Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.

Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1-3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding α7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy.

Microstructure of frontoparietal connections predicts cortical responsivity and working memory performance.

We investigated how the microstructure of relevant white matter connections is associated with cortical responsivity and working memory (WM) performance by collecting diffusion tensor imaging and verbal WM functional magnetic resonance imaging data from 29 young adults. We measured cortical responsivity within the frontoparietal WM network as the difference in blood oxygenation level-dependent (BOLD) signal between 3-back and 1-back conditions. Fractional anisotropy served as an index of the integrity of the superior longitudinal fasciculi (SLF), which connect frontal and posterior regions. We found that SLF integrity is associated with better 3-back performance and greater task-related BOLD responsivity. In addition, BOLD responsivity in right premotor cortex reliably mediated the effects of SLF integrity on 3-back performance but did not uniquely predict 3-back performance after controlling for individual differences in SLF integrity. Our results suggest that task-related adjustments of local gray matter processing are conditioned by the properties of anatomical connections between relevant cortical regions. We suggest that the microarchitecture of white matter tracts influences the speed of signal transduction along axons. This in turn may affect signal summation at neural dendrites, action potential firing, and the resulting BOLD signal change and responsivity.

Are the Chinese Saving for Old Age?: The Relationship between Future Pension Benefits of 45-60 Years Old Chinese and Current Household Expenditures.

Worldwide, older people's support used to be the adult children's responsibility. In China, two generations after introducing the one-child policy in the late 70-ies, this becomes an increasingly demanding obligation. The Chinese government took the responsibility to mitigating old- age poverty risks and realized unprecedented progress in pension coverage. At the same time, the household savings increased to about 30 % of disposable income. Built on previous research on the politics of ageing, this study analyses households responses to the established governmental and firm pension programs as well as to the New Rural Pension Scheme (NRPS), introduced in 2009. The central question is: will participation in the established and new pension programs lead to higher current Chinese household expenditures and therefore to lower savings? The China Health and Retirement Longitudinal Study (CHARLS) dataset of 2011 offered the opportunity to study the influence of the recently introduced NRPS. We find that Chinese households with members between 45 and 60 years who expect future benefits of NRPS do not have higher expenditures than those not covered by NRPS. For the participants in the established, mostly urban pension programs a correlation was found with higher current expenditures (28 % more spending on basic needs, 80 % more on luxury) However, further analysis shows that this correlation cannot be interpreted as a causal relationship. This implies that coverage by pensions, be it in urban or rural programs, does not determine higher current expenditures and lower savings.

The binding of hemoglobin to membranes of normal and sickle erythrocytes.

The binding of hemoglobins A, S, and A2 to red cell membranes prepared by hypotonic lysis from normal blood and blood from persons with sickle cell anemia was quantified under a variety of conditions using hemoglobin labelled by alkylation with 14C-labelled Nitrogen Mustard. Membrane morphology was examined by electron microscopy. Normal membranes were found capable of binding native hemoglobin A and hemoglobin S in similar amounts when incubated at low hemoglobin: membrane ratios, but at high ratios hemoglobin saturation levels of the membranes increased progressively for hemoglobin A, hemoglobin S and hemoglobin A2, respectively, in order of increasing electropositivity. Binding was unaffected by variations in temperature (4-22 degrees C) and altered little by the presence of sulfhydryl reagents, but was inhibited at pH levels above 7.35; disrupted at high ionic strength; and dependent on the ionic composition of the media. These findings suggest that electrostatic, but not hydrophobic or sulfhydryl bonds are important in membrane binding of the hemoglobin under the conditions studied. An increased retention of hemoglobin in preparations of membranes from red cells of patients with sickle cell anemia (homozygote S) was attributable to the dense fraction of homozygote S red cells rich in irreversibly sickled cells, and the latter membranes had a smaller residual binding capacity for new hemoglobin. This suggests that in homozygote S cells which have become irreversibly sickled cells in vivo, there are membrane changes which involve alteration and/or blockade of hemoglobin binding sites. These findings support the notion that hemoglobin participates in the dynamic structure of the red cell membrane in a manner which differs in normal and pathological states.

The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing.

To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139-251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7-22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0-24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2-12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.

An ultrastructural study of chronic sodium cyanate-indiuced neuropathy.

Fifteen rats were given a sodium cyanate-rich diet for 18 months and at the end of that period, all of them had developed motor weakness and were perfused for ultrastructural study. A peripheral neuropathy involving mostly the roots and sciatic nerves was found and the main ultrastructural lesion was vacuolization of myelin. There was marked distinction of the myelin sheaths and phagocytosis of myelin. Axoplasmic changes were minimal and consisted of accumulation of glycogen within vacuoles. Invaginations of adaxonal Schwann cell membranes and axolemma forming loops and separate chambers were also present. There was active participation of macrophages in the splitting of myelin as well as in phagocytosis of myelin remnants. There was evidence of remyelination with the toxic damage. We concluded that cyanate induced neuropathy is due mostly to a myelinotoxic effect of the drug, although parallel but less intense axonal damage cannot be excluded.

Mucolipidosis IV. Clinical, ultrastructural, histochemical, and chemical studies of a case, including a brain biopsy.

A 7-year-old Ashkenazi Jewish boy with normal early development started to regress at 8 months of age and made no further developmental progress. Corneal clouding was noted at age 10 months. Corneal and conjunctival biopsy at 14 months, cerebral biopsy at 24 months, and fibroblast cultures at 32 months showed lysosomal inclusions, suggesting the storage of lipid-like and mucopolysaccharide-like material. In the brain, dense fluorescent inclusions resembled those in ceroid-lipofuscinosis. Total ganglioside content of white matter was raised, but the pattern was normal. The level of nonlipid hexosamine in the brain was normal. The cornea and conjunctiva contained electronlucent vacuoles resembling those in the mucopolysaccharidoses. Cornea, brain, and lymphocytes contained concentric membranous lamellar structures reminiscent of those in the gangliosidoses. The clinical picture and ultrastructural findings support the impression that this case belongs to a new variant of the mucolipidoses, mucolipidosis IV.

Huntington disease: normal lipid composition of purified neuronal perikarya and whole cortex.

This is the first report of the lipid composition of human neurons. Neuronoal perikarya were isolated from frozen samples of the cerebral cortex of persons with Huntington disease and two normal controls. These were analyzed for total lipid, individual lipids, and gangliosides. No differences were detected between diseased and normal cells. In addition, gray matter samples from the same patients, and one additional patient and control sample, were analyzed and found not to differ. Thus the ultrastructural abnormalities seen in cortical biopsies are not reflected in the concentration of the major lipid classes.

Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies.

A brain biopsy from a 20-year-old patient whose clinical course was marked by progressive dementia and chorea since age 10 years showed increased amounts of lipofuscin, abnormal mitochondria, and other organelles in cortical neurons, neurites, and astrocytes. Juvenile Huntington chorea was confirmed at autopsy. High levels of three histone-like proteins (molecular weight 10,000 to 16,000) in the microsomal fraction of purified neurons were found by SDS-polyacrylamide gel electrophoresis. Fatty acids were abnormal in white matter sphingomyelin. These ultrastructural and biochemical findings conformed to those established in adult Huntington chorea, thus strengthening the concept of a uniform pathologic process in adult and juvenile Huntington diseases in spite of some clinical and histologic differences.

[Structure and process quality of quality-assured mamma diagnostics in Schleswig-Holstein]. / Struktur- und Prozessqualität in der qualitätsgesicherten Mammadiagnostik in Schleswig-Holstein.

PURPOSE: To demonstrate the structure and process quality of quality-assured mamma diagnostics (QuaMaDi) by means of quality indicators as defined in the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis and in the National Guideline on Early Detection of Cancer in Germany. Furthermore, spatial differences and changes in the chronological sequence were analyzed. MATERIALS AND METHODS: We used administrative data as documented in the time period 2006 - 2009 in QuaMaDi in Schleswig-Holstein (SH), Germany, and analyzed quality indicators as defined in the abovementioned guidelines (absolute and relative frequencies, 95 % confidence intervals). RESULTS: Each year approximately 6 % of all women age 20 or older living in SH are examined using QuaMaDi. Only minor differences regarding age and clinical data were seen between the patients in the four regions of SH. Reference values for the quality indicators are largely reached (i. e., proportion of women with breast density ACR 3 or 4 plus additional ultrasound = 96.2 %; proportion with repeated mammography = 0.2 %). Spatial differences are only minor. In the chronological sequence, quality indicators improve, if they did not reach the reference values in the beginning, or indicate a high and constant quality. CONCLUSION: With regard to those quality indicators that were computable, reference values as defined in the guidelines were reached in 9 of 12 cases. In one case the difference between the observed value and the reference values is system-immanent and in another case the difference is less than four percentage points (reference value 90 %).