Proopiomelanocortin Neurons in Nucleus Tractus Solitarius Are Activated by Visceral Afferents: Regulation by Cholecystokinin and Opioids

The nucleustractus solitarius (NTS) receives dense terminations from cranial visceral afferents, including those from the gastrointestinal (GI) system. Although the NTS integrates peripheral satiety signals and relays this signal to central feeding centers, little is known about which NTS neurons are involved or what mechanisms are responsible. Proopiomelanocortin (POMC) neurons are good candidates for GI integration, because disruption of the POMC gene leads to severe obesity and hyperphagia. Here, we used POMC– enhanced green fluorescent protein (EGFP) transgenic mice to identify NTS POMC neurons. Intraperitoneal administration of cholecystokinin (CCK) induced c-fos gene expression in NTS POMC–EGFP neurons, suggesting that they are activated by afferents stimulated by the satiety hormone. We tested the synaptic relationship of these neurons to visceral afferents and their modulation by CCK and opioids using patch recordings in horizontal brain slices. Electrical activation of the solitary tract (ST) evoked EPSCs in NTS POMC–EGFP neurons. The invariant latencies, low failure rates, and substantial paired-pulse depression of the ST-evoked EPSCs indicate that NTS POMC–EGFP neurons are second-order neurons directly contacted by afferent terminals. The EPSCs were blocked by the glutamate antagonist 2,3- dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. CCK increased the amplitude of the ST-stimulated EPSCs and the frequency of miniature EPSCs, effects attenuated by the CCK1 receptor antagonist lorglumide. In contrast, the orexigenic opioid agonists [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. These findings identify a potential satiety pathway in which visceral afferents directly activate NTS POMC–EGFP neurons with excitatory inputs that are appropriately modulated by appetite regulators

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation ( P  < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty‐nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1 , TGFBR2 , and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections. © 2011 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87019/1/34050_ftp.pd

T‐wave and its association with myocardial fibrosis on cardiovascular magnetic resonance examination

Background: Risk stratification in non-ischemic myocardial disease poses a challenge. While cardiovascular magnetic resonance (CMR) is a comprehensive tool, the electrocardiogram (ECG) provides quick impactful clinical information. Studying the relationships between CMR and ECG can provide much-needed risk stratification. We evaluated the electrocardiographic signature of myocardial fibrosis defined as presence of late gadolinium enhancement (LGE) or extracellular volume fraction (ECV) ≥29%. Methods: We evaluated 240 consecutive patients (51% female, 47.1 ± 16.6 years) referred for a clinical CMR who underwent 12-lead ECGs within 90 days. ECG parameters studied to determine association with myocardial fibrosis included heart rate, QRS amplitude/duration, T-wave amplitude, corrected QT and QT peak, and Tpeak-Tend. Abnormal T-wave was defined as low T-wave amplitude ≤200 µV or a negative T wave, both in leads II and V5. Results: Of the 147 (61.3%) patients with myocardial fibrosis, 67 (28.2%) had ECV ≥ 29%, and 132 (54.6%) had non-ischemic LGE. An abnormal T-wave was more prevalent in patients with versus without myocardial fibrosis (66% versus 42%, p < .001). Multivariable analysis demonstrated that abnormal T-wave (OR 1.95, 95% CI 1.09-3.49, p = .03) was associated with myocardial fibrosis (ECV ≥ 29% or LGE) after adjustment for clinical covariates (age, gender, history of hypertension, and heart failure). Dynamic nomogram for predicting myocardial fibrosis using clinical parameters and the T-wave was developed: https://normogram.shinyapps.io/CMR_Fibrosis/. Conclusion: Low T-wave amplitude ≤ 200 µV or negative T-waves are independently associated with myocardial fibrosis. Prospective evaluation of T-wave amplitude may identify patients with a high probability of myocardial fibrosis and guide further indication for CMR

HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer

Introduction: Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.Methods: We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain.Results: Most brain metastases were triple negative and basal-like. the brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. in particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors.Conclusions: Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. the need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules.Ludwig Institute of Cancer ResearchNational Breast Cancer FoundationUniv Queensland, Clin Res Ctr, Brisbane, Qld 4029, AustraliaQueensland Inst Med Res, Brisbane, Qld 4006, AustraliaUniversidade Federal de São Paulo, EPM, Dept Anat Patol, BR-04024000 São Paulo, BrazilGriffith Univ, Brisbane, Qld 4011, AustraliaUniv Queensland, Ctr Magnet Resonance, Brisbane, Qld 4072, AustraliaEijkman Inst, Jakarta 10430, IndonesiaInst Nacl Canc, Dept Patol, BR-20230130 Rio de Janeiro, BrazilLab Salomao & Zoppi, Dept Patol, BR-04104000 São Paulo, BrazilCharles Univ Prague, Fac Med, Dept Pathol, Plzen 30605, Czech RepublicUniv Sydney, Inst Clin Pathol & Med Res, Sydney W Area Hlth Serv, Sydney, NSW 2145, AustraliaUniv Sydney, Westmead Millennium Inst, Sydney W Area Hlth Serv, Sydney, NSW 2145, AustraliaPeter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3002, AustraliaUniv Queensland, Queensland Brain Inst, Brisbane, Qld 4072, AustraliaRoyal Brisbane & Womens Hosp, Brisbane, Qld 4029, AustraliaUniversidade Federal de São Paulo, EPM, Dept Anat Patol, BR-04024000 São Paulo, BrazilWeb of Scienc