Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clinical phenotype.

BACKGROUND: Thoracic and abdominal aortic aneurysms and dissection often develop in hypertensive elderly patients. At higher risk are smokers and those who have a family history of aortic aneurysms. In most affected families, the aortic aneurysms and dissection is inherited in an autosomal dominant manner with decreased penetrance and variable expressivity. Mutations at two chromosomal loci, TAA1 at 11q23 and the TAA2 at 5q13-14, and eight genes, MYLK, MYH11, TGFBR2, TGFBR1, ACTA2, SMAD3, TGFB2, and MAT2A, have been identified as being responsible for the disease in 23% of affected families. RESULTS: Herein, we inform on the clinical, genetic and pathological characteristics of nine living and deceased members of a large consanguineous Arab family with thoracic aortic aneurysm and dissection who carry a missense mutation c.4471G > T (Ala1491Ser), in exon 27 of MYLK gene. We show a reduced kinase activity of the Ala1491Ser protein compared to wildtype protein. This mutation is expressed as aortic aneurysm and dissection in one of two distinct phenotypes. A severe fatal and early onset symptom in homozygous or mild late onset in heterozygous genotypes. CONCLUSIONS: We found that MYLK gene Ala1491Ser mutation affect the kinase activity and clinically, it presents with vascular aneurysms and dissection. We describe a distinct genotype phenotype correlation where; heterozygous patients have mild late onset and incomplete penetrance disease compared with the early onset severe and generally fatal outcome in homozygous patients.

The predictive value of ventilation-perfusion scanning for the diagnosis of pulmonary embolism in patients with impaired renal function.

BACKGROUND: Computed tomography pulmonary angiography (CTPA) is considered the method of choice for diagnosing pulmonary embolism (PE). In most patients with impaired renal function, ventilation-perfusion (V/Q) scanning is the preferred modality. OBJECTIVES: To evaluate the predictive value of V/Q scanning in patients with impaired renal function. METHODS: We assessed all patients with impaired renal function who underwent V/Q scanning. The patients studied included those who also had CTPA (group 1) and those who did not (group 2). We recorded the results ofV/Q scanning, chest X-rays, CTPA, D-dimer levels, ultrasound of deep veins, and clinical probability for PE (Wells' score) in group 1. CTPA results were considered true results. Anticoagulant treatment was documented in all the patients. RESULTS: Of the 45 patients in group 1, 12 (22%) had positive CTPA for PE. The positive predictive value (PPV) for patients with high probability results on V/Q scanning for PE was 30%. Restricting results to D-dimer levels > or = 1000 ng/ml added little to this value. Restricting results to Wells' score > or = 7 resulted in 72% PPV. The negative predictive values for low or moderate probability were approximately 79% and approximately 67% respectively Of the 95 patients in group 2, all those with high probability for PE were treated with anticoagulants. CONCLUSIONS: Patients with impaired renal function and high probability for PE on V/Q scanning had very low PPV for PE. Due to the lack of CTPA studies, patients with high probability for PE on V/Q scanning were treated with anticoagulants.

Local effects of intra-articular corticosteroids.

Intra-articular corticosteroid injection (IACI) is a very popular procedure. In this review, we wanted to review all that had been published about local effects of IACIs. English literature search was made through PubMed using the terms intra-articular and local effect. Effects on subjective, functional, structural, cellular, humoral, molecular, and imaging aspects were included. Also, all local adverse effects were documented. The main beneficial effect of IACI is pain relief. The duration of this effect is variable and depends on underlying disease, type of disease, amount of structural damage, type of IACI, dose of IACI, presence of joint effusion, level of inflammatory mediators, emptiness of joint effusion, availability of imaging, and others. At large, inflammatory problems had higher rate of favorable response in terms of pain and function. IACI at the knee joint in juvenile idiopathic arthritis patients resulted in remission for >6 months in >80% of the patients with a mean duration of approximately 1.2 years, while in the osteoarthritic knee there was a pain relief for 3 weeks only and in rheumatoid arthritis (RA) knee for 8 weeks. There was no joint space loss at the knee joint following multiple IACI in osteoarthritis and also no increase in cartilage or bone erosions in RA following a single IACI. IACI guide imaging is important in achieving better results in particular joints. Joint infection rate is very low. Other adverse effects included intra-articular and periarticular calcifications, cutaneous atrophy, cutaneous depigmentation, avascular necrosis, rapid destruction of the femoral head, acute synovitis, Charcot's arthropathy, tendinopathy, Nicolau's syndrome, and joint dislocation. IACI is associated with a wide range of local effects. Subjective and functional favorable response is prominent mainly in juvenile idiopathic arthritis patients. Adverse effects are either rare or insignificant.

Excessive prolongation of prothrombin time among patients treated with warfarin and admitted to the emergency room.

INTRODUCTION: Patients treated with warfarin are uncommonly admitted with excessive prolongation of international normalized ratio (INR) of prothrombin time (PT) to the emergency room (ER). Here we wanted to evaluate the reasons behind this prolongation, clinical and laboratory parameters, course and outcome of these patients. PATIENTS AND METHODS: Consecutive patients admitted to the ER with prolonged PT-INR>6 under warfarin treatment and who gave sufficient information regarding history of warfarin treatment, were followed prospectively. Patients or care-givers were asked about warfarin treatment, PT monitoring, current and new medications especially antibiotics and diet. Clinical and laboratory parameters, course and outcome were also documented. Age and gender matched patients with therapeutic INR level were used as a control group. RESULTS: 75 patients finished the study. The median INR level among the patients was 8.5 and a range of 6.1-59.5. The median duration of warfarin treatment was 12 months among the patients vs. 36 in the control group, p<0.001 and family physician was the sole decider on warfarin dose in 71 patients vs. 49 in the control group, p<0.100. 19 patients adhered to balanced diet vs. 34 in the control group, p=0.01. Dose increment of warfarin was the most common definite cause of prolonged PT followed by adding new medication especially amiodarone and recently started warfarin. Significantly more patients had evidence of bleeding than the control group but no difference in mean hemoglobin level or number of patients transfused with packed cells. No difference in the number of patients hospitalized or duration of hospitalization, but 5 in-hospital fatalities in the patients' group vs. none in the control group. CONCLUSION: Excessive PT prolongation is mainly due to warfarin dose increment, adding new medication especially amiodarone and recently started warfarin. It is significantly more associated with bleeding and higher in-hospital mortality.

Penicillamine and nephrotic syndrome.

BACKGROUND: Penicillamine (PA) treatment may be associated with a wide spectrum of adverse effects. There are many case reports and small series of PA-induced nephrotic syndrome (NS). In addition to our patient, in this study, we review all the cases of NS due to PA treatment in the English literature. METHODS: A retrospective Medline search was done for the years 1963-2004 using the terms "penicillamine" and "proteinuria" or "penicillamine" and "nephrotic". Cases were also located through article references. Cases were included in our review only if they had enough clinical and laboratory data and if the NS was considered by the authors to be mainly or solely due to PA treatment. Diagnosis of the patient, dose and duration of PA treatment, maximal amount of proteinuria, kidney function, urine analysis, serological markers, clinical data, kidney biopsy results, treatment, and course of proteinuria were documented. RESULTS: Sixty-three patients met our criteria. The female/male ratio was 40:23. Seventy-five percent of the patients had rheumatoid arthritis (RA). Mean age at diagnosis of NS was 44 (+/-S.D. 14) years. Mean dose of PA at diagnosis was 1.09 (+/-S.D. 0.413) g. Mean duration of PA treatment prior to proteinuria was 7.6 (+/-S.D. 3.90) months and mean duration of PA treatment until diagnosis of NS was 11.9 (+/-S.D. 18.8) months. Peak level of proteinuria was 10.79 (+/-S.D. 9.436) g. Some 33% of the patients developed mild to moderate renal failure at the time of diagnosis of NS, and one patient developed acute renal failure. Fifty-five percent of the patients had membranous glomerulonephritis and 27% had minimal change disease. Twelve patients were treated with corticosteroids (CS) at a dose ranging from 40 to 90 mg/day. In the overwhelming majority of patients, the proteinuria decreased significantly or disappeared within 7 months after stopping PA treatment. Patients treated with CS had a faster response. Five patients died, two of them from the CS-treated group, due to sepsis. CONCLUSION: The mean duration of PA treatment prior to the development of NS is nearly 1 year (5 months after the development of proteinuria). The most common histopathological finding is membranous glomerulonephritis. Most patients will have a significant reduction in, or disappearance of, proteinuria within 7 months after stopping PA treatment. The decrease in proteinuria is faster with CS treatment.

Hypergammaglobulinemic purpura in two sisters with Sjogren's syndrome responding to colchicine treatment.

Purpura is the hallmark of hypergammaglobulinemic purpura (HP). It appears mainly after strenuous activity in the dependent areas of the body. Treatment is mostly symptomatic. Here we report two sisters with Sjogren's syndrome (SS) and HP who had a remarkable response to colchicine treatment.

Diabetic muscular infarction: emphasis on pathogenesis.

Diabetic muscular infarction is a rare complication of diabetes. It usually occurs in those with target organ involvement of diabetes, generally affecting one or a group of muscles of the thigh, and can recur. The pathogenesis of the disease is still not clear. Here we report an unusual case of extensive muscle involvement of both thighs and calves, with special emphasis on pathogenesis.