Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.      

Ectopic ureter and ureterocele: their varied sonographic manifestations

The sonographic examinations of four patients with simple ectopic ureters and 11 with ectopic ureteroceles were reviewed to determine distinguishing characteristics. Ectopic ureters, in cases of extreme dilatation and tortuosity, sometimes mimic multiseptated, cystic abdominal masses. However, the proximal portions of some severely dilated ureters are surprisingly small. Ectopic ureters sometimes indent the lower vesical wall, simulating a ureterocele. Ectopic ureteroceles are dynamic structures, changing in shape and size according to intravesical pressure. The lower pole of a duplex kidney may be difficult to detect because of displacement by the dilated upper renal pelvis and ureter. The renal parenchyma associated with an ectopic ureter may be equally difficult or impossible to find because of diminutive dysplasia or, less commonly, acquired atrophy. Dysplasia is characterized sonographically by highly echogenic parenchyma, lack of corticomedullary differentiation, and occasionally massive enlargement by cysts. Ectopic ureters and ureteroceles can be identified by fetal sonography.     

Are vitamin B12 and folate deficiency clinically important after roux-en-Y gastric bypass?

Although iron, vltamm B₁₂, and folate deficiency have been well documented after gastric bypass operations performed for morbid obesity, there is surprisingly little information on either the natural course or the treatment of these deficiencies in Roux-en-Y gastric bypass (RYGB) patients Durmg a l0-year period, a complete blood count and serum levels of iron, total iron-binding capacity, vltamin B₁₂, and folate were obtained in 348 patients preoperatively and postoperatively at 6-month intervals for the first 2 years, then annually thereafter The principal objectives of this study were to determine how readily patients who developed metabolic deficiencies after Roux-en-Y gastric bypass responded to postoperative supplements of the deficient micronutrient and to learn whether the risk of developmg these deficiencies decreases over time Hemoglobin and hematocrit levels were slgnificantly decreased at all postoperative intervals in comparison to preoperative values Moreover, at each successive interval through 5 years, hemoglobin and hematocrit were decreased signifiantly compared to the preceding interval Folate levels were significantly increased compared to preoperative levels at all time intervals Iron and vltamin B₁₂ levels were lower than preoperative measurements and remained relatively stable postoperatively Half of the low hemoglobin levels were not associated with iron deficiency Taking multivltamin supplements resulted in a lower incidence of folate deficiency but did not prevent iron or vitamin B₁₂ deficiency Oral supplementation of iron and vitamin B₁₂ corrected defiaencies in 43% and 81% of cases, respectively Folate deficiency was almost always corrected with multivitamins alone No patient had symptoms that could be attributed to either vitamin B₁₂ or folate deficiency Conversely, many patients had symptoms of iron deficiency and anenua Lack of symptoms of vitamin B₁₂ and folate deficiency suggests that these deficiencies are not clinically important after RYGB Conversely, iron deficiency and anemia are potentially serious problems after RYGB, particularly in younger women Hence we recommend prophylactic oral iron supplements to premenopausal women who undergo RYGB     

Safety of drotrecogin alfa (activated) in severe sepsis: Data from adult clinical trials and observational studies

Drotrecogin alfa (activated) (DrotAA), or recombinant human activated protein C, represents the only Food and Drug Administration-approved therapy for mortality reduction in adult patients with severe sepsis. Drotrecogin alfa (activated) has properties that address microvascular injury in severe sepsis through its direct effects on endothelial cells and leukocytes while also having antithrombotic and indirect profibrinolytic properties. Sepsis bundle and guideline implementation has been associated with improved survival and includes DrotAA administration in appropriate patients. Several DrotAA postapproval clinical studies have yielded additional outcome and safety data, better defining its benefit/risk profile. Bleeding is more common in DrotAA-treated patients; therefore, a careful assessment of bleeding risk and an understanding of the safety profile is required. This summary provides a detailed review of safety data and outcomes of patients treated with DrotAA in recent clinical studies enrolling more than 7000 adult patients.