Ultrastructural morphometry of capillary basement membrane thickness in normal and transgenic diabetic mice

Capillary basement membrane (CBM) thickening is an ultrastructural hallmark in diabetic patients and in animal models of diabetes. However, the wide variety of tissues sampled and diverse methods employed have made the interpretation of thickness data difficult. We showed previously that acellular glomerular BMs in OVE26 transgenic diabetic mice were thickened beyond normal age-related thickening, and in the current study we hypothesized that other microvascular BMs likewise would show increased widths relative to age-matched controls. Accordingly, a series of tissues, including skeletal and cardiac muscle, ocular retina and choriod, peripheral nerve, lung, pancreas, and renal glomerulus was collected from 300-350-day-old normal and transgenic mice. Transmission electron micrographs of cross sections through capillary walls were prepared, and CBM thickness (CBMT) was determined by the "orthogonal intercept" method. Morphometric analyses showed highly variable transgene-related BMT increases in the sampled tissues, with glomerular BM showing by far the greatest increase (+87%). Significant thickness increases were also seen in the retina, pulmonary alveolus, and thoracoabdominal diaphragm. BMT increases were not universal; however, most were modestly widened, and those that were thickest in controls generally showed the greatest increase. Although the pathogenesis of diabetes-related increases in CBM is poorly understood, data in the current study showed that in OVE26 transgenic mice increased BMT was a frequent concomitant of hyperglycemia. Accordingly, it seems likely that hyperglycemia-induced microvascular damage may be a contributing factor in diabetic BM disease, and that microvessel cellular and extracellular heterogeneity may limit the extent of CBM thickening in diverse tissues.     

Expression of HLA-DR and common acute lymphoblastic leukemia antigens on glioma cells

The expression on several established human glioma cell lines of two well-defined differentiation antigens, HLA-DR and the common acute lymphoblastic leukemia antigen (CALLA) has been demonstrated. Rabbit anti-CALLA antiserum and monoclonal anti-la antibodies specifically lysed glioma cells in the presence of complement. Absorption of anti-CALLA antiserum and anti-Ia antibodies by glioma cells abolished their cytotoxicity against blasts isolated from a common acute lymphoblastic leukemia. Immunoprecipitation of solubilized glioma cells by monoclonal anti-Ia antibodies revealed two polypeptide chains of 28 and 33 kDa, whereas the anti-CALLA antiserum precipitated a single polypeptide chain of 100 kDa.     

Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3

Genetic linkage studies have indicated that chromosome 14q24.3harbours a major locus for early-onset (onset age <65 years)Alzheimer's disease (AD3). Positional cloning efforts have identifieda novel gene S182 or presenilin 1 as the AD3 gene. We have mappedS182 in the AD3 candidate region between D14S277 and D14S284defined by genetic linkage studies in the two chromosome 14linked, early-onset AD families AD/A and AD/B. We have shownthat S182 is expressed in lymphoblasts and have determined thecomplete cDNA in both brain and lymphoblasts by RT-PCR sequencing.S182 is alternatively spliced in both brain and lymphoblastswithin a putative phosphorylation site located 5' in the codingregion. We identified two novel mutations, Ile143Thr and Gly384Alalocated in, respectively, the second transmembrane domain andin the sixth hydrophilic loop of the putative transmembranestructure of S182. As families AD/A and AD/B have a very similarAD phenotype our observation of two mutations in functionallydifferent domains suggest that onset age and severity of ADmay not be very helpful predictors of the location of putativeS182 mutations.     

A novel patient with White–Sutton syndrome refines the mutational and clinical repertoire of the POGZ‐related phenotype and suggests further observations

A rare developmental delay (DD)/intellectual disability (ID) syndrome with craniofacial dysmorphisms and autistic features, termed White–Sutton syndrome (WHSUS, MIM#614787), has been recently described, identifying truncating mutations in the chromatin regulator POGZ (KIAA0461, MIM#614787). We describe a further WHSUS patient harboring a novel nonsense de novo POGZ variant, which afflicts a protein domain with transposase activity less frequently impacted by mutational events (DDE domain). This patient displays additional physical and behavioral features, these latter mimicking Smith–Magenis syndrome (SMS, MIM#182290). Considering sleep–wake cycle anomalies and abnormal behavior manifested by this boy, we reinforced the clinical resemblance between WHSUS and SMS, being both chromatinopathies. In addition, using the DeepGestalt technology, we identified a different facial overlap between WHSUS patients with mutations in the DDE domain (Group 1) and individuals harboring variants in other protein domains/regions (Group 2). This report further delineates the clinical and molecular repertoire of the POGZ‐related phenotype, adding a novel patient with uncommon clinical and behavioral features and provides the first computer‐aided facial study of WHSUS patients.     

Do dysfunctional cognitions mediate the relationship between risk factors and postnatal depression symptomatology?

BACKGROUND: This study investigated the mediating role of general and maternal-specific dysfunctional cognitions, in the relationship between non-cognitive risk factors and postnatal depressive symptomatology. METHODS: An Australian community sample comprising 406 postnatal women responded to the Dysfunctional Attitude Scale (DAS), the Maternal Attitudes Questionnaire (MAQ), the Vulnerable Personality Style Questionnaire (VPSQ) and the Edinburgh Postnatal Depression Scale (EPDS). They also responded to several questions related to perinatal and postnatal experiences. RESULTS: Path analysis demonstrated that different mediational pathways operated for different risk factors. The relationship between having a difficult baby and postnatal depression was fully mediated by maternal-specific dysfunctional cognitions (MAQ scores), whereas the relationship between past history of depression and postnatal depression was partially mediated by general dysfunctional cognitions (DAS scores). Finally, the relationship between a vulnerable personality and depressive symptomatology was mediated by both DAS and MAQ scores. LIMITATIONS: The study employed a correlational design. Thus, all inferences regarding possible causal pathways are tentative. In addition, the generalisability of these findings to other populations needs to be demonstrated in future research. CONCLUSIONS: The results of the study are consistent with the view that risk factors may influence postnatal depression indirectly through at least two distinct cognitive mediators (dysfunctional maternal and general cognitions). It may be possible to target therapies more effectively by identifying the relevant mediating mechanism(s) for individuals with different risk profiles.