Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Recently, a case study reported a patient who became transfusion-independent in response to treatment with the amino acid L-leucine. Therefore, we have validated the therapeutic effect of L-leucine using our recently generated mouse model for RPS19-deficient DBA. Administration of L-leucine significantly improved the anemia in Rps19-deficient mice (19% improvement in hemoglobin concentration; 18% increase in the number of erythrocytes), increased the bone marrow cellularity, and alleviated stress hematopoiesis. Furthermore, the therapeutic response to L-leucine appeared specific for Rps19-deficient hematopoiesis and was associated with down-regulation of p53 activity. Our study supports the rationale for clinical trials of L-leucine as a therapeutic agent for DBA.     

Dermal innervation in healthy subjects and small fiber neuropathy patients: a stereological reappraisal

The aim of this study was to estimate dermal nerve fiber length (DNFL) using a stereological sampling technique in comparison with a previously reported manual estimation. DNFL was analyzed in skin punch biopsy specimens from 24 healthy volunteers and 18 patients with small fiber neuropathy (SFN) using global spatial sampling that yields unbiased and reliable length estimation. The estimation was carried out in 50‐µm biopsy sections after immunostaining with anti‐protein gene product (PGP) 9.5 antibodies. The length of the PGP9.5‐positive dermal nerves from the dermal–epidermal junction and 200 µm down was measured (DNFL mm^?2). Results were compared with our previously reported manual method. Patients showed a significantly (p < 0.0001) lower DNFL (105 mm^?2 ± 6.4 SD) than healthy subjects (246 mm^?2 ± 8.39 SD). Moderate correlation with age was observed for both healthy subjects (Pearson's r = ?0.33) and patients (Pearson's r = ?0.59). A significant (p < 0.001) correlation between global spatial sampling and manual estimation was observed in both patients and healthy subjects (Pearson's r = 0.62 and 0.61, respectively). These findings provide further evidence on the reliability of dermal nerve morphometry in human skin and strengthen the hypothesis that dermal nerve fibers undergo significant degeneration in SFN.     

Family history and its association to curve size and treatment in 1,463 patients with idiopathic scoliosis

Purpose

To study family history in relation to curve severity, gender, age at diagnosis and treatment in idiopathic scoliosis.

Methods

A self-assessment questionnaire on family history of scoliosis was administered to 1,463 untreated, brace or surgically treated idiopathic scoliosis patients.

Results

Out of the 1,463 patients, 51 % had one or more relatives with scoliosis. There was no significant difference between females and males, nor between juvenile and adolescent study participants in this respect (p = 0.939 and 0.110, respectively). There was a significant difference in maximum curve size between patients with one or more relatives with scoliosis (median 35°, interquartile range 25) and patients without any relative with scoliosis (median 32°, interquartile range 23) (p = 0.022). When stratifying patients according to treatment (observation, brace treatment or surgery), we found that it was more common to have a relative with scoliosis among the treated patients (p = 0.011). The OR for being treated was 1.32 (95 % CI 1.06–1.64) when the patient had a relative with scoliosis, compared to not having.

Conclusions

Larger curve sizes were found in patients with a family history of scoliosis than in the ones without. No relation between family history and gender or between family history and age at onset of idiopathic scoliosis was found. Although the presence of a family history of scoliosis may not be a strong prognostic risk factor, it indicates that these patients are at higher risk of developing a more severe curve.     

Irradiation to the young mouse brain caused long-term,progressive depletion of neurogenesis but did not disrupt the neurovascular niche

We investigated the effects of ionizing radiation on microvessel structure and complexity in the hippocampus. We also assessed neurogenesis and the neurovascular niche. Postnatal day 14 male C57BL/6 mice received a single dose of 8 Gy to the whole brain and were killed 6 hours, 1 week, 7 weeks, or 1 year later. Irradiation decreased the total number of microvessels and branching points from 1 week onwards and decreased the total microvessel area 1 and 7 weeks after irradiation. After an initial increase in vascular parameter densities, concomitant with reduced growth of the hippocampus, the densities normalized with time, presumably adapting to the needs of the surrounding nonvascular tissue. Irradiation decreased the number of neural stem and progenitor cells in the hippocampus. The relative loss increased with time, resulting in almost completely ablated neurogenesis (DCX⁺ cells) 1 year after irradiation (77% decreased 1 week, 86% decreased 7 weeks, and 98% decreased 1 year after irradiation compared with controls). After irradiation, the distance between undifferentiated stem cells and microvessels was unaffected, and very few dying endothelial cells were detected. Taken together, these results indicate that the vasculature adjusts to the surrounding neural and glial tissue after irradiation, not vice-versa.     

Mathematical Modelling of Glucose‐Dependent Insulinotropic Polypeptide and Glucagon‐like Peptide‐1 following Ingestion of Glucose

The incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), play an important role in glucose homeostasis by potentiating glucose‐induced insulin secretion. Furthermore, GLP‐1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP‐1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP‐1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP‐1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP‐1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.     

Preoperative Nutrition and Postoperative Discomfort in an ERAS Setting: A Randomized Study in Gastric Bypass Surgery

Background

Many patients experience postoperative nausea and vomiting (PONV). Preoperative treatment with carbohydrate solutions seems to improve the course after different types of surgery. This study was undertaken to investigate the potential value of different models for preoperative hydration/nutrition, in addition to our ERAS (enhanced recovery after surgery) protocol.

Methods

Ninety non-diabetic women planned for elective laparoscopic gastric bypass and aged 18–65 years were included. All were on preoperative low-calorie diet (LCD). They were randomized into three arms, either a carbohydrate-rich drink, a protein-enriched drink, or tap water and instructed to drink 800 and 200 mL 16 and 2 h, respectively, prior to operation.Risk factors for PONV were recorded preoperatively. All patients were operated before lunch and received 1500–2000 mL of Ringer-Acetate solution during the 24–30-h postoperative hospital time. Four variables (nausea, pain, tiredness, and headache) were registered on 100-mm visual analog scales six times over 22 h. The need for additional medication was registered.

Results

Out of 90 patients, 73 complete datasets were obtained. Nausea peaked at 7 p.m. but with no statistically significant differences between groups for any of the variables. Pain peaked the first 2 h postoperatively, remained longer, and had not returned to baseline values at 6 a.m. the morning after surgery but with no difference between groups.

Conclusions

Inside our ERAS protocol, additional preoperative carbohydrate- or protein-enriched fluid treatment did not further reduce immediate patient discomfort in laparoscopic gastric bypass surgery.