Risk of pulmonary embolism after a negative spiral CT angiogram in patients with pulmonary disease: 1-year clinical follow-up study

PURPOSE: To evaluate the effect of pulmonary disease on diagnostic utility of spiral computed tomographic (CT) angiography in clinical practice. MATERIALS AND METHODS: Three hundred thirty-four patients, including 215 patients with pulmonary disease (group 1) and 119 patients with no history of respiratory disorder (group 2), were referred for thin-collimation CT angiography of the pulmonary circulation as the first-line diagnostic test. Patients with negative angiograms who had not received anticoagulation therapy and who could be clinically followed up at 3 months, 6 months, and 1 year were considered in the final study groups (n = 185); 135 patients had lung disease (group 3), and 50 patients had no history of a respiratory disorder (group 4). RESULTS: Between groups 3 and 4, no significant differences were found in the referral location, age, and risk factors. Confident evaluation of pulmonary arteries down to the subsegmental level was performed in 31 (23%) patients in group 3 and in 15 (30%) in group 4 (P =.5). Three episodes of acute pulmonary embolism (PE), all fatal, were diagnosed in group 3 patients; two cases occurred 14 days and one case occurred 6 months after the negative spiral CT scan. The negative predictive value of spiral CT angiography was 98% (175 of 178) in the study group in which follow-up was performed, with no significant difference between the values in groups 3 (98% [132 of 135]) and 4 (100% [50 of 50]). CONCLUSION: Underlying respiratory disease does not affect the negative predictive value of thin-collimation CT angiography, which appears to be a reliable tool in the work-up in this subgroup of patients with acute PE.     

Bariatric Surgery Outcomes in Sarcopenic Obesity

Background

Sarcopenic obesity is the combination of low muscle mass and strength with increased fat mass. This condition is associated with negative health outcomes. We hypothesized that sarcopenia could be a pejorative factor on surgical weight loss.

Objective

The objectives of the study are to determine the influence of sarcopenic obesity on gastric bypass and sleeve gastrectomy results regarding weight loss and comorbidities resolution at 3, 6, and 12 months.

Setting

The study was conducted at the University Hospital.

Methods

Sixty-nine obese patients who benefited from bariatric surgery were included. Skeletal muscle mass was determined by the Janssen’s equation. Physical performance and muscle strength were determined using the 6-min walk test and the wall sit test. Obese subjects from the lowest tertile of the Skeletal Muscle mass Index (SMI) of Baumgartner were set as sarcopenic.

Results

Weight loss outcomes and rate of weight loss failure were not influenced by sarcopenia. At 1 year, mean EBMIL% was 75.4 %?±?5 in sarcopenic subjects vs 67.8 % ±4 in the non-sarcopenic subjects (p?=?0.242). Improvement rates of co-morbidities were similar between groups. Skeletal muscle mass was no more different between groups at 1 year after surgery. There was no patient lost to follow-up.

Conclusions

Bariatric surgery remains effective in achieving weight loss target in sarcopenic patients, with similar remission rates of main comorbidities and similar safety profile than in the non-sarcopenic group. Whether bariatric surgery could result in improvement or deterioration of daily living activities disabilities and functional autonomy in sarcopenic obese patients still have to be evaluated.

     

Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation

BACKGROUND: Stem cell transplantation (SCT) may be associated with premature aging of the hematopoietic stem cells. Telomere length reflects the proliferative history of a cell. In most studies published so far on telomere dynamics after myeloablative allogeneic SCT, recipients had shorter telomeres than their respective donors, thus reflecting "accelerated aging" of hematopoietic cells. We evaluated telomere dynamics in patients who underwent transplantation with nonmyeloablative protocols, assuming that the decreased intensity of chemotherapy might prevent telomere attrition. METHODS: Telomere length was measured using FISH-FACS method. Telomeres of recipients were compared to their respective donors. Twenty-three consecutive patients after nonmyeloablative SCT were evaluated. A control group consisted of 10 donor-recipient pairs after conventional myeloablative transplantation. RESULTS: There was significant telomere shortening in both recipients of nonmyeloablative and myeloablative conditioning (0.487+/-0.65 kb, P=0.003; 0.361+/-0.50 kb, P=0.047 respectively). The extent of telomere shortening in the two groups was not different (P=0.64). There was no correlation between the degree of shortening and parameters such as time interval from transplant, age of donor or recipient, and the number of infused cells. CONCLUSIONS: This is the first study on telomere dynamics after nonmyeloablative conditioning SCT. The study demonstrates significant shortening of telomeres in recipients in spite of decreased intensity conditioning. Results of this study suggest that the main mechanism following transplantation is the proliferative stress imposed upon the stem cells and not direct damage by cytotoxic drugs. The different kinetics of restoration of hematopoiesis and the probable ongoing process of graft-versus-leukemia in the bone marrow do not prevent the attrition of telomeric ends of chromosomes.     

Stemming Resistance to HER-2 Targeted Therapy

Although the development of trastuzumab and lapatinib has improved the outlook for women with HER-2 positive breast cancer, resistance to HER-2 targeted therapy is a growing clinical dilemma. Recent evidence indicates that the HER-2 pathway may play an important role in the maintenance of cancer stem cells (CSCs). The success of HER-2 targeted therapies may, in part, be explained by their direct activity against HER-2 positive CSCs. Our understanding of the mechanisms involved in resistance to trastuzumab, including loss or blockade of the trastuzumab binding site, activation of alternative signaling pathways, and induction of epithelial–mesenchymal transition (EMT), suggests that CSCs may be at the root of resistance of HER-2 targeted therapy. A variety of novel HER-2 targeted approaches have demonstrated promising preliminary clinical activity. Future clinical trials should involve the integration of technologies to assess the impact of novel HER-2 targeted therapies on HER-2 positive CSCs.     

Ovarian torsion. Management and ovarian prognosis: a report of 45 cases

Background/Purpose

Ovarian torsion in childhood and adolescence is a rare entity. Traditionally, treatment is oophorectomy. The aim of this study was to evaluate ovarian outcome and to propose a decision-making protocol for suspected ovarian torsion.

Methods

Between January 1986 and December 2007, 45 ovarian torsion cases in 40 girls were operated on. In all the cases, when the ovary was preserved, patients were clinically and ultrasonographically followed up for several months.

Results

Median age was 11 years. Median delay between the first symptoms and surgical procedure was 3 days. There was a statistical difference (P = .0003) between the mean of the largest diameter of twisted normal ovary and the mean of the largest diameter of twisted diseased ovary. Underlying pathology was benign in 22 cases and low-grade malignancy in 2 (one grade II immature teratoma and one steroid cell tumor). Conservative management was performed in 26 cases. At follow-up, 17 ovaries were follicular, 7 being black-bluish during surgery.

Conclusions

Conservative approach after detorsion of black-bluish ovaries is safe and effective in children. Although very unlikely, the fear of missing malignancy must incite to proceed with caution and can lead, when the size of the twisted ovary is greater than 75 mm, to prefer laparotomy to laparoscopy.     

ADC measurements in diffuse large B-cell lymphoma and follicular lymphoma: a DWI and cellularity study

Purpose

Diffusion-weighted magnetic resonance imaging (DW-MRI) allows quantifying the random motion of water molecules in tissue by means of apparent diffusion coefficient (ADC) measurements. The aim of the study was to determine whether ADC measurements allow discrimination of diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL), and to examine the relationship between cellularity and ADC value of the tumor using DWI.

Materials and methods

Thirty-two patients with histologically proven non-Hodgkin lymphoma (21 with DLBCL and 11 with FL, 17 males and 15 females, mean age 62 ± 13 years) underwent conventional MRI and DWI examination before treatment. The ADC values of DLBCL were compared to those of FL. The ADC value of the tumor was also correlated with the tumor tissue cellularity.

Results

The mean ADC value of DLBCL was not significantly different from that of FL (0.70 ± 0.16 × 10⁻³ mm²/s vs. 0.76 ± 0.12 × 10⁻³ mm²/s, P = 0.21). The cellularity of DLBCL was significantly lower than that of FL (2991 ± 351 cells/view vs. 4412 ± 767 cells/view, P < 0.001). There was no correlation between the ADC value and the tissue cellularity of the tumor in patients with DLBCL and FL.

Conclusion

ADC measurements could not differentiate between DLBCL and FL, and there was no correlation between the ADC value and cellularity of the tumor in patients with DLBCL and FL.     

Évaluation de la reproductibilité et de la validité de construit d’une forme modifiée de l’indice algofonctionnel de Lequesne dans l’arthrose du genouAssessment of the test-retest reliability and construct validity of a modified Lequesne index in knee osteo-arthritis

Objectives. – To assess the test-retest reliability and the construct validity of a modified version of the Lequesne index.Methods. – Patients with symptomatic knee osteo-arthritis fulfilling the revised criteria of the american college of rheumatology completed the Lequesne index twice at a 3 h interval. Impairment outcome measures and patients’ perceived discomfort in walking and handicap were recorded. An item by item analysis was performed. Items having insufficient psychometric properties were excluded. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC) and the Bland and Altman method. Construct validity was investigated using Spearman rank correlation coefficient and a factor analysis was performed.Results. – Eighty-eight patients were included. One question assessing pain (question IE) had a weak reliability (Kappa = 0.39) and was excluded. The test-retest reliability of the modified questionnaire was excellent (ICC = 0.95). Expected convergent and divergent correlations were achieved excepted for Vas pain and Vas handicap (0.46 and 0.40 respectively), and the “a priori” double stratification was confirmed by factor analysis, explaining 48.7% of the variance.Conclusion. – The modified form of the Lequesne index has sufficient psychometric properties to be used to assess pain and function in knee osteo-arthritis in a french population.     

The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population

OBJECTIVE— Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated, with respect to glucose, by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluated, in a general French population, the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters and to dyslipidemia and hyperglycemia risk.RESEARCH DESIGN AND METHODS— Genotype effects of rs1260326 were studied in 4,833 participants from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort both at inclusion and using the measurements at follow-up.RESULTS— The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (−1.43% per T-allele; P = 8 × 10⁻¹³) and fasting insulin levels (−4.23%; P = 3 × 10⁻⁷), lower homeostasis model assessment of insulin resistance index (−5.69%; P = 1 × 10⁻⁸), and, conversely, higher triglyceride levels (3.41%; P = 1 × 10⁻⁴) during the 9-year study. These effects relate to a lower risk of hyperglycemia (odds ratio [OR] 0.79 [95% CI 0.70–0.88]; P = 4 × 10⁻⁵) and of incident cases during the study (hazard ratio [HR] 0.83 [0.74–0.95]; P = 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (−30G) alleles conferred lower fasting glycemia (P = 1 × 10⁻¹³), insulinemia (P = 5 × 10⁻⁶), and hyperglycemia risk (P = 1 × 10⁻⁶).CONCLUSIONS— GCKR-L446 carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.The enzyme glucokinase (GCK) is the major glucose sensor of the pancreatic β-cells, where it adapts insulin secretion to blood glucose levels. GCK also participates in regulating glycogen synthesis and gluconeogenesis in the liver (1). GCK activity is allosterically controlled in hepatocytes by the glucokinase regulatory protein (GCKR), which reversibly binds to GCK and inhibits its activity in the presence of fructose 6-phosphate. GCKR acts as a competitive inhibitor of GCK with respect to glucose and is suppressed by the specific metabolite fructose 1-phosphate (2).In GCKR-deficient mice, the disruption of this regulation and the subsequent decrease in GCK activity leads to altered glucose metabolism and impaired postprandial glycemic control (3,4), although no change in fasting blood glucose concentration is observed. Adenoviral-mediated hepatic overexpression of GCKR in mice with high-fat diet–induced diabetes improves fasting and glucose-induced glycemia and leads to a concomitant increase in insulin sensitivity and triglyceride levels and a decrease in leptin levels (5). Heterozygous mutations in GCK resulting in a reduction of enzymatic activity are responsible for a subtype of monogenic diabetes (maturity-onset diabetes of the young-2) (1,6). Previous genetic studies at the GCKR locus have not reported intragenic mutations associated with type 2 diabetes in humans (7,8).The Diabetes Genetics Initiative (DGI) genome-wide association study for type 2 diabetes and quantitative metabolic traits reported an intronic polymorphism of GCKR (rs780094) explaining interindividual variability in plasma triglyceride (TG) levels and a trend toward association with lower fasting glycemia, less insulin resistance, and lower risk for type 2 diabetes (9). The HapMap II CEU data (www.hapmap.org) showed that rs780094 is in strong linkage disequilibrium (r² = 0.932) with a non-synonymous GCKR variant (Pro446Leu, rs1260326) that we previously identified by the DNA sequencing of French individuals (7). Marju Orho-Melander and colleagues recently communicated their fine-mapping data showing the strongest signal for TG levels at the coding single nucleotide polymorphism (SNP) (rs1260326; P = 1.5 × 10⁻⁹), with lesser associations to fasting glycemia and insulin sensitivity (M. Orho-Melander, O. Melander, V. Lyssenko, for the DGI, unpublished data). Similar findings for the intronic variant rs780094 were reported in a Danish population (10).We evaluated the association between GCKR rs1260326-P446L and TG levels in a middle-aged general French population with a follow-up of 9 years (11). Given the key role of GCKR in hepatic glucose metabolism, we also assessed the effect of rs1260326 on glucose homeostasis parameters and on the risk of impaired fasting glycemia and type 2 diabetes. Furthermore, as we previously showed a strong association of the GCK (−30A) promoter variant (rs1799884) to increased fasting glycemia and type 2 diabetes risk in the same study cohort (11), we also assessed possible additive effects of GCKR rs1260326-P446L and GCK −30G/A SNPs on fasting glucose, insulin, TG levels, and hyperglycemia risk.     

Calcium-sensing receptor attenuates AVP-induced aquaporin-2 expression via a calmodulin-dependent mechanism

Recent evidence suggests that arginine vasopressin (AVP)-dependent aquaporin-2 expression is modulated by the extracellular calcium-sensing receptor (CaSR) in principal cells of the collecting duct, but the signaling pathways mediating this effect are unknown. Using a mouse cortical collecting duct cell line (mpkCCD(cl4)), we found that increasing the concentration of apical extracellular calcium or treating with the CaSR agonists neomycin or Gd(3+) attenuated AVP-dependent accumulation of aquaporin-2 mRNA and protein; CaSR gene-silencing prevented this effect. Calcium reduced the AVP-induced accumulation of cAMP, but this did not occur by increased degradation of cAMP by phosphodiesterases or by direct inhibition of adenylate cyclase. Notably, the effect of extracellular calcium on AVP-dependent aquaporin-2 expression was prevented by inhibition of calmodulin. In summary, our results show that high concentrations of extracellular calcium attenuate AVP-induced aquaporin-2 expression by activating the CaSR and reducing coupling efficiency between V(2) receptor and adenylate cyclase via a calmodulin-dependent mechanism in cultured cortical collecting duct cells.