Chromatid recommensuration after segmental duplication

<p>Abstract</p> <p>Background</p> <p>Midsegment duplication (dup) of chromatid arms may be symmetric or asymmetric. It can be argued that every dup should yield a discommensured RC with (a) loss of at least one duplicated unit to the template counterpart and; (b) deletion of all sections of the replicating chromatid arm that are distal to both the gap left by the duplicating process and the segment closest to the centromere.</p> <p>Hypothesis</p> <p>Mechanisms capable of recommensuring the stack of chromatids after topological shifts of duplicated units (dups) are discussed. The mechanics might fail in few cases, which are discussed in terms of statistics and scalability.</p> <p>Conclusion</p> <p>The dynamics of the highly non-linear processes discussed here may be relevant to duplications of smaller (epsilon) subunits such as telomeric units within malignant genomes.</p

Gonadal Transcriptome Alterations in Response to Dietary Energy Intake: Sensing the Reproductive Environment

Reproductive capacity and nutritional input are tightly linked and animals' specific responses to alterations in their physical environment and food availability are crucial to ensuring sustainability of that species. We have assessed how alterations in dietary energy intake (both reductions and excess), as well as in food availability, via intermittent fasting (IF), affect the gonadal transcriptome of both male and female rats. Starting at four months of age, male and female rats were subjected to a 20% or 40% caloric restriction (CR) dietary regime, every other day feeding (IF) or a high fat-high glucose (HFG) diet for six months. The transcriptional activity of the gonadal response to these variations in dietary energy intake was assessed at the individual gene level as well as at the parametric functional level. At the individual gene level, the females showed a higher degree of coherency in gonadal gene alterations to CR than the males. The gonadal transcriptional and hormonal response to IF was also significantly different between the male and female rats. The number of genes significantly regulated by IF in male animals was almost 5 times greater than in the females. These IF males also showed the highest testosterone to estrogen ratio in their plasma. Our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment

Association between troponin level and medium-term mortality in 20 000 hospital patients.

Cardiac troponin (cTn) concentrations above the manufacturer recommended upper limit of normal (ULN) are frequently seen in hospital patients without a clinical presentation consistent with type 1 myocardial infarction, and the significance of this is uncertain. The aim of this study was to assess the relationship between medium-term mortality and cTn concentration in a large consecutive hospital population, regardless of whether there was a clinical indication for performing the test. This prospective observational study included 20 000 consecutive in-hospital and outpatient patients who had a blood test for any reason at a large teaching hospital, and in whom a hs-cTnI assay was measured, regardless of the original clinical indication. Mortality was obtained via NHS Digital. A total of 20 000 patients were included in the analysis and 18 282 of these (91.4%) did not have a clinical indication for cardiac troponin I (cTnI) testing. Overall, 2825 (14.1%) patients died at a median of 809 days. The mortality was significantly higher if the cTnI concentration was above the ULN (45.3% vs 12.3% p<0.001 log rank). Multivariable Cox analysis demonstrated that the log cTnI concentration was independently associated with mortality (HR 1.76 (95% CI 1.65 to 1.88)). Landmark analysis, excluding deaths within 30 days, showed the relationship between cTnI concentration and mortality persisted. In a large, unselected hospital population, in 91.4% of whom there was no clinical indication for testing, cTnI concentration was independently associated with medium-term cardiovascular and non-cardiovascular mortality in the statistical model tested. [Abstract copyright: © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Association of Noncontrast Computed Tomography and Perfusion Modalities With Outcomes in Patients Undergoing Late-Window Stroke Thrombectomy

Importance: There is substantial controversy with regards to the adequacy and use of noncontrast head computed tomography (NCCT) for late-window acute ischemic stroke in selecting candidates for mechanical thrombectomy. Objective: To assess clinical outcomes of patients with acute ischemic stroke presenting in the late window who underwent mechanical thrombectomy stratified by NCCT admission in comparison with selection by CT perfusion (CTP) and diffusion-weighted imaging (DWI). Design, setting, and participants: In this multicenter retrospective cohort study, prospectively maintained Stroke Thrombectomy and Aneurysm (STAR) database was used by selecting patients within the late window of acute ischemic stroke and emergent large vessel occlusion from 2013 to 2021. Patients were selected by NCCT, CTP, and DWI. Admission Alberta Stroke Program Early CT Score (ASPECTS) as well as confounding variables were adjusted. Follow-up duration was 90 days. Data were analyzed from November 2021 to March 2022. Exposures: Selection by NCCT, CTP, or DWI. Main outcomes and measures: Primary outcome was functional independence (modified Rankin scale 0-2) at 90 days. Results: Among 3356 patients, 733 underwent late-window mechanical thrombectomy. The median (IQR) age was 69 (58-80) years, 392 (53.5%) were female, and 449 (65.1%) were White. A total of 419 were selected with NCCT, 280 with CTP, and 34 with DWI. Mean (IQR) admission ASPECTS were comparable among groups (NCCT, 8 [7-9]; CTP, 8 [7-9]; DWI 8, [7-9]; P = .37). There was no difference in the 90-day rate of functional independence (aOR, 1.00; 95% CI, 0.59-1.71; P = .99) after adjusting for confounders. Symptomatic intracerebral hemorrhage (NCCT, 34 [8.6%]; CTP, 37 [13.5%]; DWI, 3 [9.1%]; P = .12) and mortality (NCCT, 78 [27.4%]; CTP, 38 [21.1%]; DWI, 7 [29.2%]; P = .29) were similar among groups. Conclusions and relevance: In this cohort study, comparable outcomes were observed in patients in the late window irrespective of neuroimaging selection criteria. Admission NCCT scan may triage emergent large vessel occlusion in the late window

Patch graft using collagen matrix (Ologen) for glaucoma drainage device exposure in a patient with Boston Keratoprosthesis type 1

Purpose: To report the first successfully treated case of recurrent tube exposure in a patient with the Boston Keratoprosthesis type 1 with a collagen matrix patch graft (Ologen). Observations: A 50 year-old female with a Boston Keratoprosthesis type 1 and a history of Axenfeld-Reiger syndrome presents to our department with recurrent glaucoma drainage device exposure in her left eye. After failed spontaneous closure with topical antibiotics and lubricants, she undergoes tube exposure repair using an Ologen patch graft. Surgery was successful and the patient did not have any recurrence up to last follow-up two years post-operatively. Conclusion: Collagen matrix patch graft seems to be advantageous in treating glaucoma tube exposure in the Boston KPro eye, which is often a more challenging entity to treat. Importance: Collagen matrix patch graft could be considered as a primary patch graft in treating tube exposure in eyes with the Boston KPro. Keywords: Boston Kpro, Glaucoma drainage device, Tube exposure, Ologe

“Fighting a Hurricane”: Tobacco Industry Efforts to Counter the Perceived Threat of Islam

Islamic countries are of key importance to transnational tobacco companies as growing markets with increasing smoking rates. We analyzed internal tobacco industry documents to assess the industry’s response to rising concerns about tobacco use within Islamic countries. The tobacco industry perceived Islam as a significant threat to its expansion into these emerging markets. To counter these concerns, the industry framed antismoking views in Islamic countries as fundamentalist and fanatical and attempted to recruit Islamic consultants to portray smoking as acceptable. Tobacco industry lawyers also helped develop theological arguments in favor of smoking. These findings are valuable to researchers and policymakers seeking to implement culturally appropriate measures in Islamic countries under the World Health Organization Framework Convention on Tobacco Control

Phosphorus Supplementation Mitigated Food Intake and Growth of Rats Fed a Low-Protein Diet

BACKGROUND: Low protein intake is associated with various negative health outcomes at any life stage. When diets do not contain sufficient protein, phosphorus availability is compromised because proteins are the major sources of phosphorus. However, whether mineral phosphorus supplementation mitigates this problem is unknown, to our knowledge. OBJECTIVE: Our goal was to determine the impact of dietary phosphorus supplementation on food intake, weight gain, energy efficiency, body composition, blood metabolites, and liver histology in rats fed a low-protein diet for 9 wk. METHODS: Forty-nine 6-wk-old male Sprague-Dawley rats were randomly allocated to 5 groups and consumed 5 isocaloric diets ad libitum that varied only in protein (egg white) and phosphorus concentrations for 9 wk. The control group received a 20% protein diet with 0.3% P (NP-0.3P). The 4 other groups were fed a low-protein (10%) diet with a phosphorus concentration of 0.015%, 0.056%, 0.1%, or 0.3% (LP-0.3P). The rats' weight, body and liver composition, and plasma biomarkers were then assessed. RESULTS: The addition of phosphorus to the low-protein diet significantly increased food intake, weight gain, and energy efficiency, which were similar among the groups that received 0.3% P (LP-0.3P and NP-0.3P) regardless of dietary protein content. In addition, phosphorus supplementation of low-protein diets reduced plasma urea nitrogen and increased total body protein content (defatted). Changes in food intake and efficiency, body weight and composition, and plasma urea concentration were highly pronounced at a dietary phosphorus content &lt;0.1%, which may represent a critical threshold. CONCLUSIONS: The addition of phosphorus to low-protein diets improved growth measures in rats, mainly as a result of enhanced energy efficiency. A dietary phosphorus concentration of 0.3% mitigated detrimental effects of low-protein diets on growth parameters

Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy.

Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1α is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1α as aTNBC-specific marker.62 TNBC, 64 HER2+, and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1α, HIF-1β, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR) evaluation of HIF-1α and VEGF transcripts was performed on 54 cases (18 from each subtype).HIF-1α protein was expressed in 35.5% TNBC, 45.3% HER2+and 25.0% ER+/PR+ (p = 0.055; χ2 test). PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1α protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1α protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; χ2 test), while MVD was comparable among all groups (p = 0.928; χ2 test). VEGFR3 was highest in TNBC expressing HIF-1α. HIF-1β protein was expressed in 32.0% of HIF-1α(+), and in (44.3%) of HIF-1α(-) breast cancer cases (p = 0.033; χ2 test). Moreover, HIF-1α expression in cases with central fibrosis and necrosis was highest in the HER2+ followed by the TNBC (p = 0.156; χ2 test).A proportion of TNBC express HIF-1α but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1α targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the setting of clinically aggressive or refractory disease