Adverse weather conditions are important contributors to mortality in new-born lambs. Previous studies have shown variation between lambs in their ability to cope with circumstances of cold stress, ...and genetic selection could be a viable option for improving animal robustness. The Elsenburg Merino flock was divergently selected on number of lambs weaned (NLW). This resulted in divergent responses in reproduction and lamb survival. This study evaluated lamb vitality and mortality of positively selected H-Line relative to the negatively selected L-Line in response to cold stress. Traits included lamb rectal temperature (RT), surface temperature (ST), shiver score (SS), lamb vigor score (LVS), breaths per minute (BPM), mortality to three days of age (M3) and to weaning (TM). Cold stress was described by a chill index derived from daily rainfall, wind speed and ambient temperature, and represented as the mean of the one (CI), two (CI-2) or three (CI-3) days since parturition. Overall, H-Line lambs had a higher neonatal RT and were less likely to succumb than L-Line contemporaries. In a significant (P < 0.05) interaction, the predicted RT of L-Line showed a non-linear decline with increased levels of CI-2, while H-Line lambs better maintained their core temperature. M3 was also affected by a significant interaction between CI-3 and selection line, further suggesting that observed lower mortality rates in the H-Line depends on H-Line lambs’ improved ability to cope with stressful environments. Long term selection for NLW in the H-Line led to improvements in both adaptations associated with lower lamb losses. The continued recording of viability traits to produce larger datasets amenable to genetic analysis is recommended, specifically for rectal temperature.
•A cold stress index derived from weather data was predictive to lamb viability.•Genetic selection for reproduction by alleviated symptoms of cold stress.•Selection line differences were most pronounced at high levels of cold stress.•A number of factors putatively contributed to the stress-coping ability.
The neural processes that underlie your ability to read and understand this sentence are unknown. Sentence comprehension occurs very rapidly, and can only be understood at a mechanistic level by ...discovering the precise sequence of underlying computational and neural events. However, we have no continuous and online neural measure of sentence processing with high spatial and temporal resolution. Here we report just such a measure: intracranial recordings from the surface of the human brain show that neural activity, indexed by γ-power, increases monotonically over the course of a sentence as people read it. This steady increase in activity is absent when people read and remember nonword-lists, despite the higher cognitive demand entailed, ruling out accounts in terms of generic attention, working memory, and cognitive load. Response increases are lower for sentence structure without meaning (“Jabberwocky” sentences) and word meaning without sentence structure (word-lists), showing that this effect is not explained by responses to syntax or word meaning alone. Instead, the full effect is found only for sentences, implicating compositional processes of sentence understanding, a striking and unique feature of human language not shared with animal communication systems. This work opens up new avenues for investigating the sequence of neural events that underlie the construction of linguistic meaning.
Objectives: To examine whether low serum albumin is associated with low muscle strength and future decline in muscle strength in community‐dwelling older men and women.
Design: Population‐based ...cohort study.
Setting: The Longitudinal Aging Study Amsterdam.
Participants: Six hundred seventy‐six women and 644 men aged 65 to 88.
Measurements: Serum albumin was determined at baseline. Muscle strength was assessed using grip strength at baseline, after 3 (n=1,009), and 6 (n=741) years. The outcomes were continuous baseline muscle strength, 3‐ and 6‐year change in muscle strength, and a dichotomous indicator for substantial decline (a decrease if ≥1 standard deviations for women=11 kg, for men=12 kg) in muscle strength.
Results: Mean serum albumin concentration±standard deviation was 45.0±3.3 g/L for women and 45.2±3.2 g/L for men. At baseline, adjusting for age, lifestyle factors, and chronic conditions, lower serum albumin was cross‐sectionally associated with weaker muscle strength (P<.001) in women and men. After 3 years of follow‐up, mean decline in muscle strength was −5.6±10.9 kg in women and −9.6±11.9 kg in men. After adjustment for potential confounders, lower serum albumin was associated with muscle strength decline over 3 years (P<.01) in women and men (β=0.57, standard error (SE)=0.18; β=0.37, SE=0.16, respectively). Lower serum albumin was also associated with substantial decline in muscle strength in women (per unit albumin (g/L) adjusted odds ratio (OR)=1.14, one‐sided 95% confidence limit (CL)=1.07) and men (per unit albumin (g/L) adjusted OR=1.14, 95% CL=1.08). Similar but slightly weaker associations were found between serum albumin and 6‐year change in muscle strength (P<.05).
Conclusion: These results suggest that low serum albumin, even within the normal range, is independently associated with weaker muscle strength and future decline in muscle strength in older women and men.
Pseudomonas aeruginosa is an opportunistic pathogen, synthesizing two major siderophores, pyoverdine (Pvd) and pyochelin (Pch), to cover its needs in iron(III). If the high affinity and specificity ...of Pvd toward iron(III) (pFe = 27.0) was well described in the literature, the physicochemical and coordination properties of Pch toward biologically relevant metals (Fe(III), Cu(II) or Zn(II)) have been only scarcely investigated. We report a thorough physico-chemical investigation of Pch (potentiometry, spectrophotometries, ESI/MS) that highlighted its moderate but significantly higher affinity for Fe(3+) (pFe = 16.0 at pH 7.4) than reported previously. We also demonstrated that Pch strongly chelates divalent metals such as Zn(II) (pZn = 11.8 at pH 7.4) and Cu(II) (pCu = 14.9 at pH 7.4) and forms predominantly 1 : 2 (M(2+)/Pch) complexes. Kinetic studies revealed that the formation of the ferric Pch complexes proceeds through a Eigen-Wilkins dissociative ligand interchange mechanism involving two protonated species of Pch and the Fe(OH)(2+) species of Fe(III). Our physico-chemical parameters supports the previous biochemical studies which proposed that siderophores are not only devoted to iron(III) shuttling but most likely display other specific biological role in the subtle metals homeostasis in microorganisms. This work also represents a step toward deciphering the role of siderophores throughout evolution.
Chronic disease and comorbidity patterns in people with intellectual disabilities (ID) are more complex than in the general population. However, incomplete understanding of these differences limits ...care providers in addressing them.
To compare chronic disease and comorbidity patterns in chronically ill patients with and without ID in Dutch general practice.
In this population-based study, a multi-regional primary care database of 2018 was combined with national population data to improve identification of adults with ID. Prevalence was calculated using Poisson regression to estimate prevalence ratios and 95% confidence intervals for the highest-impact chronic diseases (ischemic heart disease (IHD), cerebrovascular disease (CVD), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD)) and comorbidities.
Information from 18,114 people with ID and 1,093,995 people without ID was available. When considering age and sex, CVD (PR = 1.1), DM (PR = 1.6), and COPD (PR = 1.5) times more prevalent in people with than without ID. At younger age, people with ID more often had a chronic disease and multiple comorbidities. Males with ID most often had a chronic disease and multiple comorbidities. Comorbidities of circulatory nature were most common.
This study identified a younger onset of chronic illness and a higher prevalence of multiple comorbidities among people with ID in general practice than those without ID. This underlines the complexity of people with ID and chronic diseases in general practice. As this study confirmed the earlier onset of chronic diseases and comorbidities, it is recommended to acknowledge these age differences when following chronic disease guidelines.
To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.
To study the impact of the innate immune system at the level of the ...hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of
. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).
Hepatocyte-specific deletion of
predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of
in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.
Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.
Summary
Iron is an essential nutrient for bacterial growth but poorly bioavailable. Bacteria scavenge ferric iron by synthesizing and secreting siderophores, small compounds with a high affinity for ...iron. Pyochelin (PCH) is one of the two siderophores produced by the opportunistic pathogen Pseudomonas aeruginosa. After capturing a ferric iron molecule, PCH‐Fe is imported back into bacteria first by the outer membrane transporter FptA and then by the inner membrane permease FptX. Here, using molecular biology, 55Fe uptake assays, and LC–MS/MS quantification, we first find a role for PchHI as the heterodimeric ABC transporter involved in the siderophore‐free iron uptake into the bacterial cytoplasm. We also provide the first evidence that PCH is able to reach the bacterial periplasm and cytoplasm when both FptA and FptX are expressed. Finally, we detected an interaction between PchH and FptX, linking the ABC transporter PchHI with the inner permease FptX in the PCH‐Fe uptake pathway. These results pave the way for a better understanding of the PCH siderophore pathway, giving future directions to tackle P. aeruginosa infections.
The application of electrical stimulation mapping (ESM) of the brain for clinical use is approximating a century. Despite this long-standing history, the value of ESM for guiding surgical resections ...and sparing eloquent cortex is documented largely by small retrospective studies, and ESM protocols are largely inherited and lack standardization. Although models are imperfect and mechanisms are complex, the probabilistic causality of ESM has guaranteed its perpetuation into the 21st century. At present, electrical stimulation of cortical tissue is being revisited for network connectivity. In addition, noninvasive and passive mapping techniques are rapidly evolving to complement and potentially replace ESM in specific clinical situations. Lesional and epilepsy neurosurgery cases now offer different opportunities for multimodal functional assessments.
Objectives
Long‐term outcomes of endoscopic ultrasound‐guided choledochoduodenostomy (EUS‐CDS) performed with lumen apposing metal stents (LAMS) have been poorly evaluated in small or retrospective ...series, leading to an underestimation of LAMS dysfunction.
Methods
All consecutive EUS‐CDS performed in three academic referral centers were included in prospectively maintained databases. Technical/clinical success, adverse events (AEs), and dysfunction during follow‐up were retrospectively analyzed. Kaplan–Meier analysis was used to estimate dysfunction‐free survival (DFS), with Cox proportional hazard regression to evaluate independent predictors of dysfunction.
Results
Ninety‐three patients were included (male 56%; mean age, 70 years 95% confidence interval (CI) 68–72; pancreatic cancer 81%, metastatic disease 47%). In 67% of procedures, 6 mm LAMS were used. Technical and clinical success were achieved in 97.8% and 93.4% of patients, respectively, with AEs occurring in 9.7% (78% mild/moderate). Dysfunction occurred in 31.8% of patients after a mean of 166 days (95% CI 91–241), with an estimated 6 month and 12 month DFS of 75% and 52%, respectively; mean DFS of 394 (95% CI 307–482) days. Almost all dysfunctions (96%) were successfully managed by endoscopic reintervention. Duodenal invasion (hazard ratio 2.7 95% CI 1.1–6.8) was the only independent predictor of dysfunction.
Conclusions
Endoscopic ultrasound‐guided choledochoduodenostomy shows excellent initial efficacy and safety, although stent dysfunctions occurs frequently during long‐term follow‐up. Almost all stent dysfunctions can be managed successfully by endoscopic reinterventions. We propose a comprehensive classification of the different types of dysfunction that may be encountered and rescue procedures that may be employed under these circumstances. Duodenal invasion seems to increase the risk of developing EUS‐CDS dysfunction, potentially representing a relative contraindication for this technique.
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