A unique case series of autosomal recessive bestrophinopathy exhibiting multigenerational inheritance

Introduction: Autosomal recessive bestrophinopathy (ARB) is a retinal disease caused by biallelic mutations of the BEST1 gene. It has a variable phenotype with white flecks in the retina, multifocal yellow subretinal deposits, macular edema, choroidal neovascularization, hyperopia, and electrophysiological abnormalities. We describe a family with ARB and multigenerational inheritance.

Methods: Three generations of a Middle Eastern family (a woman, one son, and two grandchildren) were evaluated by our ocular genetics team. Eye examinations, fundus photography, and optical coherence tomography (OCT) were performed. Genetic testing was obtained on examined patients and available relatives.

Results: The proband demonstrated counting fingers vision and white flecks in the retinal periphery, with macular subretinal fluid (SRF), loss of outer photoreceptor segments, and epiretinal membrane (ERM) on OCT. Two grandchildren demonstrated decreased vision, multifocal yellow subretinal deposits, and SRF on OCT. Two grandchildren examined elsewhere were reported to be similarly affected. A son’s examination was normal except for extra-macular scars (from prior toxoplasmosis) and ERM. Genetic history revealed consanguinity and testing showed homozygosity for BEST1 mutations in the proband and two grandchildren c.473G>A/c.473G>A (R218H /R218H) and heterozygosity in two unaffected sons and two unaffected daughters-in-law c.473G>A/WT (p.R218H/WT).

Discussion: We present a consanguineous family of five affected individuals with ARB and four confirmed carriers. Their pedigree was consistent with dominant inheritance and incomplete penetrance. Genetic testing clarified the diagnosis and mode of inheritance. We describe the genetic findings, phenotypic variability, and recessive inheritance of an often dominantly inherited mutation as notable elements in their case.     

Comorbid psychiatric disorders in Arab children with Autism spectrum disorders

The objective of our study is to estimate the prevalence of comorbid psychiatric disorders in a sample of children with autism spectrum disorders (ASD) recruited from three Arab countries. We also examine the relationship between comorbidity and children's cognitive functioning and gender. Children who received a diagnosis of ASD (n = 60) from a child psychiatric outpatient clinic in Mansoura (Egypt), Al-Ahsa (Saudi Arabia) and Amman (Jordan) were included in this study. Comorbid diagnoses were established with a clinical interview and a semi-structured clinical interview for children and adolescents (SCICA). In addition, for all patients the cognitive evaluation was measured given the range in age and level of ability. Sixty-three percent of the children were diagnosed with at least one comorbid disorder. The most commonly reported comorbid disorders were anxiety disorders (58.3%), ADHD (31.6%), conduct disorders (23.3%), and major depressive disorder (13.3%). Out of the total sample, Obsessive compulsive disorder was the most prevalent anxiety disorder (55%). Elimination disorders were also diagnosed in 40% of patients. These findings emphasize a wide variety of psychiatric comorbidity afflicting youth with ASD and may be important targets for intervention.     

Prognostic value of serum vascular endothelial growth factor in Egyptian females with metastatic triple negative breast cancer

ObjectivesThe aim of this work was to explore the value of serum vascular endothelial growth factor-A (VEGF-A) in patients with metastatic triple negative breast cancer (TNBC) treated with chemotherapy. The primary end point was overall survival (OS). Secondary end points were response rate (RR), progression-free survival (PFS) and VEGF-A level at baseline, mid-therapy and at the end of therapy.Design and methodsFemale patients aged 18 years or above with histologically proven metastatic TNBC were included. Serum VEFG-A levels were measured at baseline, after the 3rd and 6th cycles of FAC chemotherapy regimen (Fluorourcil, Adriamycin, and Cyclophamide).ResultsThe overall RR was 57%. The median PFS and OS were 7 and 11.2 months, respectively (95% CI: 4.3–9.7 and 3.8–18.5 months, respectively). Patients whose disease progressed despite therapy had a significantly higher baseline VEGF-A level than those who did not progress. VEGF-A level did not drop with continuation of therapy. Patients with high VEGF-A level had a significantly lower PFS but not OS than patients with low levels.ConclusionThe outcome of metastatic TNBC is poor with FAC chemotherapy regimen. Alternative chemotherapeutic regimens and novel therapeutic approaches including targeting of VEGF and/or its receptors are warranted.     

Membrane expression of platelet calpain

Platelet calpain has many platelet substrates, including external membrane proteins. We thus investigated whether platelet calpain II was associated with platelet membranes in unstimulated and thrombin- activated platelets. A monospecific, goat polyclonal antibody was reared to purified platelet calpain II. Sixteen whole platelet lysates were found to contain 4.5 +/- 0.7 micrograms calpain antigen II per 10(8) platelets (mean +/- SEM) as determined by a competitive enzyme- linked immunosorbent assay. Using the dipeptide fluorogenic substrate, Suc-Leu-Tyr-MCA, 17 human platelet lysates contained 3.6 +/- 0.4 micrograms calpain activity per 10(8) platelets. Platelet calpain II was associated with the Triton X-100 insoluble platelet cytoskeletons from both unstimulated and thrombin-activated platelets. When compared with the total cell content of platelet calpain II, calpain antigen (10% to 13%) and calpain activity (24% to 28%) was associated with platelet cytoskeletons in unstimulated and thrombin-activated platelets, respectively. On immunoblot, the heavy chain (80 Kd) of calpain II was detected in platelet cytoskeletons. Subcellular fractionation studies on both unstimulated and thrombin-activated platelets, revealed that half of the total platelet calpain II antigen was associated with cytosol, and the other half was associated with the membrane fraction. Platelet calpain II was not seen on the surface of unstimulated, paraformaldehyde fixed platelets by immunofluorescence. However, on thrombin-activated platelets, rim immunofluorescence was seen, indicating that activated platelets externalize their calpain. This observation was confirmed by the finding that about 2,000 molecules per platelet of an 125I-anti-calpain II Fab' specifically bound to thrombin-activated but not unstimulated platelets. Both dibucaine (1 mmol/L) and platelet activating factor (1.86 mumol/L) in the absence of external Ca++, but not collagen (5 micrograms/mL) or ionophore A23187 (2.5 mumol/L) in the absence of external Ca++, were also able to externalize platelet calpain II antigen, as indicated by a similar level of specific 125I-anti-calpain II Fab'-platelet binding. These combined studies indicate that platelet calpain II is a major protein, comprising 2% of total platelet protein, a substantial portion of which is membrane-associated. When platelets are activated by thrombin and platelet activating factor, calpain II antigen also becomes present on the external platelet surface.     

Human influenza A (H5N1) cases, urban areas of People's Republic of China, 2005-2006

We investigated potential sources of infection for 6 confirmed influenza A (H5N1) patients who resided in urban areas of People's Republic of China. None had known exposure to sick poultry or poultry that died from illness, but all had visited wet poultry markets before illness.     

Treatment of Cushing's Disease in Childhood and Adolescence by Stereotactic Pituitary Irradiation

ABSTRACT. Eight children with Cushing's disease aged 6-18 years were treated with external radiation to the pituitary gland using ⁶⁰Co gamma radiation given with stereotactic technique. The dose given varied between 50 and 70 Gy. The observation time was 2.6 to 6.75 years. Seven children had a clinical remission with normal urinary Cortisol excretion. One child had insufficent effect of two irradiations and underwent bilateral adrenalectomy. In the patients in remission the growth velocity increased during the first year after treatment but growth retardation occurred again during the second year. Insufficient growth hormone secretion was demonstrated in all subjects. Two patients were given thyroxine substitution and three showed evidence for secondary hypogonadism. In conclusion, stereotactic pituitary irradiation was effective in normalizing the excessive glucocorticoid production in children with Cushing's disease. However, with the doses used, it was not possible to maintain a normal anterior pituitary function.     

Stimulation of human cytotoxic T cells with HIV-1-derived peptides presented by recombinant HLA-A2 peptide complexes

HLA-A2 heavy chain and beta 2-microglobulin were expressed in Escherichia coli, and refolded in the presence of peptides derived from HIV-1 RT and gag proteins. When recombinant HLA-A2 molecules were attached to cells lacking HLA-A2, the cells became susceptible to lysis by HLA-A2-restricted cytotoxic T lymphocyte (CTL) clones specific for peptides derived from RT and gag proteins. Limiting dilution analyses of peripheral blood mononuclear cells from HIV-1-infected individuals showed that the recombinant HLA-A2 peptide complexes covalently immobilized on microspheres stimulated the development of HLA-A2 peptide-specific CTL. Preformed HLA-peptide complexes may provide an alternative to immunization procedures that depend upon intracellular processing of antigen to elicit T cell responses.      

槐定碱的气相色谱测定法及其在兔体内的药代动力学

兔血浆中槐定碱的气相色谱测定条件:氮气、氢气和空气的流速分别为60,40和380ml/min。填充柱、进样室和检测室温度分别为190,280和300℃。内标物为槐胺碱,血浆中槐定碱浓度为3.0和10.0μg/ml时,测得回收率分别为103.6±2.4%(CV=2.34%)和101.5±6.5%(CV=6.35%)。线性范围为1～15/μg/ml。槐定碱在兔体内的药代动力学按二房室拟合,其混合参数值:α.0.0864 min^-1;β.0.00932 min^-1;Vc.1.19 L/kg;V_area.2.07 L/kg;V_dvv.1.99L/kg;Cl.19.3 ml/min·kg;MRT.103min。