Insuficiencia respiratoria en una paciente con síndrome de Sézary / Respiratory failure in a patient with Sézary syndrome

Paciente de 44 años de sexo femenino, sin ninguna enfermedad de base preexistente, con una historia de aproximadamente diez meses de presentar lesiones eritemato-descamativas pruriginosas inicialmente localizadas en extremidades inferiores y que luego se generalizaron en todo el cuerpo, asociándose a la pérdida de peso de aproximadamente 15 kg. El manejo inicial consistió en corticoides tópicos y antihistamínicos orales con poca respuesta clínica. Se inició el estudio por dermatología y se confirmó el diagnóstico inicial de neoplasia cutánea maligna de células T. Luego se realizó el frotis de médula ósea, en el que se identificaron células «cerebriformes¼ que confirmaron el diagnóstico de síndrome de Sézary. La paciente recibió esquema de quimioterapia ciclofosfamida, doxorrubicina, vincristina, etopósido y prednisona. La respuesta inicial fue favorable, con alta hospitalaria y seguimiento en la consulta externa. Transcurridos tres meses de tratamiento, la paciente consultó por episodio febril, tos productiva más distrés respiratorio asociado a estertores basales bilaterales, presentó insuficiencia respiratoria y durante la inducción a la ventilación mecánica sufrió un paro cardiorrespiratorio y falleció

44-year-old female patient, with no preexisting underlying disease, with a history of approximately ten months of presenting pruritic erythematous-desquamative lesions initially localized in the lower extremities and later generalized throughout the body, associated with weight loss of 15 kg. Treatment. Initial management consisted of topical corticosteroids and oral antihistamines with little clinical response. A dermatology wok-up was initiated, and the initial diagnosis of malignant T-cell neoplasm was confirmed. A bone marrow smear was performed, in which "cerebriform" cells were identified, confirming the diagnosis of Sézary syndrome. The patient received cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone chemotherapy. Outcome. The initial response was favorable, with hospital discharge and outpatient follow-up. After three months of treatment, the patient consulted for a febrile episode, productive cough plus respiratory distress associated with bilateral basal rales, presented respiratory failure, and during induction of mechanical ventilation suffered cardiorespiratory arrest and died.

Allopregnanolone: Regenerative therapeutic to restore neurological health.

Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicate failed resilience. Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic-pituitary-adrenal axis. Neurosteroids will fluctuate depending on whether the stress is acute or chronic. Advancements in neurosteroid research have led to the identification of multiple targets for drug development, but the most promising innovative target may be neurogenesis, given its potential impact in neurodegenerative disorders like Alzheimer's disease. Allopregnanolone is an endogenous pregnane neurosteroid and a reduced metabolite of progesterone, which acts as a potent allosteric modulator and direct activator of the GABA-chloride channel complex. Perhaps the most intriguing finding related to the potential therapeutic effects of allopregnanolone is its potential to promote neuroregeneration.

Effects of docosahexaenoic acid and eicosapentaoic acid supplementation on white matter integrity after repetitive sub-concussive head impacts during American football: Exploratory neuroimaging findings from a pilot RCT.

Context: Repetitive sub-concussive head impacts (RSHIs) are common in American football and result in changes to the microstructural integrity of white matter. Both docosahexaenoic acid (DHA) and eicosapentaoic acid (EPA) supplementation exerted neuroprotective effects against RSHIs in animal models and in a prior study in football players supplemented with DHA alone. Objective: Here, we present exploratory neuroimaging outcomes from a randomized controlled trial of DHA + EPA supplementation in American football players. We hypothesized that supplementation would result in less white matter integrity loss on diffusion weighted imaging over the season. Design setting participants: We conducted a double-blind placebo-controlled trial in 38 American football players between June 2019 and January 2020. Intervention: Participants were randomized to the treatment (2.442 g/day DHA and 1.020 g/day EPA) or placebo group for five times-per-week supplementation for 7 months. Of these, 27 participants were included in the neuroimaging data analysis (n = 16 placebo; n = 11 DHA + EPA). Exploratory outcome measures: Changes in white matter integrity were quantified using both voxelwise diffusion kurtosis scalars and deterministic tractography at baseline and end of season. Additional neuroimaging outcomes included changes in regional gray matter volume as well as intra-regional, edge-wise, and network level functional connectivity. Serum neurofilament light (NfL) provided a peripheral biomarker of axonal damage. Results: No voxel-wise between-group differences were identified on diffusion tensor metrics. Deterministic tractography using quantitative anisotropy (QA) revealed increased structural connectivity in ascending corticostriatal fibers and decreased connectivity in long association and commissural fibers in the DHA+EPA group compared to the placebo group. Serum NfL increases were correlated with increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = -0.52) in the corpus callosum and bilateral corona radiata irrespective of treatment group. DHA + EPA supplementation did preserve default mode/frontoparietal control network connectivity (g = 0.96, p = 0.024). Conclusions: These exploratory findings did not provide strong evidence that DHA + EPA prevented or protected against axonal damage as quantified via neuroimaging. Neuroprotective effects on functional connectivity were observed despite white matter damage. Further studies with larger samples are needed to fully establish the relationship between omega-3 supplementation, RSHIs, and neuroimaging biomarkers. Trial registration: ClinicalTrials.gov-NCT04796207.

Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial.

There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (<0.001); placebo (p < 0.05)), with starting players (vs. non-starters) showing significant higher circulating concentrations at week 26 (p < 0.01). Fish oil (DHA+EPA) supplementation did not mitigate the adverse effects of RSHI, as measured by NfL levels; however, participants with the highest plasma DHA+EPA concentrations tended to have lower NfL levels. DHA+EPA supplementation had no effects on inflammatory cytokine levels at any of the timepoints tested. These findings emphasize the need for effective strategies to protect American football participants from the effects of RSHI.

Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes.

Introduction: Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized-controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported. Methods: Twenty-four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter-regional, and network-level functional connectivity were also compared between groups using resting-state functional MRI. Results: Rate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter-regional, and network level functional connectivity in AD-vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system. Discussion: Indicators of regeneration from previous preclinical studies and these exploratory MRI-based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof-of-concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN-BRAIN study; NCT04838301).

Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial.

INTRODUCTION: Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate. METHODS: A randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini-Mental State Examination score of 20-26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers. RESULTS: A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non-serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose-response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/-7.31), 42.05 ng/mL (+/-14.55), 60.07 ng/mL (+/-12.8), and 137.48 ng/mL (+/-38.69), respectively. The MTD was established based on evidence of allopregnanolone-induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging-based imaging outcomes were evident. CONCLUSIONS: Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial. TRIAL REGISTRATION: ClinicalTrials.gov-NCT02221622.

Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.

OBJECTIVE: PhytoSERM is a selective estrogen receptor beta (ERß) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS: In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS: Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION: Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.

Safety and feasibility of estrogen receptor-ß targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial.

OBJECTIVE: PhytoSERM is a formulation of genistein, daidzein, and S-equol that has an 83-fold selective affinity for estrogen receptor-ß (ERß); and may enhance neuron function and estrogenic mechanisms in the brain without having peripheral estrogenic activity. METHODS: We conducted an overarching, two-stage, dose-ranging, double-blinded, randomized, placebo-controlled trial of 12 weeks duration comparing 50 and 100 mg/d of phytoSERM with placebo for noncognitively impaired, perimenopausal women aged 45 to 60, with intact uteri and ovaries, with at least one cognitive complaint, and one vasomotor-related symptom. Primary objectives were to assess safety and tolerability of a 50 and 100 mg daily dose; and, secondly, to evaluate potential indicators of efficacy on cognition and vasomotor symptoms over 4 and 12 weeks, and using an embedded, 4-week, 2-period, placebo-controlled crossover trial for a subset of participants. RESULTS: Seventy-one women were randomized to treatment; 70 were evaluated at 4 weeks; 12 were entered into the crossover study; 5 did not complete 12 weeks. Reasons for discontinuation were withdrawal of consent (n = 1) and lost to follow-up (n = 4). Adverse events occurred in 16.7% (n = 4) placebo, 39.1% (n = 9) 50 mg/d, and 29.2% (n = 7) 100 mg/d treated participants; 85% were mild and none was severe. Vaginal bleeding occurred in 0, placebo; 1, 50 mg; and 3, 100 mg/d participants. CONCLUSIONS: The phytoSERM formulation was well tolerated at 50 and 100 mg daily doses. Based on safety outcomes, vaginal bleeding at the 100 mg dose, and vasomotor symptoms and cognitive outcomes at 12 weeks, a daily dose of 50 mg was considered preferable for a phase 2 efficacy trial.

Factores determinantes de la desnutrición en los niños menores de 5 años atendidos en ONG Feed the Children, en la comunidad Palin, municipio de Tacuba departamento de Ahuachapán, Enero a Julio 2019 / Determinant factors of malnutrition in children under 5 years of age cared for in ONG Feed the Children, in the Palin community, municipality of Tacuba, department of Ahuachapán, January to July 2019

Propósito: Mejorar las acciones que actualmente se realizan en favor de los niños con desnutrición por parte de la ONG, con el fin de obtener un mayor conocimiento de los factores que determinan la desnutrición en los niños/as menores de 5 años ya que es primera vez que se realizará dicho estudio en la comunidad Palin. Materiales y métodos: Estudio descriptivo de corte transversal a 78 niños/as menores de 5 años con desnutrición, de enero a julio de 2019; Se realizaron una encuesta a los cuidadores de los niños/as menores de 5 años, beneficiados con el programa de la ONG Feed the Children, donde se citarán en el comedor infantil de la comunidad Palin. Resultados: Observamos que la edad representativa el 26% de 9 meses a 1 año. La principal fuente de agua para consumo el 67% la obtienen de cañerías, un 73% con desnutrición aguda no tratan el agua, el 63% de IRA y el 67% de enfermedades gastrointestinales son las más frecuentes, el 64% son agricultores, el 72% reciben salario menor al mínimo, un 53% solo ofrecen 4 tiempos de comida, la mayoría de los niños le ofrecen una cantidad inadecuada de alimentos, un 100% de desnutrición crónica y el 43% de desnutrición aguda el tipo de alimentos que reciben son granos básicos. Conclusión: El consumo de alimentos de los niños y niñas de nuestra investigación, son granos básicos (arroz, maíz y frijol), excluyendo la proteína de origen animal, como las carnes, además de vitaminas y minerales, como frutas y verduras; asimismo la cantidad y frecuencia inadecuada que se le ofrece, por lo que no reciben una alimentación apropiada según edad, que le permita al niño y niña con desnutrición, recuperar un estado nutricional óptimo, a pesar de haber recibido vitamina "A" y desparasitante en la ONG y ser la madre responsable en la alimentación. Recomendación: Enseñarles a las madres o cuidadores a través de talleres en coordinación ministerio de salud y ONG Feed the Children, la alimentación adecuada que se brinda a los niños según edad, de acuerdo a su frecuencia, cantidad y calidad de alimentos. Adoptando cambios de comportamientos nutricionales; asimismo la alimentación perceptiva en el momento de alimentar al niño con amor, paciencia, buen humor y de forma interactiva, para que los niños y niñas aprendan a comer, y gocen de un adecuado crecimiento, desarrollo físico y cognoscitivo, de esta forma aumentar sus posibilidades de supervivencia y desarrollo comunitario

Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor ß-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.

OBJECTIVE: Selected estrogen receptor ß-selective phytoestrogen (phytoSERM), a preparation of genistein, daidzein, and S-equol, has an 83-fold selective affinity for estrogen receptor (ER) ß, and may promote neuronal survival and estrogenic mechanisms in the brain without exerting feminizing activity in the periphery. The aim of this study was to assess the safety, tolerability, and single-dose pharmacokinetics of the phytoSERM formulation in perimenopausal and postmenopausal women. METHODS: Eighteen women aged 45 to 60 years from a 12-week clinical trial evaluating cognitive performance and vasomotor symptoms were randomly assigned to placebo, 50 mg, or 100 mg phytoSERM treatment groups. Plasma levels of the three parent phytoestrogens and their metabolites were measured before and at 2, 4, 6, 8, and 24 hours after ingestion by isotope dilution high-performance liquid chromatography (HPLC) electrospray ionization tandem mass spectrometry. RESULTS: Plasma concentrations of genistein, daidzein, and S-equol peaked at 9, 6, and 4 hours, respectively, for the 50-mg dose, and at 6, 6, and 5 hours, respectively, for the 100-mg dose. The maximum concentration (Cmax) and area under the curve (AUC) for the three parent compounds were greater in the 100-mg dose group, indicating a dose-dependent change in concentration with the phytoSERM treatment. No adverse events were elicited. CONCLUSIONS: A single-dose oral administration of the phytoSERM formulation was well-tolerated and did not elicit any adverse events. It was rapidly absorbed, reached high plasma concentrations, and showed a linear dose-concentration response in its pharmacokinetics. These findings are consistent with previously reported parameters for each parent compound (Clinicaltrials.gov NCT01723917).

Caracterización de los pacientes con probable de artropatía post-chikungunya en el consultorio de reumatología del "Instituto Salvadoreño del Seguro Social" en el año 2015-2016 / Characterization of patients with probable post-chikungunya arthropathy in the rheumatology office of the "Instituto Salvadoreño del Seguro Social" in the year 2015-2016

La fiebre Chikungunya es una enfermedad que puede evolucionar a una fase crónica caracterizada por artralgias-artritis recurrente que limitan la capacidad funcional de muchos pacientes. En El Salvador la enfermedad tiene su auge en el 2014 con una rápida propagación debido a los problemas sanitarios en cuanto al control de vectores, causando manifestaciones de la etapa aguda como fiebre y según estudios de Ministerio de Salud de El Salvador con artralgias en > del 80% de los casos sospechosos, que progresan a una fase crónica definida como un período de más de noventa días en el cual persisten artralgias-artritis, tenosinovitis, limitación de la actividad diaria con un difícil manejo farmacológico a largo plazo. Del total de 29.704 en el año 2015 con fiebre del Chikungunya, 17.860 se reportan en San Salvador, es decir, más del 60 por ciento. Le siguen los departamentos o provincias de La Libertad, San Vicente y Sonsonate de mayor a menor frecuencia. Según datos del MINSAL; La mayor tasa de ataque de la enfermedad se concentra en los grupos de personas entre los cinco y 19 años; igual que está sucediendo con el Dengue; también existe una buena cantidad de casos entre adultos jóvenes entre 20 y 29 años

A pilot study examining short-term changes in bone mineral density among class 3 obese users of depot-medroxyprogesterone acetate.

OBJECTIVE: To examine changes in lumbar spine-bone mineral density (LS-BMD) among normal weight (body mass index [BMI] = 18.5-24.9 kg/m(2)), Class 1-2 obese (BMI = 30-39.9 kg/m(2)), and Class 3 obese (BMI ≥ 40 kg/m(2)) women utilising depot-medroxyprogesterone acetate (DMPA). METHODS: Five normal-weight, five Class 1-2 obese, and five Class 3 obese women received subcutaneous injections of DMPA-SC at baseline and 12 weeks later. Dual Energy X-ray Absorptiometry (DEXA) scans were performed at baseline and 18 weeks after the first injection for determination of LS-BMD and analysis of fat content. Bimonthly oestradiol (E2) levels were measured by immunoassay methods for 26 weeks. RESULTS: There were no significant demographic or LS-BMD differences among the three BMI groups. Significant differences at baseline were as expected among the three groups with respect to BMI and associated parameters (mean % total body fat, absolute fat, and weight). When used as their own controls, significant changes in LS-BMD, % body fat and absolute fat determined by DEXA occurred among all three BMI strata. Class 1-2 obese and Class 3 obese women were more likely to experience E2 fluctuations, but short-term changes in LS-BMD were similar. CONCLUSIONS: DMPA-SC administration affects L-spine bone health similarly regardless of BMI status.

Late pregnancy complications can affect risk estimates of elective induction of labor.

OBJECTIVE: Multiple observational studies have emphasized the increased risk of elective induction versus spontaneous labor. We estimated the risks of elective induction before 39 weeks compared to expectant management. METHODS: Using a single institution's delivery data (1996-2004), we identified women with uncomplicated term gestations who underwent elective induction before 39 weeks (Early Induction Group). A comparison group of women eligible for elective induction before 39 weeks but who were managed expectantly was created by identifying the remaining deliveries ≥ 39 weeks and excluding women with "established" pregnancy complications such as diabetes or heart disease (Expectant Management Group), but retaining women with complications that may have developed while waiting, e.g. gestational hypertension or abruption. RESULTS: Pregnancies in the Early Induction Group were generally not at increased risk for morbidity when compared to the entire Expectant Management Group, in whom 49% developed pregnancy complications or went postdates. These pregnancies had poorer maternal and neonatal outcomes when compared to patients who remained uncomplicated with spontaneous labor onset, thus reducing the overall benefit of expectant management. CONCLUSIONS: Failure to account for the large proportion of women who develop late pregnancy complications can falsely elevate the estimated risk of elective induction prior to 39 weeks.