It's About Timing: Contrasting the Metabolic Effects of Early vs. Late Time-Restricted Eating in Humans.

PURPOSE OF REVIEW: Time-restricted eating (TRE), a form of intermittent fasting, restricts feeding time across the day, imposing a daily 'eating window'. The time of day when the eating window occurs could result in differential metabolic effects. Here, we describe recent intervention studies in humans assessing the metabolic consequences of an early- (i.e., eating window starting in the early morning) vs. late (i.e., eating window starting after midday)-TRE protocol. RECENT FINDINGS: Well-controlled studies indicate that both TRE protocols effectively reduce body weight and improve altered glucose metabolism, lipid profile, inflammation, or blood pressure levels. An early-TRE (e-TRE) might have a further positive impact on improving blood glucose, insulin levels, and insulin resistance. However, the studies directly assessing the metabolic consequences of an early- vs. late-TRE have shown dissimilar findings, and more well-controlled clinical trials are needed on the metabolic benefits of these two types of TRE. Evidence suggests that an e-TRE might have enhanced metabolic results, particularly regarding glucose homeostasis. More long-term studies, including larger sample sizes, are needed to assess the metabolic, circadian, and adherence benefits, together with socio-cultural acceptance of both TRE approaches.

Novel 1,2,4-oxadiazole compounds as PPAR-α ligand agonists: a new strategy for the design of antitumour compounds.

Modulation of PPAR-α by natural ligands is a novel strategy for the development of anticancer therapies. A series of 16 compounds based on the structure of 3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole (natural compound) with antitumour potential were designed and synthesised. The cytotoxicity and PPAR agonist activity of these synthetic 1,2,4-oxadiazoles were evaluated in the A-498 and DU 145 tumour cell lines. Preliminary biological evaluation showed that most of these synthetic 1,2,4-oxadiazoles are less cytotoxic (sulforhodamine B assay) than the positive control WY-14643. Regarding the PPAR-α modulation, compound 16 was the most active, with EC50 = 0.23-0.83 µM (PPAR-α). Additionally, compound 16 had a similar activity to the natural compound (EC50 = 0.18-0.77 µM) and was less toxic in the RPTEC and WPMY-1 cell lines (non-tumour cells) (CC50 = 81.66-92.67 µM) than the natural compound. Looking at the link between chemical structure and activity, our study demonstrates that changes to the natural 1,2,4-oxadiazole at the level of the thiophenyl residue can lead to new agonists of PPAR-α with promising anti-tumour activity.

Aspergillus Endophthalmitis: Epidemiology, Pathobiology, and Current Treatments.

Fungal endophthalmitis is one of the leading causes of vision loss worldwide. Post-operative and traumatic injuries are major contributing factors resulting in ocular fungal infections in healthy and, more importantly, immunocompromised individuals. Among the fungal pathogens, the Aspergillus species, Aspergillus fumigatus, continues to be more prevalent in fungal endophthalmitis patients. However, due to overlapping clinical symptoms with other endophthalmitis etiology, fungal endophthalmitis pose a challenge in its diagnosis and treatment. Hence, it is critical to understand its pathobiology to develop and deploy proper therapeutic interventions for combating Aspergillus infections. This review highlights the different modes of Aspergillus transmission and the host immune response during endophthalmitis. Additionally, we discuss recent advancements in the diagnosis of fungal endophthalmitis. Finally, we comprehensively summarize various antifungal regimens and surgical options for the treatment of Aspergillus endophthalmitis.

Antiplatelet Therapy And Percutaneous Coronary Interventions.

Dual antiplatelet therapy is one of the cornerstones of modern percutaneous coronary interventions. The development of new therapeutic agents has significantly reduced ischemic events at the risk of increased bleeding complications. Therefore, efforts are currently focused on optimizing therapeutic algorithms to obtain the greatest anti-thrombotic benefit associated with the lowest risk of bleeding, that is, the greater net clinical benefit. A significant number of trials evaluating different drug combinations or adjustments in treatment duration have been completed. However, clinical translation of these results is often difficult due to the heterogeneity of the therapeutic approaches. The aim of this manuscript is to provide an updated review of the literature regarding the use of dual antiplatelet therapy in patients undergoing coronary angioplasty and stenting.

Impact of Shift Work on the Eating Pattern, Physical Activity and Daytime Sleepiness Among Chilean Healthcare Workers.

We evaluated the eating pattern, physical activity, and daytime sleepiness level in Chilean shift workers. Fifty, middle-aged adult health workers from a public hospital in Santiago, Chile, were included: a group undergoing shift work (shift workers, including at least one "night shift" and one "long day", n = 33), and day workers under traditional schedule (from 8:00 to 17:00h, n = 17). Body composition, physical activity, and daytime sleepiness levels, and diet characteristics (diet composition, meals' timing, and diet quality) were assessed. Despite similar total energy intake, shift worker showed lower carbohydrate (% of energy) and higher protein intake (both P < 0.01), decreased diet quality, an irregular eating pattern, and delayed meal timing (all P < 0.05). Physical activity and daytime sleepiness levels did not differ between groups. Findings from this first Chilean study in healthcare shift workers support the fact that meal timing and diet quality appear as critical factors for upcoming intervention studies in this group.

The addition of blood flow restriction to resistance exercise in individuals with knee pain: a systematic review and meta-analysis.

BACKGROUND: Blood flow restriction (BFR) is an effective clinical intervention used to increase strength in healthy individuals. However, its effects on pain and function in individuals with knee pain are unknown. OBJECTIVE: To determine the effectiveness of adding BFR to resistance exercise for pain relief and improvement of function in patients with knee pain. METHODS: Systematic review with meta-analysis of randomized clinical trials. Medline, Central, Embase, PEDro, Lilacs, CINAHL, SPORTDiscus, and Web of Science databases were searched from inception to May 2019. Randomized clinical trials that compared resistance exercise with or without BFR to treat knee pain and function in individuals older than 18 years of age with knee pain were included. RESULTS: Eight randomized clinical trials met the eligibility criteria and for the quantitative synthesis, five studies were included. The pooled standardized mean difference (SMD) estimate showed that resistance exercises with BFR was not more effective than resistance exercises for reducing pain (SMD: -0.37cm, 95% CI=-0.93, 0.19) and improving knee function (SMD=-0.23 points, 95% CI=-0.71, 0.26) in patients with knee pain. CONCLUSION: In the short term, there is low quality of evidence that resistance exercise with BFR does not provide significant differences in pain relief and knee function compared to resistance exercises in patients with knee pain. PROSPERO registration number: CRD42018102839.

Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer.

Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.

Predictores preoperatorios de evento cerebrovascular postoperatorio en cirugía de revascularización miocárdica / Perioperative predictors of stroke after coronary artery bypass grafting

El evento cerebrovascular postoperatorio en cirugía de revascularización miocárdica es una entidad catastrófica que aumenta la morbimortalidad y los costos por atención médica. La literatura muestra una disminución en la incidencia del evento cerebrovascular posterior a cirugía cardiaca en la última década, sin embargo no se dispone de datos sobre la prevalencia de esta entidad en Latinoamérica ni en Colombia. Objetivos: Identificar los factores de riesgo para el desarrollo de evento cerebrovascular temprano, en pacientes sometidos a cirugía de revascularización miocárdica en un centro de referencia colombiano. Métodos: Estudio de casos y controles anidado en una cohorte retrospectiva. Resultados: Se incluyeron 876 pacientes, con edad promedio de 63,6 años ± 9,25 años, de los cuales el 74,5% eran hombres. La incidencia de evento cerebrovascular postoperatorio fue 1,3%. Los factores de riesgo fueron: cirugía valvular ( OR 43,92 { IC 95% 1,26-1527,05} , p = 0,037) ; evento cerebrovascular previo ( OR 14,78 { IC 95% 2,96-73,68} p = 0,01) ; calcificación aórtica ( OR 8,23 { IC 95% 2,18-31,12} , p = 0,02) . Conclusiones: La incidencia de evento cerebrovascular postoperatorio de cirugía de revascularización miocárdica en un centro de referencia colombiano es inferior a la que se reporta en la literatura mundial. Los factores predictivos son la cirugía valvular, el antecedente de evento cerebrovascular y la identificación de calcificación aórtica.

Introduction: Perioperative stroke after coronary artery bypass grafting is a catastrophic complication that increases mobility, mortality and the cost for medical attention. Recently a global decrease in perioperative stroke has been reported, however, there is a lack of data about the prevalence of perioperative stroke in Latin-American and Colombia. Objective: To identify the risk factors for early stroke after coronary artery bypass grafting in a Colombian cardiovascular center. Methods: A retrospective case and control study nested in a cohort was performed. Results: 876 patients were included with a mean age of 63.6 ± 9.25 years, 74.5% were male. The incidence of perioperative stroke was 1.3%. The risk factors identified were: previous valvular surgery OR 43.92 ( 1.26-1527.05) , p:.037, past medical history of stroke OR 14.78 ( 2.96-73.68) , p:.01 and the presence of aortic calcification OR 8.23 ( 2.18-31.12) , p:.02. Conclusions: The incidence of perioperative stroke after coronary artery bypass grafting in a Colombian cardiovascular center is lower than reported in the literature, the perioperative predictors identified in the present study were previous valvular surgery, the past medical history of stroke and aortic calcification.

El colágeno de la reestenosis post angioplastia con stent: ¿se origina en la íntima o en la adventicia? / Origin of collagen in restenosis post stenting: intima or adventitia?

Background: Restenosis post stenting is due to the deposit of extracellular matrix, mainly collagen in the neointima. Controversy exists regarding if collagen is generated locally or by immigration from the adventitia. Aim: To study the fibrocellular response after stent implantation in rabbit iliac arteries. To observe, by immunohistochemistry and in situ hybridization, if collagen type I mRNA is expressed in the neointima, in the media or in the adventitia. Material and methods: Thirty eight white rabbits (New Zealand) of 4 kg received an hypercholesterolemic diet during 1 month. After this period, in all but 6 of them, an angioplasty with stent implantation was performed via right carotid artery in both iliac arteries, using a 1:1.3 relationship regarding the reference vessel. Angiograms were performed at day 0, 4, 21, and 40, followed by paraffin fixation of the injured segments, immunohistochemistry for a-actin and in situ hybridization to detect procollagen type I (a1R1) mRNA. Results: No hybridization was observed in non injured arteries or at day 0 (n= 6). Expression of a1R1 mRNA was observed in the neointima starting at day 4 after stenting (n= 8). At day 21 (n= 8) hybridization of procollagen type I was not only observed in the neointima, but also in the media, which became equally intense in both areas. At day 40 (n= 6) hybridization was observed similarly in the media and adventitia. Conclusions: In this model, hybridization of procollagen type I started in the neointima, then involved the media and finally the adventitia. This finding might be useful for designing therapies to be delivered locally at the end of an angioplasty to prevent collagen deposition in the neointima

La hiperuricemia es un marcador del umbral anaeróbico en la insuficiencia cardíaca crónica / Hyperuricemia is a marker for anaerobic threshold in chronic cardiac failure

Background: Patients with chronic cardiac failure often have elevated plasma uric acid levels, that are associated to a dismal prognosis. Aim: To investigate possible metabolic mechanisms to explain elevated uric acid levels in these patients. Patients and methods: Eighteen patients with chronic cardiac failure aged 61 ñ 10 years old, without gout or renal failure and not using high doses of diuretics (equal or less than 80 mg/day furosemide or 50 mg/day hydrochlorothiazide) were studied. Plasma uric acid levels were correlated with anaerobic threshold, maximal oxygen uptake, plasma noradrenaline and creatinine and left ventricular ejection fraction, measured radioisotopically. Results: Mean maximal oxygen uptake was 16.6 ñ 4.2 ml/kg/min. There was a negative correlation between uric acid levels and maximal oxygen uptake or maximal oxygen uptake/body surface area (r=0.521 and -0.533 respectively, p<0.05). Patients with uric acid levels over 7 mg/dl had a lower anaerobic threshold than patients with lower levels (9.81 ñ 2.41 and 13.08 ñ 3.28 ml/kg/min respectively, p<0.05). No significant differences in maximal oxygen uptake were observed in these two groups of patients (15.5 ñ 4.24 and 18.08 ñ 3.86 ml/kg/min respectively). Uric acid levels did not correlate with plasma noradrenaline, creatinine or lefi ventricular ejection fraction. Conclusions: These results suggest that a defect in cellular oxygenation contributes to the elevation of plasma uric acid levels in patients with chronic cardiac failure

Entrenamiento selectivo de los músculos respiratorios en pacientes con insuficiencia cardíaca crónica / Selective training of respiratory muscles in patients with chronic heart failure

Background: Patients with chronic heart failure have a lower inspiratory muscle strength and fatigue endurance. Aim: To assess the effects of selective training of respiratory muscles in patients with heart failure. Patients and methods : Twenty patients with stable chronic heart failure, aged 58.3 ñ 3 years with an ejection fraction of 28 ñ 9 percent, were subjected to respiratory muscle training with threshold valves. The load was fixed in 30 percent of maximal inspiratory pressure (PImax) in 11 and in 10 percent of PImax in nine. Two sessions of 15 minutes, 6 days per week, during 6 weeks were done. Degree of dyspnea (Mahler score), maximal oxygen uptake, distance walked in 6 minutes, respiratory muscle function and left ventricular ejection fraction were measured before and after training. Results: Both training loads were associated to an improvement in dyspnea (+2.7 ñ 1.8 and +2.8 ñ 1.8 score points with 30 percent Plmax and 10 percent PImax respectively), maximal oxygen uptake (from 19 ñ 3 to 21.6 ñ 5 and from 16 ñ 5 to 18.6 ñ 7 ml/kg/min with 30 percent PImax and 10 percent PImax respectively, p< 0.05), PImax (from 78 ñ 22 to 99 ñ 22 and from 72 ñ 34 to 82.3 cm H20 with 30 percent Plmax and 10 percent PImax respectively), sustained PImax (from 63 ñ 18 to 90 ñ 22 and from 58 ñ 3 to 69 ñ 3 cm H20 with 30 percent PImax and 10 percent PImax respectively), and maximal sustained load (from 120 ñ 67 to 195 ñ 47 and from 139 ñ 120 to 192 ñ 154 g with 30 percent PImax and 10 percent PImax respectively). The distance walked in 6 min only increased in subjects trained at 30 percent PImax (from 451 ñ 78 to 486 ñ 68 m). Conclusions: Selective training of respiratory muscles results in a functional improvement of patients with chronic heart failure

Tratamiento de la insuficiencia cardíaca avanzada mediante trasplante de corazón / Heart transplantation as a treatment for advanced heart failure

Background: Heart transplantation currently provides the most effective treatment for advanced heart failure. However, medical therapy for this condition has also improved, heart donors are scarce and the cost of the procedure is high. Therefore the indications and management of these patients need reevaluation. Aim: To analyze the results of 24 patients submitted to heart transplantation for end-stage heart failure needing repeated hospitalizations and i.v. inotropes for compensation. Patients and methods: The group was comprised by 21 men and 3 women with a mean age of 36.8 years, mean left ventricular ejection fraction 19ñ4.5 percent, mean systolic pulmonary artery pressure 48ñ13 mmHg (24-70) and mean pulmonary vascular resistance 2.6 Wood Units (1-5). Fourteen patients (58 percent) had a previous median sternotomy. Immunosupression did not include induction therapy and steroids were discontinued early...

Potencia de los músculos inspiratorios en insuficiencia cardíaca crónica y en enfermedad pulmonar obstructiva crónica / Respiratory muscle power output in patients with chronic heart failure and patients with chronic pulmonary obstructive disease

Background: The maximal pressure generated by inspiratory muscles (PIMax) is an index of their strength which is diminished in both chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). Although inspiratory muscle power output (IMPO), which includes both strength and velocity of shortening, has been shown to be reduced in COPD, there is no information regarding IMPO in CHF. Aim: To measure Impo in patients with CHF and COPD. Patients and methods: We studied 9 CHF patients with functional capacity II and III and 9 patients with severe COPD. Eight normal subjects of similar ages were included as controls. Power output was measured using the incremental threshold loading test. Results: Maximal IMPO was significantly reduced in both groups of patients. Power output developed with each increasing load was also diminished, basically as a consequence of a reduction in insp. The degree of dyspnea at the end of the test was greater in COPD than in CHF patients and normal subjects. For a given level of power, dyspnea was also greater in patients than in normals subjects. There was no decrease in SpO2 during the test. Conclusions: IMPO is equally reduced in COPD and CHF patients. Power output is better related to dyspnea than PIMax, probably because of the inclusion of shortening velocity

Angina inestable: resultados inmediatos y a un año del tratamiento con angioplastía coronaria transluminal percutánea / Immediate and late results of transluminal coronary angioplasty in patients with unstable angina

Background: Unstable angina is characterized by angina at rest, angina of recent onset or accelerating angina. It is caused by a fissure or ulceration of an atheromatous plaque leading to thrombi formation and coronary spasm. Aim: To report the immediate and late results of coronary angioplasty in patients with unstable angina. Patients and methods: Eight hundred twenty eight patients were subjected to coronary arteriography between January 1994 and June 1996. Of these, 242 were subjected to a transluminal coronary angioplasty, 245 patients were subjected to surgical revascularization and 341 patients were treated without revascularization. Results: A total of 323 stenotic lesions (1.3 lesions per patient) were subjected to angioplasty. Angiographic success was obtained in 93 percent of patients. Angiographic success and lack of major complications such as death, infarction of the need for surgery, was obtained in 90 percent of patients. Five patients (2.1 percent) had a non fatal infarction and five required emergency surgery. Hospital mortality was 1.2 percent. During the year of follow up, 15 percent required a new revascularization, 3.3 percent had a non fatal infarction and 3.3 percent died. Conclusions: Coronary angioplasty had a 90 percent immediate success and 78 percent of patients were free of ischemic events after one year of follow up