Who and how in the regulation of mitochondrial cristae shape and function.

Mitochondrial adaptation to different physiological conditions highly relies on the regulation of mitochondrial ultrastructure, particularly at the level of cristae compartment. Cristae represent the membrane hub where most of the respiratory complexes embed to account for OXPHOS and energy production in the form of adenosine triphosphate (ATP). Changes in cristae number and shape define the respiratory capacity as well as cell viability. The identification of key regulators of cristae morphology and the understanding of their contribution to the mitochondrial ultrastructure and function have become an strategic goal to understand mitochondrial disorders and to exploit as therapeutic targets. This review summarizes the known regulators of cristae ultrastructure and discusses their contribution and implications for mitochondrial dysfunction.

Getting England to be more physically active: are the Public Health Responsibility Deal's physical activity pledges the answer?

BACKGROUND: The Public Health Responsibility Deal (RD) in England is a public-private partnership involving voluntary pledges between government, industry, and other organisations to improve public health by addressing alcohol, food, health at work, and physical activity. This paper analyses the RD physical activity (PA) pledges in terms of the evidence of their potential effectiveness, and the likelihood that they have motivated actions among organisations that would not otherwise have taken place. METHODS: We systematically reviewed evidence of the effectiveness of interventions proposed in four PA pledges of the RD, namely, those on physical activity in the community; physical activity guidelines; active travel; and physical activity in the workplace. We then analysed publically available data on RD signatory organisations' plans and progress towards achieving the physical activity pledges, and assessed the extent to which activities among organisations could be attributed to the RD. RESULTS: Where combined with environmental approaches, interventions such as mass media campaigns to communicate the benefits of physical activity, active travel in children and adults, and workplace-related interventions could in principle be effective, if fully implemented. However, most activities proposed by each PA pledge involved providing information or enabling choice, which has limited effectiveness. Moreover, it was difficult to establish the extent of implementation of pledges within organisations, given that progress reports were mostly unavailable, and, where provided, it was difficult to ascertain their relevance to the RD pledges. Finally, 15 % of interventions listed in organisations' delivery plans were judged to be the result of participation in the RD, meaning that most actions taken by organisations were likely already under way, regardless of the RD. CONCLUSIONS: Irrespective of the nature of a public health policy to encourage physical activity, targets need to be evidence-based, well-defined, measurable and encourage organisations to go beyond business as usual. RD physical activity targets do not adequately fulfill these criteria.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score<4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score=4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score<4 and =4, respectively; p<0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p=0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

SWI/SNF chromatin remodeling enzymes in melanocyte differentiation and melanoma.

Epidermal melanocytes are pigment-producing cells derived from the neural crest that protects skin from the damaging effects of solar radiation. Malignant melanoma, a highly aggressive cancer, arises from melanocytes. SWI/SNF enzymes are multiprotein complexes that remodel chromatin structure and have extensive roles in cellular differentiation. Components of the complex have been found to be mutated or lost in several human cancers. This review focuses on studies that implicate SWI/SNF enzymes in melanocyte differentiation and in melanoma.

Provincial screening rates for chronic diseases of lifestyle, cancers and HIV in a health-insured population.

BACKGROUND: Screening for asymptomatic diseases can reduce the burden of morbidity and mortality in all population groups. There is widespread geographical variation in the quality of care. Few data are available on national screening rates in South Africa and how these vary across the provinces. OBJECTIVE: To examine screening rates for chronic diseases of lifestyle (CDL), HIV and cancer in a privately insured population for a single insurer across all nine provinces in South Africa, and to determine whether or not there are any differences between the provinces. METHOD: Screening rates were calculated as the proportion of eligible members who had received screening tests during 2011 in each province. Mean screening rates were compared between Gauteng and the other eight provinces. RESULTS: Nationwide screening rates were 20.5% for CDL, 8.2% for HIV and 31.9% for cancer. Despite similar insurance coverage, screening rates ranged from 0.3% to 0.95% lower in other provinces compared with Gauteng. Of all the provinces, Gauteng had the highestannual screening rates for CDL, breast cancer, prostate cancer and HIV (p < 0.001), while the Western Cape had the highest rate for cervical cancer (p < 0.001). CONCLUSION: There is much variation in preventive care utilisation across the provinces within this health-insured population. Provinces with more abundant healthcare resources have higher screening rates. Further research is required to understand the reasons for the variation, given equal payment access.

Congenital paediatric atlantoaxial dislocation: clinico-radiological profile and surgical outcome.

INTRODUCTION: Congenital atlantoaxial dislocation (AAD) is the most common bony abnormality affecting the craniovertebral junction. The paediatric population has specific problems like preoperative diagnostic difficulties, precise neurological examination, radiological diagnosis, surgical problems including physical fitness to tolerate surgery (including problems of anaesthesia), technical difficulties in surgery and problems related to immobilization. MATERIAL AND METHODS: A total of 229 consecutive paediatric (≤18 years) patients of AAD visited our centre from the period of January 1997 to August 2011. Twenty-nine cases were excluded from the study as these cases were diagnosed as CVJ tuberculosis, 31 cases were excluded as they were traumatic and the remaining 169 cases were retrospectively analysed. These patients were operated by a single experienced surgeon (the senior author) at the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. The preoperative and the postoperative clinical evaluation of the patient was done by the Kumar and Kalra myelopathic scoring system. The score was recorded in the preoperative period, at the time of discharge, at 3 months follow-up and at 6 months follow-up. RESULTS: Ninety-four were males and 75 were females. The age range was 4 to 18 years with mean age 9.96±3.78 years. The follow-up ranged from 3 to 120 months with mean follow-up being 39.03±13.38 months. One hundred five cases were of fixed/irreducible AAD, and 64 were cases of mobile/reducible AAD. Majority of these cases presented with features of pyramidal tract involvement, and 108 cases had compromised pulmonary function test. One hundred thirty-seven cases had improved outcome, and 18 cases were in the same grade in the postoperative period with only 14 cases either deteriorated or died. CONCLUSIONS: Congenital paediatric AAD are a different subset of abnormalities and have a satisfactory outcome. Preoperative evaluation must also include identification of various syndromes associated with paediatric AAD and respiratory reserve. Cormack-Lehane grade can be helpful in selecting borderline cases for postoperative need of tracheostomy. Majority of the cases have a good outcome, and therefore, surgery should be offered even in severe grade.

Adenosine-induced ventricular fibrillation.

The use of adenosine has been suggested as a diagnostic tool in the evaluation of wide ORS complex tachycardia. However, adenosine shortens the antegrade refractoriness of accessory atrioventricular connections and may cause acceleration of the ventricular rate during atrial fibrillation. We observed ventricular fibrillation in 2 patients who presented to the emergency department with pre-excited atrial fibrillation and were given 12 mg of adenosine.

Polymerase chain reaction vs. conventional diagnosis in fine needle aspirates of tuberculous lymph nodes.

OBJECTIVE: To compare four conventional methods of diagnosing tuberculous lymphadenophathy (TL)--namely fine needle aspiration cytology (FNAC), Zeihl-Neelsen staining of smears for acid-fast bacilli (AFB), culture for Mycobacterium tuberculosis (MTB) and lymph node biopsies--with the polymerase chain reaction (PCR) in order to assess the practicability and advantage of its use in routine diagnosis in a developing country. STUDY DESIGN: Fine needle aspirates from 142 consecutive patients presenting with lymphadenopathy (mainly cervical) without any known systemic involvement underwent cytomorphologic diagnosis, AFB smears, culture for MTB, confirmatory biopsy and PCR for MTB. The aspirates from cases other than TL served as controls for PCR. RESULTS: Correct diagnosis of tuberculosis could be made in 94.87% of cases by a combination of the four methods. PCR was done in 52 cases, 39 confirmed TL and 13 controls. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value of PCR were 94.44%, 38.23%, 44.73% and 92.85%, respectively, when culture alone was considered the gold standard. However, specificity (38.23-92.30%) and PPV (44.73-97.36%) of PCR increased remarkably when response to treatment was taken as the final arbiter. CONCLUSION: The four conventional tests were found to be the methods of choice for the diagnosis of TL in developing countries. PCR should be reserved for problem cases.

Immunohistochemical localization of transferrin in human breast cancer tissue.

The present study was planned to detect the iron binding protein, transferrin (TR) in paraffin sections of the human breast tumors. The distribution of transferrin has been studied in 153 cases (63 benign lesions and 90 malignant tumors). The extent of staining reaction was determined by semiquantitative grading (weak, moderate and consistent). Positivity rate for transferrin was higher (92.2%) in malignant tumors as compared to benign breast lesions (28.5%) with significant p value (P = .0001) for both the groups. The intensity was variable in both the groups, being more intense in the malignant tumors. Tumors with higher grade of malignancy presented consistent positive staining along with the lymph nodes involved. The extent of immunoreactivity revealed a significant positive correlation with axillary lymph node status. However, no significant correlation was found with the age of the patients. Thus the study of transferrin in breast tumors besides being of prognostic significance helps in the further management of malignant lesions of the breast.

Fibromatoses of the extremities: clinicopathologic study of 36 cases.

BACKGROUND AND OBJECTIVES: Fibromatoses of the extremities are rare and often recalcitrant to treatment. We evaluated the clinical and pathologic features of a group of extremity fibromatoses treated by surgical excision with or without adjuvant therapy to determine if any clinical or pathologic parameters were predictive of clinical outcome. METHODS: Thirty-six extremity fibromatoses were evaluated. A number of clinical and histologic features were correlated with risk of local recurrence. RESULTS: The cohort included 19 females and 17 males with ages ranging from 11-72 years (mean: 35 years), with 12 tumors of the upper and 24 tumors of the lower extremity. Tumors ranged in size from 1.5-15.5 cm (mean: 7.5 cm).Histologically, 26 were infiltrative, 3 had pushing borders and 7 had both. Mitotic counts ranged from 0-5/50 high-power fields (mean: 0.74). Surgical margins were positive in 22 cases. Seventeen patients were treated with postoperative adjuvant therapy including radiation therapy and tamoxifen. Follow-up information was available in 34 cases (from 1-202 months; mean: 83 months). Nineteen patients (56%) had recurrences, including 11 with multiple recurrences (range to first recurrence: 5-61 months; mean 23 months). Seventy-one percent of patients with a positive surgical margin and clinical follow-up had a local recurrence, compared to 31%with a negative surgical margin (P < 0.05). None of the other clinical or histologic parameters correlated with the risk for local recurrence. CONCLUSIONS: Local control in fibromatoses of the extremities remains problematic. Aside from positive surgical margins, none of the other clinical or histologic parameters evaluated in this study were useful in predicting the risk of local recurrence.

Immunohistochemical localization and correlation of p53 and PCNA expression in breast carcinoma.

The object of the present study is to detect the p53 tumour suppressor gene and proliferation cell nuclear antigen (PCNA) expression in breast carcinoma by immunohistochemistry and correlate them with the prognostic parameters. Total 35 cases of primary breast carcinoma were studied and classified histologically. Paraffin sections were stained by using monoclonal antibody D07 for p53 protein and PC-10 for PCNA. Out of 35 cases, 16 (45.7%) were p53 positive and 25 (71.4%) were PCNA positive. The mean PCNA labelling index (PCNA LI +/- SD) was 58.97 +/- 22.72 in tumors positive for both p53+ and PCNA+ while cases negative for p53- and positive for PCNA+ has higher PCNA LI +/- SD (59.24 +/- 18.97). The difference in the two groups was not significant. Most cases were positive for both p53+ and PCNA+ in the age group < 30 with higher mean PCNA LI +/- SD (62.20 +/- 27.13) than in the group > 30 (57.88 +/- 18.47). In the pre-menopausal group 57.1% cases were positive for p53+ with higher PCNA LI +/- SD (59.94 +/- 24.22). Maximum p53 and PCNA positivity was observed in grade III tumors (63.2% and 84.2%). The mean PCNA LI +/- SD was also highest in grade III carcinomas (66.83 +/- 13.97). No significant correlation was found between p53 and PCNA status with morphological type and tumour size except that logistic regression showed a positive correlation with tumour grade. Therefore the present study suggests that both p53 expression and PCNA are markers of poor differentiation in breast cancer.

Immunohistochemical localization of transferrin in human breast cancer tissue.

The present study was planned to detect the iron binding protein, transferrin (TR) in paraffin sections of the human breast tumors. The distribution of transferrin has been studied in 153 cases (63 benign lesions and 90 malignant tumors). The extent of staining reaction was determined by semiquantitative grading (weak, moderate and consistent). Positivity rate for transferrin was higher (92.2%) in malignant tumors as compared to benign breast lesions (28.5%) with significant p value (p = 0.0001) for both the groups. The intensity was variable in both the groups, being more intense in the malignant tumors. Tumors with higher grade of malignancy presented consistent positive staining along with the lymph nodes involved. The extent of immunoreactivity revealed a significant positive correlation with axillary lymph node status. However, no significant correlation was found with the age of the patients. Thus the study of transferrin in breast tumors besides being of prognostic significance helps in the further management of malignant lesions of the breast.

Cytopathology and AgNOR counts in fine-needle aspiration cytology smears of thyroid lesions.

The object of the present work is to study the cytomorphological features and the value of silver colloidal staining method in distinguishing the non-neoplastic, benign, and malignant neoplasm in fine-needle aspiration cytology (FNAC) smears of thyroid nodules. One hundred forty histologically confirmed aspirated samples of thyroid lesions were studied and classified cytologically. These smears were stained for AgNOR counts. The number and location of AgNOR dots as well as clusters in nuclei were studied by two different observers independently. Lower AgNOR counts were recorded in cases of thyroiditis (1.375 +/- 0.414), whereas follicular carcinoma had a higher number of AgNOR counts (5.04 +/- 0.52). The clusters of AgNOR dots were centrally located in colloid goitre, but no cluster arrangement was observed in cases of carcinomas. Increased nuclear size, nucleoli, and chromocentres were helpful in the diagnosis of follicular carcinoma. AgNOR counting cannot be reliably used on an individual case basis to differentiate adenoma from carcinoma. Therefore, AgNOR study in thyroid lesions can be used as an additional diagnostic method with cytomorphological features to differentiate benign and malignant follicular neoplasms.

Statistical significance of AgNOR counts in FNAC smears and corresponding histopathological sections.

The object of the present study was to determine the statistical significance of AgNOR counts in fine needle aspiration cytology (FNAC) smears and corresponding paraffin sections by using an one step silver colloidal staining method. Ninety five cases (31 benign and 64 malignant) were taken and a correlation between smears and sections was studied by two different observers. The total number of mean (SD) AgNOR counts was significantly higher in FNAC smears in benign (3.081 +/- .753) and malignant (7.101 +/- 1.544) neoplasms in comparison to paraffin sections in the same group of cases. FNAC smears had a cut off point 4 with proliferation index 1% in benign tumors and 97.5% in malignant tumors. Sections had an overlapping of AgNOR counts (5-7) with proliferation index 3.8 and 82% for benign and malignant groups respectively. The difference in the coefficient of variations was 3% in benign group and 2% in malignant group in FNAC smears while sections had 6 and 8% difference in the coefficient of variations. Smears present a superior staining and accurate number of AgNOR dots in nucleus as compared to paraffin sections. Therefore the results suggest that AgNOR technique can be successfully used in FNAC smears in comparison to paraffin sections to differentiate benign and malignant tumors in routine laboratory diagnosis.

Diagnostic relevance of silver stained nucleolar organizer region (AgNORs) in benign and malignant breast lesions.

The present study is planned to assess the diagnostic relevance of silver stained nucleolar organizer regions (NORs) in discriminating benign from malignant lesions of the breast and to ascertain the interobserver variability in the enumeration of AgNOR counts. Forty four specimens of benign and malignant breast tissues were studied and mean number of silver stained nucleolar organizer regions (MNORA) have been counted in paraffin sections. Malignant lesions have a higher number of MNORA than benign lesions. These results also showed correlation between the AgNOR counts and size of the tumor, axillary lymph node status and age of the patient. Our results also indicate a close agreement between the two observers with limits of agreement. However, AgNOR counts are of little diagnostic importance since a broad zone of overlap exists between benign and malignant breast diseases despite significant higher mean counts in malignant lesions. AgNOR sequence could perhaps be of use to differentiate those two histological indistinguishable lesions. The tumor size and axillary lymph node involvement suggested to its prognostic significance also. Interobserver agreement further suggests the utility of AgNOR counts as diagnostic or prognostic discriminants in breast malignancies.