Author Correction: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list. Their affiliations are: I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA (A.F.K.); Mitobridge, Inc. 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.A.P.); and China Novartis Institutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China (C.W.). These authors contributed to the interpretation of results and design of compounds. In addition, author 'Edward A. Kesicki' was misspelled as 'Ed Kesicki'. These errors have been corrected online.

Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467.

ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

The differentiating effect of COVID-19-associated stress on the morbidity of blood donors with symptoms of hidradenitis suppurativa, hyperhidrosis, or psoriasis.

PURPOSE: The burden of different skin diseases may vary leading individuals to have different sensitivity to stress. Therefore, we compared the health-related quality of life (HRQoL) and stress before and during the universal stress from the severe acute respiratory syndrome coronavirus-2-pandemic in individuals with and without hyperhidrosis, hidradenitis suppurativa, or psoriasis. METHODS: The study cohort was the Danish Blood Donor Study. Overall, 12,798 participants completed a baseline questionnaire before the pandemic, in 2018-2019, and a follow-up questionnaire during the pandemic, in 2020. Regression determined the association between the skin diseases and outcomes. Outcomes were the physical and mental component summary (MCS, PCS, respectively), which assess the mental and physical HRQoL, and the perceived stress scale, which assesses stress in the past four weeks. RESULTS: Overall, 1168 (9.1%) participants had hyperhidrosis, 363 (2.8%) had hidradenitis suppurativa, and 402 (3.1%) had psoriasis. At follow-up, the participants with hyperhidrosis had worse MCS (coefficient -0.59 [95% confidence interval (CI) -1.05, -0.13]) and higher odds of moderate-to-severe stress (odds ratio 1.37 [95% CI 1.13, 1.65]) and the participants with hidradenitis suppurativa worse PCS (coefficient -0.74 [95% CI -1.21, -0.27]) than the control groups. The associations were independent of baseline HRQoL, stress, the Connor-Davidson Resilience scale, and other covariables. Psoriasis was not associated with the outcomes. CONCLUSION: Individuals with hyperhidrosis or hidradenitis suppurativa experienced worse mental or physical well-being and individuals with hyperhidrosis also had higher stress during the pandemic compared to healthy individuals. This suggests that individuals with these skin diseases are particularly susceptible to external stress.

Female advantage in verbal learning revisited: a HUNT study.

The argument for a female advantage in word list learning is often based on partial observations that focus on a single component of the task. Using a large sample (N = 4403) of individuals 13-97 years of age from the general population, we investigated whether this advantage is consistently reflected in learning, recall, and recognition and how other cognitive abilities differentially support word list learning. A robust female advantage was found in all subcomponents of the task. Semantic clustering mediated the effects of short-term and working memory on long-delayed recall and recognition, and serial clustering on short-delayed recall. These indirect effects were moderated by sex, with men benefiting more from reliance on each clustering strategy than women. Auditory attention span mediated the effect of pattern separation on true positives in word recognition, and this effect was stronger in men than in women. Men had better short-term and working memory scores, but lower auditory attention span and were more vulnerable to interference both in delayed recall and recognition. Thus, our data suggest that auditory attention span and interference control (inhibition), rather than short-term or working memory scores, semantic and/or serial clustering on their own, underlie better performance on word list learning in women.

Patients with knee osteoarthritis can be divided into subgroups based on tibiofemoral joint kinematics of gait - an exploratory and dynamic radiostereometric study.

OBJECTIVE: Patients with advanced knee osteoarthritis (KOA) frequently alter their gait patterns in an attempt to alleviate symptoms. Understanding the underlying pathomechanics and identifying KOA phenotypes are essential to improve treatments. We investigated kinematics in patients with KOA to identify subgroups of homogeneous knee joint kinematics. METHOD: A total of 66 patients with symptomatic KOA scheduled for total knee arthroplasty and 15 age-matched healthy volunteers with asymptomatic, non-arthritic knees were included. We used k-means clustering to divide patients into subgroups based on dynamic radiostereometry-assessed tibiofemoral joint kinematics. Clinical characteristics such as knee ligament lesions and KOA scores were graded by magnetic resonance imaging and radiographs, respectively. RESULTS: We identified four clusters that were supported by clinical characteristics. The flexion group (n = 20) consisted primarily of patients with medial KOA. The abduction group (n = 17) consisted primarily of patients with lateral KOA. The anterior draw group (n = 10) was composed of patients with medial KOA, some degree of anterior cruciate ligament lesion and the highest KOA score. The external rotation group (n = 19) primarily included patients with medial collateral and posterior cruciate ligament lesions. CONCLUSION: Based on tibiofemoral gait patterns, patients with advanced KOA can be divided into four subgroups with specific clinical characteristics and different KOA-affected compartments. The findings add to our understanding of how knee kinematics may affect the patient's development of different types of KOA. This may inspire improved and more patient-specific treatment strategies in the future.

Signal and noise in circRNA translation.

Within recent years, circular RNAs (circRNAs) have been an attractive new field of research in RNA biology and disease. Consequently, numerous studies have been published towards the disclosure of circRNA biogenesis and function. Initially, circRNAs were described as a subclass of cytoplasmic non-coding RNA, however, a few recent observations have proposed that circRNAs may instead be templates for protein production. The extent to which this is the case is currently debated, and therefore using rigorous data analysis and proper experimental setups is instrumental to settle the current controversies. Here, the conventional experiments used for detecting circRNA translation are outlined, and guidelines to distinguish signal from the inherent noise are discussed. While these guidelines are specific for circRNA translation, most also apply to other aspects of non-canonical translation.

Postoperative surgical site infection rate in patients with diabetes following Mohs micrographic surgery: a retrospective analysis.

BACKGROUND: Incidence of surgical site infection (SSI) following Mohs micrographic surgery (MMS) amongst patients with diabetes is largely unknown. OBJECTIVE: Evaluate diabetes as a potential SSI risk factor in MMS by comparing SSI incidence in a cohort of patients with and without diabetes. METHODS: A 5-year retrospective review to determine SSI rate in patients with diabetes compared to patients without diabetes. SSI incidence in patients with diabetes was further compared by A1c, and the impact of antibiotics on SSI rate was also examined. RESULTS: Overall rate of SSI was 1.47% (53/3597 cases). SSI rate amongst patients with diabetes was 1.95% (14/719 cases) compared to 1.35% (39/2878 cases) in patients without diabetes, with a non-significant odds ratio for SSI of 1.45 (95% CI = 0.78-2.68, P = 0.241). Multivariable logistic regression analysis revealed no difference in SSI. Stratification of diabetic patients by A1c into ≥7.0 and <7.0 compared to patients without diabetes yielded no statistically significant difference in SSI amongst all groups (P = 0.815). Whether an antibiotic was prescribed did not significantly impact SSI rate between groups. CONCLUSION: No significant difference in postoperative SSI was found in patients with diabetes compared to patients without diabetes following MMS regardless of degree of glycaemic control.

Incidence and remission rates of self-reported hidradenitis suppurativa - A prospective cohort study conducted in Danish blood donors.

BACKGROUND: A large discrepancy between physician-diagnosed and self-reported Hidradenitis suppurativa (HS) exists. Knowledge regarding incidence and remission rates of self-reported HS is missing, but may help bridge the gap in understanding between these two phenotypes. OBJECTIVES: To determine the incidence and remission rates of self-reported HS, and to what degree these are affected by sex, smoking and BMI. METHODS: A prospective cohort of 23 930 Danish blood donors. Information on self-reported HS, symptom-localisation, sex, age, BMI and smoking status was collected at baseline and study termination. Self-reported HS fulfilled clinical obligatory diagnostic criteria. Cox proportional hazards regression analyses were conducted for both incidence and remission rates providing a hazard ratio (HR) of risk for each variable in the regression. RESULTS: Incidence rate of self-reported HS was 10.8/1000 person-years (95% confidence interval (CI): 9.9-11.7), decreasing as a function of numbers of areas affected. Female BMI points above 25 (HR = 1.11, 95% CI: 1.09-1.13), male BMI points above 25 (HR = 1.07, 95% CI: 1.04-1.11), active smoking (HR = 1.72, 95% CI: 1.15-2.57), male sex (HR = 0.55, 95% CI: 0.45-0.67) and years of age above 25 (HR = 0.97, 95% CI: 0.96-0.97) were all statistically associated with the development of self-reported HS. Remission rate of self-reported HS was 256.7/1000 person-years (95% CI: 223.9-292.6), decreasing as a function of numbers of affected areas. Symptoms in ≥3 areas (HR = 0.54, 95% CI: 0.34-0.85), active smoking (HR = 0.49, 95% CI: 0.32-0.76) and female weight loss (every percentage drop in BMI: HR = 1.07, 95% CI: 1.05-1.11) all significantly affected the remission rate. CONCLUSIONS: Both incidence and remission rates of self-reported HS are high, indicating that many with self-reported HS are unlikely to be diagnosed, as they to a higher degree experience mild transient HS symptoms.

The application of nonlinear programming on ration formulation for dairy cattle.

The objective of this study was to compare the application of iterative linear programming (iteLP), sequential quadratic programming (SQP), and mixed-integer nonlinear programming-based deterministic global optimization (MINLP_DGO) on ration formulation for dairy cattle based on Nutrient Requirements of Dairy Cattle (NRC, 2001). Least-cost diets were formulated for lactating cows, dry cows, and heifers. Nutrient requirements including energy, protein, and minerals, along with other limitations on dry matter intake, neutral detergent fiber, and fat were considered as constraints. Five hundred simulations were conducted, with each simulation randomly selecting 3 roughages and 5 concentrates from the feed table in NRC (2001) as the feed resource for each of 3 animal groups. Among the 500 simulations for lactating cows, 57, 45, and 21 simulations did not yield a feasible solution when using iteLP, SQP, and MINLP_DGO, respectively. All the simulations for dry cows and heifers were feasible when using SQP and MINLP_DGO, but 49 and 11 infeasible simulations occurred when using iteLP for dry cows and heifers, respectively. The average ration costs per animal per day of the feasible solutions obtained by iteLP, SQP, and MINLP_DGO were $4.78 (±0.71), $4.45 (±0.65), and $4.44 (±0.65) for lactating cows; $2.39 (±0.52), $1.48 (±0.26), and $1.48 (±0.26) for dry cows; and $0.98 (±0.72), $0.97 (±0.15), and $0.91 (±0.14) for heifers, respectively. The average computation time of iteLP, SQP, and MINLP_DGO were 0.59 (±1.87) s, 1.15 (±0.62) s, and 58.69 (±68.45) s for lactating cows; 0.041 (±0.070) s, 0.76 (±0.37) s, and 14.84 (±39.09) s for dry cows; and 1.60 (±2.90) s, 0.51 (±0.19) s, and 16.45 (±45.56) s for heifers, respectively. In conclusion, iteLP had limited capability of formulating least-cost diets when nonlinearity existed in the constraints. Both SQP and MINLP_DGO handled the nonlinear constraints well, with SQP being faster, whereas MINLP_DGO was able to return a feasible solution under some situations where SQP could not.

Poor Response Inhibition and Symptoms of Inattentiveness Are Core Characteristics of Lifetime Illicit Substance Use among Young Adults in the General Norwegian Population: The HUNT Study.

BACKGROUND: Impairments in neurocognitive functioning are associated with substance use behavior. Previous studies in neurocognitive predictors of substance use typically use self-report measures rather than neuropsychological performance measures and suffer from low sample sizes and use of clinical diagnostic cut offs. METHODS: Crossectional data from the HUNT4 Study (Helseundersøkelsen i Trøndelag) was used to study executive neuropsychological performance and self-reported measures of neurocognitive function associated with a history of illicit substance use in a general population sample of young adults in Norway. We performed both between group comparisons and logistic regression modeling and controlled for mental health symptomatology. RESULTS: Subjects in our cohort with a self-reported use of illicit substances had significantly higher self-reported mental health and neurocognitive symptom load. A logistic regression model with substance use as response included sex, commission errors and self-reported inattentiveness and anxiety as significant predictors. After 10-fold cross-validation this model achieved a moderate area under the receiver-operator curve of 0.63. To handle the class imbalance typically found in such population data, we also calculated balanced accuracy with a optimal model cut off of 0.234 with a sensitivity of 0.50 and specificity of 0.76 as well as precision recall-area under the curve of 0.28. CONCLUSIONS: Subtle cognitive dysfunction differentiates subjects with and without a history of illicit substance use. Neurocognitive factors outperformed the effects of depressive symptoms on substance use behavior in this cohort. We highlight the need for using adequate statistical tools for evaluating the performance of models in unbalanced datasets.

Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases.

p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.

[Uncommon tumor of the gastric wall]. / Ungewöhnlicher Magenwandtumor.

We report on a 72-year-old male patient suffering from weight loss, diarrhea, and epigastric pain. By means of endosonographic ultrasound, a well-circumscribed tumor mass was found in the gastric wall, suggesting a gastrointestinal stromal tumor (GIST). Biopsies were taken and processed for standard histopathological analysis. The microscopy revealed uniform, small, round cells with central nuclei and prominent cell borders embedded in vascularized stroma. Immunohistochemistry demonstrated the expression of actin, but showed negativity for cytokeratin, CD34, CD117, DOG­1, desmin, and CD45. The tumor was diagnosed as a gastral glomus tumor. The diagnosis was confirmed in the wedge resection specimen. Gastral glomus tumors are rare intramural tumors of the stomach. GIST and neuroendocrine tumor (NET) present the main differential diagnoses. Especially with regard to the epithelioid variant of GIST, clear separation can be difficult. Besides standard histological examination, immunohistochemistry and molecular analysis can be helpful since gastral glomus tumors do not obtain c­Kit- or PDGFRα mutations. Based on the fact that this tumor most commonly shows a benign biological behavior, the prognosis of gastral glomus tumors is favorable.

Chromosome aberrations in pressure-induced triploid Atlantic salmon.

BACKGROUND: Triploid organisms have three sets of chromosomes. In Atlantic salmon, hydrostatic pressure treatment of newly fertilized eggs has been extensively used to produce triploids which are functionally sterile due to their unpaired chromosomes. These fish often perform poorly on commercial farms, sometimes without explanation. Inheritance patterns in individuals subjected to pressure treatment have not been investigated in Atlantic salmon thus far. However, work on other species suggests that this treatment can result in aberrant inheritance. We therefore studied this in Atlantic salmon by genotyping 16 polymorphic microsatellites in eyed eggs and juveniles which had been subjected to pressure-induction of triploidy. Communally reared juveniles including fish subjected to pressure-induction of triploidy and their diploid siblings were included as a control. RESULTS: No diploid offspring were detected in any of the eggs or juveniles which were subjected to hydrostatic pressure; therefore, the induction of triploidy was highly successful. Aberrant inheritance was nevertheless observed in 0.9% of the eggs and 0.9% of the juveniles that had been subjected to pressure treatment. In the communally reared fish, 0.3% of the fish subjected to pressure treatment displayed aberrant inheritance, while their diploid controls displayed 0% aberrant inheritance. Inheritance errors included two eyed eggs lacking maternal DNA across all microsatellites, and, examples in both eggs and juveniles of either the maternal or paternal allele lacking in one of the microsatellites. All individuals displaying chromosome aberrations were otherwise triploid. CONCLUSIONS: This is the first study to document aberrant inheritance in Atlantic salmon that have been subjected to pressure-induction of triploidy. Our experiments unequivocally demonstrate that even when induction of triploidy is highly successful, this treatment can cause chromosome aberrations in this species. Based upon our novel data, and earlier studies in other organisms, we hypothesize that in batches of Atlantic salmon where low to modest triploid induction rates have been reported, aberrant inheritance is likely to be higher than the rates observed here. Therefore, we tentatively suggest that this could contribute to the unexplained poor performance of triploid salmon that is occasionally reported in commercial aquaculture. These hypotheses require further investigation.

Circulating lectin pathway proteins do not predict short-term cardiac outcomes after myocardial infarction.

Despite improvements in treatment, coronary artery disease is still responsible for one-third of all deaths globally, due predominantly to myocardial infarction (MI) and stroke. There is an important potential in developing new strategies for treatment of patients with these conditions. Inflammation, and in particular the actions of the complement system, has emerged as part of the pathogenesis in reperfusion injury in patients with MI. To further qualify this, we examined the association between the plasma levels of lectin pathway proteins and myocardial end-points, left ventricular ejection fraction (LVEF) and infarct size in a cohort of patients with ST-elevation myocardial infarction (STEMI). A blood sample was drawn the day after percutaneous coronary intervention from 73 patients with STEMI. The primary end-points, LVEF and infarct size, were measured with magnetic resonance imaging 6-9 days after the infarct. Complement pattern-recognition molecules of the lectin pathway (mannan-binding lectin, H-ficolin, L-ficolin and M-ficolin) were analysed along with soluble membrane attack complex (sMAC) and C-reactive protein (CRP) in plasma with immunofluorometric assays <50%. CRP correlated negatively with LVEF, regression coefficient = -0·17 (P = 0·01). None of the lectin pathway proteins correlated to LVEF or infarct size, nor did soluble membrane attack complex (sMAC). There were no differences in plasma levels of these complement proteins when comparing patients with ejection fraction <50% to patients with ejection fraction <50%. Pattern-recognition molecules of the lectin pathway and sMAC do not predict short-term cardiac outcomes after MI.

Estimating glomerular filtration rate in youth with obesity and type 2 diabetes: the iCARE study equation.

BACKGROUND: The validity of pediatric estimated glomerular filtration rate equations (eGFRs) in early stages of CKD including hyperfiltration is unknown. The purpose of this study was to develop an eGFR equation for adolescents with obesity and type 2 diabetes (T2D). METHODS: eGFRs were developed from iohexol-derived GFRs (iGFRs) in 26 overweight/obese (BMI > 85th percentile) youth and 100 with T2D from the iCARE (Improving renal Complications in Adolescents with T2D through REsearch) cohort. Twenty percent of the cohort was withheld as a validation dataset. Linear regression analyses were used to develop the best formula based on body size, sex, creatinine, urea, ± cystatin C. Comparable validity of commonly used eGFR equations was assessed. RESULTS: Mean age 15.4 + 2.4 years, BMI Z-score 2.5 + 1.2, 61% female, and mean iGFR 129.0 + 27.7 ml/min/ 1.73 m2. The best adjusted eGFR formula (ml/min/1.73 m2) was 50.7 × BSA0.816 × (height (cm)/creatinine)0.405 × 0.8994 if sex = female | 1 otherwise. It resulted in 53.8% of eGFRs within 10% of measured iGFR and 96.2% within 30%. Bland-Altman 95% limits of agreement in the external dataset were - 37.6 to 45.5 ml/min/1.73m2 (bias = 3.96), and the correlation was 0.62. This equation performed better than all previously published creatinine-based eGFRs. cystatin C did not significantly improve results; however, some other cystatin C formulas also performed well. CONCLUSIONS: The iCARE equation provides a more accurate creatinine-based eGFR in obese youth with and without T2D. Further studies are warranted to evaluate within-subject variability and applicability to lower GFRs and other populations.

Normal radiological lymph node appearance in the thorax.

Modern treatment of esophageal cancer is multimodal and highly dependent on a detailed diagnostic assessment of clinical stage, which includes nodal stage. Clinical appraisal of nodal stage is highly dependent on knowledge of normal radiological appearance, information of which is scarce. We aimed to describe lymph node appearance on computed tomography (CT) investigations in a randomly selected cohort of healthy subjects. In a sample of the Swedish Cardiopulmonary bioimage study, which investigates a sample of the Swedish population aged 50-64 years, the CT scans of 426 subjects were studied in detail concerning intrathoracic node stations relevant in clinical staging of esophageal cancer. With stratification for sex, the short axis of visible lymph nodes was measured and the distribution of lymph node sizes was calculated as well as proportion of patients with visible nodes above 5 and 10 millimeters for each station. Probability of having any lymph node station above 5 and 10 millimeters was calculated with a logistic regression model adjusted for age and sex. In the 214 men (aged: 57.3 ± 4.1 years) and 212 women (aged: 57.8 ± 4.4 years) included in this study, a total of 309 (72.5%) had a lymph node with a short axis of 5 mm or above was seen in at least one of the node stations investigated. When using 10 mm as a cutoff, nodes were visible in 29 (6.81%) of the subjects. Men had higher odds of having any lymph node with short axis 5 mm or above (OR 3.03 95% CI 1.89-4.85, P < 0.001) as well as 10 mm or above (OR 2.31 95% CI 1.02-5.23, P = 0.044) compared to women. Higher age was not associated with propensity for lymph nodes above 5 or 10 millimeters in this sample. We conclude that, in a randomly selected cohort of patients between 50 and 64 years, almost 10% of the men and 4% of the women had lymph nodes above 10 millimeters, most frequently in the subcarinal station (station 107). More than half of the patients had nodes above 5 millimeters on CT and men were much more prone to have this finding. The probability of finding lymph nodes in specific stations relevant of esophageal cancer is now described.

[Bronchoalveolar lavage in hairy cell leukemia with pulmonary infiltration]. / Bronchoalveoläre Lavage bei Haarzellleukämie mit Lungeninfiltration.

We report a 78-year-old male patient suffering from hairy cell leukemia, presenting clinically mainly with dyspnea. Radiology exhibited bilateral ground-glass shadows. In order to prevent pneumonia as a possible side effect due to conventional chemotherapy, it was decided to first treat the patient with rituximab; however, dyspnea persisted. Therefore, bronchoscopy was performed and specimens were sampled for both histological examination and bronchoalveolar lavage (BAL) analysis. BAL showed lymphocytosis (28.7%), and by means of immunocytochemistry a few CD79a+ B­lymphocytes as well as lymphoid cells positive for the hairy cell marker DBA44 were observed. In addition, molecular study revealed the BRAF V600E mutation. Thus, the findings of BAL were interpreted as lung infiltration by hairy cell leukemia. This result was confirmed by histology. Following a therapy switch to cladribine, a significant improvement was reached. Pulmonary infiltrates by hairy cell leukemia were rarely described. This case represents the first report of hairy cell leukemia diagnosed by means of BAL. It may be difficult to clearly separate between lymphoma infiltration of the lung and medicamentous pneumonitis, but this differential diagnosis can be supported by morphological methods.

Genetics of metabolic traits in Greenlanders: lessons from an isolated population.

In this review, we describe the extraordinary population of Greenland, which differs from large outbred populations of Europe and Asia, both in terms of population history and living conditions. Many years in isolation, small population size and an extreme environment have shaped the genetic composition of the Greenlandic population. The unique genetic background combined with the transition from a traditional Inuit lifestyle and diet, to a more Westernized lifestyle, has led to an increase in the prevalence of metabolic conditions like obesity, where the prevalence from 1993 to 2010 has increased from 16.4% to 19.4% among men, and from 13.0% to 25.4% among women, type 2 diabetes and cardiovascular diseases. The genetic susceptibility to metabolic conditions has been explored in Greenlanders, as well as other isolated populations, taking advantage of population-genetic properties of these populations. During the last 10 years, these studies have provided examples of loci showing evidence of positive selection, due to adaption to Arctic climate and Inuit diet, including TBC1D4 and FADS/CPT1A, and have facilitated the discovery of several loci associated with metabolic phenotypes. Most recently, the c.2433-1G>A loss-of-function variant in ADCY3 associated with obesity and type 2 diabetes was described. This locus has provided novel biological insights, as it has been shown that reduced ADCY3 function causes obesity through disrupted function in primary cilia. Future studies of isolated populations will likely provide further genetic as well as biological insights.