Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex

The multisubunit Golgi-associated retrograde protein (GARP) complex is required for tethering and fusion of endosome-derived transport vesicles to the trans-Golgi network. Mutation of leucine-967 to glutamine in the Vps54 subunit of GARP is responsible for spinal muscular atrophy in the wobbler mouse, an animal model of amyotrophic lateral sclerosis. The crystal structure at 1.7 Å resolution of the mouse Vps54 C-terminal fragment harboring leucine-967, in conjunction with comparative sequence analysis, reveals that Vps54 has a continuous α-helical bundle organization similar to that of other multisubunit tethering complexes. The structure shows that leucine-967 is buried within the α-helical bundle through predominantly hydrophobic interactions that are critical for domain stability and folding in vitro. Mutation of this residue to glutamine does not prevent integration of Vps54 into the GARP complex but greatly reduces the half-life and levels of the protein in vivo. Severely reduced levels of mutant Vps54 and, consequently, of the whole GARP complex underlie the phenotype of the wobbler mouse.     

Valor de la ecoendoscopia transesofágica en el diagnóstico de localización en el hiperparatiroidismo primario

Aim

Our aim was to estimate the usefulness of oesophageal endoscopic ultrasound in the accurate location of recurrent or persistent primary hyperparathyroidism (HPT).

Material and method

A total of 352 patients with primary hyperparathyroidism were operated on over the last seven years. A preoperative parathyroid 99Tc- sestamibi gammagraphy and an intraoperative PTH determination were performed routinely. Only 5 patients (1.4%) had localization problems: three with persistent HPT after parathyroid extirpation, one recurrent HPT and one HPT after a right hemithyroidectomy. An oesophageal endoscopic ultrasound was carried out before any new exploratory neck surgery in order to find the definitive location.

Results

The endoscopic ultrasound showed a clear image of adenoma with an accurate location in four patients. No tumour was present in one patient. All five patients were operated on. The exact location was confirmed in the four patients with positive endoscopic ultrasound images. The fifth surgical exploration revealed a parathyreosis. All five patients had a favourable post-operative period, with no nerve lesions or morbidity associated with the endoscopic ultrasound.

Conclusions

Oesophageal endoscopic ultrasound is a very useful diagnostic tool in HPT patients with location problems, particularly in cases having anatomical changes due to previous surgery. It is a procedure that helps the surgeon to make a more selective and efficient exploration of parathyroid glands.     

Predictors of acute treatment response in patients with a first episode of non-affective psychosis: sociodemographics, premorbid and clinical variables

Approximately 60% of patients with a first episode of psychosis will significantly reduce the severity of their positive symptomatology with antipsychotic drugs. The aim of this study was to investigate predictors of response to antipsychotic treatment during the first episode of non-affective psychosis. 172 patients (107 male) with a diagnosis of schizophreniform, schizophrenia, schizoaffective, brief reactive psychosis, schizotypal personality disorder or psychosis non-otherwise specified entered the study. Sociodemographic, premorbid and clinical data at baseline were evaluated. Unpaired t-test for continuous and chi2 for categorical data, respectively, were used to compare responders and non-responders selected variables. Multivariate logistic regression was used to establish a prediction model. 57.6% of study subjects (99 of 172) responded to antipsychotic treatment. The following variables were significantly associated with less likelihood of response: 1.--lower severity of general psychopathology, positive symptoms and disorganized symptoms at baseline; 2.--earlier age of onset; 3.--diagnosis of schizophrenia; 4.--longer DUP; 5.--poorer premorbid adjustment during adolescence, and 6.--hospitalization. Multivariate logistic regression demonstrated that differences between responders and non-responders were largely accounted for by BPRS total score, age of onset, premorbid adjustment at early adolescence, and diagnosis. Patients with an early age of onset of schizophrenia, a poor premorbid adolescent functioning, and with a lower severity of psychopathology at intake seem to have a decrease likelihood of responding to antipsychotic treatment. Helping clinicians to identify non-responders is meant as a first step to optimise therapeutic effort to benefit individuals in this vulnerable group.