The distribution and excretion of endogenous Zn, including the role of the pancreas, were examined in fasted MT+/+ and MT-/- mice. At 3 and 6 h after receiving 65Zn tracer by subcutaneous injection, 65Zn levels were compared in tissues of MT+/+ and MT-/- mice. 65Zn levels were significantly higher in the liver and pancreas of the MT+/+ mice, whereas in the MT-/- mice, 65Zn levels were significantly higher in muscle, skin, and most of the gastrointestinal tract other than the stomach and upper small intestine. In MT-/- mice, 3% of the injected 65Zn was recovered in the luminal contents of the small intestine over 3-6 h, compared with <1.5% in the MT+/+ mice. A loading dose of Zn (150 microg, s.c.) sufficient to raise the plasma Zn concentration by fourfold to fivefold in both MT+/+ and MT-/- mice resulted in similar increases in pancreatic Zn levels in each genotype, although more Zn appeared in the lower small intestine of MT-/- mice. Pancreatectomy decreased the level of 65Zn in the small intestine of MT-/- but not MT+/+ mice. Longer-term studies over 4 days demonstrated few differences in tissue 65Zn between MT+/+ and MT-/- mice, with the exception of the pancreas, where 65Zn retention after fasting in MT-/- mice was half that of MT+/+ mice. MT-/- mice also had significantly lower Zn concentrations in the pancreas. Fecal excretion of 65Zn in MT-/- mice was greater than that of MT+/+ mice in the first 24 h (24.7 vs. 18.2% of injected dose; p < 0.05). Besides metallothionein (MT), there were no significant differences in the molecular weight distribution of Zn binding ligands in the lumen of the small intestine between MT+/+ and MT-/- mice. Mice lacking MT I and II lose more endogenous Zn into the gut because of a relative failure of the pancreas to retain Zn. However, increased Zn secretion via the small intestinal mucosa may also contribute to intestinal Zn loss in MT-/- mice.
Chronic obstructive pulmonary disease (COPD) embraces a number of pathological processes including chronic bronchitis, chronic bronchiolitis and emphysema. The chronic and progressive course of COPD is often aggravated by short periods of increasing symptoms. Respiratory tract infections (RTIs) are the most common causes of COPD exacerbations. Detection and enumeration of respiratory bacteria are important techniques in diagnosing RTIs and in the validation of new treatment methods. We describe here the development and evaluation of real-time PCR assays for the simultaneous direct detection and quantification of a range of respiratory bacteria in individuals with COPD during stable periods and during acute exacerbations of the disease. Sputum samples from 30 subjects in a COPD study were analysed, and results compared with the current gold standard of culture. Real-time PCR assays proved highly sensitive, with no cross-reactivity with other species. The prevalence of bacteria detected by real-time PCR compared with that by culture was substantially higher for Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus spp. and Moraxella catarrhalis. Multiple pathogens were also found with real-time PCR but were not detected by culture. This study demonstrates the potential of such methods in the detection and enumeration of respiratory bacteria.
We have previously demonstrated that ethanol teratogenicity is associated with metallothionein-induced fetal zinc (Zn) deficiency, and that maternal subcutaneous Zn treatment given with ethanol in early pregnancy prevents fetal abnormalities and spatial memory impairments in mice. Here we investigated whether dietary Zn supplementation throughout pregnancy can also prevent ethanol-related dysmorphology.Pregnant mice were injected with saline or 25% ethanol (0.015 ml/g intraperitoneally at 0 and 4 hours) on gestational day (GD) 8 and fed either a control (35 mg Zn/kg) or a Zn-supplemented diet (200 mg Zn/kg) from GD 0 to 18. Fetuses from the saline, saline + Zn, ethanol and ethanol + Zn groups were assessed for external birth abnormalities on GD 18. In a separate cohort of mice, postnatal growth and survival of offspring from these treatment groups were examined from birth until postnatal day 60.Fetuses from dams treated with ethanol alone in early pregnancy had a significantly greater incidence of physical abnormalities (26%) compared to those from the saline (10%), saline + Zn (9%), or ethanol + Zn (12%) groups. The incidence of abnormalities in ethanol + Zn-supplemented fetuses was not different from saline-treated fetuses. While ethanol exposure did not affect the number of fetal resorptions or pre- or postnatal weight, there were more stillbirths with ethanol alone, and cumulative postnatal mortality was significantly higher in offspring exposed to ethanol alone (35% deaths) compared to all other treatment groups (13.5 to 20.5% deaths). Mice supplemented with Zn throughout pregnancy had higher plasma Zn concentrations than those in un-supplemented groups.These findings demonstrate that dietary Zn supplementation throughout pregnancy ameliorates dysmorphology and postnatal mortality caused by ethanol exposure in early pregnancy.
Exposure to alcohol during pregnancy is associated with an increased risk of spontaneous abortion, growth retardation, congenital malformations and central nervous system dysfunction [1, 2]. These negative birth outcomes, which are collectively referred to as fetal alcohol spectrum disorder (FASD), range in severity from full fetal alcohol syndrome (FAS) through milder although clinically significant forms which can affect physical and behavioural outcomes (i.e. alcohol-related birth defects (ARBD) and alcohol-related neurodevelopmental disorders (ARND)). These outcomes are associated not only with chronic consumption of alcohol at high intakes and frequency but also with a single episode of alcohol intake, which is commonly called 'binge drinking' (>4 drinks/occasion). Although abstinence from alcohol during pregnancy would prevent these disorders, the motivation for self-restraint from drinking alcohol is not uniformly accepted among women [3–6]. Moreover, up to two-thirds of pregnancies are reported to be unplanned, indicating that many women may be unaware of their pregnancy when consuming alcohol [3, 5, 6]. Thus, the consumption of alcohol during pregnancy will continue to negatively impact on birth outcomes well into the future.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly evolving RNA virus that mutates within hosts and exists as viral quasispecies. Here, we evaluated the within-host diversity among vaccinated and unvaccinated individuals (n = 379) infected with different SARS-CoV-2 Variants of Concern. The majority of samples harbored less than 14 intra-host single-nucleotide variants (iSNVs). A deep analysis revealed a significantly higher intra-host diversity in Omicron samples than in other variants (p value < 0.05). Vaccination status and type had a limited impact on intra-host diversity except for Beta-B.1.315 and Delta-B.1.617.2 vaccinees, who exhibited higher diversity than unvaccinated individuals (p values: <0.0001 and <0.0021, respectively). Three immune-escape mutations were identified: S255F in Delta and R346K and T376A in Omicron-B.1.1.529. The latter 2 mutations were fixed in BA.1 and BA.2 genomes, respectively. Overall, the relatively higher intra-host diversity among vaccinated individuals and the detection of immune-escape mutations, despite being rare, suggest a potential vaccine-induced immune pressure in vaccinated individuals.
Abstract This study demonstrated that distal branches of the anterior cerebral artery (ACA) are joined by interarterial anastomoses to rami of the middle cerebral artery (MCA) in the normal Wistar rat. Arteries of 36‐ and 56‐day‐old animals were dilated with papaverine and injected with Vultex. Vultex arrived at corresponding ACA and MCA collaterals simultaneously as determined by microscopy through a skull window and photography. There were about 29 ACAMCA junctions per hemisphere. Junction density was nearly constant along the frontal‐occipital axis. The anastomoses were most numerous between 2 and 3 mm lateral to the midline and were less than 120 μm in internal diameter. No significant difference was found between total numbers of junctions for right versus left hemispheres or between age groups. The most evident collateral pattern was characterized by two ACA end rami joining two MCA end branches to form a closed, diamond‐shaped collateral unit. Considerations were given to alternate routes of blood flow into the MCA tissue field. We conclude abundant dorsal anastomoses exist in 36‐ and 56‐day‐old rats and are the prime potential source for ACA collateral supply to the MCA tissue field.
The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.
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