The embryonic genes Dkk3, Hoxd8, Hoxd9 and Tbx1 identify muscle types in a diet-independent and fiber-type unrelated way

<p>Abstract</p> <p>Background</p> <p>The mouse skeletal muscle is composed of four distinct fiber types that differ in contractile function, number of mitochondria and metabolism. Every muscle type has a specific composition and distribution of the four fiber types. To find novel genes involved in specifying muscle types, we used microarray analysis to compare the gastrocnemius with the quadriceps from mice fed a low fat diet (LFD) or high fat diet (HFD) for 8 weeks. Additional qPCR analysis were performed in the gastrocnemius, quadriceps and soleus muscle from mice fed an LFD or HFD for 20 weeks.</p> <p>Results</p> <p>In mice fed the 8-week LFD 162 genes were differentially expressed in the gastrocnemius <it>vs</it>. the quadriceps. Genes with the strongest differences in expression were markers for oxidative fiber types (e.g. <it>Tnni1</it>) and genes which are known to be involved in embryogenesis (<it>Dkk3</it>, <it>Hoxd8</it>,<it>Hoxd9 </it>and <it>Tbx1</it>). Also <it>Dkk2, Hoxa5, Hoxa10, Hoxc9, Hoxc10, Hoxc6 </it>and <it>Tbx15 </it>were detectably, but not differentially expressed in adult muscle tissue. Expression of differentially expressed genes was not influenced by an 8-week or 20-week HFD. Comparing gastrocnemius, quadriceps and soleus, expression of <it>Hoxd8 </it>and <it>Hoxd9 </it>was not related with expression of markers for the four different fiber types. We found that the expression of both <it>Hoxd8 </it>and <it>Hoxd9 </it>was much higher in the gastrocnemius than in the quadriceps or soleus, whereas the expression of <it>Dkk3 </it>was high in quadriceps, but low in both gastrocnemius and soleus. Finally, expression of <it>Tbx1 </it>was high in quadriceps, intermediate in soleus and low in gastrocnemius.</p> <p>Conclusions</p> <p>We found that genes from the Dkk family, Hox family and Tbx family are detectably expressed in adult mouse muscle. Interestingly, expression of <it>Dkk3</it>, <it>Hoxd8, Hoxd9 </it>and <it>Tbx1 </it>was highly different between gastrocnemius, quadriceps and soleus. In fact, every muscle type showed a unique combination of expression of these four genes which was not influenced by diet. Altogether, we conclude that genes important for embryogenesis identify mouse muscle types in a diet-independent and fiber type-unrelated manner.</p

Very high intact-protein formula successfully provides protein intake according to nutritional recommendations in overweight critically ill patients : a double-blind randomized trial

Background: Optimal energy and protein provision through enteral nutrition is essential for critically ill patients. However, in clinical practice, the intake achieved is often far below the recommended targets. Because no polymeric formula with sufficient protein content is available, adequate protein intake can be achieved only by supplemental amino acids or semi-elemental formula administration. In the present study, we investigated whether protein intake can be increased with a new, very high intact-protein formula (VHPF) for enteral feeding. Methods: In this randomized, controlled, double-blind, multicenter trial, 44 overweight (body mass index = 25 kg/m(2)) intensive care unit patients received either a VHPF (8 g/100 kcal) or a commercially available standard high protein formula (SHPF) (5 g/100 kcal). Protein and energy intake, gastrointestinal tolerance (gastric residual volume, vomiting, diarrhea, and constipation), adverse events, and serious adverse events were recorded. Total serum amino acid levels were measured at baseline and day 5. Results: The primary outcome, protein intake at day 5, was 1.49 g/kg body weight (95% CI 1.21-1.78) and 0.76 g/kg body weight (95% CI 0.49-1.03, P < 0.001) for VHPF and SHPF, respectively. Daily protein intake was statistically significantly higher in the VHPF group compared with the SHPF group from day 2 to day 10. Protein intake in the VHPF group as a percentage of target (1.5 g/kg ideal body weight) was 74.7% (IQR 53.2-87.6%) and 111.6% (IQR 51.7-130.7%) during days 1-3 and days 4-10, respectively. Serum amino acid concentrations were higher at day 5 in the VHPF group than in the SHPF group (P = 0.031). No differences were found in energy intake, measures of gastrointestinal tolerance, and safety. Conclusions: Enteral feeding with VHPF (8 g/100 kcal) resulted in higher protein intake and plasma amino acid concentrations than an isocaloric SHPF (5 g/100 kcal), without an increase in energy intake. This VHPF facilitates feeding according to nutritional guidelines and is suitable as a first-line nutritional treatment for critically ill overweight patients

Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings

BACKGROUND: The dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls. METHODS: From all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF). RESULTS: Mean VIQ, PIQ, and FSIQ scores differed significantly (p < 0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls. CONCLUSION: Although preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning

High Fat Diet-Induced Changes in Mouse Muscle Mitochondrial Phospholipids Do Not Impair Mitochondrial Respiration Despite Insulin Resistance

BACKGROUND: Type 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance. METHODOLOGY: C57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR. PRINCIPAL FINDINGS: At 8 weeks, mono-unsaturated FA (16∶1n7, 18∶1n7 and 18∶1n9) were decreased (-4.0%, p<0.001), whereas saturated FA (16∶0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18∶2n6, 20∶4n6, 22∶5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p = 0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks. CONCLUSIONS/INTERPRETATION: Our findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance

PReVENT - protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial

Background It is uncertain whether lung-protective mechanical ventilation using low tidal volumes should be used in all critically ill patients, irrespective of the presence of the acute respiratory distress syndrome (ARDS). A low tidal volume strategy includes use of higher respiratory rates, which could be associated with increased sedation needs, a higher incidence of delirium, and an increased risk of patient-ventilator asynchrony and ICU-acquired weakness. Another alleged side-effect of low tidal volume ventilation is the risk of atelectasis. All of these could offset the beneficial effects of low tidal volume ventilation as found in patients with ARDS. Methods/Design PReVENT is a national multicenter randomized controlled trial in invasively ventilated ICU patients without ARDS with an anticipated duration of ventilation of longer than 24 hours in 5 ICUs in The Netherlands. Consecutive patients are randomly assigned to a low tidal volume strategy using tidal volumes from 4 to 6 ml/kg predicted body weight (PBW) or a high tidal volume ventilation strategy using tidal volumes from 8 to 10 ml/kg PBW. The primary endpoint is the number of ventilator-free days and alive at day 28. Secondary endpoints include ICU and hospital length of stay (LOS), ICU and hospital mortality, the incidence of pulmonary complications, including ARDS, pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives and neuromuscular blocking agents, incidence of ICU delirium, and the need for decreasing of instrumental dead space. Discussion PReVENT is the first randomized controlled trial comparing a low tidal volume strategy with a high tidal volume strategy, in patients without ARDS at onset of ventilation, that recruits a sufficient number of patients to test the hypothesis that a low tidal volume strategy benefits patients without ARDS with regard to a clinically relevant endpoin

REACTION: Reducing the effects of aging on cognition with therapeutic intervention of an oral nutrient — A pilot interventional study for age‐related cognitive decline

Background Age‐related cognitive decline (ARCD) refers to the cognitive changes that can occur in individuals as a consequence of aging, distinct from cognitive changes due to a primary neurodegenerative process (e.g., Alzheimer’s Disease), cerebral ischemia (e.g., vascular dementia), or other pathology. However, there is sparse research into direct interventions for ARCD. Recent research suggests that the underlying mechanism behind ARCD is a loss of synaptic plasticity, which is essential for learning, memory, and the formation of memory engrams, in part through its effects on dendritic spine morphology. Therefore, therapies aimed at rescuing dendritic spine density and increasing synaptic plasticity may be viable strategies for decreasing the effects of ARCD. Souvenaid contains Fortasyn Connect, a specific combination of nutrients designed to enhance synapse formation by providing precursors and cofactors for phospholipid synthesis. In prodromal Alzheimer’s disease, Fortasyn Connect showed beneficial effects on memory, cognition, and brain atrophy [1]. In addition, the data from this study suggest a stronger effect would be expected in participants at earlier stages of prodromal AD. Souvenaid has not yet been tested in individuals with ARCD. Method Towards this end, we present the design of a 6‐month single‐center pilot clinical trial that aims to perform all assessments via a telemedicine platform. The study design specifically factors in local COVID‐19 restrictions. We plan to recruit 60 participants aged 55‐89 with age‐related cognitive decline, who will be screened and randomized to the oral multi‐nutrient combination (Souvenaid) or placebo on a 1:1 basis. The main outcome of this trial is feasibility (recruitment rate and time, adherence rate and retention rate). Other outcomes include memory (e.g. Ray Verbal Learning Task), cognition (e.g. Oral Trail Making Test), and quality of life (e.g. Amsterdam IADL Questionnaire) outcome measures. Result Results of REACTION will provide insight into the feasibility of a virtual study with Souvenaid in ARCD. Conclusion With the rapidly growing prevalence of ARCD and no pharmacological interventions currently available, nutritional interventions may potentially play an important role to reduce or delay the effects of ARCD