Placentation of the pigmy treeshrew Tupaia minor / Waldemar Meister and D. Dwight Davis.

v.35:no.4(1956)

Placentation of a primitive insectivore Echinosorex gymnura / Waldemar Meister and D. Dwight Davis.

v.35:no.2(1953)

Chondrodysplasia and Abnormal Joint Development Associated with Mutations in IMPAD1, Encoding the Golgi-Resident Nucleotide Phosphatase, gPAPP.

We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.

Abnormal sensitivity to negative feedback in late-life depression.

AIMS: The purpose of the present study was to probe sensitivity to potentially misleading negative feedback on cognitive tasks as a possible mechanism of cognitive impairment in elderly patients with mild depression. METHODS: A total of 22 mildly depressed elderly subjects were compared to 22 healthy controls, using a computerized Tower-of-London task. RESULTS: Failure and magnitude of failure were significantly worse after negative but not positive feedback. Depression predicted failure after negative feedback but not the magnitude of failure. Neither failure nor magnitude of failure increased as a consequence of repeated negative feedback. CONCLUSIONS: Altered sensitivity to negative feedback occurs in mild late-life unipolar depression and may represent a subtle context-specific phenomenon.

Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2.

Glut-2 is a low-affinity transporter present in the plasma membrane of pancreatic beta-cells, hepatocytes and intestine and kidney absorptive epithelial cells of mice. In beta-cells, Glut-2 has been proposed to be active in the control of glucose-stimulated insulin secretion (GSIS; ref. 2), and its expression is strongly reduced in glucose-unresponsive islets from different animal models of diabetes. However, recent investigations have yielded conflicting data on the possible role of Glut-2 in GSIS. Whereas some reports have supported a specific role for Glut-2 (refs 5,6), others have suggested that GSIS could proceed normally even in the presence of low or almost undetectable levels of this transporter. Here we show that homozygous, but not heterozygous, mice deficient in Glut-2 are hyperglycaemic and relatively hypo-insulinaemic and have elevated plasma levels of glucagon, free fatty acids and beta-hydroxybutyrate. In vivo, their glucose tolerance is abnormal. In vitro, beta-cells display loss of control of insulin gene expression by glucose and impaired GSIS with a loss of first phase but preserved second phase of secretion, while the secretory response to non-glucidic nutrients or to D-glyceraldehyde is normal. This is accompanied by alterations in the postnatal development of pancreatic islets, evidenced by an inversion of the alpha- to beta-cell ratio. Glut-2 is thus required to maintain normal glucose homeostasis and normal function and development of the endocrine pancreas. Its absence leads to symptoms characteristic of non-insulin-dependent diabetes mellitus.

Abnormal expression of CD54 in mixed reactions of mononuclear cells from hyper-IgE syndrome patients

Hyper-IgE syndrome (HIES) is a rare multisystem disorder characterized by increased susceptibility to infections associated with heterogeneous immunologic and non-immunologic abnormalities. Most patients consistently exhibit defective antigen-induced-T cell activation, that could be partly due to altered costimulation involving accessory molecules; however, the expression of these molecules has never been documented in HIES. Therefore, we investigated the expression of CD11a, CD28, CD40, CD54, CD80, CD86, and CD154 in peripheral blood mononuclear cells from six patients and six healthy controls by flow cytometry after autologous and mixed allogeneic reactions. Only the allogeneic stimuli induced significant proliferative responses and interleukin 2 and interferon gamma production in both groups. Most accessory molecules showed similar expression between patients and controls with the exception of CD54, being expressed at lower levels in HIES patients regardless of the type of stimulus used. Decreased expression of CD54 could partly explain the deficient T cell activation to specific recall antigens in HIES patients, and might be responsible for their higher susceptibility to infections with defined types of microorganisms.

Isolation of genetic mutation leading to abnormal phenotype in human through ultra-high-throughput sequencing (UHTS)

The introduction of Next Generation Sequencing (NGS) facilitated the task of localizing DNA variation and identifying the genetic cause of yet unsolved Mendelian disorders. Using Whole Exome Capture method and NGS, we identified the causative genetic aberration responsible for a number of monogenic disorders previously undetermined. Due to the novelty of the NGS method we benchmarked different algorithms to assess their merits and defects. This allowed us to establish a pipeline that we successfully used to pinpoint genes responsible for a form of West's syndrome, a Complex Intellectual Disability syndrome associated with patellar dislocation and celiac disease, and correcting some erroneous molecular diagnosis of Alport's syndrome in a Saudi Arabian family.

Insulinoma associated with a case of multiple endocrine neoplasia type I: Functional somatostatin receptors and abnormal glucose-induced insulin secretion.

A sporadic case of multiple endocrine neoplasia type I with coexisting insulinoma and hyperparathyroidism was investigated in vivo and in vitro. The insulinoma was localized by somatostatin receptor scintigraphy and these receptors were functionally active. Octreotide administration decreased the basal insulin and glucagon secretion by 90 and 46%, respectively. Immunocytochemistry of the insulinoma tissue was positive for insulin, chromogranin A and neuropeptide Y. The insulinoma cells were also isolated and cultured in vitro. Incubation experiments revealed that a low glucose concentration (1 mmol/l) was sufficient to increase cytosolic free calcium and to produce a maximal glucose-induced insulin release. Northern blot analysis of RNA obtained from the tumor showed a high abundance of the low Km glucose transporter GLUT1 but no transcript for the high Km glucose transporter GLUT2. The abnormal distribution of glucose transporters probably relates to the abnormal glucose sensing of insulinoma cells, and explains their sustained insulin secretion at low glucose concentrations. Whether these abnormalities share a pathogenetic link with the presence of functionally active somatostatin receptors remains to be elucidated.

Abnormal humoral immune response to influenza vaccination in pediatric type-1 human immunodeficiency virus infected patients receiving highly active antiretroviral therapy

Given that highly active antiretroviral therapy (HAART) has been demonstrated useful to restore immune competence in type-1 human immunodeficiency virus (HIV-1)-infected subjects, we evaluated the specific antibody response to influenza vaccine in a cohort of HIV-1-infected children on HAART so as to analyze the quality of this immune response in patients under antiretroviral therapy. Sixteen HIV-1-infected children and 10 HIV-1 seronegative controls were immunized with a commercially available trivalent inactivated influenza vaccine containing the strains A/H1N1, A/H3N2, and B. Serum hemagglutinin inhibition (HI) antibody titers were determined for the three viral strains at the time of vaccination and 1 month later. Immunization induced a significantly increased humoral response against the three influenza virus strains in controls, and only against A/H3N2 in HIV-1-infected children. The comparison of post-vaccination HI titers between HIV-1+ patients and HIV-1 negative controls showed significantly higher HI titers against the three strains in controls. In addition, post vaccination protective HI titers (defined as equal to or higher than 1:40) against the strains A/H3N2 and B were observed in a lower proportion of HIV-1+ children than in controls, while a similar proportion of individuals from each group achieved protective HI titers against the A/H1N1 strain. The CD4+ T cell count, CD4/CD8 T cells ratio, and serum viral load were not affected by influenza virus vaccination when pre- vs post-vaccination values were compared. These findings suggest that despite the fact that HAART is efficient in controlling HIV-1 replication and in increasing CD4+ T cell count in HIV-1-infected children, restoration of immune competence and response to cognate antigens remain incomplete, indicating that additional therapeutic strategies are required to achieve a full reconstitution of immune functions.

Abnormal EEG Synchronization Correlates with Demyelination in Alzheimer's Disease

Introduction : The pathological processes caused by Alzheimer's disease (AD) supposedly disrupt communication between and within the distributed cortical networks due to the dysfunction/loss of synapses and myelination breakdown. Indeed, recently (Knyazeva et al. 2008), we have revealed the whole-head topography of EEG synchronization specific to AD. Here we analyze whether and how these abnormalities of synchronization are related to the demyelination of cortico-cortical fibers. Methods : Fifteen newly diagnosed AD patients (CDR 0.5-1) and 15 controls matched for age, participated in the study. Their multichannel (128) EEGs were recorded during 3-5 min at rest. They were submitted to the multivariate phase synchronization (MPS) analysis for mapping regional synchronization. To obtain individual whole-head maps, the MPS was computed for each sensor considering its 2nd nearest topographical neighbors. Separate calculations were performed for the delta, theta, alpha-1/−2, and beta-1/−2 EEG bands. The same subjects were scanned on a 3 Tesla Philips scanner. The protocol included a high-resolution T1-weighted sequence and a Magnetization Transfer Imaging (MTI) acquisition. For each subject, we defined a 3mm thick layer of white matter exactly below the cortical gray matter. The magnetization transfer ratio (MTR) - an estimator of myelination - was calculated for this layer in 39 Brodmann-defined ROIs per hemisphere. To assess the between-group differences, we used a permutation version of Hotelling's T2 test or two-sample T-test (Pcorrected <0.05). For correlation analysis, Spearman Rank Correlation was calculated. Results : In AD patients, we have found an abnormal landscape of synchronization characterized by a decrease in MPS over the fronto-temporal region of the left hemisphere and an increase over the temporo-parieto-occipital regions bilaterally. Also, we have shown a widespread decrease in regional MTR in the AD patients for all the areas excluding motor, premotor, and primary sensory ones. Assuming that AD-related changes in synchronization are associated with demyelination, we hypothesized a correlation between the regional MTR values and MPS values in the hypo- and hyper-synchronized clusters. We found that MPS in the left fronto-temporal hypo-synchronized cluster directly correlates with myelination in BA42-46 of the left hemisphere: the lower the myelination in individual patients, the lower the EEG synchronization. By contrast, in the posterior hyper-synchronized cluster, MPS inversely correlated with myelination, i.e., the lower the myelination, the higher the synchronization. This posterior hyper-synchronization, more characteristic for early-onset AD, probably, results from the initial effect of the disease on cortical inhibition, reducing cortical capacity for decoupling irrelevant connections. Remarkably, it showed different topography of correlations in early- vs. late-onset patients. In the early-onset patients, hyper-synchronization was mainly related to demyelination in posterior BAs, the effect being significant in all the EEG frequency bands. In the late-onset patients, widely distributed correlations were significant for the EEG delta band, suggesting an interaction between the cerebral manifestations of AD and the age of its onset, i.e., topographically selective impairment of cortical inhibition in early-onset AD vs. its wide-spread weakening in old age. Conclusions : Overall, our results document that the degradation of white matter is a significant factor of AD pathogenesis leading to functional dysconnection, the latter being reflected in EEG synchronization abnormalities.

Kenny syndrome: evidence for idiopathic hypoparathyroidism in two patients and for abnormal parathyroid hormone in one.

We report three unrelated patients with Kenny syndrome. Clinical symptoms included severe dwarfism, with internal cortical thickening and medullary stenosis of the tubular bones, normal bone age, macrocephaly, absent diploic space, delayed closure of the anterior fontanel, and normal intelligence; two of the patients had hyperopia and papillary edema. The patients also had episodic hypocalcemic tetany and low serum levels of magnesium. In two patients the diagnosis of idiopathic hypoparathyroidism was established on the basis of undetectable serum parathyroid hormone (PTH) levels (N- and C-terminal RIAs); one of these had normal urinary cyclic adenosine monophosphate (cAMP) response to exogenous PTH. Circulating calcitonin was undetectable in either patient. In a third patient, who had abnormal body proportions, serum levels of PTH were increased in an RIA detecting predominantly intact PTH (N-RIA) and undetectable in another RIA recognizing carboxy-terminal fragments (C-RIA). Administration of PTH promptly increased urinary cAMP excretion. In this patient, serum levels of calcitonin were increased, whereas values for 25-OHD and 1,25(OH)2D were normal.