A very-low-calorie diet (VLCD) intervention for the management of prediabetes and early Type 2 diabetes mellitus in a multi-ethnic cohort in Aotearoa New Zealand: The PROGRESS NZ feasibility study.

BACKGROUND AND OBJECTIVES: Very-low calorie diets (VLCD) achieve weight loss and remission of Type 2 diabetes (T2DM), but efficacy and acceptability in non-European populations is less clear. This feasibility study examines the impact of 10% weight loss through VLCD on metabolic and body composition outcomes in a multi-ethnic cohort of Aotearoa New Zealand (AoNZ) men with prediabetes/early T2DM, and VLCD tolerability/cultural acceptability. METHODS AND STUDY DESIGN: Participants followed a VLCD intervention (mean energy 3033kJ/day) until achievement of 10% weight loss. An oral glucose tolerance test (OGTT), hyperinsulinaemic isoglycaemic clamp with stable isotopes, hood calorimetry and dual-energy Xray absorptiometry (DXA) were undertaken before and after intervention. Qualitative data on VLCD tolerability/cultural acceptability were collected. RESULTS: Fifteen participants were enrolled; nine achieved 10% weight loss. In this group, mean HbA1c reduced by 4.8mmol/mol (2.4-7.1) and reverted to normoglycaemia in n=5/9; mean body weight reduced by 12.0 kg (11.0-13.1) and whole-body glucose disposal improved by 1.5 mg kgFFM-1 min-1 (0.7-2.2). Blood pressure and fasting triglycerides improved significantly. No changes in hepatic glu-cose metabolism were found. In all participants who attended completion testing, HbA1c reduced by 3.4mmol/mol (SD 3.5) and total weight by 9.0kg (SD 5.7). The intervention was highly tolerable/culturally acceptable however challenges with fulfilment of cultural obligations were described. CONCLUSIONS: Results support VLCD use in AoNZ however further work to investigate ethnic differences in physiological response to VLCDs and to optimise protocols for multi-ethnic populations are required.

Phalangeal Fractures and Fingertip Injuries.

A comprehensive analysis of the assessment, diagnosis, and management of phalangeal fractures and fingertip injuries should emphasize the importance of achieving the right balance between undertreatment and overtreatment. Phalangeal injuries are complex, requiring an in-depth understanding of hand anatomy, fracture patterns, and treatment options to optimize patient outcomes. A thorough examination of proximal and middle phalangeal fractures and fingertip injuries, including those to the nail bed and distal phalanx, is important. A systematic approach to addressing the most prevalent injuries in this category should be implemented while highlighting the need for patient-specific approaches to treatment and a multidisciplinary perspective to ensure the best possible outcomes for patients.

Preterm-born individuals: a vulnerable population at risk of cardiovascular morbidity and mortality during thermal extremes?

NEW FINDINGS: What is the topic of this review? Thermal extremes disproportionately affect populations with cardiovascular conditions. Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a non-modifiable risk factor for cardiovascular disease. The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes. What advances does it highlight? Cardiovascular stress tests performed in preterm-born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood. This dysfunction has many similarities with populations known to be at risk in thermal extremes. ABSTRACT: Preterm-born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro- and micro-physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later-life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes.

Insights into the pathogenesis of cerebral fusiform aneurysms: high-resolution MRI and computational analysis.

BACKGROUND: Intracranial fusiform aneurysms are complex and poorly characterized vascular lesions. High-resolution magnetic resonance imaging (HR-MRI) and computational morphological analysis may be used to characterize cerebral fusiform aneurysms. OBJECTIVE: To use advanced imaging and computational analysis to understand the unique pathophysiology, and determine possible underlying mechanisms of instability of cerebral fusiform aneurysms. METHODS: Patients with unruptured intracranial aneurysms prospectively underwent imaging with 3T HR-MRI at diagnosis. Aneurysmal wall enhancement was objectively quantified using signal intensity after normalization of the contrast ratio (CR) with the pituitary stalk. Enhancement between saccular and fusiform aneurysms was compared, as well as enhancement characteristics of fusiform aneurysms. The presence of microhemorrhages in fusiform aneurysms was determined with quantitative susceptibility mapping (QSM). Three distinct types of fusiform aneurysms were analyzed with computational fluid dynamics (CFD) and finite element analysis (FEA). RESULTS: A total of 130 patients with 160 aneurysms underwent HR-MRI. 136 aneurysms were saccular and 24 were fusiform. Fusiform aneurysms had a significantly higher CR and diameter than saccular aneurysms. Enhancing fusiform aneurysms exhibited more enhancement of reference vessels than non-enhancing fusiform aneurysms. Ten fusiform aneurysms underwent QSM analysis, and five aneurysms showed microhemorrhages. Microhemorrhage-positive aneurysms had a larger volume, diameter, and greater enhancement than aneurysms without microhemorrhage. Three types of fusiform aneurysms exhibited different CFD and FEA patterns. CONCLUSION: Fusiform aneurysms exhibited more contrast enhancement than saccular aneurysms. Enhancing fusiform aneurysms had larger volume and diameter, more enhancement of reference vessels, and more often exhibited microhemorrhage than non-enhancing aneurysms. CFD and FEA suggest that various pathophysiological processes determine the formation and growth of fusiform aneurysms.

Comparative analysis of the effect of PO administered acid suppressants on gastric pH in healthy cats.

BACKGROUND: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications for esophagitis and upper gastrointestinal erosion and ulceration in cats. Newer PPIs such as lansoprazole and esomeprazole are believed to be effective in cats, but the effect of many of these PPIs on gastric pH in cats has not been explored. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of PO esomeprazole, dexlansoprazole, and lansoprazole on intragastric pH in healthy cats. We hypothesized that esomeprazole and lansoprazole would provide superior acid suppression compared to dexlansoprazole and reach pH goals extrapolated from people for the treatment of esophagitis and duodenal ulceration. ANIMALS: Twelve healthy research cats. METHODS: Randomized, 3-way crossover study. Cats were given esomeprazole and lansoprazole at a dosage of 1 mg/kg PO q12h or dexlansoprazole at 6 mg/kg PO q12h. Intragastric pH was recorded at baseline and for 4 days of treatment. Mean pH and the mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were compared among and within treatment groups. RESULTS: Cats treated with lansoprazole had a lower MPT ± SD of intragastric pH ≥3 (8.8 ± 6.8%) and mean ± SD pH (1.6 ± 0.5) than did cats treated with dexlansoprazole (41.2 ± 34.6% and 3.11 ± 1.6, respectively) or esomeprazole (54 ± 33.8% and 4.1 ± 3.9, respectively;P ≤ .04). Esomeprazole was the only treatment that achieved the goals defined for people for the treatment of duodenal ulceration by Day 4 of treatment (MPT ± SD of intragastric pH ≥4 of 77.1 ± 29.2%). CONCLUSIONS AND CLINICAL IMPORTANCE: Orally administered esomeprazole might be a superior acid suppressant in cats compared to PO lansoprazole or dexlansoprazole.

Pharmacokinetic characterization of fluorocoxib D, a cyclooxygenase-2-targeted optical imaging agent for detection of cancer.

SIGNIFICANCE: Fluorocoxib D, N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a water-soluble optical imaging agent to detect cyclooxygenase-2 (COX-2)-expressing cancer cells. AIM: We evaluated the pharmacokinetic and safety properties of fluorocoxib D and its ability to detect cancer cells in vitro and in vivo. APPROACH: Pharmacokinetic parameters of fluorocoxib D were assessed from plasma collected at designated time points after intravenous administration of 1 mg / kg fluorocoxib D in six research dogs using a high-performance liquid chromatography analysis. Safety of fluorocoxib D was assessed for 3 days after its administration using physical assessment, complete blood count, serum chemistry profile, and complete urinalysis in six research dogs. The ability of fluorocoxib D to detect COX-2-expressing cancer cells was performed using human 5637 cells in vitro and during rhinoscopy evaluation of specific fluorocoxib D uptake by canine cancer cells in vivo. RESULTS: No evidence of toxicity and no clinically relevant adverse events were noted in dogs. Peak concentration of fluorocoxib D (114.8 ± 50.5 ng / ml) was detected in plasma collected at 0.5 h after its administration. Pretreatment of celecoxib blocked specific uptake of fluorocoxib D in COX-2-expressing human 5637 cancer cells. Fluorocoxib D uptake was detected in histology-confirmed COX-2-expressing head and neck cancer during rhinoscopy in a client-owned dog in vivo. Specific tumor-to-normal tissue ratio of detected fluorocoxib D signal was in an average of 3.7 ± 0.9 using Image J analysis. CONCLUSIONS: Our results suggest that fluorocoxib D is a safe optical imaging agent used for detection of COX-2-expressing cancers and their margins during image-guided minimally invasive biopsy and surgical procedures.

Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice: an integrated metagenomics and metabolomics analysis.

BACKGROUND: The human intestine is host to an enormously complex, diverse, and vast microbial community-the gut microbiota. The gut microbiome plays a profound role in metabolic processing, energy production, immune and cognitive development, epithelial homeostasis, and so forth. However, the composition and diversity of the gut microbiome can be readily affected by external factors, which raises the possibility that exposure to toxic environmental chemicals leads to gut microbiome alteration, or dysbiosis. Arsenic exposure affects large human populations worldwide and has been linked to a number of diseases, including cancer, diabetes, and cardiovascular disorders. OBJECTIVES: We investigated the impact of arsenic exposure on the gut microbiome composition and its metabolic profiles. METHODS: We used an integrated approach combining 16S rRNA gene sequencing and mass spectrometry-based metabolomics profiling to examine the functional impact of arsenic exposure on the gut microbiome. RESULTS: 16S rRNA gene sequencing revealed that arsenic significantly perturbed the gut microbiome composition in C57BL/6 mice after exposure to 10 ppm arsenic for 4 weeks in drinking water. Moreover, metabolomics profiling revealed a concurrent effect, with a number of gut microflora-related metabolites being perturbed in multiple biological matrices. CONCLUSIONS: Arsenic exposure not only alters the gut microbiome community at the abundance level but also substantially disturbs its metabolic profiles at the function level. These findings may provide novel insights regarding perturbations of the gut microbiome and its functions as a potential new mechanism by which arsenic exposure leads to or exacerbates human diseases. CITATION: Lu K, Abo RP, Schlieper KA, Graffam ME, Levine S, Wishnok JS, Swenberg JA, Tannenbaum SR, Fox JG. 2014. Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice: an integrated metagenomics and metabolomics analysis. Environ Health Perspect 122:284-291; http://dx.doi.org/10.1289/ehp.1307429.

Gut microbiome perturbations induced by bacterial infection affect arsenic biotransformation.

Exposure to arsenic affects large human populations worldwide and has been associated with a long list of human diseases, including skin, bladder, lung, and liver cancers, diabetes, and cardiovascular disorders. In addition, there are large individual differences in susceptibility to arsenic-induced diseases, which are frequently associated with different patterns of arsenic metabolism. Several underlying mechanisms, such as genetic polymorphisms and epigenetics, have been proposed, as these factors closely impact the individuals' capacity to metabolize arsenic. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that perturbations of the gut microbial communities affect the spectrum of metabolized arsenic species and subsequent toxicological effects. In this study, we used an animal model with an altered gut microbiome induced by bacterial infection, 16S rRNA gene sequencing, and inductively coupled plasma mass spectrometry-based arsenic speciation to examine the effect of gut microbiome perturbations on the biotransformation of arsenic. Metagenomics sequencing revealed that bacterial infection significantly perturbed the gut microbiome composition in C57BL/6 mice, which in turn resulted in altered spectra of arsenic metabolites in urine, with inorganic arsenic species and methylated and thiolated arsenic being perturbed. These data clearly illustrated that gut microbiome phenotypes significantly affected arsenic metabolic reactions, including reduction, methylation, and thiolation. These findings improve our understanding of how infectious diseases and environmental exposure interact and may also provide novel insight regarding the gut microbiome composition as a new risk factor of individual susceptibility to environmental chemicals.

Temperature and solvent effects on radical scavenging ability of phenols.

In this work we have demonstrated the free radical scavenging ability of two-hydroxy (catechol, hydroquinone, resorcinol) and three-hydroxy (phloroglucinol, pyrogallol, 1,2,4-benzenetriol) phenols against the diphenylpicrylhydrazyl radical at various temperatures (15-40 degrees C) and in different solvent media. Kinetic measurements, made by the stopped-flow method, showed that the phenols with OH groups in the ortho positions have the largest rate coefficients compared to those with OH groups in the meta and para positions at all temperatures and in all solvent media. Among the ortho-structured phenols catechol, pyrogallol, and 1,2,4-benzenetriol, pyrogallol (three OH groups ortho to each other) had the greatest radical scavenging ability. This suggested that intramolecular hydrogen bonding in phenols controlled the rate of radical scavenging ability. The radical scavenging ability of phenols was fastest in methanol and slowest in THF, which emphasized the importance of the interactive behavior of the phenolic OH with the solvent. We concluded from our kinetic data together with our theoretically calculated OH bond dissociation enthalpies of phenols that the OH position played a crucial role in addition to the temperature and nature of the medium in determining the rate of the radical scavenging ability of polyphenols.

Investigation of the influence of hydroxy groups on the radical scavenging ability of polyphenols.

Recently, O-H bond dissociation enthalpies (BDEs) have been successfully used to express the free radical scavenging ability of polyphenolic antioxidants. In this work, the BDEs of phenol, catechol, resorcinol, hydroquinone, pyrogallol, phloroglucinol, 1,2,4-benzenetriol, and 5-hydroxypyrogallol have been calculated at B3LYP/6-311G++(3df, 3pd) and used to elucidate the effect of OH groups. Increasing the number of OH groups in the adjacent (vicinal) position decreases the BDE of phenols. Increasing the number of O-H groups in the alternative position C(1,3) as in resorcinol and C(1,3,5) as in phloroglucinol does not show any notable change in the BDEs when compared to that of OH in C(1) as in phenol. 5-Hydroxypyrogallol has the smallest BDE (250.3 kJ mol(-1)) followed by pyrogallol (289.4 kJ mol(-1)), then 1,2,4-benzenetriol (294.8 kJ mol(-1)), and then catechol (312.8 kJ mol(-1)). Overall, our results indicated that the presence of ortho and para hydroxy groups reduces the BDEs. An intramolecular hydrogen bond (IHB) develops due to the ortho arrangement of OH's and plays a dominant role in decreasing the BDEs. This key study on phenols showed that the reactive order of OH position in the benzene ring is the following: 5-hydroxypyrogallol > pyrogallol > 1,2,4-benzenetriol > catechol > hydroquinone >> phenol approximately resorcinol approximately phloroglucinol.