospital. A common element in guidance and pathways to facilitate the provision of palliative care to infants and their families is the importance of good education and training to develop high-quality staff and services. This article presents a mixed-methods, sequential, explanatory design evaluation of 1 day palliative care education workshops delivered using a network-wide approach to multidisciplinary professionals. Workshops were delivered by healthcare professionals and bereaved parents and evaluated using questionnaires, adapted for neonatal staff from standardized measures, and follow-up interviews. The workshop content and shared learning approach resulted in significant improvements in participant's knowledge, attitude, self-beliefs and confidence in neonatal palliative care, enhanced awareness of services, and improved links between professionals. Participants cascaded their learning to their teams and provided examples of changes in their clinical practice following the workshop. Parent stories were identified as a very powerful component of the training, with lasting impact on participants. Formal, integrated palliative care education programs for perinatal and neonatal staff and longitudinal research into the impact on practice and the experience received by families are needed

Influence of a knot on the strength of a polymer strand

Many experiments have been done to determine the relative strength of different knots, and these show that the break in a knotted rope almost invariably occurs at a point just outside the `entrance' to the knot. The influence of knots on the properties of polymers has become of great interest, in part because of their effect on mechanical properties. Knot theory applied to the topology of macromolecules indicates that the simple trefoil or `overhand' knot is likely to be present with high probability in any long polymer strand. Fragments of DNA have been observed to contain such knots in experiments and computer simulations. Here we use {\it ab initio} computational methods to investigate the effect of a trefoil knot on the breaking strength of a polymer strand. We find that the knot weakens the strand significantly, and that, like a knotted rope, it breaks under tension at the entrance to the knot.Comment: 3 pages, 4 figure