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Aims: To utilize the estimated glucose disposal rate (eGDR) index of insulin sensitivity, which is based on readily available clinical variables, namely, waist circumference, hypertension and glycated haemoglobin, to discriminate between metabolically healthy and unhealthy phenotypes, and to determine the prevalence of prediabetic conditions. Methods: Non‐diabetic individuals (n = 2201) were stratified into quartiles of insulin sensitivity based on eGDR index. Individuals in the upper quartiles of eGDR were defined as having metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW) or metabolically healthy obesity (MHO) according to their body mass index, while those in the lower quartiles were classified as having metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW) and metabolically unhealthy obesity (MUO), respectively. Results: The frequency of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG + IGT status was comparable among the MHNW, MHOW and MHO groups, while it increased from those with MUNW status towards those with MUOW and MUO status. As compared with participants with MHNW, the odds ratio of having IFG, IGT, or IFG + IGT was significantly higher in participants with MUOW and MUO but not in those with MUNW, MHOW and MHO, respectively. Conclusions: A metabolically healthy phenotype is associated with lower frequency of IFG, IGT, and IFG + IGT status across all body weight categories. [ABSTRACT FROM AUTHOR]

Background: Artificial intelligence (AI) has numerous applications in pathology, supporting diagnosis and prognostication in cancer. However, most AI models are trained on highly selected data, typically one tissue slide per patient. In reality, especially for large surgical resection specimens, dozens of slides can be available for each patient. Manually sorting and labelling whole‐slide images (WSIs) is a very time‐consuming process, hindering the direct application of AI on the collected tissue samples from large cohorts. In this study we addressed this issue by developing a deep‐learning (DL)‐based method for automatic curation of large pathology datasets with several slides per patient. Methods: We collected multiple large multicentric datasets of colorectal cancer histopathological slides from the United Kingdom (FOXTROT, N = 21,384 slides; CR07, N = 7985 slides) and Germany (DACHS, N = 3606 slides). These datasets contained multiple types of tissue slides, including bowel resection specimens, endoscopic biopsies, lymph node resections, immunohistochemistry‐stained slides, and tissue microarrays. We developed, trained, and tested a deep convolutional neural network model to predict the type of slide from the slide overview (thumbnail) image. The primary statistical endpoint was the macro‐averaged area under the receiver operating curve (AUROCs) for detection of the type of slide. Results: In the primary dataset (FOXTROT), with an AUROC of 0.995 [95% confidence interval [CI]: 0.994–0.996] the algorithm achieved a high classification performance and was able to accurately predict the type of slide from the thumbnail image alone. In the two external test cohorts (CR07, DACHS) AUROCs of 0.982 [95% CI: 0.979–0.985] and 0.875 [95% CI: 0.864–0.887] were observed, which indicates the generalizability of the trained model on unseen datasets. With a confidence threshold of 0.95, the model reached an accuracy of 94.6% (7331 classified cases) in CR07 and 85.1% (2752 classified cases) for the DACHS cohort. Conclusion: Our findings show that using the low‐resolution thumbnail image is sufficient to accurately classify the type of slide in digital pathology. This can support researchers to make the vast resource of existing pathology archives accessible to modern AI models with only minimal manual annotations. [ABSTRACT FROM AUTHOR]

Introduction: This cross‐sectional study aimed to investigate the association between myocardial mechano‐energetic efficiency (MEE) and whole blood viscosity (WBV) in nondiabetic adults participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study. Methods: 1143 participants underwent an oral glucose tolerance test and an echocardiogram for myocardial MEE per gram of left ventricular mass (MEEi) measurement. WBV was measured as: [0.12 × h] + [0.17 × (p‐2.07)], where h is haematocrit and p is plasma protein levels. Results: Study population includes 595 males and 548 females with a mean age of 46 ± 12 years and a mean BMI of 30.0 ± 6.2 kg/m2. Individuals with normal glucose tolerance were 63%, while those with impaired fasting glucose, impaired glucose tolerance and or the combination of both were 14.3%, 13% and 9.7%, respectively. A univariate analysis showed that MEEi was significantly associated with sex, age, smoking, BMI, waist circumference, total cholesterol, HDL, triglycerides, fasting glucose, fasting insulin, HOMA‐IR index, glucose tolerance, C‐reactive protein, haematocrit, haemoglobin, plasma protein and WBV. In a multivariable regression model including variables that were significantly associated with MEEi in univariate analysis, MEEi was associated with HOMA‐IR (β = −0.144, p <.001), age (β = −0.140, p <.001), WBV (β = −0.129, p <.001) and glucose tolerance (β = −0.064, p =.04). The independent association between WBV and MEEi remained statistically significant (β = −0.122, p <.001) when antihypertensive therapy and lipid‐lowering therapy were included in the model. Conclusion: WBV is associated with decreased myocardial MEE independently of other cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Prolonged droughts and heatwaves are common causes of agricultural failure in Australia, yet the origins of these climate anomalies remain understudied. Here, we use a Lagrangian trajectory model driven by atmospheric reanalysis and constrained by satellite data to unravel the sources of precipitation and heat over the Southeastern Australia wheat belt. Furthermore, we assess the impact of local and upwind drought conditions on the moisture and heat imports to the region. Results indicate that the most extreme crop failure events over the wheat belt (i.e., 1994, 2002, and 2006) were associated with persistent high‐pressure systems. The ocean provided on average 72% of the moisture for precipitation and 39% of the heat arriving over the wheat belt, with the moisture sources substantially decreasing during crop failure events. Upwind drought further intensified rainfall deficits and heat stress during these events due to lower moisture and higher heat imports to the region. This was particularly clear during the initial phase of the Millennium Drought in 2002. Then, yield deficits exceeded 50%, and ∼4% of the precipitation originated from drought‐affected regions upwind, compared to the 9% that was expected climatologically from those regions. Simultaneously, the heat import from these regions upwind increased by ∼10 W m−2, from the climatological 23%–25%, during this event. While these results indicate a limited potential for upwind land management to mitigate downwind agricultural loss in the Southeastern Australia wheat belt, other agricultural regions with a higher climatic dependency on remote land may benefit from such strategies. Plain Language Summary: Droughts and heatwaves are posing threats to wheat production worldwide. In Australia, one of the largest wheat producers, the relationship between crop yield and climate anomalies remains understudied. Here, we use a novel framework dedicated to track heat and moisture across the atmosphere, which enables the identification of the sources of precipitation and temperature over the Southeastern Australia wheat belt, and the quantification of the influence of droughts on agricultural productivity. Results show that upwind droughts intensify precipitation deficits and heat stress by providing less moisture and more heat to the wheat belt during the years in which wheat production decays. This holds potential implications for land use management strategies dedicated to ensuring agricultural food supply by influencing weather patterns. Key Points: Crop failure events in the Australian wheat belt relate to anomalies in precipitation and its contribution from land and oceanic originsLand surfaces provide less moisture but more heat than the oceans and this difference tends to be aggravated during crop failure eventsUpwind droughts amplify the precipitation deficits and heat accumulation in the Australian wheat belt [ABSTRACT FROM AUTHOR]

Introduction: Considering the reported efficacy of monoclonal antibodies (mAbs) directed against the Spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in reducing disease severity, the aim of this study was to investigate the innate immune response before and after mAbs treatment in 72 vaccinated and 31 unvaccinated SARS‐CoV‐2 patients. Methods: The mRNA levels of IFN‐I, IFN‐related genes and cytokines were evaluated using RT/real‐time quantitative PCR. Results: Vaccinated patients showed increased rate of negative SARS‐CoV‐2 PCR tests on nasopharyngeal swab compared with unvaccinated ones after mAbs treatment (p =.002). Unvaccinated patients had lower IFN‐α/ω and higher IFN‐related genes (IFNAR1, IFNAR2, IRF9, ISG15, ISG56 and IFI27) and cytokines (IL‐6, IL‐10 and TGF‐β) mRNA levels compared to vaccinated individuals before mAbs (p <.05 for all genes). Increased IFN‐α/ω, IFNAR1, IFNAR2 and IRF9 levels were observed in unvaccinated patients after mAbs treatment, while the mRNA expression ISGs and IL‐10 were reduced in all patients. Conclusion: These data suggest that anti‐S vaccinated patients have increased levels of innate immune genes compared to unvaccinated ones. Also, gene expression changes in IFN genes after mAbs administration are different according to the vaccination status of patients. [ABSTRACT FROM AUTHOR]

Background: Poor performance is a multifactorial syndrome of racehorses, commonly associated with subclinical disorders, which can be diagnosed by exercise testing. Objectives: Describe the prevalence of medical causes of poor performance in Standardbreds unassociated with lameness, and evaluate their relationships with fitness variables measured by exercise treadmill test. Animals: Hospital population of 259 nonlame Standardbred trotters referred for poor performance. Methods: The horses' medical records were retrospectively reviewed. Horses underwent a diagnostic protocol including resting examination, plasma lactate concentration, treadmill test with continuous ECG and assessment of fitness variables, creatine kinase activity, treadmill endoscopy, postexercise tracheobronchoscopy, bronchoalveolar lavage (BAL), and gastroscopy. The prevalence of different disorders was evaluated, including cardiac arrhythmias, exertional myopathies, dynamic upper airway obstructions (DUAOs), exercise‐induced pulmonary hemorrhage (EIPH), moderate equine asthma (MEA), and gastric ulcers (EGUS). The associations of these disorders with fitness variables were investigated individually and using multivariable models. Results: Moderate equine asthma and EGUS were the most common disorders, followed by EIPH, DUAOs, cardiac arrhythmias, and exertional myopathies. Hemosiderin score was positively correlated with BAL neutrophils, eosinophils, and mast cells; increased creatine kinase activity was associated with BAL neutrophilia, DUAOs, premature complexes, and squamous gastric disease. Treadmill velocity at a plasma lactate concentration of 4 mmol/L and at heart rate of 200 beats per minute was negatively affected by BAL neutrophilia, multiple DUAOs, exertional myopathies, and squamous gastric disease. Conclusions: The multifactorial nature of poor performance was confirmed, with MEA, DUAOs, myopathies and EGUS representing the main diseases involved in fitness impairment. [ABSTRACT FROM AUTHOR]

Functional and structural damage of the intestinal mucosal barrier significantly contribute to translocation of gut microbial products into the bloodstream and are largely involved in HIV‐1 associated chronic immune activation. This microbial translocation is largely due to a progressive exhaustion of intestinal macrophage phagocytic function, which leads to extracellular accumulation of microbial derived components and results in HIV‐1 disease progression. This study aims to better understand whether the modulation of gut microbiota promotes an intestinal immune restoration in people living with HIV (PLWH). Long‐term virologically suppressed PLWH underwent blood, colonic, and fecal sampling before (T0) and after 6 months (T6) of oral bacteriotherapy. Age‐ and gender‐matched uninfected controls (UC) were also included. 16S rRNA gene sequencing was applied to all participants' fecal microbiota. Apoptosis machinery, mitochondria, and apical junctional complex (AJC) morphology and physiological functions were analyzed in gut biopsies. At T0, PLWH showed a different pattern of gut microbial flora composition, lower levels of occludin (p = 0.002) and zonulin (p = 0.01), higher claudin‐2 levels (p = 0.002), a reduction of mitochondria number (p = 0.002), and diameter (p = 0.002), as well as increased levels of lipopolysaccharide (LPS) (p = 0.018) and cCK18 (p = 0.011), compared to UC. At T6, an increase in size (p = 0.005) and number (p = 0.008) of mitochondria, as well as amelioration in AJC structures (p < 0.0001) were observed. Restoration of bacterial richness (Simpson index) and biodiversity (Shannon index) was observed in all PLWH receiving oral bacteriotherapy (p < 0.05). Increased mitochondria size (p = 0.005) and number (p = 0.008) and amelioration of AJC structure (p < 0.0001) were found at T6 compared to T0. Moreover, increased occludin and zonulin concentration were observed in PLWH intestinal tracts and decreased levels of claudin‐2, LPS, and cCK18 were found after oral bacteriotherapy (T0 vs. T6, p < 0.05 for all these measures). Oral bacteriotherapy supplementation might restore the balance of intestinal flora and support the structural and functional recovery of the gut mucosa in antiretroviral therapy treated PLWH. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to evaluate the association between SARS‐CoV‐2 infection and serum hepatic biomarker levels among women with obstetric cholestasis. Methods: In this prospective study, we recruited all pregnant women admitted in our hospital with obstetric cholestasis. Among those with a concurrent SARS‐CoV‐2 infection, we evaluated the following serum hepatic biomarkers: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and biliar acids (BA). Results: Among the 88 women enrolled in the study, 20 presented with a SARS‐CoV‐2 infection while 68 were negative. SARS‐CoV‐2 infected women were younger (mean age 30.5 ± 5.7 vs. 34.3 ± 5.4; p < 0.01) and in a greater percentage of non‐Caucasian ethnicity when compared to noninfected women (60.0% vs. 17.6%; p < 0.01). Regarding levels of hepatic biomarkers, they showed higher levels of AST (111.5 ± 134.1 vs. 37.3 ± 43.4 UI/L; p = 0.02), ALT (132.2 ± 115.7 vs. 50.5 ± 73.173.1 UI/L; p < 0.01), and BA (41.4 ± 46.8 vs. 18.4 ± 13.4 μmol/L; p = 0.04) compared to noninfected patients. No significant differences in maternal or fetal outcomes were found between infected and noninfected women. Conclusion: SARS‐CoV‐2 infection was associated with higher levels of liver enzymes in patients with obstetric cholestasis. This could be the result of a possible hepatic involvement in patients with SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Introduction: Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first‐choice treatment or regarded as a major treatment option. Materials and methods: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. Results: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. Conclusion: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public‐private partnerships. [ABSTRACT FROM AUTHOR]

Objectives: To assess labour characteristics in relation to the occurrence of Composite Adverse neonatal Outcome (CAO) within a cohort of fetuses with metabolic acidaemia. Design: Retrospective cohort study. Setting: Three Italian tertiary maternity units. Population: 431 neonates born with acidaemia ≥36 weeks. Methods: Intrapartum CTG traces were assigned to one of these four types of labour hypoxia: acute, subacute, gradually evolving and chronic hypoxia. The presence of CAO was defined by the occurrence of at least one of the following: Sarnat Score grade ≥2, seizures, hypothermia and death <7 days from birth. Main outcome measures: To compare the type of hypoxia on the intrapartum CTG traces among the acidaemic neonates with and without CAO. Results: The occurrence of a CAO was recorded in 15.1% of neonates. At logistic regression analysis, the duration of the hypoxia was the only parameter associated with CAO in the case of an acute or subacute pattern (odds ratio [OR] 1.3; 95% CI 1.02–1.6 and OR 1.04; 95% CI 1.0–1.1, respectively), whereas both the duration of the hypoxic insult and the time from PROM to delivery were associated with CAO in those with a gradually evolving pattern (OR 1.13; 95% CI 1.01–1.3 and OR 1.04; 95% CI 1.0–1.7, respectively). The incidence of CAO was higher in fetuses with chronic antepartum hypoxia than in those showing CTG features of intrapartum hypoxia (64.7 vs. 13.0%; P < 0.001). Conclusions: The frequency of CAO seems related to the duration and the type of the hypoxic injury, being higher in fetuses showing CTG features of antepartum chronic hypoxia. This study demonstrates that in a large population of neonates with metabolic acidaemia at birth, the overall incidence of short‐term adverse outcome is around 15%. Such risk seems closely correlated to the duration and the type of hypoxic injury, being higher in fetuses admitted in labour with antepartum chronic hypoxia than those experiencing intrapartum hypoxia. This study demonstrates that in a large population of neonates with metabolic acidaemia at birth, the overall incidence of short‐term adverse outcome is around 15%. Such risk seems closely correlated to the duration and the type of hypoxic injury, being higher in fetuses admitted in labour with antepartum chronic hypoxia than those experiencing intrapartum hypoxia. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant therapy with dual HER2 blockade improved pathological complete response (pCR) rate in HER2‐positive breast cancer patients. Nevertheless, it would be desirable to identify patients exquisitely responsive to single agent trastuzumab to minimize or avoid overtreatment. Herein, we evaluated the predictive and prognostic value of basal primary tumor miRNA expression profile within the trastuzumab arm of NeoALTTO study (ClinicalTrials.gov Identifier: NCT00553358). Methods: RNA samples from baseline biopsies were randomized into training (n = 45) and testing (n = 47) sets. After normalization, miRNAs associated with Event‐free survival (EFS) and pCR were identified by univariate analysis. Multivariate models were implemented to generate specific signatures which were first confirmed, and then analyzed together with other clinical and pathological variables. Results: We identified a prognostic signature including hsa‐miR‐153‐3p (HR 1.831, 95% CI: 1.34–2.50) and hsa‐miR‐219a‐5p (HR 0.629, 95% CI: 0.50–0.78). For two additional miRNAs (miR‐215‐5p and miR‐30c‐2‐3p), we found a statistically significant interaction term with pCR (p.interaction: 0.017 and 0.038, respectively). Besides, a two‐miRNA signature was predictive of pCR (hsa‐miR‐31‐3p, OR 0.70, 95% CI: 0.53–0.92, and hsa‐miR‐382‐3p, OR: 1.39, 95% CI: 1.01–1.91). Notably, the performance of this predictive miRNA signature resembled that of the genomic classifiers PAM50 and TRAR, and did not improve when the extended models were fitted. Conclusion: Analyses of primary tumor tissue miRNAs hold the potential of a parsimonious tool to identify patients with differential clinical outcomes after trastuzumab based neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Greater amberjack (Seriola dumerili) is a very promising candidate for the diversification of the Mediterranean aquaculture due to its high demand, excellent flesh quality and high market prices. Its production expansion has, however, failed so far, due to several bottlenecks mainly related to pathology. This review addresses the major pathogens, which hinder the culture of greater amberjack with special focus in the Mediterranean region, and highlights possible treatment solutions. Among the important recorded pathogens of caged greater amberjack in the Mediterranean, the gill monogenean Zeuxapta seriolae seems to be the most problematic, causing significant losses. While formalin immersions are inefficient to combat this parasite, baths with hydrogen peroxide are extremely effective and praziquantel administration could be a more practical in‐feed treatment solution. The digenean blood flukes, Paradeontacylix spp., also account for important losses in greater amberjack farms in the same region. Dietary administration of praziquantel constitutes an effective therapeutic measure against those infections. Vibrio harveyi is also a bacterial pathogen severely affecting fish maintained both in land‐based facilities and in cages, whereas Epitheliocystis is a disease reported frequently that can be fatal when it occurs at early stages. Skin flukes such as Benedenia seriolae and Neobenedenia girellae as well as other parasites bacteria and viruses mentioned herein, which have caused substantial losses in Asian enterprises, but have not been identified yet in greater amberjack farmed in the Mediterranean, should be considered as potential threats. [ABSTRACT FROM AUTHOR]

Introduction: The objective of the present study is to compare the sonographic measurement of subcutaneous adipose thickness and visceral adipose thickness during 1st trimester screening for aneuploidies between non-diabetic pregnant women and patients who develop 1st trimester or 2nd trimester gestational diabetes mellitus (GDM).Material and Methods: Adipose thickness was measured by transabdominal ultrasound imaging in pregnant women attending our clinic for screening for fetal aneuploidies between 11 and 13 weeks of gestation. During the 1st trimester all patients were evaluated for fasting glycemia in accordance with the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommendations. Patients with confirmed fasting glycemia (FPG) ≥92 mg/dL were diagnosed as 1st trimester GDM. Patients with FPG <92 mg/dL underwent a 75-g oral glucose tolerance test between 24 and 28 weeks.Results: The study population included 238 non-diabetic women, 29 women with 1st trimester GDM and 28 women with 2nd trimester GDM. Mean subcutaneous adipose thickness and visceral adipose thickness values in non-diabetic women were 9.8 mm (standard deviation [SD = 4.9) and 7.2 mm (SD = 3.5), respectively. Values in women with 1st trimester GDM were 12.8 mm (SD = 6.5) and 9.9 mm (SD = 4.4). In the 2nd trimester GDM group, the mean subcutaneous adipose thickness was 11.1 mm (SD = 4.6) and the mean visceral adipose thickness 10.5 mm (SD = 5.3). Multiple logistic regression analysis showed that visceral adipose thickness, but not subcutaneous adipose thickness, was significantly and independently associated with both 1st trimester GDM (OR 1.15, 95% CI 1.02-1.29) and 2nd trimester GDM (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.05-1.34).Conclusions: Sonographic thickness of maternal visceral adipose tissue was greater in women with GDM than in non-diabetic patients, independently of other known risk factors associated with GDM in the 1st and in the 2nd trimester of pregnancy. Thus, this measurement may be considered of clinical use in 1st trimester screening. [ABSTRACT FROM AUTHOR]

Background: Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline‐directed standard genetic testing identifies a disease‐causing mutation in less than one‐third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death. Methods: We report on a case of sudden unexpected death of a 37‐year‐old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several "in silico" tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants. Results: WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death. Conclusion: Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths. [ABSTRACT FROM AUTHOR]

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One‐hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns—COMPASS 31+ESC and COMPASS 31 and/or ESC—were associated with CAN and DPN (P <.01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality. [ABSTRACT FROM AUTHOR]

Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes. [ABSTRACT FROM AUTHOR]

Background: The increasing age of the population and prolonged life expectancy result in a widening of age limit criteria for a variety of surgical procedures. Oesophagectomy and total gastrectomy are complex operations associated with significant risks of post‐operative complications. Methods: This is a single‐centre cohort study of patients operated with curative intent due to oesophageal or gastric cancer. Results: From 2007 to 2017, 548 patients underwent surgery with curative intent, with 122 patients (22.3%) classified as elderly (≥75 years). There was no difference in total complication rates between the groups. The adjusted odds ratio for 90‐day mortality after oesophageal resection in the elderly group was 3.65 (95% confidence interval (CI): 1.33–10.03) and after gastrectomy was 1.62 (95% CI: 0.55–4.79). The adjusted hazard ratio for 1‐year mortality after oesophagectomy was 2.29 (95% CI: 1.25–4.19), and after gastrectomy the adjusted hazard ratio was 1.48 (95% CI: 0.75–2.92). In the event of a complication with Clavien–Dindo score IIIb or higher, there was a statistically significant increase of 90‐day mortality to over 50% among elderly patients both after oesophagectomy and gastrectomy (50.0% versus 19.8%; P = 0.005 and 57.1% versus 17.4%; P = 0.012, respectively). Conclusion: There is a statistically significant increase in 90‐day mortality after oesophageal and gastric cancer surgery in elderly compared with younger patients. Post‐operative complications with high Clavien–Dindo score in patients undergoing oesophagectomy or gastrectomy, with age ≥75 years, are a dramatic risk factor for post‐operative death. [ABSTRACT FROM AUTHOR]

After 7 months of therapy, since medical treatment was no longer effective in stopping of neoplasm shrinkage, a surgical resection was performed. 2 Nguyen AH, Detty SQ, Gonzaga MI, Huerter C. Clinical features and treatment of dermatofibrosarcoma protuberans affecting the vulva: a literature review. Long-term results of treatment of advanced dermatofibrosarcoma protuberans (DFSP) with imatinib mesylate - the impact of fibrosarcomatous transformation. [Extracted from the article]

The ATPase family, AAA domain‐containing protein 2 (ATAD2) has a C‐terminal bromodomain, which functions as a chromatin reader domain recognizing acetylated lysine on the histone tails within the nucleosome. ATAD2 is overexpressed in many cancers and its expression is correlated with poor patient outcomes, making it an attractive therapeutic target and potential biomarker. We solved the crystal structure of the ATAD2 bromodomain and found that it contains a disulfide bridge near the base of the acetyllysine binding pocket (Cys1057‐Cys1079). Site‐directed mutagenesis revealed that removal of a free C‐terminal cysteine (C1101) residue greatly improved the solubility of the ATAD2 bromodomain in vitro. Isothermal titration calorimetry experiments in combination with the Ellman's assay demonstrated that formation of an intramolecular disulfide bridge negatively impacts the ligand binding affinities and alters the thermodynamic parameters of the ATAD2 bromodomain interaction with a histone H4K5ac peptide as well as a small molecule bromodomain ligand. Molecular dynamics simulations indicate that the formation of the disulfide bridge in the ATAD2 bromodomain does not alter the structure of the folded state or flexibility of the acetyllysine binding pocket. However, consideration of this unique structural feature should be taken into account when examining ligand‐binding affinity, or in the design of new bromodomain inhibitor compounds that interact with this acetyllysine reader module. [ABSTRACT FROM AUTHOR]

Summary: Background: Children born small for gestational age (SGA) are at increased risk of metabolic dysfunction. Dysregulation of specific microRNAs (miRNAs) contributes to aberrant gene expression patterns underlying metabolic dysfunction. Objective: We aimed to determine and compare circulating miRNA (c‐miRNA) profile of SGA and appropriate for gestational age (AGA) children with obesity and with normal weight, in order to identify biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity. Methods: Small non‐coding RNAs from serum of 15 SGA children with obesity (OB‐SGA), 10 SGA children with normal weight (NW‐SGA), 17 AGA children with obesity (OB‐AGA) and 12 AGA children with normal weight (NW‐AGA) (mean age 11.2 ± 2.6) have been extracted and sequenced in order to detect and quantify miRNA expression profiles. Results: RNA‐seq analyses showed 28 miRNAs dysregulated in OB‐SGA vs. NW‐SGA and 19 miRNAs dysregulated in OB‐AGA vs. NW‐AGA. Among these, miR‐92a‐3p, miR‐122‐5p, miR‐423‐5p, miR‐484, miR‐486‐3p and miR‐532‐5p were up regulated, and miR‐181b‐5p was down regulated in both OB‐SGA and OB‐AGA compared with normal weight counterparts. Pathway analysis and miRNA target prediction suggested that these miRNAs were particularly involved in insulin signalling, glucose transport, insulin resistance, cholesterol and lipid metabolism. Conclusion: We identified a specific profile of c‐miRNAs in SGA and AGA children with obesity compared with SGA and AGA children with normal weight. These c‐miRNAs could represent specific biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity. [ABSTRACT FROM AUTHOR]

Abstract: Cationic polylysine promotes, under neutral conditions, the spontaneous aggregation of opposite charged ZnTPPS in water. Spectroscopic investigations evidence a different preorganization of ZnTPPS onto the polypeptide matrix depending on the chain length. Spinodal decomposition theory in confined geometry is used to model this mechanism by considering the time evolution of a homogeneous distribution of randomly adsorbed particles (porphyrins) onto a rodlike polyelectrolyte (polymer) of variable length L. [ABSTRACT FROM AUTHOR]

Objective: The aim was to investigate whether vitamin D supplementation, combined with a hypocaloric diet, could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters, body composition, glucose tolerance, and insulin secretion were considered as secondary outcomes.Methods: Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI > 25 kg/m2 were randomized (1:1) in a double-blind manner to a hypocaloric diet + either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months. Hyperinsulinemic-euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention.Results: Body weight in both groups decreased significantly (-7.5% in the vitamin D group and -10% in the placebo group; P < 0.05 for both), with no between-group differences. Serum 25-hydroxyvitamin D levels in the vitamin D group increased considerably (from 36.7 ± 13.2 nmol/L to 74.8 ± 18.7 nmol/L; P < 0.001). Insulin sensitivity in the vitamin D group improved (from 4.6 ± 2.0 to 6.9 ± 3.3 mg·kg-1 ·min-1 ; P < 0.001), whereas no changes were observed in the placebo group (from 4.9 ± 1.1 to 5.1 ± 0.3 mg·kg-1 ·min-1 ; P = 0.84).Conclusions: Cholecalciferol supplementation, combined with a weight loss program, significantly improves insulin sensitivity in healthy subjects with obesity and might represent a personalized approach for insulin-resistant subjects with obesity. [ABSTRACT FROM AUTHOR]

Objectives To explore the performance of the neutrophil-to-lymphocyte ratio ( NLR), an index of systemic inflammation that predicts prognosis of several diseases, in a cohort of elderly adults with community-acquired pneumonia ( CAP). Design Prospective clinical study from January 2014 to July 2016. Setting Unit of Internal Medicine, University of Catania, Catania, Italy. Participants Elderly adults admitted for CAP (N = 195). Measurements Clinical diagnosis of CAP was defined as the presence of a new infiltrate on plain chest radiography or chest computed tomography associated with one or more suggestive clinical features such as dyspnea, hypo- or hyperthermia, cough, sputum production, tachypnea (respiration rate >20 breaths per minute), altered breath sounds on physical examination, hypoxemia (partial pressure of oxygen <60 mmHg), leukocytosis (white blood cell count >10,000/μL). Clinical examination, traditional tests such as Pneumonia Severity Index ( PSI); Confusion, Urea, Respiratory rate, Blood pressure, aged 65 and older (CURB-65), and NLR were evaluated at admission. The accuracy and predictive value for 30-day mortality of traditional scores and NLR were compared. Results NLR predicted 30-day mortality ( P < .001) and performed better than PSI ( P < .05), CURB-65, C-reactive protein, and white blood cell count ( P < .001) to predict prognosis. No deaths occurred in participants with a NLR of less than 11.12. Thirty-day mortality was 30% in those with a NLR between 11.12% and 13.4% and 50% in those with a NLR between 13.4 and 28.3. All participants with a NLR greater than 28.3 died within 30 days. Conclusions These results would encourage early discharge of individuals with a NLR of less than 11.12, short-term in-hospital care for those with a NLR between 11.12 and 13.4, middle-term hospitalization for those with a NLR between 13.4 and 28.3, and admission to a respiratory intensive care unit for those with a NLR greater than 28.3. [ABSTRACT FROM AUTHOR]

The neuromuscular junction has retained through evolution the capacity to regenerate after damage, but little is known on the inter-cellular signals involved in its functional recovery from trauma, autoimmune attacks, or neurotoxins. We report here that CXCL12α, also abbreviated as stromal-derived factor-1 ( SDF-1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by α-latrotoxin. CXCL12α acts via binding to the neuronal CXCR4 receptor. A CXCL12α-neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration in vivo. Recombinant CXCL12α in vivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons in vitro. These findings indicate that the CXCL12α- CXCR4 axis plays an important role in the regeneration of the neuromuscular junction after motor axon injury. The present results have important implications in the effort to find therapeutics and protocols to improve recovery of function after different forms of motor axon terminal damage. [ABSTRACT FROM AUTHOR]

Recent developments in vitreoretinal surgery have increased the need for suitable vitreous substitutes. A successful substitute should maintain all the physical and biochemical properties of the original vitreous, be easy to manipulate, and be long lasting. Substitutes can be gaseous or liquid, both of which have associated advantages and disadvantages related to their physical properties and use. Furthermore, new surgical techniques with smaller vitreoretinal instruments have driven the use of more viscous substitutes. In this review, we analyze and discuss the most frequently used vitreous substitutes and look ahead to future alternatives. We classify these compounds based on their composition and structure, discuss their clinical use with respect to their associated advantages and disadvantages, and analyze how new vitreoretinal surgical techniques have modified their use. [ABSTRACT FROM AUTHOR]

The Otway Basin in the south of Victoria, Australia underwent three phases of deformation during breakup of the southern Australian margin. We assess the geometry and kinematics of faulting in the basin by analysing a 3-D reflection seismic volume. Eight stratigraphic horizons and 24 SW-dipping normal faults as well as subordinate antithetic faults were interpreted. This resulted in a high-resolution geological 3-D model ( ca. 8 km × 7 km × 4 km depth) that we present as a supplementary 3-D PDF (Data S1). We identified hard- and soft-linking fault connections over the entire area, such as antithetic faults and relay ramps, respectively. Most major faults were continuously active from Early to Late Cretaceous, with two faults in the northern part of the study area active until at least the Oligocene. Allan maps of faults show tectonic activity continuously waned over this time period. Isopach maps of stratigraphic volumes quantify the amount of syn-sedimentary movement that is characteristic of passive margins, such as the Otway Basin. We show that the faults possess strong corrugations (with amplitudes above the seismic resolution), which we illustrated by novel techniques, such as cylindricity and curvature. We argue that the corrugations are produced by sutures between sub-vertical fault segments and this morphology was maintained during fault growth. Thus, they can be used to indicate the kinematics vector of the fault movement. This evidences, together with left-stepping relay ramps, that 40% of the faults had a small component (up to 25°) of dextral oblique slip as well as normal (dip-slip) movement. [ABSTRACT FROM AUTHOR]

The presence and localization of caspase 3, a master enzyme in apoptosis, have been analyzed in tissues of four species of Molluscs: the Bivalves Callista chione and Adamussium colbecki and the Gastropods Helix pomatia and Neobuccinum eatoni. Western blotting and immunocytochemical analyses show that a 32 kDa caspase 3 is present in guts, in gill lamellae and in digestive glands during digestion but not in heart tissue or in resting digestive glands. The enzyme is also found in gonads of both sexes but there are significant differences between Bivalves and Gastropods and between male and female germ cells, especially in late stages of differentiation. In particular, caspase 3 is abundant in Bivalves oocytes and in Gastropods spermatozoa but not in Gastropods oocytes; in Callista spermatozoa it appears only after sea water activation. TUNEL staining and PCNA immunolocalization, carried out on C. chione and H. pomatia tissues, suggest that caspase 3 is primarily associated with degenerative processes in gut, digestive gland and early stage germ cells while in gills, oocytes and mature spermatozoa it is primarily correlated with cell function and/or differentiation. J. Exp. Zool. 319A: 548-559, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose: The aim of this review was to evaluate the survival rate of upright and tilted implants supporting fixed prosthetic reconstructions for the immediate rehabilitation of partially and fully edentulous jaws, after at least 1 year of function. Materials and Methods: An electronic search of databases plus a hand search on the most relevant journals up to December 2009 was performed. The articles were selected using specific inclusion criteria, independent of the study design. Results: The literature search yielded 347 articles. A first screening based on the title and abstract identified 25 eligible studies. After full-text review of these studies, 10 articles were selected for analysis. Seven were prospective single-cohort studies and three had a retrospective design. A total of 462 patients have been rehabilitated with 470 immediately loaded prostheses (257 in the maxilla, 213 in the mandible), supported by a total of 1,992 implants (1,026 upright and 966 tilted). Twenty-five implants (1.25%) failed in 20 patients within the first year. All failures except one occurred in the maxilla. No significant difference in failure rate was found between tilted and upright implants, nor between maxillary and mandibular implants. No prosthesis failure was reported. Limited peri-implant bone loss was reported with no difference between upright and tilted implants. Full patients' satisfaction for function, phonetics, and esthetics was reported in three studies, based on questionnaires. Conclusions: The use of tilted implants to support immediately loaded fixed prostheses for the rehabilitation of edentulous jaws can be considered a predictable technique, with an excellent prognosis in the short-medium term. However, randomized long-term trials are needed to determine the efficacy of this surgical approach. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate the prevalence of white-coat effect (WCE), and its association with individual anxiety and insight of disease, among older patients evaluated for suspected cognitive impairment. METHODS: This prospective cohort study, conducted in an Alzheimer Evaluation Unit, involved patients aged 55 years or older with suspected cognitive impairment. WCE was defined as a difference of at least 20 mmHg in systolic or 10 mmHg in diastolic blood pressure (BP) measured either by a physician during the visit or by a nurse (before and after the visit), compared with home self-blood pressure measurement (SBPM). Severity of cognitive impairment was evaluated through the Mini-Mental State Examination (MMSE); the Clinical Insight Rating Scale (CIR) and the Guidelines for the Rating for Awareness Deficits (GRAD) were used to evaluate the subject's insight; anxiety disorder was evaluated using the seven-question Generalized Anxiety Disorder scale (GAD-7). RESULTS: Among 273 subjects, prevalence of WCE was 52%, 32.6% and 30.4%, according to physician and nurse BP measurements, respectively (p = 0.000). Prevalence of WCE did not differ between patients diagnosed with and without dementia, but was higher among patients with than in those without anxiety disorder (70.7% vs 38.2%, p = 0.000). Positive relations were observed between severity of anxiety and insight of disease, which were both inversely related with severity of cognitive impairment. CONCLUSIONS: WCE is extremely common and is correlated to individual anxiety and insight of disease among older outpatients with suspected cognitive impairment; overestimation of hypertension severity might lead to unnecessary drug treatment and greater health costs in this setting. [ABSTRACT FROM AUTHOR]

Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B-cell non-Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y-ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed – 30 MBq/kg (0·8 mCi/kg), 45 MBq/kg (1·2 mCi/kg) and 56 MBq/kg (1·5 mCi/kg) – and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin® administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non-haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high-activity Zevalin® with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high-dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphoma (ALCL) is characterized by preferential paracortical and intrasinusoidal lymph node involvement by large anaplastic tumor cells expressing the CD30 antigen. Up to 80% of pediatric patients with ALCL can be cured with multi-agent chemotherapeutic regimens. Patients resistant to chemotherapy or suffering from early relapse have a poor prognosis and a poor chance of survival. In these cases, the highly aggressive clinical course of ALCL, associated with systemic symptoms and extranodal involvement, has been treated with different approaches in various cooperative trials, including conventional chemotherapy and human stem cell transplantation (HSCT). However, the optimal treatment has not yet been defined, in particular in cases of relapse. More recently, radioimmunotherapy has been studied with encouraging results in cancer patients, including non-Hodgkin’s lymphoma. Here we describe the case of a pediatric ALCL, relapsing after HSCT, treated with pretargeted antibody-guided radioimmunotherapy, obtaining a complete remission, with excellent quality of life over the past 10 months. [ABSTRACT FROM AUTHOR]

Serum deprivation induced in human lymphoblastoid Raji cells oxidative stress-associated apoptotic death and G0/G1 cell cycle arrest. Addition into culture medium of the immunomodulatory protein Seminal vesicle protein 4 (SV-IV) protected these cells against apoptosis but not against cycle arrest. The antiapoptotic activity was related to: (1) decrease of endocellular reactive Oxygen species (ROS) (2) increase of mRNAs encoding anti-oxidant enzymes (catalase, G6PD) and antiapoptotic proteins (survivin, cox-1, Hsp70, c-Fos); (3) decrease of mRNAs encoding proapoptotic proteins (c-myc, Bax, caspase-3, Apaf-1). The biochemical changes underlaying these effects were probably induced by a protein tyrosine kinase (PTK) activity triggered by the binding of SV-IV to its putative plasma membrane receptors. The ineffectiveness of SV-IV to abrogate the cycle arrest was accounted for by its downregulating effects on D1,3/E G1-cyclins and CdK2/4 gene expression, ppRb/pRb ratio, and intracellular ROS concentration. In conclusion, these experiments: (1) prove that SV-IV acts as a cell survival factor; (2) suggest the involvement of a PTK in SV-IV signaling; (3) point to cell cycle-linked enzyme inhibition as responsible for cycle arrest; (4) provide a model to dissect the cycle arrest and apoptosis induced by serum withdrawal; (5) imply a possible role of SV-IV in the survival of hemiallogenic implanting embryos. J. Cell. Physiol. 212:610–625, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Among children, medication palatability is crucial for adherence to therapeutic regimen. • Several studies have measured the palatability of antimicrobial suspensions in paediatric patients by means of a visual analogue scale palatability score. What this study adds • This is the first analysis comparing the taste and smell acceptability of angiotensin II receptor blockers among paediatric patients with kidney disease. • From the perspective of the child with kidney disease, the taste of pulverized candesartan is significantly superior to that of pulverized irbesartan, losartan, telmisartan or valsartan. Aim Angiotensin II receptor blockers are widely prescribed in kidney disease. Among children, medication palatability is crucial for adherence. Methods Taste and smell acceptability of five angiotensin II receptor blockers were compared among 21 nephropathic children using a visual analogue scale palatability score. Results The score assigned to pulverized tablets of candesartan cilexetil was significantly higher than that assigned to pulverized tablets of irbesartan, losartan, telmisartan and valsartan. Conclusions From the perspective of the nephropathic child, the taste of pulverized candesartan cilexetil is superior to that of irbesartan, losartan, telmisartan or valsartan. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a polygenic and multifactorial complex disease, whose etiopathology is still unclear, however several genetic factors have shown to increase the risk of developing the disease. Purine nucleotides and nucleosides play an important role in the brain. Besides their role in neurotransmission and neuromodulation, they are involved in trophic factor release, apoptosis, and inflammatory responses. These mediators may also have a pivotal role in the control of neurodegenerative processes associated with AD. In this report the distribution of the exonic G/A single nucleotide polymorphism (SNP) in purine nucleoside phosphorylase (PNP) gene, resulting in the amino acid substitution serine to glycine at position 51 (G51S), was investigated in a large population of AD patients (n = 321) and non-demented control (n = 208). The PNP polymorphism distribution was not different between patients and controls. The polymorphism distribution was also analyzed in AD patients stratified according to differential progressive rate of cognitive decline during a 2-year follow-up. An increased representation of the PNP AA genotype was observed in AD patients with fast cognitive deterioration in comparison with that from patients with slow deterioration rate. Our findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in AD patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Reverse Cover: The cover image is based on the Structure Note Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain by Jamie C. Gay et al., DOI: 10.1002/prot.25636. [ABSTRACT FROM AUTHOR]

Aim To quantify the expression of sodium-glucose co-transporter ( SGLT)2 and SGLT1, their cognate basolateral transporters, GLUT2 and GLUT1, and the transcriptional regulator of SGLTs in renal tissue obtained from people with T2DM and a group of well-matched people without diabetes. Methods We measured SGLT2 and SGLT1 expression in unaffected renal tissue from 19 people with T2DM and 20 people without diabetes, matched for age and estimated glomerular filtration rate (controls), undergoing unilateral nephrectomy. Expression of SGLT2 and SGLT1, as well as that of GLUT2 and GLUT1, was quantified using real-time and digital PCR; an affinity-purified antibody against human SGLT2 was used to localize SGLT2 by immunohistochemistry. Results SGLT2 expression was higher in control than T2DM tissue (median [interquartile range] target/β-actin 1.62 [2.02] vs 0.67 [0.61]; P < .0001), and SGLT1 trended in the same direction (0.98 [1.19] vs 0.44 [0.48]; P = .08). Immunohistochemistry clearly localized SGLT2 to the tubular brush-border membranes, and was semi-quantitatively stronger in control than T2DM tissue (5.0 [1.0] vs 4.0 [1.0] score units; P = .043). GLUT2 (control vs T2DM: 1.00 [0.69] vs 0.49 [0.36]) and GLUT1 expression (control vs T2DM: 0.86 [0.73] vs 0.35 [0.30]; P = .0007 for both) were closely correlated with those of the respective SGLT partner. Hypoxia-inducible factor 1α, more abundant in control than T2DM tissue, might be a transcription factor involved in the modulation of SGLT2 expression. Conclusions In whole renal tissue, expressions of SGLT2/ GLUT2 and SGLT1/ GLUT1 are coupled and slightly lower in typical people with T2DM as compared with well-matched people without diabetes. [ABSTRACT FROM AUTHOR]

Review: 267 refs. [ABSTRACT FROM AUTHOR]

Review: 159 refs. [ABSTRACT FROM AUTHOR]

Pheochromocytoma/paraganglioma (Pheo/PGL) associated with pituitary adenoma (PA) is rare in clinical practice, and a common pathogenic mechanism has been suggested owing to the germline pathogenic variants found in some cases. Our aim is to propose a reassignment for a recurrent MEN1 genetic variant found in a 54-year-old male patient with bilateral pheochromocytoma and GH-secreting PA. Pheo/PGL genes study was carried out in DNA samples from Pheo as well as PA and no pathological variants or large deletions were detected. Additionally, a MEN1 gene analysis was performed, and a heterozygous germline variant in exon 10: c.1618C>T; p.(Pro540Ser) was found. No MEN1 gene deletions/duplications were detected. In evaluating a causal relationship between the c.1618C>T MEN1 variant and both tumors, we took into account that missense variants are common pathogenic variants in MEN1, and the population frequency of this variant is too high to be considered pathogenic. His son (aged 38 and carrier) is asymptomatic, and computational analysis showed discrepancies. We propose that this recurrent variant, previously considered as likely pathogenic, subsequently as variant of uncertain significance, and likely benign should now be reclassified as benign., (© 2021 Wiley Periodicals LLC.)

The data shown here were collected with an open label prospective design from March 2001 to February 2004 while conducting routine recruitment and therapy of heroin-addicted patients. All of the data collected demonstrate the safety and efficacy of buprenorphine therapy and different characteristics observed in buprenorphine patients versus methadone patients.