Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo

The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (K(i) = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses approximately 2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.     

Embryonal rhabdomyosarcoma of the orbit in a 38-year-old woman

Primary embryonal rhabdomyosarcoma of the orbit is an extremely rare tumor in adults. A 38 year old female patient with immunohistochemically proved embryonal rhabdomyosarcoma of the right orbit is reported. The histologic types, diagnosis, management and out come of rhabdomyosarcoma is discussed.     

The effects of respiratory training with inspiratory flow resistive loads in premature infants.

Respiratory training of premature infants was performed to determine whether improved respiratory muscle strength and/or endurance would result. Twenty-two premature infants were randomized into control and training groups for 2 wk, using inspiratory flow-resistive loads for training (75 cm H2O.L-1.s in wk 1 and 90 cm H2O.L-1.s in wk 2). Respiratory endurance was assessed by the time interval required for the development of a 5-torr rise in transcutaneous CO2 tension during the hypoventilation induced by loaded breathing, using a moderately severe resistive load (250 cm H2O.L-1.s at 1 L.min-1). Respiratory strength was assessed by the maximum negative airway pressure generated during occluded breaths, a pressure-time integral, and an effort index. Results revealed that respiratory muscle endurance, which was not initially different between control and trained groups, increased significantly after 2 wk in the trained group by 137% (median value, p less than 0.05), whereas it remained unchanged in the control group (-24%). The trained group of infants also showed a significant decrease in baseline breathing frequency between the initial and final measurements taken 2 wk apart when compared with controls (p less than 0.05) and a lesser increase in inspiratory time with loading in the final measurement as compared with the initial value (p less than 0.05). There was no significant difference between the control and trained groups in initial or subsequent measures of respiratory muscle strength. Inspiratory flow-resistive load training appears to improve the respiratory endurance of premature infants in whom respiratory muscle fatigue has been described to play a role in the development of respiratory failure.     

Noise exposure as a risk factor for acoustic neuroma: a systematic review and meta-analysis

Objective: To investigate whether acoustic neuroma is associated with noise.

Design: PubMed, Cochrane, Embase and CINAHL databases were searched. A meta-analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI) using quality-effect models.

Study sample: A total of eight studies with moderate or high quality involving 75,571 participants met the inclusion criteria.

Results: There was no significant relationship between overall noise exposure and acoustic neuroma (OR:1.02, 95% CI: 0.64–1.63). However, further subgroup analysis showed that leisure noise exposure (OR: 1.73, 95% CI: 1.10–2.73), above five years’ exposure (OR: 1.81, 95% CI: 1.14–2.85) and continuous exposure (OR:2.77, 95% CI: 1.70–4.49) were associated with an increased risk of acoustic neuroma.

Conclusions: These results suggest an elevated risk of acoustic neuroma among individuals who have been exposed to occupational noise when some subgroup analysis are conducted. Leisure noise in particular seems to play a significant role in the development of acoustic neuroma. However, due to the heterogeneity among the included studies, this conclusion should be interpreted with cautions, even though the continuous long-term consequences should not be ignored.     

Seroprevalence of Helicobacter pylori in dyspeptic patients and its relationship with HIV infection, ABO blood groups and life style in a university hospital, Northwest Ethiopia

AIM:To determine the prevalence of Helicobacter pylori(H pylori)among dyspeptic patients and to assess therelationship between H pylori infection,blood group,HIVinfection and life style of the patients.METHODS:In a hospital-based cross-sectional study,patients attending Outpatient Department of Universityof Gondar Hospital were enrolled.Socio-demographicinformation was collected using questionnaires.Serumwas analyzed for anti-H pylori IgG antibodies usinga commercial kit.HIV serostatus was determined byenzyme-linked immunosorbent assay(ELISA).Bloodgrouping was performed by slide agglutination tests.RESULTS:A total of 215 dyspeptic patients wereincluded in the study.One hundred and sixteen patients(54%)were females and 99(46%)were males.Anti-Hpylori IgG antibodies were detected in sera of 184(85.6%)patients.The prevalence was significantly higherin patients aged 50 years and above.Twenty point fivepercent of the patients were found to be seropositive forHIV.No significant association was found between sex,ABO blood groups,consumption of spicy diets,socio-economic status and seropositivity for Hpylori.However, alcohol consumption was significantly associated with Hpylori serology.CONCLUSION:The prevalence of H pylori infection isassociated with a history of alcohol intake and older age.The effect of different diet,alcohol and socioeconomicstatus as risk factors for H pylori infection needs furtherstudy.     

Use of IIb/IIIa inhibitors in patients with in-stent restenosis treated with intracoronary gamma-radiation. Integrilin WRIST.

The Integrilin Washington Radiation for In-Stent Restenosis Trial (WRIST) aimed to study the impact of IIb/IIIa inhibitors as adjunct therapy to intracoronary radiation therapy (IRT) for patients with in-stent restenosis (ISR). The impact of GP IIb/IIIa inhibitor (eptifibatide) as adjunct therapy to vascular brachytherapy using (192)Ir emitter was examined in patients with in-stent restenosis. In the study, 150 patients were assigned to eptifibatide (Integrilin) and 150 patients to heparin only. Clinical composite endpoints at 30 days were similar between the patients treated with and without eptifibatide (4.7% vs. 4.0%; P = 0.78). There was a similarity in the non-Q-wave myocardial infarction (MI) rates between the eptifibatide and the control group. Major bleeding was similar in patients treated with and without eptifibatide. Overall, the use of eptifibatide as adjunct therapy for patients with ISR that are treated with IRT did not impact the clinical outcome at 30 days.     

A five-year antimicrobial resistance pattern of Shigella isolated from stools in the Gondar University hospital, northwest Ethiopia

Shigellosis is a global health problem. However, developing countries, where there is poor hygiene and unsafe water supplies, are especially affected. In the last two decades Shigella isolates have become increasingly resistant to many commonly used drugs. We investigated the antibiotic susceptibility pattern of Shigella isolated from stool specimens processed over five years in the bacteriology laboratory of the University of Gondar Teaching Hospital in northwest Ethiopia. Stool specimens were processed using standard bacteriological methods and data on bacterial culture, isolation and antimicrobial sensitivity were collected in the laboratory logbook. From a total of 2891 cultures stool specimens, 214 yielded Shigella. The overall sensitivity of Shigella to the commonly used antibiotics was: gentamicin (92.1%), ciprofloxacin (91.1%), chloramphenicol (47.2%), cotrimoxazole (26.6%), ampicillin (20.1%) and tetracycline (14%). About 46% of the isolates were resistant to at least three of the most commonly used drugs and 1.4% were resistant to all the commonly used drugs. The results demonstrated continued sensitivity of Shigella to gentamicin and ciprofloxacin and widespread resistance to tetracycline, ampicillin and cotrimoxazole. It is recommended that the use of gentamicin and ciprofloxacin be strictly regulated in the treatment of severe cases in regions where shigellosis is endemic and where the occasional epidemics result in high mortality.     

HIV and syphilis infection among elderly people in northwest Ethiopia

The prevalence of HIV has been continually increasing both in urban and rural Ethiopia. As yet, there has been no report on the magnitude of the problem in the elderly and rural population. This study assessed the seroprevalence of HIV and syphilis infection among 706 elderly and predominantly rural subjects in Northwest Ethiopia. Socio-demographic information was collected using a structured questionnaire. Venous blood was collected and the serostatus of HIV and that of syphilis were checked by ELISA and RPR, respectively. The total HIV-1 seroprevalence was 5% (35/706). Sex-specific prevalences of HIV for males and females were 5.6 and 4.7% respectively. A 4.2% difference in prevalence was observed by area of residence, which was statistically significant, P = 0.018. Only 6% of subjects positive for syphilis were also positive for HIV, while 4.9% of subjects negative for syphilis were positive for HIV. The data indicates that the prevalence of HIV among elderly people in Northwest Ethiopia was high. This indicates the importance of involving the elderly in HIV/AIDS prevention and control programs.     

Differential impact of longitudinal medication non-adherence on mortality by race/ethnicity among veterans with diabetes

OBJECTIVE

To examine the differential effect of medication non-adherence over time on all-cause mortality by race/ethnicity.

RESEARCH DESIGN AND METHODS

Data on a longitudinal cohort of veterans with type 2 diabetes was examined. The main outcome was time to death. Primary independent variables were race/ethnicity and mean medication possession ratio (MPR) categorized into quintiles over the study period. Cox regression was used to model the association between time to death and MPR quintiles and race/ethnicity, adjusting for relevant covariates.

RESULTS

The cohort of 629,563 veterans was followed for 5 years. After adjusting for all covariates, the hazard ratios (HR) for subjects in the lowest versus highest MPR quintile was 12.21 (95 % CI 11.89, 12.55) for non-Hispanic white (NHW), 10.01 (95 % CI 9.18, 10.91) for non-Hispanic black (NHB), 12.65 (95 % CI 11.10, 14.43) for Hispanic and 10.41 (95 % CI 9.06, 11.96) for Other race veterans. Furthermore, type of diabetes therapy (oral versus insulin) maintained a significant relationship with mortality that varied by racial/ethnic group.

CONCLUSIONS

This study demonstrates the differential impact of medication non-adherence on mortality by race. It also demonstrates that type of diabetes therapy (insulin with or without oral agents) is associated with mortality and varies by racial/ethnic group.