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This study aimed to evaluate the effect of early time-restricted eating (eTRE) on metabolic markers and body composition in individuals with overweight or obesity. Seventeen subjects completed a randomized, crossover, and controlled clinical trial. Twelve women and five men participated, with a mean age of 25.8 ± 10.0 years and a BMI of 32.0 ± 6.3 kg/m2. The eTRE intervention included 16 h of fasting (3:00 pm to 7:00 am) and 8 h of ad libitum eating (7:00 am to 03:00 pm) (16:8). The trial included four weeks of interventions followed by a four-week washout period. Body weight, waist and hip circumferences, and body composition measurements were taken. Additionally, a venous blood sample was collected for biochemical determinations. In a before-after analysis, eTRE induced a reduction in BW and BMI in women but this was not significant when compared to the control group. eTRE did not modify any other anthropometric measurements, fasting biochemical parameters, glycemic and insulinemic responses, blood pressure, or subjective appetite. In conclusion, eTRE did not induce beneficial effects on the glycemic and lipid metabolisms, body composition, subjective appetite, or blood pressure. These findings may be attributed to the special characteristics of the population and the short intervention period.

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Introduction: PACS1-related neurodevelopmental disorder (PACS1-related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement. Case Presentation: Here, we describe 4 individuals with PACS1-related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1-related NDD. Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1-related NDD and the overlaps with WDR37- and PACS2-related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes.

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PURPOSE: Resistant starch (RS) content has exhibited beneficial effects on glycemic control; however, few studies have investigated the effects of this substance on postprandial responses and appetite in subjects with type 2 diabetes (T2D). Here, we aimed to examine the effects of RS from two sources on glycemic response (GR), postprandial lipemia, and appetite in subjects with T2D. METHODS: In a randomized and crossover study, 17 subjects with T2D consumed native banana starch (NBS), high-amylose maize starch (HMS) or digestible maize starch (DMS) for 4 days. On day 5, a 6-h oral meal tolerance test (MTT) was performed to evaluate glycemic and insulinemic responses as well as postprandial lipemia. Besides, subjective appetite assessment was measured using a visual analogue scale. RESULTS: NBS induced a reduction on fasting glycemia, glycemia peak and insulinemic response during MTT. However, no modifications on postprandial lipemia were observed after RS treatments. Both NBS and HMS reduced hunger and increased satiety. CONCLUSION: NBS supplementation induced more beneficial effects on glycemic metabolism than HMS even when all interventions were matched for digestible starch content. RS intake did not modify postprandial lipemia, however, positively affected subjective appetite rates. TRIAL REGISTRATION: This trial was retrospectively registered at www.anzctr.org.au (ACTRN12621001382864) on October 11, 2021.

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Asthma is an etiologically heterogeneous disease resulting from a complex interaction between genetic. The genetic aspects involved in asthma, which were analyzed from the perspective of the traditional model of multifactorial inheritance, were susceptibility, host factors, and environmental exposures. In the present paper, studies on their family aggregation, concordance in twins, and heritability were analized; as well as the current knowledge about candidate genes, genome wide association studies, and epigenomics contributions and other omic studies that have increased our knowledge about their pathophysiology and environmental interactions.

El asma es una patología etiológicamente heterogénea resultante de una compleja interacción entre una susceptibilidad genética, factores del huésped y exposiciones ambientales. En el presente trabajo se revisan los aspectos genéticos implicados en el asma, los cuales fueron analizados desde la perspectiva del modelo tradicional de la herencia multifactorial. Fueron incluidos los estudios sobre su agregación familiar, concordancia en gemelos y heredabilidad, así como el conocimiento actual sobre genes candidatos, estudios de asociación amplia del genoma y las recientes contribuciones de la epigenómica y otros estudios ómicos, que en conjunto han aumentado nuestro conocimiento sobre su fisiopatología e interacciones ambientales.

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We previously observed beneficial effects of native banana starch (NBS) with a high resistant starch (RS) content on glycemic response in lean and obese participants. Here, we aimed to determine the effects of NBS and high-amylose maize starch (HMS) on glycemic control (GC) and glycemic variability (GV) in patients with type 2 diabetes (T2D) when treatments were matched for digestible starch content. In a randomized, crossover study, continuous glucose monitoring (CGM) was performed in 17 participants (aged 28-65 years, BMI ≥ 25 kg/m2, both genders) consuming HMS, NBS, or digestible maize starch (DMS) for 4 days. HMS and NBS induced an increase in 24 h mean blood glucose during days 2 to 4 (p < 0.05). CONGA, GRADE, and J-index values were higher in HMS compared with DMS only at day 4 (p < 0.05). Yet, NBS intake provoked a reduction in fasting glycemia changes from baseline compared with DMS (p = 0.0074). In conclusion, under the experimental conditions, RS from two sources did not improve GC or GV. Future longer studies are needed to determine whether these findings were affected by a different baseline microbiota or other environmental factors.

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BACKGROUND: Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated. OBJECTIVE: Report the results of the first years (2017-2019) of the Mexican FH registry. METHODS: There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations. RESULTS: To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C <100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033). CONCLUSION: The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.

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We determine the prevalence and trends of open neural tube defects (ONTDs) during 1991 to 2019 at the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Mexico). Also, details of potential risks were obtained in 662 newborns, including those 143 patients with anencephaly and open spina bifida (OSB) classified as isolated (cases) and 519 controls. Data were analyzed using multivariable logistic regression. Among 267 201 live births during the study period, 336 were born with ONTDs, yielding an overall prevalence of 12.6 per 10 000. After folic acid (FA)-related programs began in Mexico (2003-2019), only OSB showed a decline of 20.6%. For anencephaly, associated risks included relatives with neural tube defects (NTDs) (adjusted odds ratio [aOR]: 67.9, 95% confidence interval [95% CI]: 11.3-409.8), pre-pregnancy body mass index (BMI) ≥25 kg/m2 (aOR: 2.6, 95% CI: 1.1-6.0), insufficient gestational weight gain (aOR: 3.0, 95% CI: 1.3-7.1), parity ≥4 (aOR: 3.2, 95% CI: 1.3-7.7), and exposure to analgesic/antipyretic drugs (aOR: 9.0; 95% CI: 2.5-33.0). For OSB, associated risks included consanguinity (aOR: 14.0, 95% CI: 3.5-55.9), relatives with NTDs (aOR: 22.4, 95% CI: 4.5-112.9), BMI ≥25 kg/m2 (aOR: 2.5, 95% CI: 1.6-4.2), insufficient gestational weight gain (aOR: 1.9, 95% CI: 1.1-3.1), and exposures to hyperthermia (aOR: 2.3, 95% CI: 1.2-4.3), common cold (aOR: 6.8, 95% CI: 3.6-12.7), and analgesic/antipyretic drugs (aOR: 3.6, 95% CI: 1.3-10.0). Our high rate probably results from exposures to preventable risks, most related to FA, indicating a need for strengthening existing FA-related programs in Mexico.

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Esta investigación indaga sobre las percepciones y prácticas acerca de la estimulación del lenguaje que refieren los/las cuidadores de los niños/as con diagnóstico de trastorno del lenguaje que asisten a tratamiento psicopedagógico en el Área Programática del Hospital General de Agudos Dr. J.M. Ramos Mejía (HRM). La finalidad de esta investigación será mejorar las intervenciones y orientaciones realizadas por el equipo de psicopedagogía a las familias de dichos pacientes. Se utilizarán dos instrumentos: se trabajará con enumeración completa para la aplicación de un cuestionario autoadministrado a 11 cuidadores sobre prácticas que refieren los mismos en relación a la estimulación de las cuatro dimensiones del lenguaje (fonética-fonológica, morfosintáctica, semántica y pragmática) en actividades cotidianas. Este cuestionario fue validado conceptualmente y se realizaron pruebas piloto previamente a ser administrado a la muestra. El mismo cuenta con indicadores (actividades de estimulación) para cada dimensión del lenguaje, los cuales habrán sido identificados por los cuidadores según frecuencia de realización, mediante estas respuestas se realizará una síntesis (a partir de criterios pre-establecidos) que indicará la frecuencia de estimulación de cada dimensión (frecuencia de estimulación adecuada, frecuencia de estimulación medianamente adecuada y frecuencia de estimulación insuficiente). El segundo instrumento consiste en una entrevista semiestructurada a los/las cuidadores cuya muestra se definirá por saturación teórica. La misma pretende relevar información sobre cuatro dimensiones que se indagarán mediante una guía de pautas validada por expertos en la temática: el recorrido atravesado por los/las cuidadores para establecer el diagnóstico de Trastorno del Lenguaje de los/las pacientes; sus percepciones acerca de dicho diagnóstico; sus percepciones y las prácticas que refieren con respecto a la estimulación del lenguaje; las orientaciones brindadas por los profesionales de salud y sus respectivas valoraciones en relación a las estas últimas. (AU)

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Human islet amyloid peptide (hIAPP1-37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1-37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1-37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1-37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1-37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A-F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.

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Nitric oxide (NO) regulates numerous physiological process and is the main source of reactive nitrogen species (RNS). NO promotes cell survival, but it also induces apoptotic death having been involved in the pathogenesis of several neurodegenerative diseases. NO and superoxide anion react to form peroxynitrite, which accounts for most of the deleterious effects of NO. The mechanisms by which these molecules regulate the apoptotic process are not well understood. In this study, we evaluated the role of NO and peroxynitrite in the apoptotic death of cultured cerebellar granule neurons (CGN), which are known to experience apoptosis by staurosporine (St) or potassium deprivation (K5). We found that CGN treated with the peroxynitrite catalyst, FeTTPs were completely rescued from St-induced death, but not from K5-induced death. On the other hand, the inhibition of the inducible nitric oxide synthase partially protected cell viability in CGN treated with K5, but not with St, while the inhibitor L-NAME further reduced the cell viability in St, but it did not affect K5. Finally, an inhibitor of the soluble guanylate cyclase (sGC) diminished the cell viability in K5, but not in St. Altogether, these results shows that NO promotes cell survival in K5 through sGC-cGMP and promotes cell death by other mechanisms, while in St NO promotes cell survival independently of cGMP and peroxynitrite results critical for St-induced death. Our results suggest that RNS are differentially handled by CGN during cell death depending on the death-inducing conditions.

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An abnormal glycemic profile, including postprandial glycemia and acute glucose spikes, precedes the onset of overt diabetes in obese subjects. Previous studies have shown the beneficial effects of chronic native banana starch (NBS) supplementation. In this study, we examined the effects of acute ingestion of NBS on glycemic profiles by means of continuous glucose monitoring in obese and lean subjects. In a crossover study, obese and lean subjects consumed beverages containing either 38.3 g of NBS or 38.3 g of digestible corn starch (DCS) twice daily during 4 days. On day 5, a 3-h meal tolerance test (MTT) was performed to evaluate glucose and insulin responses. After 1 week of washout period, treatments were inverted. NBS supplementation reduced the 48-h glycemia AUC in lean, obese, and in the combined group of lean and obese subjects in comparison with DCS. Postprandial glucose and insulin responses at MTT were reduced after NBS in comparison with DCS in all groups. However, no changes were observed in glycemic variability (GV) indexes between groups. In conclusion, acute NBS supplementation improved postprandial glucose and insulin responses in obese and lean subjects during 48 h of everyday life and at MTT. Further research to elucidate the mechanism behind these changes is required.

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Cell death implies morphological changes that may contribute to the progression of this process. In astrocytes, the mechanisms involving the cytoskeletal changes during cell death are not well explored. Although NADPH oxidase (NOX) has been described as being a critical factor in the production of ROS, not much information is available about the participation of NOX-derived ROS in the cell death of astrocytes and their role in the alterations of the cytoskeleton during the death of astrocytes. In this study, we have evaluated the participation of ROS in the death of cultured cerebellar astrocytes using staurosporine (St) as death inductor. We found that astrocytes express NOX1, NOX2, and NOX4. Also, St induced an early ROS production and NOX activation that participate in the death of astrocytes. These findings suggest that ROS produced by St is generated through NOX1 and NOX4. Finally, we showed that the reorganization of tubulin and actin induced by St is ROS independent and that St did not change the level of expression of these cytoskeletal proteins. We conclude that ROS produced by a NOX is required for cell death in astrocytes, but not for the morphological alterations induced by St.

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BACKGROUND: Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase.

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Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases is a promising cancer therapy. Experimental data demonstrate that these inhibitors in combination do not only show synergy in antitumor effects but also in whole genome global expression. Ten pairs of pre- and post-treatment cervical tumor samples were analyzed by microarray analysis. Treatment for seven days with hydralazine and valproate (HV) in patients up-regulated 964 genes. The two pathways possessing the highest number of up-regulated genes comprised the ribosome protein and the oxidative phosphorylation pathways, followed by MAPK signaling, tight junction, adherens junction, actin cytoskeleton, cell cycle, focal adhesion, apoptosis, proteasome, Wnt signaling, and antigen processing and presentation pathways. Up-regulated genes by HV, clustered with down-regulated genes in untreated primary cervical carcinomas and were more alike as compared with up-regulated genes from untreated patients in terms of gene ontology. Increased acetylated p53 was also observed. Epigenetic therapy with HV leads to gene reactivation in primary tumors of cervical cancer patients as well as protein acetylation. A number of these reactivated genes have a definitive role as a tumor suppressors. The global expression pattern induced by HV suggests this therapy has an impact on pathways related to energy production which may promote apoptosis.

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We studied the effects of injecting agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) muscimol (GABA-A receptor agonist) and baclofen (GABA-B receptor agonist) in the medial preoptic area (MPOA) and neighboring brain regions, the bed nucleus of the stria terminalis (BNST), and lateral preoptic area (LPO) on maternal behavior. Lactating female rats were implanted with bilateral cannulae in the MPOA/BNST on day 1 postpartum. On day 5, a maternal behavior test was conducted in the home cage after females received injections of muscimol or baclofen (0, 12.5, 50 or 200 ng per side). On day 7, after MPOA/BNST injections, a second maternal behavior test was conducted with pups placed at the end of a T-runway projecting from the home cage. Finally, after injections on day 9 maternal aggression, olfaction, and locomotor behavior were tested. The GABA receptor agonists injected in the MPOA/BNST produced dose-dependent deficits in all components of maternal behavior, including maternal aggression, except licking. Muscimol produced deficits in the active component, nest building at lower doses than baclofen, both agonists produced deficits in retrieving, while baclofen produced deficits in passive components (hovering and crouching over pups) at lower doses than muscimol. Both GABA receptor agonists increased locomotor activity and reduced olfactory responsiveness but these were only correlated with deficits in retrieving and crouching in baclofen-treated females.

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