The membranous part of the human interventricular cardiac septum

The arrangement of collagen and elastic fibers of the membranous part of the interventricular septum (PMS) was studied in hearts from adult humans. Connective bundles formed a network of fairly independent tendons arranged in two layers. The tendinous bundles consisted essentially of type I collagen fibers while type III fibers were visible as a thin network with transversely and longitudinally oriented meshes around the muscle bundles. Cranial and caudal to the PMS were narrow and irregular bands of collagen fibers that apparently represented zones of low resistance to the high blood pressures acting from the left to the right heart chambers. The predominance of fiber bundles arranged in an approximately transverse direction with regard to the arterial cone axis suggests a resistance to enlargement resulting from high aortic blood pressure. Elastic fibers were observed in the transitional zone between the cardiac muscle and the PMS. They were continuous with elaunin fibers and these with oxytalan fibers closely intermingled with the narrow network of type I collagen fibers of the PMS. The successive transformation of elastic fibers, which were very numerous in the muscle-tendon transition, into elaunin and these into oxytalan fibers toward the central portions of the PMS suggests a functional sequence characterized by a high elasticity and consequent mobility of the transition region itself and by a progressive increase of resistance in this portion.     

Isolation and characterization of an IGROV-1 human ovarian cancer cell line made resistant to Ecteinascidin-743 (ET-743)

By exposing Igrov-1 human ovarian cancer cells to increasing concentrations of Ecteinascidin-743 (ET-743), either for a short or prolonged time, we obtained sublines resistant to ET-743 which overexpress Pgp. The most resistant clone (Igrov-1/25 ET) was evaluated for biological and pharmacological characterizations. The increased Pgp levels of Igrov-1/25 ET were not due to amplification of the mdr-1 gene but to increased mRNA levels. No increase in other multidrug resistance-related proteins such as MRP or LRP was observed in Igrov-1/25 ET. The IC50 values of ET-743 against Igrov-1/25 ET was approximately 50 times higher than the parental cell line. Resistance was not reversed while maintaining the cell line in drug-free medium for at least 24 months. Igrov-1/25 ET was cross-resistant to Doxorubicin and VP16 while it was equally sensitive to L-PAM, MNNG, CPT and only marginally less sensitive to Cis-DDP and Oxaliplatin compared to the parental cell line. Igrov-1/25 ET exposed to Doxorubicin retained this drug much less, mainly because of a more efficient drug efflux. The cyclosporine analogue SDZ PSC-833 reversed the resistance of Igrov-1/25 ET to ET-743, without any enhancement of the drug activity against the parental Igrov-1 cell line. Igrov-1/25 ET exhibits typical features of cell lines overexpressing the mdr-1 gene and can be a potentially useful tool in selecting ET-743 non-cross-resistant analogues as well as to investigate methods to counteract resistance to this drug.     

Functional characterization of MLH1 missense variants identified in lynch syndrome patients

Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise to single amino acid substitutions. The functional consequences in regard to pathogenicity of many of these variants are unclear. We have examined the functionality of a panel of MLH1 missense mutations found in LS families, by testing the variant proteins in functional assays, addressing subcellular localization, and protein–protein interaction with the dimer partner PMS2 and the MMR‐associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein–protein interactions, which is suspected to lead to the cancer phenotype observed in patients. Moreover, the obtained results correlate well with reported MMR activity and with in silico analysis for a majority of the variants. Hum Mutat 33:1647–1655, 2012. © 2012 Wiley Periodicals, Inc.     

Effect of post-nephrectomy acute kidney injury on renal outcome: a retrospective long-term study

Purpose

The effects on renal prognosis of acute kidney injury after elective unilateral nephrectomy are ill-defined. We evaluated as whether post-operative acute kidney injury modifies renal outcome over the long term.

Methods

This is a retrospective study examining all consecutive adult patients referred to three Nephrology Units and that had previously undergone elective unilateral nephrectomy. We evaluated the association of post-nephrectomy acute kidney injury with the combined renal outcome of chronic dialysis requirement, ≥ 40% decline in glomerular filtration rate or new-onset severe proteinuria (> 500 mg/24 h). Clinical correlates of acute kidney injury and renal outcome were also examined.

Results

106 patients were enrolled. 52 patients had post-operative acute kidney injury with a median increment of serum creatinine of 0.67 [0.48–0.86] mg/dl; in these patients, serum creatinine and urea increased from the first day post-nephrectomy while contraction of urinary output was found in 7 patients. Older age [OR: 1.72; 95% CI 1.05–2.82; P = 0.030] associated with post-operative acute kidney injury. Over a median follow-up of 8.9 [95% CI 3.1–24.2] years, the combined renal outcome occurred, respectively, in 28 (53.8%) and 14 (25.9%) patients with and without acute kidney injury (P = 0.003). Logistic regression analysis showed that acute kidney injury (OR: 3.22; 95% CI 1.35–7.66; P = 0.008) and male gender (OR: 2.72; 95% CI 1.08–6.85; P = 0.034) were associated with poor renal outcome after adjustment for main comorbidities.

Conclusions

In our population of referred patients, acute kidney injury after unilateral nephrectomy was common and associated with progressive chronic kidney disease, especially in older males.

     

Hormonal state rather than age influences cut-off values of protein S: reevaluation of the thrombotic risk associated with protein S deficiency.

Of the well known risk factors for thrombosis protein S deficiency is one of the most difficult to diagnose with certainty. Reliable estimates for the prevalence of protein S deficiency in the general population are not available and the risk of thrombosis is a controversial issue. It has been shown that levels of protein S fluctuate over time. However the determinants of low levels of protein S in the healthy population are not clear. Therefore. we evaluated the influence of sex, age and hormonal state on the antigen levels of protein S in 474 healthy control subjects of the Leiden Thrombophilia Study (LETS). In univariate analysis, sex, age, oral contraceptive (OC) use and post-menopausal state all influenced protein S antigen levels. In a multivariate model for the whole sample only menopausal state and OC use had still an effect on the levels of total protein S and only menopausal state had an independent effect on the values of free protein S. On the basis of this analysis we established different cut-off levels for these subgroups and we re-evaluated in the Leiden Thrombophilia Study the risk of thrombosis for individuals with low protein S using these different reference ranges. With these specific cut-off points, we did not observe an increase in the risk of thrombosis in patients deficient of total protein S (OR 1.2, 95% CI 0.5-2.9) or free protein S (OR 1.3, 95% CI 0.5-3.5). When men and women were analyzed separately, the risk in women was 1.5 (95% CI 0.4-5.4) and 2.4 (95% CI 0.6-9.2) for total and free protein S deficiencies, respectively; and there was no increase in thrombotic risk for men. We conclude that it may be helpful to apply separate cut-off levels in the assessment of protein S levels. This does not, however explain the differences between our results and those of others in the estimate of thrombotic risk of protein S deficiency.     

Effects of coping skills training in school‐age children with type 1 diabetes

Children with type 1 diabetes are at risk for negative psychosocial and physiological outcomes, particularly as they enter adolescence. The purpose of this randomized trial (n = 82) was to determine the effects, mediators, and moderators of a coping skills training intervention (n = 53) for school‐aged children compared to general diabetes education (n = 29). Both groups improved over time, reporting lower impact of diabetes, better coping with diabetes, better diabetes self‐efficacy, fewer depressive symptoms, and less parental control. Treatment modality (pump vs. injections) moderated intervention efficacy on select outcomes. Findings suggest that group‐based interventions may be beneficial for this age group. © 2009 Wiley Periodicals, Inc. Res Nurs Health 32: 405–418, 2009     

Basilar expansion of the human sphenoidal sinus: an integrated anatomical and computerized tomography study

Basilar expansion of the sphenoidal sinus (BESS) was studied in order to demonstrate its critical relevance in endoscopic or microscopic endonasal surgical interventions, including access to the sphenoidal sinus itself or in transsphenoidal pituitary approaches. Direct evaluation of anatomical specimens (25 dry skulls and 25 formalin-fixed hemi heads) and the use of computerized tomography (CT) (50 dry skulls and 750 patients) showed a high BESS frequency (69%). The authors considered BESS to be critical when the posterior wall of the clivus was 2-mm thick and found a high incidence of this important anatomical variation (44%). This study also evaluated the relationship between the sinonasal septa, the clivus, and the internal carotid arteries, and a considerable regularity in the location of these structures was seen. The septa were anatomically related to the internal carotid arteries in 55% and to the clivus in 33% of the cases. In conclusion, the high frequency of critical BESS here described is relevant to endoscopic or microscopic endonasal surgical interventions, including access to the sphenoidal sinus itself or in transsphenoidal pituitary approaches.