Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.     

Evaluation of RapiDEC Staph for identification of Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus saprophyticus.

RapiDEC Staph is a test for presumptive identification of the principal human staphylococcal species, Staphylococcus aureus, S. epidermidis, and S. saprophyticus. The test includes control and test cupules for fluorogenic detection of coagulase and chromogenic substrates for alkaline phosphatase and beta-galactosidase. These tests identify S. aureus, S. epidermidis, and S. saprophyticus, respectively. Positive results with both chromogenic substrates provide a presumptive identification of S. xylosus or S. intermedius (S. xylosus-S. intermedius). Test cupules are inoculated with an organism suspension, and reactions are read after a 2-h incubation. RapiDEC-Staph was evaluated with 303 clinical and stock staphylococcal strains. Identifications were compared with those obtained by the tube coagulase test, a latex slide coagulase test (StaphAUREX), another commercial identification system (Staph-TRAC), and additional conventional tests. RapiDEC-Staph correctly identified 100% of 130 S. aureus strains, 70.3% of 74 S. epidermidis strains, and 81.3% of 32 S. saprophyticus strains. Four of five S. xylosus isolates were called S. xylosus-S. intermedius. Unidentified S. epidermidis and S. saprophyticus strains were called "Staphylococcus spp." Among the 62 other coagulase-negative staphylococci, 4 were misidentified as S. epidermidis and 7 were misidentified as S. saprophyticus. While the sensitivity and specificity of the fluorogenic coagulase test for S. aureus were 100%, failure to detect alkaline phosphatase activity in several S. epidermidis isolates resulted in fewer correct identifications by the RapiDEC-Staph test for this species.     

Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

OBJECTIVE: The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. PATIENTS AND MEASUREMENTS: Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. RESULTS: Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. CONCLUSIONS: PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity.     

Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte-predominant Hodgkin lymphoma

The pathological background in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consists of lymphocytes and histocytes. This study analysed the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis (ALC/AMC-DX) on the impact of survival in NLPHL. One hundred and three consecutive NLPHL patients that were followed at Mayo Clinic from 1974 to 2010 were included in the study. Receiver operating characteristic and area under the curve were used for ALC/AMC-DX cut-off value analysis and proportional-hazards models were used to compare survival based on the ALC/AMC-DX ratio. With a median follow-up of 8·9 years (range: 0·3-31 years), an ALC/AMC-DX ≥2·1 was the best cut-off value for survival with an area under the curve of 0·82, a sensitivity of 70% and specificity of 84%. After adjusting for the International Prognostic Score (IPS), ALC/AMC-DX remained an independent prognostic factor for overall survival [Hazard Ratio (HR), 0·33, 95% confidence interval (CI), 0·15-0·71%, P < 0·004]; lymphoma-specific survival (HR, 0·05; 95%CI, 0·01-0·68%, P < 0·002); progression-free survival (HR, 0·30; 95%CI, 0·14-0·60%, P < 0·006), and time to progression (HR, 0·06, 95%CI, 0·04-0·30%, P < 0·004). ALC/AMC-DX is a low cost, already standarized, biomarker to predict clinical outcomes in NLPHL.     

Effects of reduction in dose and discontinuation of hydrochlorothiazide in patients with controlled essential hypertension

We studied the effects of a reduction in dose of hydrochlorothiazide from 50 to 25 mg/d, and its discontinuation for up to 22 months in 36 well-controlled hypertensive patients. Hydrochlorothiazide was discontinued if the diastolic blood pressure remained less than or equal to 94 mm Hg after a 6-month period on the lower dose of hydrochlorothiazide. No other changes were made in medications or diet. Sitting systolic blood pressure rose from 135 +/- 15 mm Hg to 140 +/- 14 mm Hg on reduction of the hydrochlorothiazide dose and rose still further to 145 +/- 20 mm Hg on discontinuation. Even greater increases in standing blood pressure were observed. There were no significant effects on the diastolic blood pressure with reduction of dose or discontinuation of hydrochlorothiazide. A significant decrease in the serum uric acid and a rise in serum potassium occurred. There were no changes in serum glucose or lipids on reduction in the dose of hydrochlorothiazide; whereas, with discontinuation, the serum lipids and hemoglobin A1C fell significantly. These results suggest that the benefits of a reduced dose of hydrochlorothiazide may not be as great as considered heretofore.     

Does regular zoledronic acid change the bone turnover of the jaw in men with metastatic prostate cancer: A possible clue to the pathogenesis of bisphosphonate related osteonecrosis of the jaw?

Purpose

To find out whether the most popular pathogenesis hypothesis of the bisphosphonate (BP) related osteonecrosis of the jaw (BRONJ) is comprehensible: (1) is there a higher bone remodeling in the jaw compared with other skeletal sites? (2) Is the bone turnover (BT) of the jaw overly altered after BP intake? (3) Are there gender- or entity-specific differences in BT before and after BP intake?

Methods

Bone scintigraphies of 42 patients with prostate cancer were retrospectively analyzed (n = 21 with BP intake; n = 21 no BP). All patients received bone scintigraphy prior to the therapy and in the course of the treatment (after 12 and 24 months). Data were quantitatively analyzed using six predetermined regions of interest and compared with a breast cancer cohort.

Results

The mandible revealed a similar BT as the femur and a significant lower BT compared with the maxilla. All investigated bone regions showed no significant changes under BP administration. Inter-gender differences revealed significantly lower BT values for the prostate cancer compared with the female breast cancer cohort, changes over the course of time could not be found.

Conclusions

The finding that the mandible revealed a significant lower BT than the maxilla and the fact that 2/3 of the BRONJ cases occur in the mandible are inconsistent with the investigated hypothesis. Furthermore, the BT in the jawbone is not overly suppressed by BP. Thus, it seems implausible that a high BT and its over-suppression play the key role in the pathomechanism of BRONJ.     

Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases?

BACKGROUND: The objective of the authors' study was to characterize the clinical and pathologic differences between patients who develop posttransplant lymphoproliferative disorders (PTLD) early or late after transplantation and to assess the overall survival in these two groups. METHODS: One hundred seven adult solid organ transplant patients were identified at the Mayo Clinic between December 1970 and May 2003. RESULTS: Forty-nine patients developed PTLD within the first year (early PTLD, 1-11.8 months) and 58 patients developed PTLD after 1 year (late PTLD, 14 months-17 years). Patients with early PTLD more commonly had the following characteristics: positive Epstein-Barr virus (EBV) in situ hybridization status (P < 0.0001), CD20-positive status (P = 0.002), and involvement of the grafted organ (P = 0.02). Overall survival did not differ between the two groups (P = 0.25). PTLD may occur in two different settings with different characteristics. CONCLUSIONS: Early PTLD is more commonly EBV in situ hybridization-positive and CD20-positive, and more commonly involves the grafted organ.     

The polycystic ovary syndrome per se is not associated with increased chronic inflammation

OBJECTIVE: The syndrome of polycystic ovaries (PCOS) is a known risk factor for type 2 diabetes. It is not known, however, whether the increase in diabetes risk is related to endocrine abnormalities associated with PCOS such as hyperandrogenemia, or whether it is a consequence of the anthropometric or metabolic alterations frequently observed in PCOS women. DESIGN: Since markers of inflammation are supposed to predict type 2 diabetes, interleukin-6 (IL-6) and C-reactive protein (CRP) in combination with parameters of obesity, insulin resistance and hyperandrogenism were determined in 57 PCOS women and in 20 age-matched healthy controls. In addition, the C-174G IL-6 promoter polymorphism was analyzed as a determinant in influencing IL-6, obesity, and androgen levels in women. RESULTS: Neither CRP nor IL-6 were significantly elevated in lean or obese PCOS women compared with age-matched lean or obese controls. In PCOS patients, variables of body composition (body mass index (BMI), waist to hip ratio, dual-energy X-ray-absorptiometry fat mass) and of insulin resistance were correlated with IL-6 or CRP, while parameters of hyperandogenism were not. Multivariate linear regression analysis revealed that obesity is the dominant force, thus explaining 18% and 24% of the IL-6 or CRP levels, respectively, in PCOS women. No association of IL-6 or BMI to a certain genotype at C-174G could be demonstrated in 50 PCOS patients. The heterozygous GC genotype, however, was associated with lower androstendione levels. Metformin treatment of 9 obese, insulin-resistant PCOS patients over a period of 6 months caused a significant decrease in body weight, body fat mass and total testosterone, but showed no significant decline in IL-6 or CRP concentrations. CONCLUSIONS: In PCOS women, plasma levels of IL-6 and CRP were not increased when compared with age- and BMI-matched controls. BMI was, however, the parameter most strongly related to IL-6 and CRP in PCOS; thus PCOS-related endocrine abnormalities do not appear to activate inflammatory parameters thereby enhancing the risk of diabetes. In PCOS, the type 2 diabetes risk may, therefore, be confined to those with obesity and/or metabolic alterations rather than affecting all women suffering from the syndrome.     

Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro

Friedreich ataxia is an inherited disorder caused by decreased expression of frataxin protein. Increasing evidence suggests that this protein might detoxify reactive oxygen species (ROS) by an unknown mechanism. Here we demonstrate that transgenic overexpression of human frataxin increases cellular antioxidant defense via activation of glutathione peroxidase and elevation of reduced thiols, thereby reducing the incidence of malignant transformation induced by ROS, as observed by soft agar assays and tumour formation in nude mice. These findings expand the understanding of antioxidant properties of frataxin, and tentatively suggest a role in the early induction of cancer.