Combinatorial effect of TIMP-1 and α1AT gene polymorphisms on development of chronic obstructive pulmonary disease

Objective

To study the role of α₁AT and TIMP-1 gene polymorphisms in development of COPD.

Design and methods

Blood samples from total 408 subjects (217 COPD patients and 191 controls) were used for genotyping and estimating biolevels of α₁AT, TIMP-1 and inflammatory cytokines. Data was analyzed to determine the role of interaction of TIMP-1 and α₁AT genes; and interplay between various genotypes and biolevels of α₁AT, TIMP-1 and inflammatory cytokines in development of COPD.

Results

Significantly low levels of α₁AT and TIMP-1 were observed in COPD patients as compared to controls (P = 0.001), where as the inflammatory cytokines were found to be increased in patients. PIM3 allele of α₁AT gene in COPD patients was found to be associated with low levels of α₁AT (P = 0.001), the effect being more pronounced when PIM3 combined with rs6609533 of TIMP-1 gene (P = 0.0001). Combination of genotypes rs6609533 of TIMP-1 and PIM3 of α₁AT containing the risk alleles was over-represented in patients (P = 0.005).

Conclusion

The SNP rs6609533 of TIMP-1 gene interacted with PIM3 of α₁AT to make a possible risk combination for development of COPD.     

The best of both worlds? Potential of hybrid prospective/concurrent risk adjustment

BACKGROUND: There remains considerable uncertainty about whether prospective or concurrent risk adjustment (RA) is preferable. Although concurrent models have better predictive power than prospective models, the large payments associated with concurrent RA create incentives for fraudulent coding. A hybrid strategy--in which prospective payments were used for patients with low expected costs and concurrent payments were available upon the diagnosis of a small number of common, expensive conditions--might improve predictive performance while requiring less auditing than fully concurrent RA. In addition, within-condition RA (using clinical data) for the selected conditions could further improve predictive power. OBJECTIVES: To assess how such a hybrid strategy might perform, focusing on a small number of chronic, expensive conditions that are verifiable (hence auditable). SUBJECTS AND MEASURES: All patients from seven health plans who had two complete years of utilization data were considered. RA models were estimated among patients younger than 65 (n = 319,209) using the Hierarchical Coexisting Conditions (HCC) model with and without stratification of the sample based on the presence of one or more of 100 verifiable, expensive, predictive conditions (VEP100). R2 and predictive ratios were calculated for each model studied. RESULTS: Patients with a VEP100 condition (9.3% of the population) accounted for 84.3% of the variation in cost. R2 was 0.08 using a prospective HCC model on the entire population, but increased to 0.26 for a hybrid using prospective HCCs on the 90.7% of the sample without a VEP100 condition and a simple concurrent model consisting of dummy variables for each of the VEP100 conditions. CONCLUSION: Combined with targeted auditing, a hybrid approach to RA could improve our ability to match payments to costs. However, because this would require additional, costly data collection, more research is needed to determine whether this benefit justifies the data collection and auditing burden.     

Clinicopathological differential diagnosis of mycosis fungoides/Sézary syndrome from the cutaneous type of adult T-cell leukemia/lymphoma

Mycosis fungoides/Sézary syndrome(MF/SS) is considered as a distinct clinical entity in the latest classifications, including the revised European-American classification of lymphoid neoplasm(REAL), and the ones by the WHO and the European Organization for Research and Treatment of Cancer(EORTC). In Japan, where is an endemic area for human T-cell lymphotropic virus type 1(HTLV-1), we have been facing some problems concerning the differential diagnosis of MF/SS. We have observed many cutaneous types of adult T-cell leukemia/lymphoma(cATL/L) that can initiate as erythematous infiltrating plaques similar to MF or as an erythrodermic lesion similar to SS and also as tumoral and nodular lesions, solitary or multiple that resemble d'emblée type MF. The importance of the differential diagnosis between MF/SS and cATL/L lies on the significant difference on the prognosis. It is worth to differentiate MF/SS from cATL/L, especially in MF patients positive for HTLV-1 antibody. We emphasize on the characteristics that differentiate MF/SS from cATL/L as well as on the new findings regarding clinical, histopathological, phenotypical and genotypical aspects of MF/SS.     

Detection of metallo-β-lactamase–encoding genes among clinical isolates of Pseudomonas aeruginosa in northwest of Iran

The prevalence of metallo-β-lactamase (MBL) production among 104 clinical isolates of Pseudomonas aeruginosa from northwest of Iran was investigated by phenotypic and polymerase chain reaction (PCR) methods. Thirty-nine (37.50%) of isolates were MBL positive by double-disk synergy test. Results of PCR revealed that 18 (17.31%) and 6 (5.77%) imipenem nonsusceptible isolates of P. aeruginosa carried bla_VIM and bla_IMP genes respectively, while 92.4% (62/67) of isolates contained class 1 integron gene. This is the first report of MBL-producing P. aeruginosa from northwest of Iran.     

GMDP augments antitumor action of the CP/TNFα combination in vivo

We have shown that glucosaminyl muramyl dipeptide (GMDP) has been augmented the antitumor action of chemotherapy drug cisplatin and tumor necrosis factor-α (TNFα) on the Ehrlich ascites carcinoma and melanoma B-16 mouse tumor models. The doses of cisplatin, TNFα and GMDP and also the conditions of the drugs combination injection provided 100% survival of mice with Ehrlich ascites carcinoma were found. Furthermore, it was shown first that GMDP has been decreased toxicity of the cisplatin/TNFα combination and normalized the changes in the experimental mice hematological parameters which were produced by the CP/TNFα combination.     

Cloning and expression of ODF/OPGL/RANKL gene related to osseous absorption disease

Objective To clone,express and purify recombinant OPG/RANKL/TRANCE.Method RNA was extracted from the fetal liver and was reverse transcribed into cDNA.RANKL gene was amplified by RT-PCR with designed primers and cDNA as template. The product of PCR were cloned into His-tagged expression vector-pProEX^TM The and sent to sequence.Induced by IPTG, recombinant protein of the RANKL was expressed in Escherichia .coli stably. The protein was purified by Niion exchange colum. Result Weight of PCR product was 500 bp and sequence of it were correct. Molucular weight of recombinant protein was 20 kD.Conclusion ODF/OPGL/RANKL/TRANCE gene can be amplified simply and conveniently by RT-PCR from the cDNA of fetal liver. Recombinant RANKL protein could be obtained by inducing Prokaryotic expression of it.     

Detection of high-burden coronary artery disease by exercise-induced changes of the E/E’ ratio

To investigate whether exercise-induced changes of the E/E’ average ratio can detect high-burden coronary artery disease (CAD) in patients with chest pain and normal left ventricular (LV) systolic function. The study population consisted of 359 patients admitted for chest pain (59.8 ± 9.8 years, 75% male). Patients underwent exercise echocardiography, scintigraphy and coronary angiography. The average of the lateral and septal ratios of early diastolic transmitral velocity to early diastolic tissue velocity (E/E’) at baseline and immediately after exercise was calculated. Exercise induced wall motion abnormalities were also calculated. Coronary angiography showed flow limiting CAD in 238 patients (66%). The exercise-induced changes of E/E’ average ratio had a sensitivity of 87.3% and a specificity of 75.2% for detection of flow limiting CAD, whereas myocardial scintigraphy showed 79.2% sensitivity and 80.1% specificity and exercise induced wall motion abnormalities had a sensitivity of 74.3% and a specificity of 66.9%. Likelihood ratio chi square showed an incremental value of the exercise-induced changes of E/E’ average ratio over regional perfusion technique (from 121.37 to 194.15, P < 0.001) and over wall motion abnormalities (from 57.03 to 146.50, P < 0.001). The exercise-induced change of the E/E’ average ratio detects flow limiting CAD in patients with chest pain and normal LV systolic function showing an incremental value over regional perfusion technique and wall motion abnormalities.     

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma

Asthma is considered a Th2 cell–associated disorder. Despite this, both the Th1 cell–associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ. In the present studies, we tested the hypothesis that IFN-γ regulates mast cell function in our model of chronic asthma. Engraftment of mast cell–deficient KitW(-sh/W-sh) mice, which develop markedly attenuated features of disease, with wild-type mast cells restored disease pathology in this model of chronic asthma. However, disease pathology was not fully restored by engraftment with either IFN-γ receptor 1–null (Ifngr1–/–) or Fcε receptor 1γ–null (Fcer1g–/–) mast cells. Additional analysis, including gene array studies, showed that mast cell expression of IFN-γR contributed to the development of many FcεRIγ-dependent and some FcεRIγ-independent features of disease in our model, including airway hyperresponsiveness, neutrophilic and eosinophilic inflammation, airway remodeling, and lung expression of several cytokines, chemokines, and markers of an alternatively activated macrophage response. These findings identify a previously unsuspected IFN-γ/mast cell axis in the pathology of chronic allergic inflammation of the airways in mice.     

The role of lopinavir/ritonavir (Kaletra®) in the management of HIV infected adults

As the HIV pandemic enters its third decade, more sophisticated and efficacious therapies are continually being developed. This article provides an in-depth review of the first coformulated boosted protease inhibitor available on the world market, lopinavir/ritonavir (Kaletra®). Included in this review is an overview of the current market place, the chemistry, pharmacokinetics, clinical efficacy and side-effect profile of lopinavir/ritonavir. In addition, an expert opinion and commentary on the clinical applications of this drug is provided.     

Topological investigation of the ethanol/water system and its implications for the mode of action of homœopathic medicines

Available molar excess volumes V^E and molar excess enthalpies H^E data at 250°C in the ethanol (E) and Water (W) system have been analysed in terms of a graphtheoretical approach to suggest that both E and W (in the pure state) exist as equilibrium mixture of various r-meric forms, that the particular configuration that they acquire in their mixture is dictated by their relative proportions. Although E undergoes hydrophobic interactions in W, specific interactions between E and W favour their mutual dissolution. The process of succussion (or trituration) of homœopathic drugs with E (or lactose) produces potentized E or W molecules that mimic the properties of the drugs. Homœopathic medicines have been postulated to operate via electron-transfer processes in the Central Nervous System. A mode of action of homœopathic medicines, consistent with the recent concepts of chemistry and physics is proposed to explain the scientific basis of the law of similars and some other characteristic pharmacologic actions of homœopathic medicines.     

Changes of expression of Fas and FasL protein in rats after renal ischemia/reperfusion injury

AIM：To study the relationship between the expression of Fas/FasL protein and apoptosis in rats after renal ischemia/reperfusion.METHODS:Establish the models of renal ischemia/reperfusion injury in rat and SABC immunohistochemical methods were used to detect the changes of expression of Fas/FasL protein.Pathomorphological changes in renal ischemia/reparfusion injury were observed.RESULTS:The expression of Fas/FasL proteins was negative in the sham operated group.Fas/FasL proteins were increased in renal in ischemia/reperfusion group,and gradually upregulated with the duration of ischemia or reperfusion and peaked at 72h of reperfusion.The expression of Fas/FasL proteins was stronger in 60min ischemia group than 30min ischemia group and they were mainly expressed in renal tubule.We observed local necrosis and inflammatory cells infiltration around infracted areain ischemia/reperfusion group by HE dyeing methods.And the necrosis area was mainly occurred around proximal convoluted tubule.CONCLUSIONS:These findings suggested that Fas/FasL proteins were over expressed after ischemia/reperfusion injury in rats renal.And Fas/FasL system was involved in the process of renal ischemia/reperfusion injury.     

Serial measurements of f/VT can predict extubation failure in patients with f/VT ≤ 105?

Objective

To evaluate is serial measurements of respiratory rate (frequency to tidal volume, f/VT) may predict extubation failure (EF) from mechanical ventilation in patients following a successful spontaneous breathing trial (SBT) with first measurement of f/V_T ≤ 105.

Design

Prospective cohort study.

Setting

Two medical-surgical intensive care units.

Patients

Seventy-three patients ventilated for more than 48 hours after successful SBT were extubated and followed up for postextubation respiratory distress during 48 hours.

Results

Extubation failure occurred in 16 (21.9%) of 73 patients. Factors such as age, sex, Apache II score, days on mechanical ventilation, respiratory failure cause, and hemodynamic or ventilatory parameters did not predict EF. Patients were evaluated during 120 minutes of SBT, and f/V_T was measured at the 1st minute (f/V_T−1), 30th minute (f/V_T−30), and 120th minute (f/V_T−120). The f/V_T−30 increased as compared with f/V_T−1 (79 ± 24 vs 68 ± 30, P = .01) but did not differ from f/V_T−120 (79 ± 44 vs 81 ± 42, P = .79). The f/V_T−1 was lower in successful extubation (ES) as compared with EF patients (62 ± 29 vs 82 ± 15, P = .01), and this difference was unchanged during the trial (f/V_T−30: ES [63 ± 22] vs EF [85 ± 24], P = .02; and f/V_T−120: ES [65 ± 26] vs EF [88 ± 20], P = .01)].

Conclusions

Serial f/V_T measurements during 120 minutes of SBT were unable to detect EF in patients following a successful SBT with initial f/V_T lower than 105.     

A randomised comparison of safety and efficacy of nevirapine vs. atazanavir/ritonavir combined with tenofovir/emtricitabine in treatment-naïve patients

Background: We report data from NEWART, a randomised phase 4 clinical trial comparing virologic efficacy and safety of nevirapine (NVP) vs. ritonavir‐boosted atazanavir (ATV/r) on a background of tenofovir/emtricitabine (TDF/FTC) in HIV‐1‐infected treatment‐naïve patients. This study enrolled patients according to CD4‐based initiation criteria for NVP (<250 cells/mm³ for women and <400 cells/mm³ for men), to reduce the likelihood of symptomatic hepatic events. NEWART was designed to support and confirm results from ARTEN, an international trial with similar design and study endpoints. Methods: A total of 152 patients were randomised 1 : 1 to open‐label NVP 200 mg twice daily or ATV/r (300/100 mg) once daily, plus once daily TDF/FTC (300/200 mg). All participants met CD4⁺ guidelines at entry. The primary endpoint for non‐inferiority was virologic response prior to and at week 48 (confirmed HIV plasma viral load <50 copies/ml, without rebound or change in ARVs). Safety data, including plasma lipids, were recorded throughout the study. Results: The primary endpoint was achieved in 46/75 (61.3%) and 50/77 (64.9%) of patients taking NVP and ATV/r, respectively. Frequency of adverse events (AEs) was similar between arms, with 88.0% of NVP‐treated patients and 94.8% of ATV/r‐treated patients experiencing at least one AE. Nine patients (12%) in each arm experienced an AE that led to discontinuation. At week 48, a significantly greater increase was seen in mean plasma HDL cholesterol (HDL‐C) in the NVP arm (9.6 mg/dl) vs. the ATV/r arm (3.5 mg/dl); p = 0.016. Also, total cholesterol (TC):HDL‐C ratio on‐treatment was ?0.38 and ?0.02 for the NVP and ATV/r arms, respectively (p = 0.038). Conclusions: Efficacy results were consistent with the ARTEN study demonstrating that NVP was non‐inferior to ATV/r when taken in combination with TDF/FTC. Rates of AEs were similar between the two arms, whereas HDL‐C increased and TC:HDL‐C decreased significantly more in patients taking NVP than ATV/r.     

Report of 2 indigenous cases of leprosy from a European country: use of polymerase chain reaction–restriction fragment length polymorphism analysis of hsp65 gene for identification of Mycobacterium leprae directly from a clinical sample

In this article, we report on 2 indigenous cases of leprosy detected in a European country. We also report on the use of polymerase chain reaction–restriction fragment length polymorphism analysis of hsp65 gene for rapid identification of Mycobacterium leprae directly from the clinical sample.     

Additional Value of FDG-PET/CT in Management of “Solitary” Liver Metastases: Preliminary Results of a Prospective Multicenter Study

Background and aim

The most common malignancy affecting the liver is metastasis from a wide variety of tumors, particularly those of gastrointestinal origin. Successful surgical removal of a solitary liver metastasis may significantly extend survival and optimal preoperative assessment in this regard is a mandatory prerequisite for proper patient selection. The addition of positron emission tomography/computed tomography (PET/CT) to other more conventional imaging procedures (e.g., ultrasound (US), CT, and magnetic resonance) has the potential to greatly improve the selection process by the combination of high-resolution anatomy afforded by CT directly combined with the functional scintigraphic map of intra- and extrahepatic lesions depicted by 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-PET. In this study, we assess the additional value of PET/CT in the management strategy of patients with solitary liver metastasis from colorectal and other cancers identified by conventional imaging methods.

Methods

We evaluated 43 consecutive patients (17 males, 26 females, mean age 53?±?6 years) with known solitary liver metastasis. This sample consisted of 18 patients with colorectal cancer, 15 with nonsmall cell lung cancer, six with breast carcinoma, and four ovarian cancers. In addition to contrast-enhanced CT and US, all patients were studied with FDG-PET/CT before surgery. PET/CT was performed within 3 weeks of the initial diagnosis and the scans were read by two experienced radiologists/nuclear medicine specialists blinded to the clinical data. A final diagnosis was obtained at surgery in 31 patients, by fine needle biopsy in five, and long-term clinical, biochemical, and follow-up imaging in seven patients.

Results

In 12 out of 43 patients (28%), PET/CT resulted in restaging disease and a change in therapy. Twenty-two of 31 patients with confirmed solitary liver lesions (71%) were disease-free, eight of 31 (26%) developed a new recurrence, and one of 31 (3%) died from disease progression over a 17?±?6-month follow-up interval. Nine of 12 patients (75%) with multiple metastases demonstrated by FDG-PET/CT were alive with disease and three of 12 (25%) deceased due to disease progression (p?<?0.01) over a 17?±?6-month follow-up interval.

Conclusion

The addition of FDG-PET/CT to the routine assessment of patients with liver metastasis has a significant impact on disease staging and selection of suitable candidates for solitary liver metastasis resection and outcome.