The steroid hormone vitamin D is required for normal calcium and phosphorus metabolism and is thus an important contributor to musculoskeletal health. Recent data have linked low vitamin D levels to a wide range of diseases, including cancer, cardiovascular disease, autoimmune disease and infection. Adequate levels of vitamin D are maintained through its cutaneous photosynthesis and oral ingestion. By some estimates, one billion people worldwide have vitamin D deficiency or insufficiency. A number of factors influence the photosynthesis and bioavailability of vitamin D and contribute to risk of impaired vitamin D status. These factors include variation in sun exposure due to latitude, season, time of day, atmospheric components, clothing, sunscreen use and skin pigmentation, as well as age, obesity and the incidence of several chronic illnesses. This review will focus on factors that influence vitamin D status and contribute to the prevalence of low vitamin D levels.

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GRP1 and the related proteins ARNO and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. Here we show the PH domains of all three proteins exhibit relatively high affinity for dioctanoyl phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P 3 ), with K D values of 0.05, 1.6 and 1.0 M for GRP1, ARNO, and cytohesin-1, respectively. However, the GRP1 PH domain was unique among these proteins in its striking selectivity for PtdIns(3,4,5)P 3 versus phosphatidylinositol 4,5-diphosphate (PtdIns(4,5)P 2 ), for which it exhibits about 650-fold lower apparent affinity. Addition of a glycine to the Gly 274 -Gly 275 motif in GRP1 greatly increased its binding affinity for PtdIns(4,5)P 2 with little effect on its binding to PtdIns(3,4,5)P 3 , while deletion of a single glycine in the corresponding triglycine motif of the ARNO PH domain markedly reduced its binding affinity for PtdIns(4,5)P 2 but not for PtdIns(3,4,5)P 3 . In intact cells, the hemagglutinin epitope-tagged PH domain of GRP1 was recruited to ruffles in the cell surface in response to insulin, as were full-length GRP1 and cytohesin-1, but the PH domain of cytohesin-1 was not. These data indicate that the unique diglycine motif in the GRP1 PH domain, as opposed to the triglycine in ARNO and cytohesin-1, directs its remarkable PtdIns(3,4,5)P 3 binding selectivity.Cell signaling processes are often initiated by the recruitment of protein complexes to the cytoplasmic face of the plasma membrane, where they act to elicit signaling events. Specialized regions or domains within such signaling proteins function as adapters in the recruitment process, linking these proteins to chemical motifs generated by receptor activation. For example, specific membrane-bound protein phosphotyrosine sites appear in response to activation of transmembrane receptor tyrosine kinases by growth factors and other stimuli, attracting Src homology (SH) 1 2 domains within proteins that bind these sites (1). The proteins that contain SH2 domains are enzymes, regulator proteins, or simply adapters themselves that connect other proteins to the localized protein phosphotyrosines. This paradigm has been extended to a large number of protein domains and their respective ligands, and provides for an effective means of mobilizing cellular signaling machines (2). A particularly interesting membrane localization domain that has been identified in over 100 proteins is the PH domain, which spans approximately 120 residues and contains an invariant tryptophan in its COOH-terminal region (3). Several PH domain structures have been solved by NMR and by x-ray crystallography, giving rise to the concept that their overall protein fold is formed from seven ␤ sheets with connecting loops that form a ligand binding scaffold (4 -10). The PH domain fold is similar to that of several other ligand binding protein domains that differ substantially in amino acid sequence, and has therefore been ...

The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.

IMPORTANCE Pyoderma gangrenosum is an inflammatory neutrophilic dermatosis. Current knowledge of this rare disease is limited owing to a lack of validated diagnostic criteria and large population studies. OBJECTIVE To evaluate the association of age with the clinical presentation and comorbidities of pyoderma gangrenosum. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter retrospective cohort study performed at tertiary academic referral centers in urban settings. Adults (Ն18 years) who were evaluated and diagnosed as having pyoderma gangrenosum at the Brigham and Women's and Massachusetts General Hospitals from 2000 to 2015 and the University of Pennsylvania Health System from 2006 to 2016 were included. MAIN OUTCOMES AND MEASURES Patient demographics, clinical features, medical comorbidities, and treatment. RESULTS Of the 356 validated cases of pyoderma gangrenosum included in the study, 267 (75%) were women and 284 (84.8%) were white. The mean (SD) age at presentation was 51.6 (17.7) years. Pathergy was recorded in 100 patients (28.1%). A total of 238 patients (66.9%) had associated medical comorbidities: inflammatory bowel disease in 146 patients (41.0%); inflammatory arthritis in 73 patients (20.5%); solid organ malignant neoplasms in 23 patients (6.5%); hematologic malignant neoplasms in 21 patients (5.9%); and hematologic disorders, specifically monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, and polycythemia vera in 17 patients (4.8%). When stratified by age, pathergy was more common in patients 65 years or older (36.3% vs 24.3%; P = .02). Inflammatory bowel disease was the only medical comorbidity that was more common in patients younger than 65 years (47.7% vs 26.6%; P < .001), while a number of medical comorbidities were more common in those 65 years or older, including rheumatoid arthritis (13.3% vs 6.2%; P = .03), ankylosing spondylitis (1.8% vs 0%; P = .04), solid organ malignant neoplasms (13.3% vs 3.3%; P < .001), hematologic malignant neoplasms (9.7% vs 4.1%; P = .04), and the aforementioned hematologic disorders (10.6% vs 2.1%; P < .001). CONCLUSIONS AND RELEVANCE Although clinical presentation in this large cohort was similar between different age groups, disease associations varied by age. The findings of this study may allow for a more focused, age-specific evaluation of patients with pyoderma gangrenosum.

Intralesional sodium thiosulfate may be an effective and well-tolerated treatment for localized calciphylaxis. This novel approach requires further research and investigation.

In order to assess the systemic prognosis of children with leukaemic ocular involvement, 63 of 131 patients admitted to hospital with acute leukaemia were evaluated ophthalmically. A total of 28 of 63 showed ophthalmic involvement and were followed up for up to 84 months.

Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutations with Parkinson's disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2(+/-) mice survive to adulthood with no evident metabolic or growth defects. At 12-15 months of age, the Gigyf2(+/-) mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are alpha-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.