Discovery of novel benzimidazole derivatives as selective and reversible monoamine oxidase B inhibitors for Parkinson's disease treatment.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC50 value of 67.3 nM, comparable to safinamide (IC50 = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (Ki = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.

Comprehensive safety evaluation of a novel multitargeting compound XYY-CP1106: A candidate for Alzheimer's disease.

Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering the complexity of molecular mechanisms in AD pathology. In most pre-clinical studies, the effectiveness of these multi-targeted anti-AD drugs has been demonstrated but comprehensive safety assessments are lacking. Here, the safety evaluation of a novel multi-targeted candidate in AD (XYY-CP1106), characterized by its dual-property of iron chelation and monoamine oxidase B inhibition, was conducted by multifaceted analysis. Acute toxicity in mice was conducted to investigate the safety of oral administration and the maximum tolerated dose of the agent. In vitro Ames analysis, CHL chromosomal aberration analysis, and bone marrow micronucleus analysis were executed to evaluate the genotoxicity. A teratogenesis investigation in pregnant mice were meticulously performed to evaluate the teratogenesis of XYY-CP1106. Furthermore, a 90-day long-term toxicity analysis in rats was investigated to evaluate the cumulative toxicity after long-term administration. Strikingly, no toxic phenomena were found in all investigations, demonstrating relatively high safety profile of the candidate compound. The securing of safety heightened the translational significance of XYY-CP1106 as a novel multi-targeted anti-AD candidate, supporting the rationality of multitargeting strategy in the designs of smart anti-AD drugs.

miR-224-5p Attenuates Allergic Responses in Mice with Allergic Rhinitis by Modulating the Th1/Th2 Response.

Background: Allergic rhinitis (AR) is a common chronic respiratory disease that has become a global health problem. miRNAs play an important role in multiple immune and inflammatory diseases, including AR. In this work, the mechanism by which miR-224-5p regulates AR in vivo and in vitro was examined. Methods: Human nasal epithelial cells (HNEpCs) were used to establish an AR cell model induced by Der P1, and C57BL/6 mice were used to establish an AR animal model induced by OVA (ovalbumin). RT-qPCR was used to determine the level of miR-224-5p; western blot analysis was used to determine GATA3; ELISA was used to determine the levels of OVA-specific IgE, IFN-γ, IL-4, IL-5, and IL-13; flow cytometry was used to determine the differentiation of Th1 and Th2 cells; and HE and PAS staining was used to observe the histopathological alterations in the mouse nasal mucosa and spleen. Results: miR-224-5p was downregulated in nasal mucosa from mice with AR and an AR cell model. Overexpressed miR-224-5p can improve AR development and attenuate AR symptoms by regulating GATA3-mediated Th1/Th2 responses. Conclusion: miR-224-5p attenuates allergic reactions in mice with AR by regulating the Th1/Th2 response.

Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling.

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.

Ni-Electrocatalytic Enantioselective Doubly Decarboxylative C(sp3)-C(sp3) Cross Coupling.

The first examples of enantioselective doubly decarboxylative cross coupling are disclosed. Malonate half amides are smoothly coupled to a variety of primary carboxylic acids after formation of the corresponding redox-active esters under Ni-electrocatalytic conditions using a new chiral ligand based on PyBox, resulting in amides with α-alkylated stereocenters. The scope of the reaction is broad, tolerating numerous functional groups, and uniformly proceeds with high ee. Finally, the potential utility of this enantioselective radical-radical reductive cross coupling to simplify synthesis is demonstrated with numerous case studies.

STING pathway contributes to the prognosis of hepatocellular carcinoma and identification of prognostic gene signatures correlated to tumor microenvironment.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most malignant solid tumors worldwide. Recent evidence shows that the stimulator of interferon genes (STING) pathway is essential for anti-tumor immunity via inducing the production of downstream inflammatory cytokines. However, its impact on the prognosis and tumor microenvironment of HCC was still limited known. METHODS: We obtained gene expression profiles of HCC from GEO, TCGA, and ICGC databases, and immune-related genes (IRGs) from the ImmPort database. Multivariate Cox regression was performed to identify independent prognostic factors. Nomogram was established to predict survival probability for individual patients. Kaplan-Meier curve was used to evaluate the survival difference. Afterward, ESTIMATE, TISCH, and TIMER databases were combined to assess the immune cell infiltration. Furthermore, the qPCR, western blotting, and immunohistochemistry were done to evaluate gene expression, and in vitro cell models were built to determine cell migratory ability. RESULTS: We found that gene markers of NLRC3, STING1, TBK1, TRIM21, and XRCC6 within STING pathway were independent prognostic factors in HCC patients. Underlying the finding, a predictive nomogram was constructed in TCGA-training cohort and further validated in TCGA-all and ICGC datasets, showing credible performance. Experimentally, up-regulated TBK1 promotes the ability of HCC cell migration. Next, the survival-related immune-related co-expressed gene signatures (IRCGS) (VAV1, RHOA, and ZC3HAV1) were determined in HCC cohorts and their expression was verified in human HCC cells and clinical samples. Furthermore, survival-related IRCGS was associated with the infiltration of various immune cell subtypes in HCC, the transcriptional expression of prominent immune checkpoints, and immunotherapeutic response. CONCLUSION: Collectively, we constructed a novel prognostic nomogram model for predicting the survival probability of individual HCC patients. Moreover, an immune-related prognostic gene signature was determined. Both might function as potential therapeutic targets for HCC treatment in the future.

Gasdermin D-mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy.

Pyroptosis is a kind of programmed cell death primarily mediated by gasdermin D (GSDMD) and shown to regulate multiple diseases. However, its contribution to liver regeneration, a fine-tuned tissue repair process mediated primarily by hepatocytes after mass loss, remains unclear. Herein, we found that caspase-11/GSDMD-mediated pyroptosis was activated in regenerating liver after 70% partial hepatectomy. Impeding pyroptosis by deleting GSDMD significantly reduced liver injury and accelerated liver regeneration. Mechanistically, GSDMD deficiency up-regulates the activation of hepatocyte growth factor/c-Met and epidermal growth factor receptor mitogenic pathways at the initiation phase. Moreover, activin A and glypican 3 (GPC3), two terminators of liver regeneration, were inhibited when GSDMD was absent. In vitro study suggested the expressions of activin A and GPC3 were induced by interleukin (IL)-1ß and IL-18, whose maturations were regulated by GSDMD-mediated pyroptosis. Similarly, pharmacologically inhibiting GSDMD recapitulates these phenomena. Conclusion: This study characterizes the role of GSDMD-mediated pyroptosis in liver regeneration and lays the foundation for enhancing liver restoration by targeting GSDMD in liver patients with impaired regenerative capacity.

CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway.

The treatment of hepatocellular carcinoma (HCC) has been dominated by multikinase inhibitors for more than a decade. However, drug resistance can severely restrict the efficacy of these drugs. Using CRISPR/CAS9 genome library screening, we evaluated Kelch-like ECH-associated protein 1 (KEAP1) as a key regulator of sorafenib's susceptibility in HCC. We also investigated whether KEAP1's knockdown can stabilize nuclear factor (erythroid-derived 2)-like 2 (NRF2) protein levels that led to sorafenib's resistance, including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC's growth in vitro and in vivo. Furthermore, we clarified that fibroblast growth factor 21 (FGF21) is an important downstream regulator of NRF2 in HCC. Intriguingly, we observed that FGF21 bound to NRF2 through the C-terminus of FGF21, thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC. These findings, therefore, propose that targeting FGF21 is a promising strategy to combat HCC sorafenib's resistance.

Cobalt-Catalyzed Markovnikov-Selective Radical Hydroacylation of Unactivated Alkenes with Acylphosphonates.

Acylphosphonates having the 5,5-dimethyl-1,3,2-dioxophosphinanyl skeleton are developed as efficient intermolecular radical acylation reagents, which enable the cobalt-catalyzed Markovnikov hydroacylation of unactivated alkenes at room temperature under mild conditions. The protocol exhibits broad substrate scope and wide functional group compatibility, providing branched ketones in satisfactory yields. A mechanism involving the Co-H mediated hydrogen atom transfer and subsequent trapping of alkyl radicals by acylphosphonates is proposed.

Photothermal therapy with AuNRs and EGFRmAb-AuNRs inhibits subcutaneous transplantable hypopharyngeal tumors in nude mice.

The present study aimed to investigate the effects of photothermal therapy with gold nanorods (AuNRs) or epidermal growth factor receptor monoclonal antibody­conjugated AuNRs (EGFRmAb­AuNRs) on hypopharyngeal carcinoma (HC) in nude mice. In addition, the associated signaling pathways were explored. Briefly, a subcutaneous transplantable hypopharyngeal tumor model was established in nude mice injected with FaDu human HC cells. A total of 70 nude mice were randomly divided into seven groups, each of which received a different treatment. Mice were treated with AuNRs, locally or through intravenous injection, whereas EGFRmAb or EGFRmAb­AuNRs were only administered locally. Near infrared spectroscopy (NIR) was also applied for plasmonic photothermal therapy (PPTT). The growth curve and the inhibitory rate for tumor growth were used to evaluate the effects of each treatment. Flow cytometry and the terminal­deoxynucleotidyl transferase dUTP nick end labeling assay were adopted to detect apoptosis of cells in the transplanted tumors. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of target genes, respectively. Local treatment with AuNRs + NIR or EGFRmAb significantly inhibited tumor growth, and EGFRmAb conjugation further increased the inhibitory effects. Furthermore, there was a significant increase in apoptosis of tumor cells in the AuNRs + NIR, EGFRmAb and EGFRmAb­AuNRs + NIR groups; treatment with EGFRmAb­AuNRs + NIR induced the highest apoptotic effect. Mechanistic studies indicated that EGFRmAb­AuNRs + NIR may inhibit tumors through the AKT serine/threonine kinase (Akt) and DNA damage signaling pathways. In the AKT pathway, the mRNA and protein expression levels of phosphatase and tensin homolog were increased, whereas the expression levels of Akt and glycogen synthase kinase 3ß were decreased. In the DNA damage signaling pathway, the mRNA and protein expression levels of ATR serine/threonine kinase, checkpoint kinase 1 and p53 were enhanced, whereas phosphorylated­p53 protein expression was reduced. The present findings indicated that AuNRs + NIR inhibited HC tumor growth, and conjugating EGFRmAb to AuNRs further enhanced the inhibitory effects. EGFRmAb conjugation may increase the antitumor effects of AuNRs­induced PPTT by downregulating the phosphatidylinositol­3­kinase/Akt pathway and upregulating the DNA damage pathway. These findings may provide novel insights into tumor­targeting PPTT in vivo.

Photothermal treatment with EGFRmAb-AuNPs induces apoptosis in hypopharyngeal carcinoma cells via PI3K/AKT/mTOR and DNA damage response pathways.

Hypopharyngeal carcinoma (HC) is one of the most malignant tumors in the upper aerodigestive tract. Currently, there are no effective treatments for HC. Gold nanoparticles (AuNPs) are a promising tool that can be used for plasmonic photothermal therapy (PPTT), which refers to the use of electromagnetic radiation, most often in near infrared (NIR) region, for the treatment of various medical conditions including cancer. AuNPs have been proved to be a promising tool for NIR spectroscopy-mediated photothermal therapies. In this study, we chemically conjugated AuNPs with a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), a cell-surface receptor that is overexpressed in many cancers. We then assessed the effect of NIR photothermal treatment with the EGFRmAb-AuNPs in FaDu HC cells. Our data showed that nanoparticle conjugation with the EGFRmAb improved the specific targeting towards FaDu cells and reduced cytotoxicity towards normal (293 T) cells which do not overexpress the EGFR. A significant amount of our EGFRmAb-conjugated AuNPs could enter the nucleus. Moreover, the expression levels of double strand DNA break repair proteins, including p-ATR, p-CHK1, and p-CHK2 were increased following AuNPs treatment, indicating the presence of DNA damage. These findings suggest that the AuNPs can potentially disrupt genome integrity and induce apoptosis. In addition, EGFRmAb-AuNPs+NIR could induce FaDu cell apoptosis, accompanied by the inhibition of the PI3K/AKT/mTOR pathway and stimulation of DNA damage response. Based on these data, PPTT using the EGFRmAb-AuNPs could be a new promising treatment for HC.

Sex-Specific Response to Cardiac Resynchronization Therapy: Effect of Left Ventricular Size and QRS Duration in Left Bundle Branch Block.

OBJECTIVES: In this study, the authors sought to assess the impact of body and heart size on sex-specific cardiac resynchronization therapy (CRT) response rate, according to QRS duration (QRSd) as a continuum. BACKGROUND: Effects of CRT differ between sexes for any given QRSd. METHODS: New York Heart Association functional class III/IV patients with nonischemic cardiomyopathy and "true" left bundle branch block (LBBB) were evaluated. Left ventricular mass (LVM) and end-diastolic volume were measured echocardiographically. Positive response was defined by left ventricular ejection fraction (LVEF) improvement post-CRT. RESULTS: Among 130 patients (LVEF 19 ± 7.1%; QRSd 165 ± 20 ms; 55% female), CRT improved LVEF to 32 ± 14% (p < 0.001) during a median 2 years follow-up. Positive responses occurred in 103 of 130 (79%) (78% when QRSd <150 ms vs. 80% when QRSd ≥150 ms; p = 0.8). Body surface area (BSA), QRSd, and LVM were lower in women, but QRSd/LVM ratio greater (p < 0.0001). Sexes did not differ for pharmacotherapy and comorbidities, but female CRT response was greater: 90% (65 of 72) versus 66% (38 of 58) in males (p < 0.001). With QRSd as a continuum, the overall CRT-response relationship showed a progressive increase to plateau between 150 and 170 ms, then a decrease. Sex-specific differences were conspicuous: among females, a peak effect was observed between 135 and 150 ms, thereafter a decline, with the male response rate lower, but with a gradual increase as QRSd lengthened. Sex-specific differences were unaltered by BSA, but resolved with integration of LVM or end-diastolic volume. CONCLUSIONS: Sex differences in the QRSd-response relationship among CRT patients with LBBB were unexplained by application of strict LBBB criteria or by BSA, but resolved by QRSd normalization for heart size using LV mass or volume.

Routine venous thromboembolism screening after pneumonectomy: The more you look, the more you see.

OBJECTIVES: Symptomatic venous thromboembolism (VTE) after pneumonectomy is associated with poor prognosis. We describe a new care pathway for patients undergoing pneumonectomy in which asymptomatic lower-extremity VTE screening was performed to determine if it increases VTE detection and potentially decreases sequelae. METHODS: 112 patients underwent pneumonectomy from 2006 to 2013 at Cleveland Clinic and were enrolled in a care pathway that included VTE prophylaxis and routine, predischarge, lower-extremity VTE screening. These data were contrasted with a previously published cohort of 336 patients (1990-2001) who underwent pneumonectomy without routine VTE screening. RESULTS: 10 of 112 patients (8.9%) had VTE detected by screening before discharge. An additional 4 patients (3.6%) with a negative predischarge screen developed symptomatic VTE within 30 days. Six patients (5.4%) developed VTE after pneumonectomy beyond the first 30 days. Prevalence of in-hospital VTE in the screened cohort was significantly higher than that of the non-screened cohort (3.0%; P = .008). Similarly, VTE within 30 days in the screened cohort (13%) was significantly higher than in the nonscreened cohort (5.0%; P = .007). In both cohorts, a peak was observed approximately 6 days after pneumonectomy and plateaued after 30 days. The presence of a VTE portended worse long-term survival: 66% at 1 year versus 85% for those not developing a VTE. CONCLUSIONS: Prevalence of VTE after pneumonectomy is higher than previously thought. The risk of developing a VTE peaks at 6 days after pneumonectomy, and remains increased until 30 days, suggesting a need for additional screening or longer prophylaxis.

Sequentially Updated Discharge Model for Optimizing Hospital Resource Use and Surgical Patients' Satisfaction.

BACKGROUND: The ability to estimate cardiac surgical patients' length of stay (LOS) and discharge to a continuing care facility (nonhome discharge) may allow earlier discharge planning and optimal use of limited hospital resources. We developed a sequentially updated tool for postoperative discharge planning. METHODS: Using preoperative, intraoperative, and postoperative day (POD) 2 and POD 4 variables, we created and validated a model to predict early discharge (less than 4 days), standard discharge (5 to 8 days), delayed discharge (9 to 14 days), late discharge (more than 15 days), and nonhome discharge. RESULTS: When predicting LOS, model accuracy using preoperative variables alone had a C-statistic of 0.80, but improved with sequential addition of intraoperative and POD 2 (0.87) and POD 4 variables (0.89). At 48 hours, the strongest predictors of longer LOS were higher preoperative creatinine, elevated blood urea nitrogen, lower postoperative albumin, atrial fibrillation, and longer intensive care unit stay. On POD 4, the strongest predictors were red blood cell transfusion, lower postoperative albumin, white blood cell transfusion, longer intensive care unit stay, and readmission to the intensive care unit. For nonhome discharge, however, preoperative variables alone produced a highly predictive model (C-statistic 0.88), and sequential addition of intraoperative and POD 2 (C-statistic 0.91) and POD 4 data (C-statistic 0.90) did not significantly improve it. CONCLUSIONS: This sequentially updated model of postoperative LOS can be used by the discharge planning team to identify both patients imminently ready for discharge and patients with a high likelihood of nonhome discharge, with the goals of decreasing unnecessary hospital days, managing patients' expectations, and engaging patients early in the discharge process.

Increasing Disadvantage of "Watchful Waiting" for Repairing Degenerative Mitral Valve Disease.

BACKGROUND: Successful durable repair of severe degenerative mitral regurgitation with low operative mortality encourages intervention in asymptomatic patients rather than "watchful waiting." Our objectives were to assess trends in patient characteristics, timing of intervention, and evolving surgical techniques at a high-volume center, and determine effects of these changes on outcomes after mitral valve (MV) repair over a 25-year period. METHODS: From January 1, 1985, to January 1, 2011, 5,902 patients underwent isolated repair (with or without tricuspid repair for functional regurgitation) for degenerative MV disease at Cleveland Clinic. For illustration, the experience is presented in 3 eras: 1985 to 1997 (era 1, n = 1,184), 1997 to 2005 (era 2, n = 2,400), and 2005 to 2011 (era 3, n = 2,318). RESULTS: In era 3, more patients were asymptomatic on presentation (44% in New York Heart Association [NYHA] class I vs 25% in era 1), with less heart failure (11% vs 29%) and atrial fibrillation (9.9% vs 23%). Full sternotomy decreased from era 1 (n = 1,100/93%) to era 2 (n = 602/25%) (era 3, n = 717/31%), and robotic surgery emerged (n = 577/25%) in era 3. Median length of stay shortened (era 1 = 7 days, era 2 = 5.9 days, era 3 = 5.2 days, p < 0.0001), and in-hospital mortality remained low (era 1 = 5/0.42%, era 2 = 5/0.21%, era 3 = 1/0.043%); 0.73% overall required reoperation on the repaired valve before discharge, and 97% had 0 to 1+ regurgitation at discharge. CONCLUSIONS: Treatment trends over 25 years reveal that rather than watchful waiting, a more aggressive approach to degenerative MV disease, with earlier intervention for severe regurgitation in asymptomatic patients and less invasive operative techniques, is successful, safe, and effective.

Distal aortic interventions after repair of ascending dissection: the argument for a more aggressive approach.

OBJECTIVE: Survivors of ascending aortic dissection repair frequently require downstream aortic interventions. Because of a paucity of data, we assessed early and long-term outcomes, and risk factors, of these distal procedures. METHODS: From January 1993 to January 2011, 305 patients underwent 429 distal aortic interventions after acute type A (95% DeBakey type I) dissection repair performed 3.8 years earlier (median); 11% of interventions used an endovascular approach. Maximum aortic size was 5.9 ± 1.3 cm. Median follow-up was 3.6 years. RESULTS: Hospital mortality was 6.1%. Risk factors included graft infection, concomitant coronary artery bypass grafting, combined open arch and descending procedures, and lower distal anastomotic site. Within 10 years, the probability of patients undergoing a reintervention was 38%, with a cumulative incidence of 55 per 100 patients; however, 40 (9.3%) were stage-II elephant trunks. Patients with larger aortic diameters distal to the initial repair, and a stage-I elephant trunk, were more likely to undergo distal interventions. Survival was 65% at 10 years. Higher body mass index, a longer time between reinterventions, graft infection, combined open arch and descending procedures, and lower distal anastomosis sites were risk factors. The extent of aorta replaced was not associated with increased morbidity or mortality, unless it involved a combined open arch and descending aorta procedure. CONCLUSIONS: Distal interventions after ascending aortic dissection repair are feasible, but they are associated with early morbidity and subsequent reinterventions. Rigorous follow-up with early reintervention is important for improving short- and long-term outcomes. An extended hybrid endovascular repair for initial dissection warrants study.

[Determination of polysaccharides content of Gentiana farreri from different producing areas based on anthrone-sulfuric acid method].

Study a method for the detemination of the content of polysaccharides in Gentiana farreri, and analysis of the content of polysaccharides from different producing areas. The results showed that using the anthrone-sulfuric acid method, simple operation, accurate result. Sample was measured at 620 nm absorbance after anthrone-sulfuric acid color, at this wavelength, solution absorption and glucose showed a good linear relationship; The linearity was in the range of 0.01-0.07 g x L(-1) (r = 0.996 7). The recovery rate was 99.41%, with RSD of 2.0%. Considering the experimental conditions, to determine the solid-liquid ratio 1:60, extracting time 50 min, concentration of ethanol 80%. The mass fraction of polysaccharides was the highest to reached 0.743% in G. farreri from Gansu Xiahe. This experiment has laid a good foundation for further study on G. farreri.

Probability and magnitude of response to cardiac resynchronization therapy according to QRS duration and gender in nonischemic cardiomyopathy and LBBB.

BACKGROUND: QRS morphology and QRS duration (QRSd) determine cardiac resynchronization therapy (CRT) candidate selection but criteria require refinement. OBJECTIVE: To assess CRT effect according to QRSd, treated by dichotomization vs a continuous function, and modulation by gender. METHODS: Patients selected were those with New York Heart Association class III/IV heart failure and with left bundle branch block and nonischemic cardiomyopathy (to test "pure" CRT effect) with pre- and postimplant echocardiographic evaluations. Positive response was defined as increased left ventricular ejection fraction (LVEF) post-CRT. RESULTS: In 212 patients (LVEF 19% ± 7.1%; QRSd 160 ± 23 ms; 105 (49.5%) women), CRT increased LVEF to 30% ± 15% (P < .001) during a median follow-up of 2 years. Positive response occurred in 150 of 212 (71%) patients. Genders did not differ for QRSd, pharmacotherapy, and comorbidities, but response to CRT among women was greater: incidence 84% (88 of 105) in women vs 58% (62 of 107) in men (P < .001); increase in LVEF 15% ± 14% vs 7.2% ± 13%, respectively (P < .001). Overall, the response rate was 58% when QRSd <150 ms and 76% when QRSd ≥150 ms (P = .009). This probability differed between genders: 86% in women vs 36% in men (P < .001) when QRSd <150 ms and 83% vs 69%, respectively, when QRSd ≥150 ms (P = .05). Thus, female response rates remained high whether QRSd was <150 ms or ≥150 ms (86% vs 83%; P = .77) but differed in men (36% vs 69%; P < .001). With QRSd as a continuum, the CRT-response relationship was nonlinear and significantly different between genders. Female superiority at shorter QRSd inverted with prolongation >180 ms. CONCLUSION: The QRSd-CRT response relationship in patients with heart failure and with left bundle branch block and nonischemic cardiomyopathy is better described by a sex-specific continuous function and not by dichotomization by 150 ms, which excludes a large proportion of women with potentially favorable outcome.

Contributors to diffusion impairment in HIV-infected persons.

Abnormal diffusing capacity is common in HIV-infected individuals, including never smokers. Aetiologies for diffusing capacity impairment in HIV are not understood, particularly in those without a history of cigarette smoking. Our study was a cross-sectional analysis of 158 HIV-infected individuals without acute respiratory symptoms or infection with the aim to determine associations between a diffusing capacity of the lung for carbon monoxide (D(LCO)) % predicted and participant demographics, pulmonary spirometric measures (forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity), radiographic emphysema (fraction of lung voxels < -950 Hounsfield units), pulmonary vascular/cardiovascular disease (echocardiographic tricuspid regurgitant jet velocity, N-terminal pro-brain natriuretic peptide) and airway inflammation (induced sputum cell counts), stratified by history of smoking. The mean D(LCO) was 65.9% predicted, and 55 (34.8%) participants had a significantly reduced D(LCO) (<60% predicted). Lower D(LCO) % predicted in ever-smokers was associated with lower post-bronchodilator FEV1 % predicted (p<0.001) and greater radiographic emphysema (p=0.001). In never-smokers, mean±SD D(LCO) was 72.7±13.4% predicted, and D(LCO) correlated with post-bronchodilator FEV1 (p=0.02), sputum neutrophils (p=0.03) and sputum lymphocytes (p=0.009), but not radiographic emphysema. Airway obstruction, emphysema and inflammation influence D(LCO) in HIV. Never-smokers may have a unique phenotype of diffusing capacity impairment. The interaction of multiple factors may account for the pervasive nature of diffusing capacity impairment in HIV infection.

The bidirectional relationship between body mass index and treatment outcome in adolescents with treatment-resistant depression.

OBJECTIVE: Depression and obesity are associated, but the impact of obesity on depression treatment outcome, or, conversely, the impact of treatment on body mass index (BMI) in depressed adolescents has not been reported. In this article, we examine the bidirectional relationships between BMI and treatment response in adolescents with treatment-resistant depression. METHOD: Participants in the Treatment of Selective Serotonin Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) study had height and weight assessed at baseline, weekly for the first 6 weeks, biweekly for the next 6 weeks, and monthly from weeks 12 through 24. The impact of baseline BMI as a predictor and moderator of treatment response was assessed. In addition, participants' changes in BMI were assessed as a function of specific treatment assignment and treatment response. RESULTS: Participants assigned to SSRIs had a greater increase in BMI-for-age-sex z-score and weight than did those assigned to venlafaxine. Post-hoc, those treated with paroxetine or citalopram had the biggest increases in BMI, relative to fluoxetine or venlafaxine. Overweight or obesity was neither a predictor nor a moderator of treatment outcome, nor of subsequent BMI change. CONCLUSIONS: Overweight status does not appear to affect treatment response in adolescents with resistant depression. The successful treatment of depression does not appear to favorably affect weight or BMI. Fluoxetine and venlafaxine are less likely to cause an increase in BMI than paroxetine or citalopram.