Mapping of gene loci in the Q13–Q15 region of chromosome 12

The gene loci CDK4, GLI, CHOP and MDM2 have been mapped to the q13–q15 region of chromosome 12. Using fluorescencein situ hybridization onto simultaneously DAPI-banded metaphase chromosomes and interphase nuclei, we have more precisely mapped and ordered these loci, together with a number of Genethon microsatellite markers. GLI and CHOP localize to 12q13.3–14.1, CDK4 to 12q14 and MDM2 to 12q14.3–q15, and the gene order is cen-GLI/CHOP-CDK4-MDM2. The Genethon microsatellites D12S80 and D12S83 flank MDM2.     

Triazin-polymere. II. Polyphenylentriazine

Condensation of benzamidine hydrochloride with acetanhydride gives 2-methyl-4.6-diphenyl-s-triazine with yields of more than 90%. The corresponding reaction of terephthaldiamidine dihydrochloride leads to poly[(6-methyl-2.4-s-triazinediyl)-1.4-phenylene] of low degree of polymerization, soluble in conc. sulfuric acid. Benzamidine-N-carboxylic acid ethylester is converted to 2-hydroxy-4.6-diphenyl-s-triazine in a yield of 99% by heating. Terephthaldiamidine-di-N-carboxylic acid ethylester decomposes by heat treatment under loss of ethyl carbamate to the insoluble white poly[(6-hydroxy-2.4-s-triazinediyl)-1.4-phenylene].     

Neuroanatomical Correlates of Skin Conductance Orienting in Normal Humans: A Magnetic Resonance Imaging Study

Although little is known about the neuroanatomical basis of skin conductance orienting in intact normal humans, the limited literature on animals and humans with neurological and clinical disorders implicate prefrontal, temporal/amygdala, and pons brain areas in mediating skin conductance orienting. This study relates area of these structures using magnetic resonance imaging techniques to skin conductance orienting responses in 17 normal humans in order to test hypotheses that larger area of these excitatory structures will be associated with more orienting responses. Left and right hand skin conductance orienting was significantly associated with left and right prefrontal area (r = .44-.60), area of the pons (r = .43-.54), and left but not right temporal/amygdala area (r = .47-.53). No relationships were observed with areas thought to be unrelated to skin conductance activity (cerebellum, nonfrontal cortical area), medial prefrontal cortex, or the third ventricle. This appears to be the first study relating brain structure to skin conductance orienting in intact normal humans. Although preliminary at the present time, these results implicate prefrontal, pons, and temporal/amygdala areas in the mediation of skin conductance orienting in normal humans.     

A comparison of genetic chromosomal loci for intracranial, thoracic aortic, and abdominal aortic aneurysms in search of common genetic risk factors.

BACKGROUND: Genetic factors are likely to be involved in the pathogenesis of intracranial, ascending thoracic aorta, and infrarenal aortic abdominal aneurysms. Common genetic risk factors for these three types of aneurysms have been suggested. This review describes the results of whole-genome linkage studies on intracranial, thoracic aorta, and aortic abdominal aneurysms, and compares the genomic loci identified in these studies in search of possible common genetic risk factors for the three aneurysmal types. METHODS: A literature search of all whole-genome linkage studies performed on intracranial, thoracic aorta, and aortic abdominal aneurysms was performed. The genomic loci identified in these studies were described and compared in search of similarities between them. RESULTS: Five chromosomal regions on 3p24-25, 4q32-34, 5q, 11q24, and 19q that may play a role in the pathogenesis of two or more aneurysmal types were identified: 3p24-25 for thoracic aorta and intracranial aneurysms; 4q32-34 for aortic abdominal and intracranial aneurysms; 5q for thoracic aorta and intracranial aneurysms; 11q24 for thoracic aorta, aortic abdominal, and intracranial aneurysms; and 19q for aortic abdominal and intracranial aneurysms. CONCLUSIONS: Five chromosomal regions that may include common genetic factors for intracranial, thoracic aorta, and aortic abdominal aneurysms were identified. Further studies are needed to explore these chromosomal regions in different aneurysm patient groups and may further help to unravel the disease pathogenesis of aneurysms in general.     

Increased CD8+ T Cell Apoptosis in Scleroderma Is Associated with Low Levels of NF-κB

Our objectives were (1) to compare lymphocyte subpopulation apoptosis rates in SSc patients versus healthy controls and (2) to compare Bcl-2 and NF-kappa B expression in cultured CD8 lymphocytes of SSc patients versus controls. Peripheral blood samples were obtained from 27 SSc patients meeting the American College of Rheumatology criteria for SSc and 28 healthy individuals. Mononuclear cells were isolated by Ficoll-Hypaque density gradient separation and cultured for 48 hr. For determination of apoptosis within specific cell populations, samples were labeled with PE-conjugated monoclonal antibody to CD8, CD4, and a FITC-conjugated monoclonal antibody to Annexin V. Flow cytometry was carried out with a FACS operating with Cellquest software. CD8+ lymphocytes were positively selected with magnetic microbeads conjugated to antihuman CD8. CD8 T cells were separated, then incubated with activation for 48 hr, and NF-kappa B and Bcl-2 analysis was carried out using Western immunoblotting. The CD4:CD8 ratio was increased in SSc compared to controls (2.6 +/- 1.13 vs.1.87 +/- 0.76; P = 0.018). The spontaneous apoptosis rate of SSc CD8 lymphocytes was increased compared to that of controls of (21.9 +/- 13.7 vs. 13.3 +/- 9.9; P = 0.019). No difference was found in the rate of CD4 apoptosis of SSc patients versus controls (9.8 +/- 5.2 vs. 7.18 +/- 4.89%; P = ns). The expression of NF-kappa B in SSc CD8 lymphocytes was decreased compared with that of CD8 lymphocytes from healthy controls (144 +/- 13 vs. 188 +/- 11; P = 0.018). Whereas expression of Bcl-2 was similar in activated CD8+ T cells of SSc patients and healthy controls, CD8+ T cell apoptosis rate was found to be in reverse correlation with expression of NF-kappa B in these cells ( r = - 0.53, P = 0.029). The increased CD4:CD8 ratio in SSC may result from increased CD8+ T cell apoptosis. Increased SSc CD8 T cell apoptosis is associated with low levels of NF-kappa B.     

CCR2-64I and CXCL12 3'A alleles confer a favorable prognosis to AIDS patients undergoing HAART therapy.

BACKGROUND: The chemokine receptor polymorphisms CCR5Delta32, CXCL12 3'A, CCR2-64I and CCR5-59029 G/A have been demonstrated to affect HIV-1 infection and progression. OBJECTIVE: We studied the impact of the above polymorphisms on the effectiveness of a 30-month treatment with highly active antiretroviral therapy (HAART) in 149 HIV-1 patients. STUDY DESIGN: We stratified the patients according to CD4 CDC criteria and applied Kaplan-Meier analysis using the following end-point criteria: (a) the time from HAART initiation to undetectable viral load (VL) counts (VL<50 copies/ml), (b) the duration of undetectable VL status and (c) the time required for CD4+ T-cell counts to pass over the 500 cells/ml threshold. RESULTS: Our results in the second group (CD4 201-500) revealed that patients with the CCR2-64I allele achieved undetectable VL counts at 3.5+/-0.48 months as compared to 10.26+/-1.42 months in the control group (p=0.018). The VL remained undetectable for 28+/-2 months, in contrast to 20+/-2 months in the control group (p=0.048). Patients carrying CXCL12 3'A restored the CD4 population faster than the control group (9+/-2 and 14+/-2 months, respectively, p=0.023). The CCR5Delta32 and CCR5-59029 G/A alleles did not appear to affect the parameters studied. CONCLUSIONS: Our results suggest that patients carrying either CCR2-64I or CXCL12 3'A have a more favorable prognosis during HAART treatment.     

A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT,the gene associated with Sanfilippo C mucopolysaccharidosis

Pathogenic variants in the gene HGSNAT (heparan‐α‐glucosaminide N‐acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)—a severe childhood‐onset lysosomal storage disorder, and adult‐onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to‐date of HGSNAT‐associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late‐onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543‐2A>C; c.1708delA], three of which were considered to be retina‐disease‐specific alleles. The most prevalent retina‐disease‐specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans‐acting genetic or environmental modifying factors.