Maca (Lepidium meyenii Walp.) inhibits HIV-1 infection through the activity of thiadiazole alkaloids in viral integration.

ETHNOPHARMACOLOGY RELEVANCE: Lepidium meyenii Walp. (maca) has been traditionally used for centuries in the Central Andes region both as food and as medicine. In the last decades, its fertility enhancer properties have gained importance, with the majority of the scientific literature related to this topic. However, other traditional uses are less known as metabolic or infectious diseases. AIM OF THE STUDY: The main purpose of this study is to investigate the anti-infectious activity of L. meyenii, specifically in HIV-1 infection. There are previous reports of the transcriptional related activity of L. meyenii extracts in human T lymphocytes via transcription factors as NF-κB. Since T lymphocytes are the main target of HIV-1 infection and NF-κB is strongly involved in HIV-1 transcription, L. meyenii could display antiviral activity. MATERIAL AND METHODS: Chromatography and spectroscopy techniques were used to isolate and identify the compounds in the active extracts. An antiviral assay system based on recombinant viruses was used to evaluate the anti-HIV activity. Cell toxicity was tested for all the extracts and compounds. Viral entry was studied using VSV-HIV chimera viruses and reverse transcription and viral integration were studied by qPCR of viral DNA in infected cells. Finally, viral transcription was studied in primary lymphocytes transfected with HIV-1 or NF-κB luciferase reporter plasmids. RESULTS: n-Hexane extracts of purple maca displayed anti-HIV activity in an in vitro assay. A bioassay-guided fractionation led to the identification of three thiadiazole alkaloids with antiviral activity. All the compounds were able to inhibit HIV infection of MT-2 cell lines and primary lymphocytes (PBMCs) with IC50 values in the low micromolar range. The mechanism of action differs between the three compounds: one of them showed activity on viral entry, and all the three compounds inhibited viral integration at low concentrations. Remarkably, none of the compounds inhibited reverse transcription or viral transcription. CONCLUSIONS: n-Hexane extracts of the purple ecotype of L. meyenii inhibit HIV-1 infection in vitro and three active thiadiazole alkaloids were isolated acting mainly on viral integration and viral entry.

Stent en una fístula sistémico-pulmonar de Blalock-Taussig modificada en un adulto paliado con atresia tricúspide con estenosis infundibular pulmonar crítica / Stenting of a modified Blalock-Taussig shunt in an adult with palliated tricuspid atresia and critical pulmonary stenosis

Resumen: Los adultos con cardiopatía congénita compleja, con fisiología univentricular y flujo pulmonar disminuido, constituyen un reto terapéutico. Muchos de ellos reciben tratamiento paliativo con fístula sistémico-pulmonar desde la etapa pediátrica. Dicha fístula puede presentar oclusión o estenosis y ocasionar deterioro de la capacidad funcional y clínica. Colocar una nueva fístula sistémico-pulmonar a través de una cirugía se considera de alto riesgo, por lo que el uso de stents a través de cateterismo cardíaco surge como una opción que ha tenido buenos resultados. Se describe el caso de un adulto con atresia tricúspide con fístula sistémico-pulmonar en la etapa pediátrica, quien acudió al servicio de urgencias por deterioro de su clase funcional y desaturación en aire ambiente de hasta un 64%; en la tomografía cardíaca se evidenció estenosis del tercio distal de la fístula sistémico-pulmonar, por lo que se decidió colocar, mediante cateterismo cardíaco intervencionista, dos stents (Express LD vascular 6 x 37 mm y 6 x 27 mm), luego de lo cual la saturación sistémica fue del 75%, por lo que se consideró exitosa la colocación de los dispositivos. La oclusión de estas fístulas es una complicación habitual, que genera disminución de la perfusión pulmonar con los subsecuentes síntomas respiratorios, disminución de la saturación y la oxigenación, cianosis y acidosis metabólica, y puede generar un evento que amenaza la vida si se presenta de manera aguda. La recanalización transcatéter de una fístula sistémico-pulmonar con stent es una alternativa adecuada para evitar un riesgo quirúrgico y arroja resultados óptimos.

Abstract: Adults with complex congenital heart disease with univentricular physiology and decreased in the pulmonary flow constitute a therapeutic challenge, many of these patients are palliated with modified Blalock-Taussig shunt (mBTS). The mBTS can develop occlusion or stenosis over time with deterioration of functional class and poor exercise tolerance. Dysfunction of a mBTS is a life-threatening situation requiring urgent therapy. A new surgical palliation is a high-risk procedure, so stenting a mBTS can be an alternative. We report a 29-year-old female with tricuspid atresia and pulmonary infundibular stenosis palliated with mBTS with progressive cyanosis (oxygen saturation of 54%) and dyspnea; computed tomography revealed a stenosed mBTS, and an interventional percutaneous approach was made. The stenting of the mBTS was made with two stents (Express LD vascular 6 x 37 mm and 6 x 27 mm). Oxygen saturation post-procedure increase to 70-75%. Occlusion of these shunts are a common major complication, leading to a decrease in pulmonary perfusion with subsequent respiratory symptoms, low saturation and oxygenation, cyanosis, metabolic acidosis and can generate a life-threatening event if it occurs acutely. Stent implantation into a previous mBTS through cardiac catheterization can be an alternative to shunt operation in patients with cyanotic congenital heart disease having a good long-term results.

Role of serendipity in the discovery of classical antidepressant drugs: Applying operational criteria and patterns of discovery.

The role played by serendipity in the origin of modern psychopharmacology has proven to be controversial in scientific literature. In its original meaning (Walpole), serendipity refers to discoveries made through a combination of accidents and sagacity. We have implemented an operational definition of serendipity based on finding something unexpected or unintended, regardless of the systematic process that led to the accidental observation, and we have established four different patterns of serendipitous attributability. In this paper, we have analyzed the role of serendipity in the discovery and development of classical antidepressant drugs, tricyclic antidepressants and monoamine oxidase inhibitors as well as heterocyclic, "atypical" or "second generation" antidepressants. The discovery of the antidepressant properties of imipramine and iproniazid, the prototypes of tricyclic antidepressants and monoamine oxidase inhibitors, respectively, fits the mixed type II pattern; initial serendipitous discoveries (imipramine was an antipsychotic and iproniazid was an anti-tuberculosis agent) led secondarily to non-serendipitous discoveries. But the other components of these two families of drugs were developed specifically as antidepressants, modifying the chemical structure of the series leaders, thereby allowing all of them to be included in the type IV pattern, characterized by the complete absence of serendipity. Among the heterocyclic drugs, mianserin (originally developed as an antihistamine) also falls into the type II pattern.

Diferencias en los parámetros lineales del balance autonómico basal entre estudiantes de medicina y atletas juveniles de béisbol / Differences in linear parameters of the basal autonomic balance between medical students and young baseball players

RESUMEN Introducción: La modulación autonómica cardiovascular puede ser considerada como una herramienta útil en la determinación del estado fisiológico de la interacción entre los sistemas nervioso autónomo y cardiovascular. Objetivo: Determinar las diferencias en los parámetros lineales del balance autonómico basal entre estudiantes de medicina y atletas juveniles de béisbol. Método: Se realizó un estudio analítico de tipo transversal en el Laboratorio de Ciencias Básicas Biomédicas de la Facultad Nº. 1 de la Universidad de Ciencias Médicas de Santiago de Cuba. Universo y muestra de 36 individuos (Grupo 1: 18 atletas juveniles de béisbol de alto rendimiento, Grupo 2: 18 estudiantes de medicina). Los datos fueron recolectados mediante de polígrafo PowerLab de 8 canales, y fueron procesados usando el software Kubios® versión 3.0.4 Premium. Resultados: Existieron diferencias significativas en los valores de pNN50 (p=0,009), índice de estrés (stress index [p=0,044]), y en los índices parasimpático (p=0,005) y simpático (p=0,001) entre estudiantes y atletas. La capacidad discriminatoria del índice parasimpático para asociarse con la mejor forma física de los atletas fue buena (área bajo la curva 0,784). El punto de corte óptimo por encima del cual el índice parasimpático se asocia al grupo de los atletas, quedó establecido en 0,57. Conclusiones: El índice parasimpático se asoció con el grupo de atletas, lo que evidencia el predominio vagal en la modulación de la actividad cardíaca en los sujetos de este grupo.

ABSTRACT Introduction: Cardiovascular autonomic modulation can be considered a useful tool in determining the physiological state of the interaction between the autonomic nervous system and the cardiovascular system. Objective: To determine the differences in linear parameters of the basal autonomic balance between medical students and young baseball players. Method: A cross-sectional analytical study was carried out in the Biomedical Basic Sciences Laboratory, Faculty No.1, of the Universidad de Ciencias Médicas in Santiago de Cuba. The population and sample consisted of 36 individuals (Group 1: 18 high-performance young baseball athletes, Group 2: 18 medical students). Data was collected using an 8-channel PowerLab polygraph and it was processed using the Kubios® Software version 3.0.4 Premium. Results: There were significant differences in the values between students and athletes: pNN50 (p=0.009), stress index (p=0.044) and in parasympathetic (p=0.005) and sympathetic (p=0.001) indexes. The discriminatory ability of the parasympathetic index to be associated with the best physical fitness of the athletes was good (area under the curve 0.784). The optimum cut-off point above which the parasympathetic index is associated with the group of athletes was set at 0.57. Conclusions: The parasympathetic index was associated with the group of athletes, showing the vagal predominance in the modulation of cardiac activity in the individuals belonging to this group.

Improved diabetes control among low-income Mexican Americans through community-clinical interventions: results of an RCT.

INTRODUCTION: This randomized controlled trial investigated community-clinical intervention strategies for a Mexican American population who had not demonstrated control of their diabetes. We tested a control program (Salud y Vida 1.0) supporting diabetes management versus an enhanced version (Salud y Vida 2.0) for reductions in HbA1c at 12 months. RESEARCH DESIGN AND METHODS: Adults with uncontrolled diabetes (n=353) were enrolled if they had an HbA1c≥9.0% during a program or doctor's visit between 6 and 36 months of their receipt of SyV 1.0 services, were patients at one of two clinics in local counties, and had an HbA1c≥8.0% at SyV 2.0 baseline enrollment. The control and intervention arms were coordinated by community health workers and the intervention arm included the control program enhanced with medication therapy management; behavioral health services; peer-led support groups; and additional community-based lifestyle programs also open to the family. RESULTS: At 12 months, both study arms improved HbA1c (mean, (CI), Control (-0.47 (-0.74 to -0.20)) and intervention (-0.48 (-0.76 to -0.19)). The intervention group maintained HbA1c levels after month 6, whereas control group HbA1c levels slightly increased (adjusted mean from 9.83% at month 6%-9.90% at month 12). Also, HbA1c was examined by level of participant engagement. The high engagement group showed a decreasing trend over the study period, while control and lower engagement groups failed to maintain HbA1c levels at month 12. CONCLUSIONS: Improved HbA1c was found among a population that had not demonstrated diabetes management prior; however, mean HbA1c values were above clinical guideline recommendations. The randomized control trial findings provide additional evidence that extended time and intervention supports may be needed for populations experiencing inequities in social determinants of health. TRIAL REGISTRATION NUMBER: NCT04035395.

Model-Free Rheo-AFM Probes the Viscoelasticity of Tunable DNA Soft Colloids.

Atomic force microscopy rheological measurements (Rheo-AFM) of the linear viscoelastic properties of single, charged colloids having a star-like architecture with a hard core and an extended, deformable double-stranded DNA (dsDNA) corona dispersed in aqueous saline solutions are reported. This is achieved by analyzing indentation and relaxation experiments performed on individual colloidal particles by means of a novel model-free Fourier transform method that allows a direct evaluation of the frequency-dependent linear viscoelastic moduli of the system under investigation. The method provides results that are consistent with those obtained via a conventional fitting procedure of the force-relaxation curves based on a modified Maxwell model. The outcomes show a pronounced softening of the dsDNA colloids, which is described by an exponential decay of both the Young's and the storage modulus as a function of the salt concentration within the dispersing medium. The strong softening is related to a critical reduction of the size of the dsDNA corona, down to ≈70% of its size in a salt-free solution. This can be correlated to significant topological changes of the dense star-like polyelectrolyte forming the corona, which are induced by variations in the density profile of the counterions. Similarly, a significant reduction of the stiffness is obtained by increasing the length of the dsDNA chains, which we attribute to a reduction of the DNA density in the outer region of the corona.

Targeting of Aberrant αvß6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.

Expression of the αvß6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting αvß6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28+CD3 endodomain. To achieve selective expansion of CAR T cells ex vivo, an IL-4-responsive fusion gene (4αß) was co-expressed, which delivers a selective mitogenic signal to engineered T cells only. In vivo efficacy was demonstrated in mice with established ovarian, breast, and pancreatic tumor xenografts, all of which express αvß6 at intermediate to high levels. SCID beige mice were used for these studies because they are susceptible to cytokine release syndrome, unlike more immune-compromised strains. Nonetheless, although the CAR also engages mouse αvß6, mild and reversible toxicity was only observed when supra-therapeutic doses of CAR T cells were administered parenterally. These data support the clinical evaluation of αvß6 re-targeted CAR T cell immunotherapy in solid tumors that express this integrin.

A survey of clinicians addressing the approach to the management of severe sepsis and septic shock in the United States.

PURPOSE: Mortality in severe sepsis and septic shock (SS/SS) remains high. Surviving Sepsis Campaign (SSC) guidelines were published in 2004 with the goal of improving outcomes in SS/SS. We tested the hypothesis that adherence to SSC guidelines and management of patients with SS/SS were influenced by physician specialty. MATERIALS AND METHODS: A survey was mailed to 4998 randomly selected physicians, 1666 each for emergency medicine (EM), critical care medicine (CCM), and internal medicine (IM) from the American Medical Association database. Demographics, compliance with SSC guidelines, and approaches to management of patients with SS/SS were analyzed by specialty. RESULTS: Four hundred ninety-nine respondents were included for final analysis. There were no differences between 3 specialties in obtaining blood cultures and in administering intravenous fluids, pressors, and antibiotics. The CCM physicians were more likely to measure serum lactate and central venous pressure, use corticosteroids and drotrecogin α, and aim for normoglycemia and plateau pressures less than 30 cm H(2)O in mechanically ventilated patients (all P < .001). CONCLUSIONS: We observe that adherence with SSC guidelines continues to be a challenge for CCM, IM, and EM physicians. Significant differences in management of SS/SS exist for the 3 specialties. Because guideline implementation impacts patient outcomes, further evaluation of these differences is warranted.

Los abusos psiquiátricos y psicofarmacológicos durante el régimen nacional-socialista alemán y el legado del Código Nüremberg / Psychiatric and psychopharmacological abuses under the nazi regime an the legacy of the Nüremberg code

Tras finalizar la Segunda Guerra Mundial, un tribunal militar internacional juzgó a veinte médicos nazis y tres colaboradores por crímenes contra la humanidad. Este proceso, practicado en el marco de los Juicios de Nüremberg, de cuyo inicio se cumplen sesenta años, puso de manifiesto la instauración de un perverso sistema de utilización criminal de la medicina en materia de salud pública e investigación human durante el régimen nacional-socialista. Los planteamientos eugenésicos y las políticas de higiene racial constituyeron los ejes fundamentales de los programas de eutanasia nazi, en los que no se respetaron los mínimos éticos de la medicina. La psiquiatría alemana, que gozaba previamente de una extraordinaria reputación internacional, desempeñó un papel capital en estos programas y los enfermos mentales supusieron el principal grupo de riesgo para estas prácticas. En el presente trabajo revisamos, desde la perspectiva histórica, los antecedentes que habilitaron el desastre de los programas de eutanasia de los enfermos mentales, los procedimientos para su ejecución y el empleo de los enfermos mentales como herramientas de investigación. Como consecuencia directa del mencionado proceso penal nació el Código de Nüremberg, considerado como el primer código internacional de ética para la investigación con seres humanos. Durante los últimos sesenta años se ha avanzado sustancialmente en la instauración de normas y códigos éticos en el ámbito particular de la psiquiatría y la psicofarmacología, cuya culminación fue la Declaración de Madrid de 1996. Sin embargo, la erradicación del ejercicio no ético en esta materia está lejos de lograrse, ya que continúan los abusos psiquiátricos gubernamentales y el empleo ilegítimo de psicofármacos en distintos países

At the end of World War II, and International Military Court tried twenty Nazi doctors and three collaborations for crimes against humanity. These proceedings, part of the Nüremberg Trials which began sixty years ago, revealed a perverse system of criminal use of medicine in public health and human research under the Nazi regime. Theories of eugenics and policies of ethnic cleansing formed the basis of the Nazi programs of euthanasia, with no regard for the ethical limits of medicine. German psychiatry, which had until then enjoyed an extraordinary international reputation, played a key role in these programs of euthanasia of mental patients, the procedures by which they were carried out and the use of mental patients as guinea pigs for research. The above-mentiones trial gave rise of the Nüremberg Code, considered to be the first international code of ethics for research using human subjects. Over the past sixty years there has been considerable progress in establishing ethical codes and norms in psychiatry and psychopharmacology, culminating in the Declaration of Madrid in 1996. Neverthless, the eradication of unethical practice in this field is far from having been achieved, with government psychiatric abuse and the illegitimate use of psychotropic drugs continuing in manu countries

Management of depression in primary care: a survey of general practitioners in Spain.

OBJECTIVE: The objective of this study was to analyze the current situation of health care for depression in Spain according to general practitioners' (GPs') opinion and how it has evolved over the last 20 years on the basis of comparisons with the results of two previous social-health studies (published in 1997 and 1982). METHOD: Throughout 2002, we recorded the opinions of 238 GPs after asking them to fill up structured questionnaires in which they rated care, clinical, therapeutic and care quality aspects. RESULTS: Only 40% of patients with depression visit a doctor, implying a very high level of "concealed epidemiology." The diagnostic instruments most commonly used are assessment of symptoms and patient interview. Pharmacological treatment is the option GPs most commonly choose once a depression diagnosis is established (80% vs. 50% in 1997; P<.001). Selective serotonin reuptake inhibitors (SSRIs), together with anxiolytics, are the drugs most commonly used in the treatment of depression. SSRIs are the first choice drugs, being preferred to tricyclic antidepressants and anxiolytics, which were the most popular options for GPs in the 1997 survey. Areas where there is a need for improvement are time devoted to consultation, coordination between GPs and psychiatrists and waiting lists. CONCLUSIONS: The quality of health care for depression has improved in recent years, thanks to changes in the attitudes of GPs and the evolution of pharmacological treatment.

Cardiac device infections due to Mycobacterium fortuitum.

Two cases of cardiac device infection due to Mycobacterium fortuitum are reported along with a discussion of their clinical management. Long-term therapy and removal of the infected device is needed. The slow progression and absence of systemic signs and symptoms suggest a low pathogenicity of M fortuitum.

Implante ocular de plascol liso en la cirugía extractiva del bulbo ocular / Smooth plascol ocular implanting in extractive surgery of the ocular bulb

Se presenta el estudio realizado con el uso del plascol liso en forma de esferas en la cirugía extractiva del bulbo ocular. De un total de 70 pacientes operados se obtuvieron buenos resultados en el 72,8 por ciento y fue considerado como regular el 22,8 por ciento. Sólo una mínima parte tuvo mala evolución . Los éxitos quirúrgicos se evaluaron a partir de la obtención de movilidad en el muñón, aplicando la cirugía rehabilitadora a 2 grupos de casos: eviscerados con implante inmediato, eviserados con implante y conservación corneal, y reintervención a pacientes ya evicerados. La conservación del surco orbitario obtuvo cifras elevadas en los 2 primeros grupos quirúrgicos. El fracado por la expulsión del implante ocurrió sólo en 2 pacientes en observaciones de más de un año (AU)

Pronóstico visual en el hipema traumático / Visual prognosis in trauatic hypema

Se presenta el estudio del hipema traumático en 82 ojos con trauma cerrado (contusiones), en que relacionan los grados del mismo con la agudeza visual inicial y final, lesiones asociadas en el segmento anterior y posterior y con los estudios electrofisiológicos: electrorretinograma (ERG) y potenciales evocados visuales (PEV). Los resultados demostraron una relación directa entre los grados del hipema y la agudeza visual final con el 27 por ciento de los ojos ciegos en el grado III, un incremento en el número y gravedad de las lesiones asociadas en el hipema grado III y una respuesta electrofisiológica (ERG y PEV) deteriorada. LOs autores concluyen que el grado del hipema guarda relación directa o indirecta con el grado y la gravedad del traumatismo pudiendo considerarse como un indicador de pronóstico (AU)

Pronóstico visual en el hipema traumático / Visual prognosis in traumatic hypema

Se presenta el estudio del hipema traumático en 82 ojos con trauma cerrado (contusiones), en que relacionan los grados del mismo con la agudeza visual inicial y final, lesiones asociadas en el segmento anterior y posterior y con los estudios electrofisiológicos: electrorretinograma (ERG) y potenciales evocados visuales (PEV). Los resultados demostraron una relación directa entre los grados del hipema y la agudeza visual final con el 27 por ciento de los ojos ciegos en el grado III, un incremento en el número y gravedad de las lesiones asociadas en el hipema grado III y una respuesta electrofisiológica (ERG y PEV) deteriorada. LOs autores concluyen que el grado del hipema guarda relación directa o indirecta con el grado y la gravedad del traumatismo pudiendo considerarse como un indicador de pronóstico