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Mutations in BEST1 account for autosomal dominant vitreoretinochoroidopathy (ADVIRC), a rare inherited retinal dystrophy with presenile cataracts and incomplete anterior segment development. The long-term clinical findings and visual prognosis of these patients continues to evolve over time.The retina was assessed by fundus photography, fluorescein angiography, and spectral domain optical coherence tomography. Sanger dideoxy chain-termination sequencing identified mutations in BEST1. Bioinformatic tools were used to predict changes in splicing. An in vitro splicing assay was applied to evaluate for altered pre-mRNA splicing.Long-term follow up of the first ever reported ADVIRC proband revealed progressive foveal atrophy in both eyes 3 decades after his initial presentation. Progressive retinal ischemia, bilateral iris atrophy, and pseudophakodnesis were observed on follow up. The patient was heterozygous for a c.248G A missense mutation in exon 4 of BEST1, affecting a highly conserved transmembrane domain. Although computational prediction models suggest a change in the binding probability of splicing-associated SR proteins, in vitro splicing assays failed to demonstrate an effect of the c.248G A mutation on splicing of BEST1 exon 3 or exon 4.Progressive posterior chorioretinal changes occurred over time in the initial ADVIRC proband, leading to visual loss. The causative mutation in this patient falls in the transmembrane domain of the BEST1 protein, with unclear functional consequences. Although previous studies showed alteration in pre-mRNA splicing, in vitro splicing assays failed to demonstrate this in our patient.

Nucleotide oligomerization domain 2 (NOD2) has been associated with intestinal immunity after the discovery that its polymorphisms are linked to Crohn's disease (CD). Intestinal failure (IF) represents a wider spectrum of diseases where intestinal homeostasis has been disrupted.To evaluate the prevalence of NOD2 mutations in a population with IF as well as its association with the different conditions causing this problem.One hundred ninety-two consecutive patients with IF and 103 healthy controls were genotyped for the three most common NOD2 polymorphisms. Genotypes were compared between the groups and were related to the entities causing IF.A high percentage (26%) of patients had at least one of the three most common NOD2 polymorphisms, while only a 4.8% of healthy controls had a mutant genotype. In patients with IF, specific mutations for the 702W, 908R and 1007fs alleles were 11, 5 and 12.5%, respectively, compared with 0.9% (P = 0.0003), 1.9% (P = 0.1) and 1.9% (P = 0.001) in the control group. If we consider patients with any cause of IF other than CD, the percentage is still as high as 18.8%, with specific mutation frequencies of 7.6% (702W; P = 0.01), 5.8% (908R; P = 0.1) and 8.2% (1007fs; P = 0.002). We could not establish an association between a NOD2 mutant genotype with any other specific clinical condition other than CD.Our finding supports the importance of NOD2 in the maintenance of intestinal immune homeostasis and may be important to a variety of intestinal stressors.

Small bowel transplantation has been limited by high rates of rejection and graft loss. In June 2000, we began using sirolimus, an immunosuppression agent with proven efficacy in kidney transplantation. We reviewed results among intestinal transplant recipients before and after the introduction of sirolimus.Thirty-one intestinal transplants were performed in 29 patients at our center between July 1998 and April 2001. All patients were followed for at least 30 days posttransplant. In the first 19 transplants (group 1), patients received tacrolimus, steroids, and antibody induction therapy (either daclizumab or OKT3). In the next 12 consecutive transplants (group 2), patients received tacrolimus, steroids, basiliximab, and sirolimus.Eighteen children (7 males and 11 females, mean age 2.1+/-2.2 years) and 11 adults (9 males and 2 females, mean age 38.1+/-12.4 years) underwent transplantation. All patients survived transplantation. The overall reoperation rate was 1.7 procedures per patient in group 1 and 1.1 procedures per patient in group 2. The most common indications were abscess (n=7), planned second look (n=7), leaks/fistulas (n=6), dehiscence (n=6), obstruction (n=4), ischemic bowel (n=3), perforations (n=3), stomal complications (n=3), and graft removal (n=3). The incidence of biopsy-proven rejection in the first 30 days was 73.7% in group 1 and 16.7% in group 2 (P0.002). Sirolimus was temporarily held or discontinued in 66.7% of patients. Actuarial 1-year graft survival was 91.7% with sirolimus and 57.9% without sirolimus (P0.04). Actuarial 1-year patient survival was 91.7% with sirolimus and 79% without sirolimus (P=0.12).An immunosuppressive regimen that includes sirolimus has improved graft survival. Furthermore, this regimen has significantly decreased the incidence of early rejection and has eliminated early graft loss caused by fulminant rejection.

The pattern of pulmonary venous flow was studied in 52 normal fetuses between 16 weeks gestation and term. A characteristic flow profile was defined. This was similar to that described in the child and adult and different from the pattern of flow in the systemic veins described in the fetus. The velocity of flow increased with gestation and was not influenced by heart rate. The velocity-time integral showed that systolic flow was 2.0 +/- 0.3 times the flow in diastole. Pulsed Doppler echocardiography demonstrates a distinctive pattern of pulmonary venous blood flow that reflects left atrial hemodynamics.

Autosomal dominant vitreoretinochoroidopathy is a newly described fundus dystrophy characterized by abnormal chorioretinal hypopigmentation and hyperpigmentation, usually lying between the vortex veins and the ora serrata for 360 degrees. In this zone, there are a discrete posterior boundary, preretinal punctate white opacities, retinal arteriolar narrowing and occlusion, and, in some cases, choroidal atrophy. Most affected family members have diffuse retinal vascular incompetence, cystoid macular edema, and presenile cataracts. The vitreous is characterized by fibrillar condensation and a moderate number of cells. Electroretinograms are normal in younger affected individuals and are only moderately abnormal in older ones. Preretinal neovascularization, present in the posterior pole, is progressive in the proband. There are no identifiable systemic or skeletal abnormalities, high myopia, optically empty vitreous, lattice degeneration, areas of white-without-pressure, retinal breaks, or retinal detachment; thus, previously described vitreoretinopathies can be excluded from diagnostic consideration. Progression of this diagnostic seems to be extremely slow in most family members.