Direct Catalytic Asymmetric Mannich-Type Reaction of α- and ß-Fluorinated Amides.

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and ß-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and ß-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched ß-amino acids for medicinal chemistry.

Phosphine-Catalyzed ß,γ-Umpolung Domino Reaction of Allenic Esters: Facile Synthesis of Tetrahydrobenzofuranones Bearing a Chiral Tetrasubstituted Stereogenic Carbon Center.

An enantio-, diastereo-, regio-, and chemoselective phosphine-catalyzed ß,γ-umpolung domino reaction of allenic esters with dienones has been developed for the first time. The designed sequence, involving oxy-Michael and Rauhut-Currier reactions, produced highly functionalized tetrahydrobenzofuranones, bearing a chiral tetrasubstituted stereogenic center, in up to 96 % ee.

Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have emerged as major global health threats. WHO recommends contact investigation in close contacts of patients with MDR and XDR tuberculosis. We aimed to assess the burden of tuberculosis disease in household contacts of such patients. METHODS: We undertook a retrospective cohort study of household contacts of patients treated for MDR or XDR tuberculosis in Lima, Peru, in 1996-2003. The primary outcome was active tuberculosis in household contacts at the time the index patient began MDR tuberculosis treatment and during the 4-year follow-up. We examined whether the occurrence of active tuberculosis in the household contacts differed by resistance pattern of the index patient: either MDR or XDR tuberculosis. FINDINGS: 693 households of index patients with MDR tuberculosis were enrolled in the study. In 48 households, the Mycobacterium tuberculosis isolate from the index patient was XDR. Of the 4503 household contacts, 117 (2·60%) had active tuberculosis at the time the index patient began MDR tuberculosis treatment-there was no difference in prevalence between XDR and MDR tuberculosis households. During the 4-year follow-up, 242 contacts developed active tuberculosis-the frequency of active tuberculosis was nearly two times higher in contacts of patients with XDR tuberculosis than it was in contacts of patients with MDR tuberculosis (hazard ratio 1·88, 95% CI 1·10-3·21). In the 359 contacts with active tuberculosis, 142 (40%) had had isolates tested for resistance against first-line drugs, of whom 129 (90·9%, 95% CI 85·0-94·6) had MDR tuberculosis. INTERPRETATION: In view of the high risk of disease recorded in household contacts of patients with MDR or XDR tuberculosis, tuberculosis programmes should implement systematic household contact investigations for all patients identified as having MDR or XDR tuberculosis. If shown to have active tuberculosis, these household contacts should be suspected as having MDR tuberculosis until proven otherwise. FUNDING: The Charles H Hood Foundation, the David Rockefeller Center for Latin American Studies at Harvard University, and the Bill & Melinda Gates Foundation.

Multiple introductions of multidrug-resistant tuberculosis into households, Lima, Peru.

Two cases of multidrug-resistant tuberculosis (MDR TB) in a household are assumed to reflect within-household transmission. However, in high-incidence areas of MDR TB, secondary cases may arise through exposure to MDR TB in the community. To estimate the frequency of multiple introductions of MDR TB into households, we used spoligotyping and 24-loci mycobacterial interspersed repetitive unit- variable number tandem repeats to classify isolates from 101 households in Lima, Peru, in which >1 MDR TB patient received treatment during 1996-2004. We found different MDR TB strains in >10% of households. Alternate approaches for classifying matching strains produced estimates of multiple introductions in <38% of households. At least 4% of MDR TB patients were reinfected by a second strain of MDR Mycobacterium tuberculosis. These findings suggest that community exposure to MDR TB in Lima occurs frequently. Rapid drug sensitivity testing of strains from household contacts of known MDR TB patients is needed to identify optimal treatment regimens.

Matching social support to individual needs: a community-based intervention to improve HIV treatment adherence in a resource-poor setting.

From December 2005 to April 2007, we enrolled 60 adults starting antiretroviral therapy (ART) in Lima, Peru to receive community-based accompaniment with supervised antiretrovirals (CASA), consisting of 12 months of DOT-HAART, as well as microfinance assistance and/or psychosocial support group according to individuals' need. We matched 60 controls from a neighboring district, and assessed final clinical and psychosocial outcomes at 24 months. CASA support was associated with higher rates of virologic suppression and lower mortality. A comprehensive, tailored adherence intervention in the form of community-based DOT-HAART and matched economic and psychosocial support is both feasible and effective for certain individuals in resource-poor settings.

Risk factors and mortality associated with default from multidrug-resistant tuberculosis treatment.

BACKGROUND: Completing treatment for multidrug-resistant (MDR) tuberculosis (TB) may be more challenging than completing first-line TB therapy, especially in resource-poor settings. The objectives of this study were to (1) identify risk factors for default from MDR TB therapy (defined as prolonged treatment interruption), (2) quantify mortality among patients who default from treatment, and (3) identify risk factors for death after default from treatment. METHODS: We performed a retrospective chart review to identify risk factors for default from MDR TB therapy and conducted home visits to assess mortality among patients who defaulted from such therapy. RESULTS: Sixty-seven (10.0%) of 671 patients defaulted from MDR TB therapy. The median time to treatment default was 438 days (interquartile range, 152-710 days), and 27 (40.3%) of the 67 patients who defaulted from treatment had culture-positive sputum at the time of default. Substance use (hazard ratio, 2.96; 95% confidence interval, 1.56-5.62; P = .001), substandard housing conditions (hazard ratio, 1.83; 95% confidence interval, 1.07-3.11; P = .03), later year of enrollment (hazard ratio, 1.62, 95% confidence interval, 1.09-2.41; P = .02), and health district (P = .02) predicted default from therapy in a multivariable analysis. Severe adverse events did not predict default from therapy. Forty-seven (70.1%) of 67 patients who defaulted from therapy were successfully traced; of these, 25 (53.2%) had died. Poor bacteriologic response, <1 year of treatment at the time of default, low education level, and diagnosis with a psychiatric disorder significantly predicted death after default in a multivariable analysis. CONCLUSIONS: The proportion of patients who defaulted from MDR TB treatment was relatively low. The large proportion of patients who had culture-positive sputum at the time of treatment default underscores the public health importance of minimizing treatment default. Prognosis for patients who defaulted from therapy was poor. Interventions aimed at preventing treatment default may reduce TB-related mortality.

Deficiencia de hierro en enfermedad renal crónica

Contexto: la deficiencia de hierro es un trastorno frecuentemente observado en pacientes con enfermedad renal crónica (ERC), sobre todo en estadios avanzados. Su presencia se asocia a una mayor morbilidad y mortalidad. La deficiencia de hierro puede ser absoluta o funcional. La deficiencia absoluta se refiere a una ausencia o una reducción de las reservas de hierro, mientras que la deficiencia funcional se define por la presencia de depósitos de hierro adecuados pero con una disponibilidad insuficiente de hierro para su incorporación en los precursores eritroides. Varios factores de riesgo contribuyen a la deficiencia absoluta y funcional de hierro en ERC, incluyendo pérdidas hemáticas, absorción alterada de hierro e inflamación crónica. Objetivo: con esta revisión narrativa se pretende presentar las definiciones, los aspectos fisiopatológicos, los criterios diagnósticos y las medidas terapéuticas en el paciente con diagnóstico de ERC con deficiencia de hierro. Metodología: se realizó una revisión no sistemática de la literatura en la base de datos PubMed, incluyendo además las guías internacionales más utilizadas que abordan el tema de deficiencia de hierro en ERC. Resultados: se incluyeron un total de 30 referencias bibliográficas. La deficiencia de hierro puede ser absoluta o relativa y el déficit absoluto de hierro se produce con valores de ferritina 100 mcg/l, pero con una TSAT < 20 %. El tratamiento del déficit absoluto consta de reposición de hierro oral o endovenoso y en pacientes que aún no reciben diálisis, se puede hacer una prueba terapéutica con hierro oral, de no haber respuesta se optará por hierro endovenoso, mientras que en pacientes que sí reciben diálisis, la medida ideal es el hierro endovenoso, preferiblemente en preparaciones que permitan esquemas de altas dosis y bajas frecuencias de administración. Las metas propuestas por las distintas guías presentan variaciones entre 500 y 700 mcg/l de ferritina. Conclusiones: el déficit de hierro debe buscarse activamente en pacientes con ERC, ya que su presencia y la falta de intervención conlleva a un incremento en los desenlaces adversos. La terapia con hierro es el pilar del tratamiento y la elección del agente a utilizar dependerá de las características individuales del paciente y de la disponibilidad de las preparaciones de hierro oral o endovenoso.

Background: Iron deficiency is a disorder frequently observed in patients with chronic kidney disease (CKD), especially in advanced stages. Its presence is associated with increased morbidity and mortality. Iron deficiency can be absolute or functional. Absolute deficiency refers to absent or reduced iron stores, while functional deficiency is defined by the presence of adequate iron stores but insufficient iron availability for incorporation into erythroid precursors. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood fi, impaired iron absorption, and chronic inflammation. Purpose: With this narrative review, it is intended to present the details, pathophysiological aspects, diagnostic criteria and therapeutic options in patients diagnosed with chronic kidney disease with iron deficiency. Methodology: A non-systematic review of the fi ron ra was carried out, in the PubMed database, also including the most used international guidelines that address the issue fi ron deficiency in chronic kidney disease. Results: A total of 30 bibliographical references were included. Iron deficiency can be absolute or relative. The absolute iron deficiency occurs with ferritin values 100 mcg/l but with a TSAT <20 % Treatment of absolute deficiency consists of oral or intravenous iron replacement. In a patient who is not yet receiving dialysis, a therapeutic trial with oral iron can be done, if there is no response, intravenous iron will be chosen. In patients receiving dialysis, the ideal measure is intravenous iron, preferably in preparations that allow high-dose schemes and low frequencies of administration. The goals proposed by the different guidelines present variations between 500 and 700 mcg/l d ferritin. Conclusions: iron deficiency should be actively sought in patients with CKD, since its presence and lack of intervention leads to an increase in adverse outcomes. Iron therapy is the mainstay of treatment; the choice of the agent to be used depends on the individual characteristics of the patient and the availability of oral or intravenous iron preparations.

Multifunctional catalysis: stereoselective construction of α-methylidene-γ-lactams via an amidation/Rauhut-Currier sequence.

Mixing of acryloylchloride, dienone 2, N,N-diisopropylethylamine with chiral organocatalyst 5a, which could simultaneously act as Brønsted and Lewis base catalysts, led to a one-pot amidation/Rauhut-Currier sequence, affording α-methylidene-γ-lactams 4. Catalyst 5a could be recovered and reused by acid/base extraction without any loss of catalytic activity in the stepwise protocol.

Direct Catalytic Asymmetric Aldol Reaction of α-Alkylamides.

A catalytic asymmetric aldol reaction directly employing amides as latent enolates has remained elusive because of the resistance of amides to enolization. A direct aldol reaction of α-alkylamides without any electron-withdrawing group harnessed by specific activation of 7-azaindoline amides under soft Lewis acid/Brønsted base cooperative catalysis is reported. Diastereo- and enantioselective coupling with ynals and aromatic aldehydes as well as divergent functional group interconversion of the amide provided expeditious access to a variety of aliphatic and aromatic chiral building blocks.

Direct Catalytic Asymmetric Mannich-Type Reaction of Alkylamides.

Direct enolate formation coupled with subsequent enantioselective C-C bond formation remains a topic of intense interest in asymmetric catalysis. This methodology is achieved even with low acidic amides without an electron-withdrawing group at the α-position in the context of a Mannich-type reaction. Acetate-, propionate-, and butyrate-type 7-azaindoline amides served as enolate precursors to afford the desired Mannich adducts with high stereoselectivity, and ligand-enabled diastereo-divergency provided access to both anti/syn diastereomers. The facile transformation of the amide moiety ensures the synthetic utility of the Mannich adducts.

Facile regio- and stereoselective metal-free synthesis of all-carbon tetrasubstituted alkenes bearing a C(sp3)-F unit via dehydroxyfluorination of Morita-Baylis-Hillman (MBH) adducts.

Highly E-selective all-carbon tetrasubstituted alkenes with a C(sp(3))-F unit have been synthesized through a dehydroxyfluorination of Morita-Baylis-Hillman (MBH) adducts which can be readily prepared from α,ß-unsaturated carbonyl compounds and α-keto esters. A variety of subsequent transformations afforded monofluoromethyl substituted heterocycles in high yields.

Organocatalyzed formal [2 + 2] cycloaddition of ketimines with allenoates: facile access to azetidines with a chiral tetrasubstituted carbon stereogenic center.

An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 + 2] cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and high enantioselectivities.

Vanadium-catalyzed enantioselective Friedel-Crafts-type reactions.

Vanadium-mediated enantioselective Friedel-Crafts (FC)-type reactions were established using the dinuclear vanadium complex (R(a),S,S)-1a. The vanadium complex promoted the FC-type reaction of imines with 2-naphthols or indoles to give corresponding adducts with high enantioselectivities.

P-chirogenic organocatalysts: application to the aza-Morita-Baylis-Hillman (aza-MBH) reaction of ketimines.

The P-chirogenic organocatalysts were found to promote the enantioselective aza-Morita-Baylis-Hillman reaction of ketimines derived from acyclic α-keto esters. In the P-chirogenic organocatalyzed aza-MBH reactions, α,α-disubstituted α-amino acid derivatives were obtained in high yields with high enantioselectivities (up to 97% ee).

Microfinance: a general overview and implications for impoverished individuals living with HIV/AIDS.

Microfinance among people living with HIV/AIDS (PLWHA) faces some opposition and remains understudied. This literature review examines microfinance's evolution and impact on a variety of social and health indicators and its emerging implementation as a primary prevention tool for HIV and economic intervention for PLWHA. There is an abundance of literature supporting the apparent utility of microfinance. However, our understanding of the subject remains clouded by the heterogeneity and methodological limitations of existing impact studies, and access limitations to microfinance curbs our understanding of microfinance for this population. Existing literature suggests PLWHA could attain economic stability from microfinance and achieve successful repayment rates in some settings. The precarious socioeconomic and health issues of PLWHA pose unique challenges to minimizing loan default risk. Carefully-designed clinical studies are needed to assess whether PLWHA can be as successful with microfinance as healthy individuals.

Correlación entre factor de crecimiento insulínico tipo 1 (IGF-1), citoquinas proinflamatorias y activación neurohumoral en pacientes con isuficiencia cardíaca crónica avanzada / Correlation of insulin like growth factor (IGF-1), cytokines and neurohumoral activation in patiens with advanced congestive heart failure

Hemos demostrado previamente que la actividad del eje hormona de crecimiento (GH) y su mediador activo, el factor de crecimiento insulínico tipo 1 (IGF-1) se encuentra disminuido en pacientes (pts) con insuficiencia cardíaca crónica (ICC). Por otra parte, se ha reportado que otras moléculas biológicamente activas, las citoquinas, se encuentran aumentadas en pts con ICC avanzada. Es posible que estas alteraciones neurohumorales contribuyan al compromiso del estado general y a un mayor deterioro de la función ventricular izquierda en estos pts. El objetivo del presente estudio fue evaluar si existe correlación entre la actividad del eje GH-IGF- 1, niveles de citoquinas proinflamatorias como el factor de necrosis tumoral (TNF) e interleuquína 6 (IL-6), y noradrenalina en reposo y ejercicio (NAD rep-NAD ex) en pts con ICC avanzada. Se estudiaron en forma prospectiva 10 pts con ICC por cardiopatía dilatada o isquémica. Se determinó consumo de 02 máximo (V02 max), Fracción de eyección (FE) radiolisotópica y niveles sóricos de GH e IGF- 1 (técnica IRMA), catecolaminas plasmáticas en reposo y en ejercicio máximo (NAD replex) (técnica RIA) y TNF e IL-6 (técnica ELISA). El análisis estadístico se realizó mediante regresión lineal Los resultados se expresaron como promedio k desviación estándar. La FE promedio del grupo fue de 17 por ciento ñ 4 por ciento y el V02 máx promedio de 15,9 ñ 3,9 ml/kg/min. LA GH fue de 3,4 ñ 4,55 ng/ml; IGF- 1 de 177,1 ñ 69,4 ng/ml, NAD rep 612,9 ñ 407,3 pg/ml y NAD ex de 4250 ñ 2620 pg/ml. El TNF del grupo fue de 1,2 ñ 1,4 pg/ml y la IL-6 de 4,4 ñ 3,55 pg/ml. Hubo correlación estadísticamente significativa entre el Logaritmo (log) IGF- 1 y Log NADex (r=-0, 66 p=0, 03 ), Log IGF- 1 y Log TNF(r=-0, 65p=0, 04)e IL-6 y NADex (r=0, 781 p=0,0l). Nuestro estudio demuestra por primera vez una correlación entre el aumento de la actividad simpática (NAD ex) y la menor actividad del eje GH-IGF- 1 en pts con ICC avanzada. Al mismo tiempo, confirma que también existe una correlación entre la actividad simpática exagerada y el aumento de citoquinas proinflamatorias en pts con ICC avanzada