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Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-ß transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.

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OBJECTIVE: To evaluate the effects of functional electric stimulation (FES) of lower limb muscles during 30 minutes of upright standing on the central and peripheral hemodynamic response in persons with spinal cord injury (SCI). DESIGN: A repeated-measure design. Subjects were used as their own control and underwent 2 testing protocols of FES-augmented standing (active standing) and non-FES standing (passive standing). SETTING: Rehabilitation hospital. PARTICIPANTS: Fourteen individuals with SCI (7 with tetraplegia, 7 with paraplegia). INTERVENTIONS: During active standing, FES was administered to 4 muscle groups of each leg in an overlapping fashion to produce a pumping mechanism during standing. During passive standing, subjects stood for 30 minutes using a standing frame with no FES intervention. MAIN OUTCOME MEASURES: Central hemodynamic responses of stroke volume, cardiac output, heart rate, arterial blood pressure, total peripheral resistance (TPR), and rate pressure product (RPP) were evaluated by impedance cardiography. All measurements were performed during supine and sitting positions before and after standing, and during 30 minutes of upright standing. RESULTS: Comparisons between the groups with paraplegia and tetraplegia showed a significant increase in heart rate in the paraplegics after 30 minutes of active standing. During active standing, paraplegics' heart rate increased by 18.2% (p = .015); during passive standing, it increased by 6% (p = .041). TPR in the tetraplegics significantly (p = .003) increased by 54% when compared with the paraplegics during passive standing. Overall, the tetraplegic group had a significantly lower systolic blood pressure (p = .013) and mean arterial pressure (p = .048) than the paraplegics during passive standing. These differences were not detected during active standing. When data were pooled from both groups and the overall groups response to active and passive standing were compared, the results showed that cardiac output, stroke volume, and blood pressure significantly decreased (p < .05) during 30 minutes of passive standing, whereas TPR significantly increased (p < .05). All of the hemodynamic variables were maintained during 30 minutes of active standing, and there were increases in RPP and heart rate after 30 minutes of active standing. CONCLUSION: FES of the lower extremity could be used by persons with SCI as an adjunct during standing to prevent orthostatic hypotension and circulatory hypokinesis. This effect may be more beneficial to those with tetraplegia who have a compromised autonomic nervous system and may not be able to adjust their hemodynamics to the change in position.

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The DYT1 locus on chromosome 9q34 is responsible for most childhood limb-onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult-onset, and predominantly cranial-cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial-cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40-cM segregates with ITD in these families, suggesting a shared mutation from the recent past.

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Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-onset primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C.

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Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait (McKusick 277600). We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals.

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Congenital cataracts are one of the most common major eye abnormalities and often lead to blindness in infants. At least a third of all cases are familial. Within this group, highly penetrant, autosomal dominant forms of congenital cataracts (ADCC) are most common. ADCC is a genetically heterogeneous group of disorders, in which at least eight different loci have been identified for nine clinically distinct forms. Among these, Armitage et al. (Nature Genet. 9: 37-40, 1995) mapped a gene for cerulean blue cataracts to chromosome 17q24. Bodker et al. (Am. J. Med. Genet. 37: 54-59, 1990) described a large family with cerulean blue cataracts, in which the affected daughter of affected first cousins was presumed to be homozygous for the purported gene. We report linkage in this family to the region on chromosome 22q that includes two beta crystallin genes (CRYBB2, CRYBB3) and one pseudogene (CRYBB2P1). The affected female in question is homozygous at all markers.

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This study evaluates the effect of chemically induced bowel denervation on survival, weight gain or loss, transit time, and d-xylose absorption in rats following 80% small bowel resection. Forty-three male Sprague-Dawley rats (150 g) underwent 80% midsmall bowel resection and anastomosis. Twenty rats were short bowel controls (group I). In 23 rats (group II), a 2.0 cm segment of jejunum proximal to the anastomosis was denervated by application of 0.1% benzalkonium chloride (BK) for 30 minutes. Ten additional rats underwent sham laparotomy without bowel resection. Five remained untreated (group III) and in 5 (BK) denervation was added (group IV). Bowel denervation was confirmed by histologic study in all (BK) rats. Weight and daily food and water intake were measured for 30 days and the groups compared. Weight in group I was 43.8 +/- 52.9 g, group II 95.0 +/- 50.1, (P less than .005), group III 177 g, and group IV 175 g. Food intake was greater in group I than II (P less than .05) and was similar to groups III and IV. Water intake calculated as animal weight (g)/mL H2O ingested was lowest in group I (P less than .05). Mortality was 30% in group I (6/20) and only 8.6% in group II (2/23). No deaths were observed in unresected controls (III and IV). Twenty-four additional rats were evaluated for d-xylose absorption and transit time by bringing out a loop enterostomy 10.0 cm from the Ligament of Treitz. Twelve rats were ostomy controls (group V).(ABSTRACT TRUNCATED AT 250 WORDS)

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This study evaluates the effect of reverse electrical pacing on intestinal absorption and transit time in an enterostomy model. Twenty-five male Sprague-Dawley rats (148 to 208 gm) underwent division and anastomosis of the proximal jejunum to eliminate the proximal gastroduodenal pacemaker. A 30.0 cm loop ileostomy was formed, and leads were placed at 1.0 and 3.0 cm proximal to the stoma. Reverse pacing was done with a 0.25 Hz, 50 msec pulse at 0.1 mA. Transit time was evaluated with 1.0 ml barium gavage and was 12 +/- 4 minutes in group I controls (n = 13) versus 27 +/- 21 minutes in group II (n = 12) reverse-paced rats (p less than 0.025). D-Xylose absorption was determined in 18 rats. Levels were 14.0 +/- 3.6 mg/dl in control rats (n = 6) and 15.5 +/- 3.4 mg/dl in reverse-paced rats (n = 6). Increasing the pulse milliamperage to 2.0 mA (n = 6) increased D-xylose serum levels to 38.8 +/- 27.7 mg/dl (p less than 0.05). Transit rate and net water flux were determined in eight additional rats with 15 cm Theiry-Vella loops. Transit rate was measured with 0.2 ml of methylene blue and was 3.00 +/- 2.32 ml/min in unpaced rats compared with 9.95 +/- 0.71 ml/min with reverse pacing (p less than 0.025). Water flux studies showed that control rats had a net secretory loss of 0.20 +/- 0.48 ml/cm while paced rats absorbed 0.08 +/- 0.12 ml/cm. These data indicate that reverse electrical pacing increases transit time and nutrient and fluid absorption. These observations suggest that reverse electrical pacing may be a useful adjunct in instances of short gut associated with an enterostomy.

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