Quantitative SPECT of 99mTc-DMSA uptake in kidneys of infants with unilateral ureteropelvic junction obstruction: assessment of structural and functional abnormalities.

We evaluated individual renal function using quantitative SPECT of dimercaptosuccinic acid (DMSA) uptake by the kidneys (QDMSA) in infants with unilateral ureteropelvic junction (UPJ) obstruction and compared our findings with infants without obstruction. METHODS: QDMSA was performed on 13 infants (mean age of 2.8 +/- 2.8 mo) with unilateral UPJ obstruction and on 15 age-matched controls without obstruction. RESULTS: Control kidneys (n = 30) had a volume of 43.5 +/- 8.8 mL, a percentage injected dose (%ID)/mL 0.62 +/- 0.12 and uptake of 26.1% +/- 3.9%. Kidneys with UPJ obstruction (n = 13) had a volume of 61.2 +/- 19.3 mL, a %ID/mL of 0.42 +/- 0.11 and uptake of 25.4% +/- 8.2%. Contralateral kidneys (n = 13) had a volume of 44.0 +/- 11.9 mL, a %ID/mL of 0.57 +/- 0.16 and uptake of 24.2% +/- 4.6%. The uptake in obstructed kidneys was similar to that observed in contralateral and control kidneys (t = -0.77, P = 0.45; t = -0.37, P = 0.71; respectively). UPJ kidneys had a statistically significant increased volume and decreased %ID/mL, compared with contralateral kidneys (t = 3.35, P < 0.006 and t = 3.75, P < 0.003, respectively) and control kidneys (t = -4.2, P < 0.001 and t = 4.7, P < 0.001, respectively). There was no significant difference between contralateral kidneys and control kidneys regarding volume (t = -0.16, P = 0.87), %ID/mL (t = 0.98, P = 0.33) and uptake (t = -1.41, P = 0.16). Of 13 infants, 11 (85%) showed large kidneys with thinning of the renal cortex. In 1 infant, there was no difference between the obstructed and contralateral kidneys regarding volume, %ID/mL and uptake, and 1 infant showed significant decreased uptake in the UPJ kidney compared with the contralateral kidney. CONCLUSION: Although the overall renal function of the obstructed kidneys remained unchanged, there was a statistically significant decrease in the %ID/mL of renal tissue in UPJ kidneys, which may represent renal dysfunction. Increased functional volume with a thin cortex may represent a compensatory mechanism of the obstructed kidney. Such changes may contribute to the understanding of pathophysiologic mechanisms and may be an early sign of obstruction in infants with hydronephrosis. Further longitudinal studies with an extended number of infants and serial measurements of kidney volumes and %ID/mL are warranted to assess the significance of QDMSA in the management of infants with asymptomatic unilateral renal pelvic dilatation.     

The Microscopic Examination of Bile in Patients with Biliary Pain and Negative Imaging Tests

We describe a 5-yr retrospective analysis of the accuracy of the microscopic examination of bile in the detection of biliary tract disease in patients with episodic upper abdominal pain who had negative imaging procedures. In 182 patients, 189 studies of bile were performed using duodenal intubation and sincalide stimulation for gallbladder contraction. The presence of cholesterol crystals, leukocytes (greater than or equal to 5/hpf) or the absence of "B" bile constituted a "positive" study. Bilirubinate sludge alone, was defined as "suspicious." Eighty-three patients underwent cholecystectomy. Among the acalculous patients who underwent cholecystectomy, 28/28 with bilirubinate sludge had symptomatic improvement as compared with the negative group of which only five of 10 improved (p less than 0.005). The sensitivity of this test for the presence of gallstones in these imaging-negative patients was 87%, while the specificity was 16%. We conclude that a single microscopic examination of bile cannot accurately predict the pathological findings or the presence of gallstones in image-negative patients with biliary pain. The presence of bilirubinate sludge may predict symptomatic improvement in those patients with acalculous gallbladder disease undergoing cholecystectomy.     

Peptide methionine sulfoxide reductase contributes to the maintenance of adhesins in three major pathogens.

Pathogenic bacteria rely on adhesins to bind to host tissues. Therefore, the maintenance of the functional properties of these extracellular macromolecules is essential for the pathogenicity of these microorganisms. We report that peptide methionine sulfoxide reductase (MsrA), a repair enzyme, contributes to the maintenance of adhesins in Streptococcus pneumoniae, Neisseria gonorrhoeae, and Escherichia coli. A screen of a library of pneumococcal mutants for loss of adherence uncovered a MsrA mutant with 75% reduced binding to GalNAcbeta1-4Gal containing eukaryotic cell receptors that are present on type II lung cells and vascular endothelial cells. Subsequently, it was shown that an E. coli msrA mutant displayed decreased type I fimbriae-mediated, mannose-dependent, agglutination of erythrocytes. Previous work [Taha, M. K., So, M., Seifert, H. S., Billyard, E. & Marchal, C. (1988) EMBO J. 7, 4367-4378] has shown that mutants with defects in the pilA-pilB locus from N. gonorrhoeae were altered in their production of type IV pili. We show that pneumococcal MsrA and gonococcal PilB expressed in E. coli have MsrA activity. Together these data suggest that MsrA is required for the proper expression or maintenance of functional adhesins on the surfaces of these three major pathogenic bacteria.     

Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse

Oxidative stress is associated with the aging process, a risk factor for neurodegenerative diseases, and decreased by reduced energy intake. Oxidative modifications can affect protein function; the sulfur-containing amino acids, including methionine, are particularly susceptible to oxidation. A methionine sulfoxide can be enzymatically reduced by the methionine sulfoxide reductase (Msr) system. Previously, we have shown that MsrA^−/− mice exhibit altered locomotor activity and brain dopamine levels as function of age. Previous studies have demonstrated that a caloric restriction enhances antioxidant defense and reduces the action of reactive oxygen species. Here we examine locomotor behavior and dopamine levels of MsrA^−/− mice after caloric restriction starting at eight months of age and ending at 17 months. The MsrA^−/− mice did not have any significant difference in spontaneous distance traveled when compared to controls at 17 months of age. In contrast, our previous report showed decreased locomotor activity in the MsrA^−/− mice at 12 months of age and older when fed ad-libitum. After completion of the caloric restriction diet, dopamine levels were comparable to control mice. This differs from the abnormal dopamine levels previously observed in MsrA^−/− mice fed ad-libitum. Thus, caloric restriction had a neutralization effect on MsrA ablation. In summary, it is suggested that caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.     

Efficacy and Safety of BRAF Inhibitors With or Without MEK Inhibitors in BRAF-Mutant Advanced Non–Small-Cell Lung Cancer: Findings From a Real-Life Cohort

BackgroundReal-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non–small-cell lung cancer (NSCLC) is lacking.Patients and MethodsConsecutive BRAFm advanced NSCLC patients (n = 58) treated in 9 Israeli centers in 2009-2018 were identified. These were divided according to mutation subtype and treatment into groups A1 (V600E, BRAFi; n = 5), A2 (V600E, BRAFi + MEKi; n = 15), A3 (V600E, no BRAFi; n = 7), B1 (non-V600E, BRAFi ± MEKi; n = 7), and B2 (non-V600E, no BRAFi; n = 23); one patient received both BRAFi and BRAFi + MEKi. Safety, objective response rate, progression-free survival with BRAFi ± MEKi, and overall survival were assessed.ResultsObjective response rate was 40%, 67%, and 33% in groups A1, A2, and B1, respectively (P = .5 for comparison between groups A1 and A2). In group B1, G469A and L597R mutations were associated with response to BRAFi + MEKi. Median progression-free survival was 1.2 months (95% confidence interval [CI], 0.5-5.3), 5.5 months (95% CI, 0.7-9.3), and 3.6 months (95% CI, 1.5-6.7) for groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .04). Median overall survival with BRAFi ± MEKi was 1.7 months (95% CI, 0.5-NR), 9.5 months (95% CI, 0.2-14.9), and 7.1 months (95% CI, 1.8-NR) in groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .6). Safety profiles differed slightly, and similar treatment discontinuation rates were observed with BRAFi and BRAFi + MEKi.ConclusionIn the real-life setting, activity and safety of BRAFi + MEKi in V600E BRAFm NSCLC are comparable to those observed in prospective clinical trials; the combination of BRAFi + MEKi is superior to monotherapy with a BRAFi. Further research should be done to explore the impact of BRAFi + MEKi treatment on the natural history of BRAFm NSCLC.     

Transfer of glyburide and glipizide into breast milk

OBJECTIVE: To determine if glyburide and glipizide are excreted into breast milk and if breast-feeding from women taking these drugs causes infant hypoglycemia. RESEARCH DESIGN AND METHODS: We studied eight women who had received a single oral dose of 5 or 10 mg glyburide. Drug concentrations were measured in maternal blood and milk for 8 h after the dose. In a separate study, five women were given a daily dosage (5 mg/day) of glyburide or glipizide, starting on the first postpartum day. Maternal blood and milk drug concentrations and infant blood glucose were measured 5-16 days after delivery. RESULTS: In the single-dose glyburide study, the mean maximum theoretical infant dose (MTID) as a percent of the weight-adjusted maternal dose (WAMD) was <1.5 and <0.7% for the 5- and 10-mg doses, respectively. For the five women taking daily dosages, the mean MTID as a percent of the WAMD was <28% for glyburide and <27% for glipizide. The high estimates were due to the insensitivity of the assay. Neither glyburide nor glipizide were detected in breast milk in either study and blood glucose was normal in the three infants (one glyburide and two glipizide) who were wholly breast-fed when the drug concentrations were at steady state. CONCLUSIONS: Neither glyburide nor glipizide were detected in breast milk, and hypoglycemia was not observed in the three nursing infants. Both agents, at the doses tested, appear to be compatible with breast-feeding.