Do alternative tobacco products induce less adverse respiratory risk than cigarettes?

RATIONALE: Due to the relatively short existence of alternative tobacco products, gaps exist in our current understanding of their long-term respiratory health effects. We therefore undertook the first-ever side-by-side comparison of the impact of chronic inhalation of aerosols emitted from electronic cigarettes (EC) and heated tobacco products (HTP), and combustible cigarettes (CC) smoke. OBJECTIVES: To evaluate the potential differential effects of alternative tobacco products on lung inflammatory responses and efficacy of vaccination in comparison to CC. METHODS: Mice were exposed to emissions from EC, HTP, CC, or air for 8 weeks. BAL and lung tissue were analyzed for markers of inflammation, lung damage, and oxidative stress. Another group was exposed for 12 weeks and vaccinated and challenged with a bacterial respiratory infection. Antibody titers in BAL and sera and pulmonary bacterial clearance were assessed. MAIN RESULTS: EC- and HTP-aerosols significantly augmented lung immune cell infiltrates equivalent to that achieved following CC-exposure. HTP and CC significantly increased neutrophil numbers compared to EC. All products augmented numbers of B cells, T cells, and pro-inflammatory IL17A+ T cells in the lungs. Decreased lung antioxidant activity and lung epithelial and endothelial damage was induced by all products. EC and HTP differentially augmented inflammatory cytokines/chemokines in the BAL. Generation of immunity following vaccination was impaired by EC and HTP but to a lesser extent than CC, with a CC > HTP > EC hierarchy of suppression of pulmonary bacterial clearance. CONCLUSIONS: HTP and EC-aerosols induced a proinflammatory pulmonary microenvironment, lung damage, and suppressed efficacy of vaccination.

Does the urinary microbiome profile change after treatment of bladder cancer?

INTRODUCTION: We sought to investigate the change in the urinary microbiome profile after transurethral resection of bladder tumor (TURBT). METHODS: Urine specimens were collected from consecutive patients with bladder cancer. Patients were divided into those with bladder tumors ("Tumor group": de novo tumors or recurrent/progressed after TURBT ± intravesical therapy) versus those without evidence of recurrence after treatment "No Recurrent Tumor group". Samples were analyzed using 16S rRNA sequencing. Alteration in the urinary microbiome was described in terms of alpha (diversity within a sample measured by Observed, Chao, Shannon, and Simpson indices), beta diversities (diversity among different samples measured by Brady Curtis Diversity index), and differential abundance of bacteria at the genus level. Analyses were adjusted for gender, method of preservation (frozen vs preservative), and method of collection (mid-stream vs. catheter). RESULTS: Sixty-eight samples were analyzed (42 in "Tumor" vs 26 in "No Recurrent Tumor" groups). The median age was 70 years (IQR 64-74) and 85% were males. All patients in the "No Recurrent Tumor" group had non-muscle invasive bladder cancer and 85% received BCG compared to 69% and 43% for the "Tumor" group, respectively. There was no significant difference in alpha diversity (p > 0.05). Beta diversity was significantly different (p = 0.04). Veillonella and Bifidobacterium were more abundant in the "Tumor" group (> 2FC, p = 0.0002), while Escherichia-Shigella (> 2FC, p = 0.0002) and Helococcus (> 2FC, p = 0.0008) were more abundant in the "No Recurrent Tumor" group. CONCLUSION: Bladder cancer patients with no recurrence and/or progression exhibited a different urinary microbiome profile compared to those with tumors.

The Urinary Microbiome and Bladder Cancer.

Bladder cancer is the 10th most common cancer worldwide. Approximately 75% of patients with bladder cancer will present with non-muscle invasive disease. Patients are usually treated with transurethral resection of bladder tumor (TURBT), in addition to adjuvant intravesical therapy (chemotherapy or anti-cancer immunotherapy with Bacillus Calmette Guerin- BCG) for those at intermediate-risk and high-risk of recurrence and progression. For many years, urine has been thought to be "sterile"; however, advanced microbiological and molecular techniques, including 16S ribosomal RNA (16S rRNA) sequencing, have negated that previous paradigm and confirmed the presence of a urinary microbiome. The urinary microbiome has been associated with several urological diseases, including interstitial cystitis, urgency urinary incontinence, neurogenic bladder dysfunction, and others. More recently, many reports are emerging about the role of the urinary microbiome in urothelial carcinogenesis, including gender disparity in bladder cancer and responses to treatments. The urinary microbiome may serve as a biomarker that can help with risk stratification as well as prediction of the response to intravesical therapies. However, the microbiome literature has been hampered by the lack of a unified standardized methodology for sample collection, type, preservation, processing, as well as bioinformatics analysis. Herein we describe and critique the literature on the association between urinary microbiome and bladder cancer and highlight some of the future directions.

Not all vaping is the same: differential pulmonary effects of vaping cannabidiol versus nicotine.

RATIONALE: Vaping has become a popular method of inhaling various psychoactive substances. While evaluating respiratory effects of vaping have primarily focused on nicotine-containing products, cannabidiol (CBD)-vaping is increasingly becoming popular. It currently remains unknown whether the health effects of vaping nicotine and cannabinoids are similar. OBJECTIVES: This study compares side by side the pulmonary effects of acute inhalation of vaporised CBD versus nicotine. METHODS: In vivo inhalation study in mice and in vitro cytotoxicity experiments with human cells were performed to assess the pulmonary damage-inducing effects of CBD or nicotine aerosols emitted from vaping devices. MEASUREMENTS AND MAIN RESULTS: Pulmonary inflammation in mice was scored by histology, flow cytometry, and quantifying levels of proinflammatory cytokines and chemokines. Lung damage was assessed by histology, measurement of myeloperoxidase activity and neutrophil elastase levels in the bronchoalveolar lavage fluid and lung tissue. Lung epithelial/endothelial integrity was assessed by quantifying BAL protein levels, albumin leak and pulmonary FITC-dextran leak. Oxidative stress was determined by measuring the antioxidant potential in the BAL and lungs. The cytotoxic effects of CBD and nicotine aerosols on human neutrophils and human small airway epithelial cells were evaluated using in vitro air-liquid interface system. Inhalation of CBD aerosol resulted in greater inflammatory changes, more severe lung damage and higher oxidative stress compared with nicotine. CBD aerosol also showed higher toxicity to human cells compared with nicotine. CONCLUSIONS: Vaping of CBD induces a potent inflammatory response and leads to more pathological changes associated with lung injury than vaping of nicotine.

Decursin inhibits EGFR-ERK1/2 signaling axis in advanced human prostate carcinoma cells.

We have shown that decursin, a coumarin compound, induces cell cycle arrest and apoptosis in human prostate cancer cells (PCa); however, its molecular mechanisms are largely unexplored. We studied the mechanisms associated with its anticancer activity in advanced human prostate carcinoma cells. We found that decursin inhibited epidermal growth factor receptor (EGFR) signaling by inhibiting its activating phosphorylation at tyrosine 1068 residue in DU145 and 22Rv1 cells. This inhibition of EGFR was associated with the downregulation of ERK1/2 phosphorylation. Both EGFR and ERK1/2 are known to be deregulated/activated in many human malignancies. Consistent with our earlier study, decursin (25-100 µM) treatment for 24-72 h inhibited DU145 cell proliferation by 49%-87% (p < 0.001) which was associated with strong G1 phase arrest and cell death. It also decreased (p < 0.001) the number of surviving colonies. Decursin moderately increased the expression of Rb-related proteins p107 and p130 but decreased the levels of E2F family transcription factors including E2F-3, E2F-4 and E2F-5. Further, decursin strongly inhibited the growth of androgen-dependent prostate carcinoma 22Rv1 cells from 61% to 79% (p < 0.001) and arrested these cells at G1 phase via induction of cyclin-dependent kinase inhibitor p27/Kip1 and downregulation of CDK2 and CDK4 protein expression. Additionally, EGFR inhibitor erlotinib- and EGF ligand-modulated EGFR activation validated EGFR signaling as a target of decursin-mediated cell growth inhibition and cytotoxicity. Decursin decreased EGF ligand-induced phosphorylation of EGFR (Y-1068) as well as activation of its downstream mediator, ERK1/2. Furthermore, inhibitory targeting of EGFR-ERK1/2 axis by combinatorial treatment of decursin and erlotinib further sensitized DU145 cells for the decursin-induced growth inhibition and cell death. Overall, these findings strongly suggest that anticancer efficacy of decursin against human PCa involves inhibitory targeting of EGFR-ERK1/2 signaling axis, a pathway constitutively active in advanced PCa.

Hypertensive Phenotypes and Pattern of Ambulatory Blood Pressure in Patients of Diabetes Mellitus of Kashmir Valley.

Background: Patients of diabetes mellitus (DM) with hypertension (HTN) have a fourfold increased risk of cardiovascular disease (CVD) as compared to normotensive nondiabetic controls. However, many patients of DM who are normotensive or have controlled blood pressure on office BP measurement (OBPM) may assume that they do not have increased risk of CVD but may be having HTN or uncontrolled blood pressure on ambulatory blood pressure monitoring (ABPM). Study Design Objective: A cross-sectional observational study to compare OBPM with ABPM and thus predict various hypertensive phenotypes like masked hypertension (MH) and white coat hypertension and pattern of blood pressure in diabetic patients of our population. Materials and Methods: Two hundred patients of DM with or without HTN were included in this study. The cases were subjected to detailed history, clinical examination, OBPM, and ABPM. Results: Out of 200 patients of DM, 32 were normotensives, 46 were hypertensives controlled on antihypertensive treatment, 22 were hypertensives not on anti-hypertensive treatment, and 100 were hypertensives uncontrolled on anti-hypertensive treatment. Among 32 normotensive diabetics, 17 (53%) patients had MH on ABPM. Out of these 32 normotensive patients, 7 (21.8%) had isolated nocturnal hypertension, 3 (9.3%) had isolated day-time HTN (IDH) and 7 (21.8%) had day-time and nocturnal HTN (DNH). Patients with MH had higher BMI, an observation that was statistically significant. Non-dipping pattern was found in 53% of patients of masked HTN. Out of 46 hypertensive diabetics with controlled OBPM on antihypertensive treatment, 26 (56.5%) had masked effect or masked uncontrolled hypertension on ABPM. Out of 22 diabetics with treatment naïve HTN, 7 (32%) were found to have white coat hypertension on ABPM. Fifteen (15%) patients out of 100 hypertensive diabetics with uncontrolled OBPM despite on anti-hypertensive were found to have white coat effect on ABPM. Patients with white coat effect had higher body mass index an observation that was statistically significant (p = 0.039). Non-dipping pattern was significantly associated with longer duration of diabetes (≥ 120 months), retinopathy and neuropathy. Conclusion: To rely exclusively on OBPM to diagnose HTN and monitor blood pressure may underestimate the CVD risk especially in diabetics. ABPM is a tool that may not only help clinicians in starting anti-HTN treatment perspicuously, but also may help in avoiding unnecessary anti-hypertensive treatment and/or withdrawing anti-hypertensive treatment as indicated and thus avoiding credulity.

A case report of the Hoffa fracture and a review of literature.

The Hoffa fracture is an uncommon fracture. There is a lot of confusion about its diagnosis and management with several conflicting reports in literature. We reported a 25-year-old patient with non-union of Hoffa fracture, and meanwhile tried to develop an algorithm-based treatment for Hoffa fractures. A systematic review of the available literature was performed. Medline, Embase, the Cochrane Library and PubMed were searched for relevant articles. Fifty-five articles were reviewed, and the clinical knowledge base was summarized. The understanding of the mechanism of trauma has become more nuanced. The literature has also evolved to classify the fracture with the purpose of surgical management in mind. This can be used to plan approach and fixation with preservation of blood supply. Classification can also prognosticate the outcomes in Hoffa fracture.

Effect of automobile exhaust on pulmonary function tests among traffic police personnel in Kashmir valley.

Background: Automobile exhaust is an important cause of air pollution, which is a leading health menace and is growing perpetually. Traffic police personnel are exposed to automobile exhaust more than anyone else, and the resulting lung involvement may be asymptomatic. Materials and Methods: This observational cross-sectional study was conducted among 136 traffic police personnel, aged 18-59 years, working for more than 6 months in the traffic police of Kashmir valley. In addition, 140 age- and sex-matched, healthy unexposed Kashmiri's served as controls. Pulmonary functions were measured by RMS Helios 401 PC based spirometer. Results: Sixteen (11.2%) out of 136 traffic police personnel had abnormal pulmonary function test (PFT) as compared to 5 (3.6%) out of 140 controls. Traffic police personnel's had significantly declined forced expiratory volume in 1 s (FEV 1) and forced vital capacity. Eight (5.8%) had obstructive, 7 (5.1%) had restrictive, and 1 (0.7%) traffic police personnel had mixed pattern on PFT. Duration of exposure to automobile exhaust of more than 10 years was significantly associated with pulmonary function abnormality (P = 0.038). Conclusion: Air pollution due to automobile exhaust may be the factor responsible for pulmonary function abnormalities in traffic police personnel. Besides protective measures during duty hours, traffic police personnel should be subjected to periodic assessment of their lung functions.

Clinical and Laboratory Profile of Dengue in Kashmir Valley.

BACKGROUND: As majority of cases of dengue are associated with thrombocytopenia, it is indispensable to study clinical presentation, biochemical parameters and outcome of dengue fever in a population known with low platelet count. METHODOLOGY: A prospective observational study was conducted from September 2016 to August 2017that included forty NS-1 antigen (IgM) Dengue positive patients. Clinical features, laboratory parameters and outcome of dengue patients were noted. RESULTS: All the patients had travel history outside the valley into the neighbouring state. Most patients (70%) had duration of stay between 21-30 days in dengue prevalent areas before catching the illness. Duration of symptoms was between 4-9 days in majority of patients (92.5%). Most patients (85%) presented in months of September to November. The three most common symptoms were fever (100%), chills (92.5%) and headache (80%). The most common laboratory features were thrombocytopenia (97.5%), leukopenia (87.5%), transaminitis (87.5%) and raised LDH (32.5%). One patient developed Dengue Hemorrhagic Fever (DHF). All patients recovered completely. CONCLUSION: DF in Kashmir is seen exclusively in travellers to other states especially in the monsoon season.DF in Kashmiri patients has a favourable outcome despite low baseline platelet count. DHF is uncommon in Kashmiri population.

AT-RvD1 Mitigates Secondhand Smoke-Exacerbated Pulmonary Inflammation and Restores Secondhand Smoke-Suppressed Antibacterial Immunity.

Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable Haemophilus influenzae (NTHI). Some groups of mice were treated with aspirin-triggered resolvin D1 (AT-RvD1) during the latter half of the smoke exposure period or during a period of smoking cessation and before infection. Treatment with AT-RvD1 markedly reduced the recruitment of neutrophils, macrophages, and T cells in lung tissue and bronchoalveolar lavage and levels of proinflammatory cytokines in the bronchoalveolar lavage. Additionally, treatment with AT-RvD1 improved Ab titers against the NTHI outer membrane lipoprotein Ag P6 following infection. Furthermore, treatment with AT-RvD1 prior to classically adjuvanted immunization with P6 increased Ag-specific Ab titers, resulting in rapid clearance of NTHI from the lungs after acute challenge. Collectively, we have demonstrated that AT-RvD1 potently reverses the detrimental effects of SHS on pulmonary inflammation and immunity and thus could be beneficial in reducing lung injury associated with smoke exposure and infection.

Acute Effects of Heated Tobacco Product (IQOS) Aerosol Inhalation on Lung Tissue Damage and Inflammatory Changes in the Lungs.

INTRODUCTION: Emerging heated tobacco products (HTPs) were designed to reduce exposure to toxicants from cigarette smoke (CS) by avoiding burning tobacco and instead heating tobacco. We studied the effects of short-term inhalation of aerosols emitted from HTP called IQOS, on lung damage and immune-cell recruitment to the lungs in mice. METHODS: Numerous markers of lung damage and inflammation including albumin and lung immune-cell infiltrates, proinflammatory cytokines, and chemokines were quantified in lungs and bronchoalveolar (BAL) fluid from IQOS, CS, or air-exposed (negative control) mice. RESULTS: Importantly, as a surrogate marker of lung epithelial-cell damage, we detected significantly increased levels of albumin in the BAL fluid of both HTP- and CS-exposed mice compared with negative controls. Total numbers of leukocytes infiltrating the lungs were equivalent following both IQOS aerosols and CS inhalation and significantly increased compared with air-exposed controls. We also observed significantly increased numbers of CD4+IL-17A+ T cells, a marker of a T-cell immune response, in both groups compared with air controls; however, numbers were the highest following CS exposure. Finally, the numbers of CD4+RORγt+ T cells, an inflammatory T-cell subtype expressing the transcription factor that is essential for promoting differentiation into proinflammatory Th17 cells, were significantly augmented in both groups compared with air-exposed controls. Levels of several cytokines in BAL were significantly elevated, reflecting a proinflammatory milieu. CONCLUSIONS: Our study demonstrates that short-term inhalation of aerosols from IQOS generates damage and proinflammatory changes in the lung that are substantially similar to that elicited by CS exposure. IMPLICATIONS: Exposure of mice to IQOS, one of the candidate modified-risk tobacco products, induces inflammatory immune-cell accumulation in the lungs and augments the levels of proinflammatory cytokines and chemokines in the BAL fluid. Such an exacerbated pulmonary proinflammatory microenvironment is associated with lung epithelial-cell damage in IQOS-exposed mice, suggesting a potential association with the impairment of lung function.

Specialized Proresolving Mediators Overcome Immune Suppression Induced by Exposure to Secondhand Smoke.

Tobacco smoke exposure is associated with multiple diseases including, respiratory diseases like asthma and chronic obstructive pulmonary disease. Tobacco smoke is a potent inflammatory trigger and is immunosuppressive, contributing to increased susceptibility to pulmonary infections in smokers, ex-smokers, and vulnerable populations exposed to secondhand smoke. Tobacco smoke exposure also reduces vaccine efficacy. Therefore, mitigating the immunosuppressive effects of chronic smoke exposure and improving the efficacy of vaccinations in individuals exposed to tobacco smoke, is a critical unmet clinical problem. We hypothesized that specialized proresolving mediators (SPMs), a class of immune regulators promoting resolution of inflammation, without being immunosuppressive, and enhancing B cell Ab responses, could reverse the immunosuppressive effects resulting from tobacco smoke exposure. We exposed mice to secondhand smoke for 8 wk, followed by a period of smoke exposure cessation, and the mice were immunized with the P6 lipoprotein from nontypeable Haemophilus influenzae, using 17-HDHA and aspirin-triggered-resolvin D1 (AT-RvD1) as adjuvants. 17-HDHA and AT-RvD1 used as adjuvants resulted in elevated serum and bronchoalveolar lavage levels of anti-P6-specific IgG and IgA that were protective, with immunized mice exhibiting more rapid bacterial clearance upon challenge, reduced pulmonary immune cell infiltrates, reduced production of proinflammatory cytokines, and less lung-epithelial cell damage. Furthermore, the treatment of mice with AT-RvD1 during a period of smoke-cessation further enhanced the efficacy of SPM-adjuvanted P6 vaccination. Overall, SPMs show promise as novel vaccine adjuvants with the ability to overcome the tobacco smoke-induced immunosuppressive effects.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Isolated Renal Artery Dissection: A Systematic Review of Case Reports.

Isolated renal artery dissection (IRAD) is a rare and often unrecognized clinical entity, with a paucity of data on its epidemiology and management. We extracted 129 cases of IRAD from the medical literature between 1972 and 2016. IRAD as a result of an extended dissection from the aorta and splanchnic or mesenteric arteries was excluded. The mean age of presentation was 42.7±12.9 years, with a male predominance (79%). Abdominal pain (75.9%) was the most common presenting symptom. Etiology was more likely to be spontaneous (76%) than traumatic (12%), iatrogenic (9%), or drug-induced (1.5%). The most common risk factors were hypertension (28.7%), fibromuscular dysplasia (8.5%), and Ehlers-Danlos syndrome (5.4%). Unilateral renal artery dissection (right 45.5%, left 40.5%) was more frequent than bilateral (14%). More than half (56.6%) of the cohort were managed medically (blood pressure control and /or anticoagulation). Of those who underwent intervention, endovascular stenting or embolization (35%) was utilized more frequently than nephrectomy or bypass (21%). Computed tomography (CT) and magnetic resonance angiography (MRA) have the highest diagnostic sensitivity (91% and 93%, respectively) as compared to ultrasonography (27%). A high degree of clinical suspicion is required to diagnose IRAD. CT and MRI have a higher diagnostic sensitivity. As compared to invasive management, conservative management has comparable outcomes.

Update on complications and their management during transradial cardiac catheterization.

Introduction: Transradial artery access (TRA) was introduced in 1989 and has been universally used as an alternative approach to the traditional transfemoral access (TFA). Complications of TRA include asymptomatic and less likely symptomatic radial artery occlusion, nonocclusive radial artery injury, radial artery spasm, radial arterial perforation, radial artery pseudoaneurysm, arteriovenous fistula, granuloma formation, access-site bleeding, nerve damage, complex regional pain syndrome along with other rare complications.Areas covered: A literature search was performed using MedLine, PubMed, and Google Scholar (dating to 1 May 2019). Authors reviewed all articles related to transradial artery catheterization, its complications, as well as novel techniques for their management. The article provides insight on the incidence, risk factors, and prevention of such complications along with a description of usual and newer techniques to decrease morbidity.Expert opinion: With increasing experience, TRA complication rate is decreasing and new very uncommon complications are being described. A 'radial first' approach should be implemented in all catheterization laboratories and a physician's familiarity with minor and major complications is a must. Distal radial artery access through the snuff box might be the preferred site of accessing the radial artery and further studies will be needed to prove its superiority to the current access site.

Cytochrome c Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer.

Although African-American (AA) patients with prostate cancer tend to develop greater therapeutic resistance and faster prostate cancer recurrence compared with Caucasian-American (CA) men, the molecular mechanisms of this racial prostate cancer disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and prostate cancer aggressiveness in AA men. In AA prostate cancer cells, decreased nuclear accumulation of nuclear respiration factor 1 (Nrf1) and its subsequent loss of binding to the cytochrome c promoter mediated cytochrome c deficiency. The activation of cellular Myc (c-Myc) and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacologic inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to cytochrome c promoter, cytochrome c expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA prostate cancer cells contributed to defective cytochrome c release and increased resistance to apoptosis, indicating that restoration of cytochrome c alone may be insufficient to induce effective apoptosis. Cytochrome c deficiency promoted the acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas cytochrome c restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA prostate cancer cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring cytochrome c may overcome therapeutic resistance and prostate cancer aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in prostate cancer racial disparity. SIGNIFICANCE: Mechanistic insights on prostate cancer health disparity among American men provide novel approaches to restore mitochondrial function, which can address therapeutic resistance and aggressiveness in African-American men with prostate cancer.

In-hospital low-cost custom made VAC: Effective method for reducing infection in late presenting Open lower limb fractures in overburdened Indian hospitals.

BACKGROUND: Open fractures are still associated with troublesome rates of infection. Thorough debridement irrigation and antibiotic cover are of paramount importance irrespective of the fixation method. VAC therapy is a well known method of accelerating the wound healing and decreasing the infection in non healing ulcers. The main drawback of VAC therapy is requirement of a special equipment and high cost. We in our hospital are using low cost custom made VAC therapy for non healing ulcers in lower socio-economic people and have seen extremely good results in wound healing and infection control. OBJECTIVE: To evaluate the role of pre operative low cost custom made VAC therapy as an adjunctive method of decreasing the rates of infection in late presenting lower limb open fractures. METHODS: A retrospective study of 26 open femur and tibia fractures for which low cost VAC therapy was used between January 2014 to January 2017. RESULTS: 2 out of 26 cases (7.4%) ended up with deep infection. CONCLUSION: Pre operative in-hospital low cost custom made VAC therapy is a useful adjunctive method of reducing infection rates in late presenting open fractures.

Validation and comparison of non-hyperemic pressure reserve to fractional flow reserve for assessment of coronary artery stenosis: A real world study.

BACKGROUND: The visual interpretation of an angiographic stenosis may not always reflect the physiological significance of a lesion. Fractional Flow Reserve (FFR) is a reliable index to assess the significance of a lesion during hyperemia. However, there are pitfalls that can lead to significant misinterpretation and adverse events. OBJECTIVE: This study sought to evaluate the accuracy and predictability of the non-hyperaemic pressure ratio (NHPR) without hyperemic stimuli, compared to hyperemic FFR. METHODS: We conducted a retrospective, multicenter study of 700 patients who underwent a pressure recording during coronary angiography using NHPR and FFR measurements. Receiver operator characteristic (ROC) curve was constructed. NHPR sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy test were calculated. The most accurate NHPR cutoff was determined. RESULTS: Of the 700 procedures, 449 cases were included. By ROC analysis, the optimal cut-point for NHPR was 0.93 to predict an FFR of ≤0.80 with an overall diagnostic accuracy of 78.84%. The sensitivity of this NHPR cutoff was 85.06%, specificity of 75.59%, PPV of 64.53% and a NPV of 90.65%. There was an overall accuracy of about 80% for predicting non-hyperemic index (FFR < 0.80) using a cutoff of NHPR ≤ 0.93. CONCLUSIONS: The use of NHPR can be considered in certain clinical scenarios where adenosine is contraindicated or there are other challenges; with the knowledge that hyperemia might be necessary if there is any high clinical suspicion as it still remains the reference standard for diagnostic certainty.

Secondhand Smoke Induces Inflammation and Impairs Immunity to Respiratory Infections.

Despite advocacy to reduce smoking-related diseases, >1 billion people worldwide continue to smoke. Smoking is immunosuppressive and an important etiological factor in the development of several human disorders including respiratory diseases like chronic obstructive pulmonary disease. However, there is a critical gap in the knowledge of the role of secondhand smoke (SHS) in inflammation and immunity. We therefore studied the influence of SHS on pulmonary inflammation and immune responses to respiratory infection by nontypeable Haemophilus influenzae (NTHI) recurrently found in chronic obstructive pulmonary disease patients. Chronic SHS-exposed mice were chronically infected with NTHI and pulmonary inflammation was evaluated by histology. Immune cell numbers and cytokines were measured by flow cytometry and ELISA, respectively. Chronic SHS exposure impaired NTHI P6 Ag-specific B and T cell responses following chronic NTHI infection as measured by ELISPOT assays, reduced the production of Abs in serum and bronchoalveolar lavage, and enhanced albumin leak into the bronchoalveolar lavage as determined by ELISA. Histopathological examination of lungs revealed lymphocytic accumulation surrounding airways and bronchovasculature following chronic SHS exposure and chronic infection. Chronic SHS exposure enhanced the levels of inflammatory cytokines IL-17A, IL-6, IL-1ß, and TNF-α in the lungs, and impaired the generation of adaptive immunity following either chronic infection or P6 vaccination. Chronic SHS exposure diminished bacterial clearance from the lungs after acute NTHI challenge, whereas P6 vaccination improved clearance equivalent to the level seen in air-exposed, non-vaccinated mice. Our study provides unequivocal evidence that SHS exposure has long-term detrimental effects on the pulmonary inflammatory microenvironment and immunity to infection and vaccination.