Sense-antisense gene-pairs in breast cancer and associated pathological pathways

More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival-significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers.     

Body composition in adults infected with human immunodeficiency virus in Khon Kaen, Thailand

A cross-sectional study of 77 patients infected with human immunodeficiency virus (HIV) in Khon Kaen, Thailand examined association of nutritional status with active opportunistic infections (AOIs)/HIV status and assessed degree of correlation between bioelectrical impedance analysis (BIA) and anthropometry. Many patients (41.3%) were malnourished using World Health Organization criteria for underweight, and malnutrition was associated with AOI status. Unconditional odds ratios (P < 0.05) for AOI as opposed to no AOI were 4.57 for underweight, 9.87 for severe underweight, 2.55 for triceps < 10th percentile, and 5.22 for mid-arm circumference < 10th percentile. Body fat composition from BIA, anthropometry, and body mass index were moderate to highly correlated (P < 0.001), with the highest correlation between BIA and subscapular skinfold (r = 0.86) and the lowest between BIA and triceps skinfold (r = 0.54). Insights were gained about relative value of using various measurements to assess nutritional status of HIV-infected populations.     

Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis

OBJECTIVES: In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels. METHODS: Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations. RESULTS: We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 +/- 2.66 mg/l, whereas in the control group the mean nevirapine concentration was 8.72 +/- 3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (< 3.1 mg/l), while in the control group two patients had low nevirapine trough concentrations (P = 0.164). In the multivariate linear regression analysis, corrected for time after drug intake, the use of rifampin was significantly (P < 0.001) associated with lower nevirapine plasma concentrations, whereas higher BMI reached borderline significance (P = 0.065). CONCLUSION: Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations > 3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.     

Perioperative Outcomes of Patients Who Were Not Candidates for Additional Nonsteroidal Anti-inflammatory Drugs in a Multimodal Pain Control Regimen for Total Knee Arthroplasty

BackgroudPostoperative pain following total knee arthroplasty (TKA) may hamper patients from a rapid recovery and increase perioperative blood loss and stress on the cardiovascular system. Therefore, our objective was to assess perioperative outcomes after TKA in patients who were not candidates for the additional nonsteroidal anti-inflammatory drugs (NSAIDs) in a multimodal pain control regimen.MethodsPropensity score matching for age, sex, body mass index, American Society of Anesthesiologists class, and preoperative hemoglobin level was conducted on patients undergoing unilateral TKA, and thereby 52 patients remained in each group. The control group comprised patients who received parenteral parecoxib every 12 hours during the first 48 hours after TKA. The No-NSAIDs group did not receive NSAIDs because of known contraindications. Identical postoperative pain control including intravenous patient-controlled analgesia was applied for all patients. Visual analog scale (VAS) score for pain, knee flexion, blood loss, serum cardiac troponin-T (cTnT), and length of stay (LOS) were determined.ResultsThe No-NSAIDs group had significantly higher VAS scores in 6–96 hours and consumed more morphine at 24 hours and 48 hours after the surgery than the control group. The No-NSAIDs group had significantly less knee flexion at 48 hours (p = 0.045) and tended to have more emesis and longer LOS than the control group. The blood loss of the No-NSAIDs and control group was 552.52 mL and 397.65 mL (p = 0.02), respectively, and blood transfusion rate was 23.1% and 17.3% (p = 0.63), respectively. The cTnT of the No-NSAIDs group rose over the first 48 hours and was significantly higher than that of the control group at 48 hours.ConclusionsPatients who were not candidates for NSAIDs had significantly higher pain scores and consumed more morphine after TKA. They also tended to have greater blood loss and the rising of cardiac biomarkers during the first 48 hours after TKA. Hence, these patients may benefit from supplementary analgesia and appropriate perioperative monitoring.     

Histoplasmosis and penicilliosis: comparison of clinical features, laboratory findings and outcome.

INTRODUCTION: Histoplasmosis and penicilliosis are infections caused by the dimorphic fungi, Histoplasma capsulatum and Penicillium marneffei, respectively. The aim of this study was to compare the clinical presentation, laboratory and radiologic findings and outcome of these infections at Srinagarind Hospital, Khon Kaen, Thailand. METHODS: The medical records of patients who had positive cultures for Histoplasma capsulatum and Penicillium marneffei during 1996-2002 were reviewed. The data were compared and analyzed by the Chi-square and Fisher's exact tests. RESULTS: There were 32 and 36 medical records of patients with H. capsulatum and P. marneffei infection, respectively, available for review. The most common underlying disease of patients with histoplasmosis and penicilliosis was acquired immunodeficiency syndrome (AIDS), which accounted for 90.6% and 91.7%, respectively. The most common clinical findings in both infections were fever, weight loss, cough, anemia, lymphadenopathy, hepatomegaly and splenomegaly. Frequencies of skin lesions were not statistically different between either group (P=0.20). Laboratory findings were similar between the two infections, except hyperbilirubinemia, which was more common in the penicilliosis group (P=0.02). There were similar abnormal X-ray findings in both groups with interstitial infiltration the most common abnormality. CONCLUSIONS: Histoplasmosis and penicilliosis had similar clinical presentations, laboratory findings and chest X-ray abnormalities. Itraconazole is recommended as secondary prophylaxis in HIV-infected patients who have histoplasmosis or penicilliosis.     

Identification of a novel 74-kiloDalton immunodominant antigen of Pythium insidiosum recognized by sera from human patients with pythiosis

The oomycetous, fungus-like, aquatic organism Pythium insidiosum is the etiologic agent of pythiosis, a life-threatening infectious disease of humans and animals that has been increasingly reported from tropical, subtropical, and temperate countries. Human pythiosis is endemic in Thailand, and most patients present with arteritis, leading to limb amputation and/or death, or cornea ulcer, leading to enucleation. Diagnosis of pythiosis is time-consuming and difficult. Radical surgery is the main treatment for pythiosis because conventional antifungal drugs are ineffective. The aims of this study were to evaluate the use of Western blotting for diagnosis of human pythiosis, to identify specific immunodominant antigens of P. insidiosum, and to increase understanding of humoral immune responses against the pathogen. We performed Western blot analysis on 16 P. insidiosum isolates using 12 pythiosis serum samples. These specimens were derived from human patients with pythiosis who had different forms of infection and lived in different geographic areas throughout Thailand. We have identified a 74-kDa immunodominant antigen in all P. insidiosum isolates tested. The 74-kDa antigen was also recognized by sera from all patients with pythiosis but not by control sera from healthy individuals, patients with thalassemia, and patients with various infectious diseases, indicating that Western blot analysis could facilitate diagnosis of pythiosis. Therefore, the 74-kDa antigen is a potential target for developing rapid serodiagnostic tests as well as a therapeutic vaccine for pythiosis. These advances could lead to early diagnosis and effective treatment, crucial factors for better prognosis for patients with pythiosis.     

Efficacy and safety of indinavir/ritonavir 400/100 mg twice daily plus two nucleoside analogues in treatment-naive HIV-1-infected patients with CD4+ T-cell counts <200 cells/mm3: 96-week outcomes

OBJECTIVE: To evaluate the efficacy and safety of indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily in antiretroviral-therapy-naive Thai HIV-1-infected patients. METHODS: This was an open-label, non-randomized single arm study. Antiretroviral-naive patients (n=80) with CD4+ cell count < 200 x 10(6)/l were started on stavudine and lamivudine plus indinavir/ritonavir 400/100 mg twice daily. CD4+ cell count and HIV RNA were determined at week 0, 12, 24, 48 and 96. HIV RNA was measured to a level of 50 copies/ml by RT-PCR assay. Primary analysis was statistically performed as intent to treat. The primary endpoint was the percentage of patients with plasma HIV RNA below 50 copies/ml at week 96. RESULT: Eighty antiretroviral-therapy-naive patients with median CD4+ cell count 19 x 10(6)/l (range: 2 - 197 x 10(6)/l) and median baseline plasma HIV RNA of 174,000 copies/ml (range 16,800-750,000 copies/ml) were enrolled. In the intent-to-treat analysis at week 96, the proportion of patients with HIV RNA of <50 copies/ml was 68.8% (95% confidence interval [CI]: 68.3-69.3), whereas it was 88.7% (95% CI: 88.1-89.3) in the on-treatment analysis at week 96. The regimen was well tolerated. Hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia were found in 8.3, 33.3 and 37.0% of the patients, respectively. Treatment was stopped in 18 patients; two from intolerance, two switched therapy, four as a result of serious adverse event-related death, and ten were lost to follow-up. CONCLUSION: Our study demonstrates that indinavir/ritonavir 400/100 mg plus stavudine and lamivudine twice daily, the least expensive boosted protease inhibitor, appears to be effective and safe up to 96 weeks despite high baseline viraemia and low CD4+ cell count in antiretroviral-naive patients.     

Time-kill curves as a tool for targeting ceftazidime serum concentration during continuous infusion for treatment of septicaemic melioidosis

Melioidosis is a fatal community-acquired infection endemic in tropical areas. Ten isolates of the causative microorganism were subjected to time-kill study using a range of ceftazidime concentrations. This study demonstrated that a ceftazidime concentration of eight times the minimum inhibitory concentration yielded an optimal bactericidal effect and should be the target concentration administered by continuous infusion.