Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein

Spastin, an ATPase belonging to the AAA family of proteins is most commonly mutated in autosomal dominant hereditary spastic paraplegias (HSP). Spastin is a multifaceted protein with versatile role in cellular events, principally involved in microtubule dynamics. To gain further insight into the molecular function of spastin, we used the yeast two-hybrid approach to identify novel interacting partners of spastin. Using spastin as bait, we identified reticulon 1 (RTN1) and reticulon 3 (RTN3) as potential spastin interacting proteins. RTN1 and RTN3 belong to the reticulon (RTN) gene family, which are primarily expressed in the endoplasmic reticulum. Moreover, RTN1 is known to play a role in vesicular transport processes. Using in vitro and in vivo immunoprecipitation experiments, we were able to demonstrate that RTN1 interacts specifically with spastin. Intracellular distribution studies using immunostaining and overexpression of epitope-tagged protein revealed an obvious colocalization of spastin and RTN1 in discrete vesicles in the cytoplasm. Spastin mediates its interaction with RTN1 through its N-terminal region containing a microtubule-interacting and trafficking domain. It is interesting to note that the aberrant intracellular distribution of a truncated spastin protein was rescued by coexpression with RTN1, which highlights the physiological significance of this interaction. Our findings strengthen the hypothesis that disruption of intracellular vesicular transport processes could cause HSP. It is interesting to note that RTN1 is localized to 14q23.1 where SPG15 locus was mapped. Therefore, we considered RTN1 as a candidate gene for the SPG15 locus, but our mutational analysis possibly excludes RTN1 as causative gene.Electronic Supplementary Material Supplementary material is available for this article at     

Baseline Predictors of Adherence in a Randomised Controlled Trial of a New Group Psychological Intervention for People with Recurrent Binge Eating Episodes Associated to Overweight or Obesity

Purpose: Understanding the high rate of treatment adherence in trials of people with eating disorders is important as it can compromise the quality of the trials. In clinical practice, it may also contribute to illness chronicity, relapse, and costs. Thus, we investigated factors associated with adherence to a new treatment HAPIFED, which integrates cognitive behavioural therapy having extended sessions with body weight loss therapy compared to cognitive behavioural therapy with extended sessions alone, for individuals with Bulimia Nervosa or Binge Eating Disorder or other eating disorders comorbid with overweight or obesity. Methods: In total, 98 participants having bulimia nervosa, binge eating disorder and other specified and unspecified eating disorders were recruited with 50 randomised to HAPIFED and 48 to the control intervention CBT-E, all administered in groups of up to 10 participants. An investigator external to the site conducted the random allocation, which was concealed from the statistician involved in the analysis, and known only to the therapists until the finalization of the 12-month follow-up after the end of active treatment. Three scenarios in the timeline treatment of a total of 30 sessions were assessed: 33% or 60% or 75% of presence. Mixed-effects logistic regression analysis was performed to find the correlates of adherence after adjusting for clustering by number of group participants. To account for heterogeneity by types of eating disorders in the sample, the latter variable was considered as a control factor in the models. A subgroup analysis was performed for those with binge eating disorder as this was the largest (N = 66) eating disorder group. Results: None of the six variables—frequency of binge eating episodes, purging, eating disorder symptom severity, weight, illness duration and mental health-related quality of life—significantly predicted adherence at 33%, but longer illness duration predicted higher treatment adherence at both 60% and 75% presence of the interventions. Also for 75% presence, higher body weight predicted lower treatment adherence. For the subgroup analysis, those having higher illness duration had significantly higher odds of treatment adherence for 60% and 75% of the sessions. Conclusions: Higher adherence due to late treatment completion was associated with longer binge eating illness length and a lower body weight. More research is needed to recognize factors that may interfere with engagement in treatments aiming to avoid early dropout.     

Simultaneous bilateral compared with unilateral percutaneous nephrolithotomy

OBJECTIVE: To compare simultaneous bilateral percutaneous nephrolithotomy (SBPCNL) and unilateral PCNL in separate sessions in patients with bilateral renal stones for several variables before and after surgery. PATIENTS AND METHODS: The results from SBPCNL carried out at two centres in different countries on 198 patients (aged 1.25-70 years) were compared with those from 300 patients undergoing unilateral PCNL in separate sessions. At one centre where extracorporeal shockwave lithotripsy (ESWL) was available SBPCNL was used for stones where at least two sessions of ESWL would have been required on each side. Other associated procedures were also used wherever required. RESULTS: The stones were cleared bilaterally in one session of SBPCNL in 190 patients; in eight, fragments of < 3 mm remained but were not clinically significant. A second session was required in six patients on one side only. Variables assessed before and after treatment (e.g. hospital stay, analgesia requirements and complications) were not significantly different between SBPCNL and PCNL. The mean (range) total operative duration for SBPCNL was 46 (20-100) min and the hospital stay 4.3 (3-8) days. CONCLUSION: From this experience, SBPCNL is a cost-effective and beneficial solution for selected patients, with clear advantages over separate unilateral PCNL in patients with bilateral stones.     

Diagnostic thinking and information used in clinical decision-making: a qualitative study of expert and student dental clinicians

Background  

It is uncertain whether the range and frequency of Diagnostic Thinking Processes (DTP) and pieces of information (concepts) involved in dental restorative treatment planning are different between students and expert clinicians.     

Salmonella enterica Serovar Typhimurium Infection-Induced CD11b+ Gr1+ Cells Ameliorate Allergic Airway Inflammation

Allergies are mainly characterized as an unrestrained Th2-biased immune response. Epidemiological data associate protection from allergic diseases with the exposure to certain infectious agents during early stages of life. Modulation of the immune response by pathogens has been considered to be a major factor influencing this protection. Recent evidence indicates that immunoregulatory mechanisms induced upon infection ameliorate allergic disorders. A longitudinal study has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection with Salmonella. Experimental studies involving Salmonella enterica serovar Typhimurium-infected murine models have confirmed protection from induced allergic airway inflammation; however, the underlying cause leading to this amelioration remains incompletely defined. In this study, we aimed to delineate the regulatory function of Salmonella Typhimurium infection in the amelioration of allergic airway inflammation in mice. We observed a significant increase in CD11b⁺ Gr1⁺ myeloid cell populations in mice after infection with S. Typhimurium. Using in vitro and in vivo studies, we confirmed that these myeloid cells reduce airway inflammation by influencing Th2 cells. Further characterization showed that the CD11b⁺ Gr1⁺ myeloid cells exhibited their inhibitory effect by altering GATA-3 expression and interleukin-4 (IL-4) production by Th2 cells. These results indicate that the expansion of myeloid cells upon S. Typhimurium infection could potentially play a significant role in curtailing allergic airway inflammation. These findings signify the contribution of myeloid cells in preventing Th2-mediated diseases and suggest their possible application as therapeutics.     

Severe brachial plexus injuries in rugby

We describe the mechanisms, pattern of injuries, management and outcomes of severe injuries to the brachial plexus sustained during the play of rugby. Thirteen cases of severe injury to the brachial plexus caused by tackles in rugby had detailed clinical assessment, and operative exploration of the brachial plexus. Seventeen spinal nerves were avulsed, two were ruptured and there were traction lesions in continuity of 24 spinal nerves. The pattern of nerve lesion was related to the posture of the neck and the forequarter at the moment of impact. Early repair by nerve transfer enabled some functional recovery, and decompression of lesions in continuity was followed by recovery of nerve function and relief of pain.     

Selective depletion of Foxp3+ Treg during sensitization phase aggravates experimental allergic airway inflammation

Recent studies highlight the role of Treg in preventing unnecessary responses to allergens and maintaining functional immune tolerance in the lung. We investigated the role of Treg during the sensitization phase in a murine model of experimental allergic airway inflammation by selectively depleting the Treg population in vivo. DEpletion of REGulatory T cells (DEREG) mice were depleted of Treg by diphtheria toxin injection. Allergic airway inflammation was induced using OVA as a model allergen. Pathology was assessed by scoring for differential cellular infiltration in bronchoalveolar lavage, IgE and IgG1 levels in serum, cytokine secretion analysis of lymphocytes from lung draining lymph nodes and lung histology. Use of DEREG mice allowed us for the first time to track and specifically deplete both CD25⁺ and CD25^? Foxp3⁺ Treg, and to analyze their significance in limiting pathology in allergic airway inflammation. We observed that depletion of Treg during the priming phase of an active immune response led to a dramatic exacerbation of allergic airway inflammation in mice, suggesting an essential role played by Treg in regulating immune responses against allergens as early as the sensitization phase via maintenance of functional tolerance.     

Screening of subclinical hypothyroidism during gestational diabetes in Pakistani population

Objective: The increased prevalence of adverse effects of altered thyroid functions in pregnancy inspired us to study the frequency of subclinical hypothyroidism (SCH) and the relationship with glycaemic control and foetal weight in pregnant females with and without gestational diabetes mellitus (GDM) in Pakistani population.

Patients and methods: Five hundred and eight pregnant females were enrolled and grouped as per the International Diabetes Association criteria into GDM (n?=?208) and healthy control (n?=?300). Random blood glucose (RBG), thyroid function tests, anthropometric analysis and foetal ultra sound scans were performed on all study subjects. Data were analysed using Mann–Whitney U test and Chi-square test wherever applicable. Spearman correlation and multiple regression analysis were performed. p values of <0.05 was considered significant.

Results: A total of 61.5% GDM subjects depicted SCH with normal circulating T4 and T3 versus 6.0% healthy controls (p-value <?0.001). Moreover, TSH remained independently associated with RBG (r?=?0.109; p?<?0.05), poor glycaemic control (r?=?0.227; p?<?0.001) and negatively associated with foetal growth (r?=??0.206; p?<?0.001).

Conclusion: The detection of high TSH with normal T3 and T4 in females with GDM strongly emphasises the need of thyroid screening as a routine in all antenatal clinics.