Effect of raloxifene on serum triglycerides in women with a history of hypertriglyceridemia while on oral estrogen therapy

OBJECTIVE: Raloxifene hydrochloride is a selective estrogen receptor modulator that to date has not been shown to cause hypertriglyceridemia in normal, diabetic, or hypertriglyceridemic women. This study was designed to assess the effect of raloxifene on serum triglycerides in postmenopausal women who have a history of increased hypertriglyceridemia with oral estrogen therapy. RESEARCH DESIGN AND METHODS: This was a single-center, uncontrolled, open-label study investigating the effects of 8 weeks of raloxifene (60 mg/day) therapy on plasma lipids. The study subjects were 12 postmenopausal women, ages 49-73 years, with a documented history of oral estrogen-induced hypertriglyceridemia (serum triglycerides > or =3.39 mmol/l [> or =300 mg/dl]). RESULTS: At week 2 of the study, three (25%) of the subjects withdrew from the trial because they developed marked hypertriglyceridemia (>or =11.3 mmol/l [> or =1,000 mg/dl]) during raloxifene therapy. These three women had higher baseline triglyceride and glucose levels, were not being treated with lipid-lowering agents, and were more likely to have diabetes than the other study subjects. The remaining nine patients (75%) completed the 8-week trial and experienced a nonsignificant increase in mean triglyceride levels from baseline to end point. Raloxifene treatment also resulted in a significant 16% decrease in hepatic lipase activity and a 26% increase in HDL(2) levels (P = 0.013 and 0.03, respectively). CONCLUSIONS: Patients with a previous history of hypertriglyceridemia on oral estrogen therapy should have serum triglyceride levels monitored closely after beginning raloxifene therapy and may even require fibrate therapy before beginning raloxifene.     

Modulation of AT-1R/CHOP-JNK-Caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice

There is evidence that the activation of renal angiotensin (Ang)-II plays a critical role in the pathogenesis of diabetic kidney diseases (DN) via the ER stress-induced renal apoptosis. Since, the potential negative role of Ang-II in the pathogenesis of ER stress-mediated apoptosis is poorly understood; we evaluated whether treatment of mice with AT-1R specific blocker, olmesartan is associated with the reduction of ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic animal model. We employed western blot analysis to measure the renal protein expressions level of NADPH oxidase subunits, ER chaperone GRP78 and the ER-associated apoptosis proteins. Furthermore, TUNEL staining was used to measure the renal apoptosis. Additionally, dihydroethidium staining and TBARS assay, and immunohistochemistry were performed to measure the renal superoxide radical production and lipid peroxidation, and activation of an Ang-II, respectively. The diabetic kidney mice were found to have increased protein expressions of NADPH oxidase subunits, GRP78 and ER-associated apoptosis proteins, such as TRAF2, IRE-1α, CHOP, p-JNK and procaspase-12, in comparison to normal mice, and which were significantly blunted by the olmesartan treatment in diabetic kidney mice. Furthermore, the diabetic kidney mice were found to have significant increment in renal apoptosis, superoxide radical production, MDA level and activation of an Ang-II and which were also attenuated by the olmesartan treatment. Considering all the findings, it is suggested that the AT-1R specific blocker-olmesartan treatment could be a potential therapy in treating ER stress-induced renal apoptosis via the modulation of AT-1R/CHOP-JNK-Caspase12 pathway in STZ-induced diabetic mice.     

Recurrence of kyphosis and its functional implications after surgical stabilization of dorsolumbar unstable burst fractures

Background contextTreatment of unstable burst fractures in the dorsolumbar spine still remains controversial. Surgical stabilization has been aimed to prevent long-term back pain and progression of deformity.PurposeThis study was aimed to analyze the degree of loss of correction of the angle of kyphosis with pedicle screw instrumentation in place and the components responsible for the recurrence of kyphosis after surgical stabilization of dorsolumbar A3 fractures and to assess the return of functional capacity in these patients.Study designRetrospective study.Patient sampleThis study involves 26 patients who had dorsolumbar unstable burst fractures (Arbeitsgemeinschaft für Osteosynthesefragen type A3).Outcome measuresRadiological assessment at injury, immediate postoperative period, and most recent follow-up along with functional assessment using short form 36 (SF-36) and return to work.MethodsAll the patients had posterior pedicle screw instrumentation without fusion for unstable dorsolumbar burst compression (A3) fractures. The mean follow-up period was 25.5 months. All of them had their fractures stabilized with Universal Spinal System (Synthes, Welwyn Garden City, UK) Fracture System. Serial standing lateral radiographs were taken from the immediate postoperative period to the most recent follow-up. The angle of kyphosis; the heights of the discs above and below the fractured vertebra; and the heights of the vertebral bodies above, at, and below the fractured level were measured. The height at each level was measured in three segments (anterior, middle, and posterior). The values were normalized to avoid discrepancies while comparing radiographs. The difference in the height of each segment measured between the immediate postoperative period and the most recent follow-up was computed.ResultsThe mean angle of kyphosis was 6.3±8.9 in the immediate postoperative period and 15.7±6.7 at the most recent follow-up (p<.001). The mean patient function score from SF-36 was 52.3%, and the mean pain score was 44.9%. There was no relationship to the loss of correction angle of kyphosis to the patient function score (r=0.06, p=.76) and the pain score (r=0.11, p=.58). The correlation between the corresponding difference in the height of each segment and the degree of loss of correction of the angle of kyphosis showed positive correlation to the decrease in the anterior and middle segment heights at the fractured vertebral level.ConclusionThere is a progressive loss of correction of the angle of kyphosis after posterior stabilization with instrumentation even without implant removal that mainly corresponds to the decrease in the anterior segment height of the fractured vertebral body.     

A critical re-appraisal of different ways of selecting ambulatory patients with suspected heart failure for echocardiography

BACKGROUND: ECG and BNP have been assessed as screening tests for LVSD and heart failure. However, echocardiography also provides information about valvular disease and LVH. We assessed how good these screening tests are in identifying whether the subsequent echocardiogram will have any significant abnormality. AIMS: To re-appraise the ECG and BNP as screening tests for echocardiography since there are important practical deficiencies in our current knowledge in this area. METHODS: General practitioners referred suspected heart failure patients for clinical assessment, echocardiography, electrocardiography, and BNP measurement. The accuracy of each screening test and combinations of screening tests were calculated for LVSD, heart failure, valvular disease, and LVH. RESULTS: The sensitivities of the ECG for LVSD, heart failure, LVH and valvular disease were 97%, 95%, 76%, and 69%, respectively. The corresponding figures for BNP were 86%, 82%, 59%, and 48%, respectively. When patients with atrial fibrillation and murmurs were excluded, the values for ECG were 94%, 87%, 53%, and 55%, while for BNP they were 83%, 73%, 50%, and 32%. CONCLUSIONS: ECG interpretation and BNP are adequate screening tests to detect LVSD or heart failure but fail to screen for other echocardiographic abnormalities, like valvular disease and LVH. This remains the case even if patients with atrial fibrillation or heart murmurs are excluded on the basis that they require echocardiography anyway.     

Chemopreventive potential of piperine in 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in Swiss albino mice

The chemopreventive potential of orally administered piperine was studied in Swiss albino mice against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis. The mechanistic pathway for the chemopreventive potential of piperine was evaluated by analysing the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants during DMBA-induced skin carcinogenesis. Skin squamous cell carcinoma was induced in the shaved back of mice, by painting with DMBA (25μg in 0.1ml acetone/mouse) two times weekly for 8 weeks. We observed severe hyperplasia, dysplasia, and well-differentiated squamous cell carcinoma in the 8th, 10th and 15th week of experimental period respectively in mice treated with DMBA alone. Marked alterations in the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants were observed in tumor bearing mice. Oral administration of piperine (50mgkg(-1) body weight) by gastric gavage significantly prevented the formation of skin tumors during DMBA-induced mouse skin carcinogenesis. Also, piperine administration brought back the status of phase I and phase II detoxification agents, lipid peroxidation by-products and antioxidants to near normal range in DMBA treated mice. The present study thus demonstrates that piperine has significant suppressing effect on cell proliferation during DMBA-induced mouse skin carcinogenesis. The chemopreventive potential of piperine is probably due to its modulating effect on the status of lipid peroxidation, antioxidants and detoxification agents during DMBA-induced skin carcinogenesis.     

Restraint asphyxia in in-custody deaths Medical examiner's role in prevention of deaths

In the United States, the office of the Medical Examiner-Coroner is responsible for investigating all sudden and unexpected deaths and deaths by violence. Its jurisdiction includes deaths during the arrest procedures and deaths in police custody. Police officers are sometimes required to subdue and restrain an individual who is violent, often irrational and resisting arrest. This procedure may cause harm to the subject and to the arresting officers. This article deals with our experiences in Los Angeles and reviews the policies and procedures for investigating and determining the cause and manner of death in such cases. We have taken a "quality improvement approach" to the study of these deaths due to restraint asphyxia and related officer involved deaths, Since 1999, through interagency coordination with law enforcement agencies similar to the hospital healthcare quality improvement meeting program, detailed information related to the sequence of events in these cases and ideas for improvements to prevent such deaths are discussed.     

Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethyl-benz[a]anthracene-induced oral carcinogenesis

Circadian time-dependent treatment with chemotherapeutic drugs (chronotherapy) optimizes the therapeutic index by maximizing treatment efficacy and minimizing toxicity. The circadian time-dependent chemopreventive and anti-lipid peroxidative efficacy of withaferin-A in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated in the present study. We induced oral squamous cell carcinoma in the buccal pouches of golden Syrian hamsters during the day (4:00, 8:00, 12:00,16:00, 20:00 and 24:00) by application of DMBA three times per week for 14 weeks. The circadian time-dependent tumor incidence, volume and burden were observed in hamsters treated with either DMBA alone or DMBA + withaferin-A. The circadian pattern of lipid peroxidation by-products, as measured by the formation of thiobarbituric acid reactive substances (TBARS) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], was also analyzed in the buccal mucosa of DMBA-treated hamsters. We found the highest incidence of tumor formation at 24.00 h in hamsters treated with DMBA alone as compared to other experimental groups. Circadian dysregulation of lipid peroxidation and antioxidant status was observed in DMBA-treated animals as compared to control animals. Oral (po) administration of withaferin-A (20 mg/kg) completely prevented the formation of tumors between 8.00 h and 12.00 h and synchronized the status of lipid peroxidation and antioxidants in the buccal mucosa of hamsters treated with DMBA alone. Also, oral administration of withaferin-A to DMBA-treated animals significantly reduced the formation of tumors and synchronized the status of lipid peroxidation and antioxidants in the rest of the time intervals. Our study thus suggests that withaferin-A has significant chemopreventive and anti-lipid peroxidative potential in DMBA-induced oral carcinogenesis, probably by interfering with DMBA-induced abnormal cell proliferation in the buccal mucosa.     

Achieving the required medial offset and limb length in total hip arthroplasty

The magnitude of the medial offset and limb length discrepancy after a total hip arthroplasty (THA) significantly affects the biomechanics of the hip. If both of these components are not properly restored, the rate of dislocation may increase. In addition limb length inequality can be a cause for legal problems. We have used a method of intraoperative assessment to restore both the length and the medial offset, and assessed this by comparing the medial offset and leg length in the pre- and post-operative radiographs in 39 consecutive THAs. The median medial offset was 93.9% (range: 85 to 100) preoperatively and 94.2% (range: 85 to 110) postoperatively, compared with the unaffected contralateral side. The median limb length discrepancy was improved from a preoperative -4.84 mm (range: 0 to -30) to a postoperative -0.06 mm (range: -9 to +16). In conclusion, this technique is a simple, accurate and reliable way of restoring the medial femoral offset and correcting the limb length inequality.     

Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: a possible role in statin-induced hepatotoxicity?

Lowering of low-density lipoprotein cholesterol is well achieved by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins inhibit the conversion of HMG-CoA to mevalonate, a precursor for cholesterol and coenzyme Q10 (CoQ10). In HepG2 cells, simvastatin decreased mitochondrial CoQ10 levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ10, reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ10 deficiency plays an important role in statin-induced hepatopathy, and that CoQ10 supplementation protects HepG2 cells from this complication.