Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1.

BACKGROUND: The significant clinical benefits of PD-1/PD-L1 immune checkpoint inhibitors (ICIP) in non-small cell lung cancer (NSCLC) have been widely recognized, emphasizing the urgent need for a reliable biomarker. In this study, we find the remarkable capacity of tumor mutational burden (TMB) to serve as an accessible and streamlined indicator. PATIENTS AND METHODS: We designed a retrospective cohort study, consisting of 600 NSCLC patients treated with ICIP. Association between TMB and overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) has been explored. RESULTS: A strong positive correlation between TMB levels and OS, PFS rates, clinical benefit has been found when TMB > = 16(TMB > = 16 mutations/megabase (mut/Mb)). However, when TMB < 16, increasing TMB values did not exhibit a gradual stepwise increase in OS and PFS rates. The median months of OS in the TMB > = 16 and < 16 are 35.58, and 10.71 months respectively with average 12.39 months (p < 0.0001). The median months of PFS in the TMB > = 16 and < 16 are not-obtained, and 2.79 months respectively with an average of 3.32 months (p < 0.0001). The DCR in the TMB > = 16 and < 16 are 71.4% and 44.2% respectively with an average of 47.7% (p < 0.0001). The ORR in the TMB > = 16 and < 16 are 49.4% and 20.8% respectively with an average of 24.5% (p < 0.0001). CONCLUSION: The TMB > = 16 shows significantly associated with optimal ICIP treatment outcomes, including higher patient survival rates, delayed disease progression, and significant clinical benefits. These results present the potential of TMB as a promising biomarker candidate for NSCLC patients undergoing ICIP treatment.

Improved bone and renal safety in younger tenofovir disoproxil fumarate experienced chronic hepatitis B patients after switching to tenofovir alafenamide or entecavir.

INTRODUCTION AND OBJECTIVES: Renal and bone impairment has been reported in chronic hepatitis B (CHB) patients receiving long-term tenofovir disoproxil fumarate (TDF) therapy. This study aimed to assess the incidence of renal and bone impairment in CHB patients with long-term TDF therapy and to identify the changes in bone mineral density (BMD) and renal function in these patients after switching to entecavir (ETV) or tenofovir alafenamide (TAF). MATERIALS AND METHODS: This retrospective study collected clinical data from CHB patients who received TDF monotherapy over 96 weeks. The changes in BMD and renal function were analyzed after 96 weeks of switching antiviral regimens (ETV or TAF) or maintenance TDF. RESULTS: At baseline, 154 patients receiving TDF monotherapy over 96 weeks were enrolled, with a younger median age of 36.75 years, 35.1% (54/154) of patients experienced elevated urinary ß2 microglobulin and 20.1% (31/154) of patients had reduced hip BMD (T<-1). At week 96, among the 123 patients with baseline normal BMD, patients who maintained TDF (n=85) had experienced a decrease in hip BMD, while patients who switched antiviral regimens (n=38) experienced an increase (-13.97% vs 2.34%, p<0.05). Among patients with a baseline reduced BMD (n=31), the alterations in BMD were similar in patients who maintained TDF (n=5) and those who switched antiviral regimens (n=26) (-15.81% vs 7.35%, p<0.05). Irrespective of baseline BMD status, renal function decreased significantly in patients who maintained TDF and improved in patients who switched antiviral regimens. CONCLUSIONS: Younger CHB patients on long-term TDF therapy are at high risk for bone and renal impairment, with the risk being reduced when switched to ETV or TAF.

Cubane-type tungsten-iron-sulfur clusters with a nitrogen atom in the core: terminal ligand substitutions and redox behaviors.

The lack of M-Fe-S (M = Mo or W) clusters incorporating a second period (2p) atom in the core has resulted in limited investigations and poor understanding of the physical and chemical properties of the M-Fe-S clusters closely related to the FeMo cofactor. In this work, systematic studies have been carried out to explore the chemical reactivities at the terminal ligand sites and the redox properties of a series of clusters comprising a [WFe3S3N] cubane core, based on the previously developed cluster [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]1-. Substitutions of the terminal chlorides with ethanethiolate, methanethiolate, thiophenolate, p-thiocresolate and azide occurred smoothly, while the replacement of the chlorides with carbene ligands required the reduction of the precursor into [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]2- first. The reduced cluster core could also be supported by thiophenolates as terminal ligands, but not thiolates or azides. It is remarkable that the thiophenolate ligated reduced cluster can be synthesized from the precursor [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]1-via different synthetic routes, either reduction followed by substitution or substitution followed by reduction, either in situ or stepwise. This work indicates that terminal ligands contribute significantly to determine the chemical and physical properties of the clusters, even though they might affect the cluster core to a limited extent from a structural point of view, which raises the possibility of delicate control in regulating the physical/chemical properties of M-Fe-S clusters with a heteroleptic core incorporating 2p atom(s).

Comparative effect of ciprofloxacin and moxifloxacin on the modulation of bile acid profiles and gut microbiota in rats

Abstract Fluoroquinolones are an important class of antimicrobial agents to manage infectious diseases. However, knowledge about how host bile acids are modified by fluoroquinolones is limited. We investigated and compared the impact of fluoroquinolones on circulating bile acid profiles and gut microbiota from in vivo studies. We administered ciprofloxacin (100 mg/kg/day) or moxifloxacin (40 mg/kg/day) orally to male Wistar rats for seven days. Fifteen bile acids (BAs) from the serum and large intestine were quantified by HPLC-MS/MS. The diversity of gut microbiota after ciprofloxacin and moxifloxacin treatment was analyzed using high-throughput, next-generation sequencing technology. The two fluoroquinolone-treated groups had different BA profiles. Ciprofloxacin significantly reduced the hydrophobicity index of the BA pool, reduced secondary BAs, and increased taurine-conjugated primary BAs in both the serum and large intestine as compared with moxifloxacin. Besides, ciprofloxacin treatment altered intestinal microbiota with a remarkable increase in Firmicutes to Bacteroidetes ratio, while moxifloxacin exerted no effect. What we found suggests that different fluoroquinolones have a distinct effect on the host BAs metabolism and intestinal bacteria, and therefore provide guidance on the selection of fluoroquinolones to treat infectious diseases.

Localization of the centre of the highest region of the triceps brachii muscle spindle abundance and its significance in muscle spasticity block / Localización del centro de la región más alta del huso del músculo tríceps braquial y su importancia en el bloqueo de la espasticidad muscular

SUMMARY: This study aimed to accurately localize the location and depth of the centre of the highest region of muscle spindle abundance (CHRMSA) of the triceps brachii muscle. Twenty-four adult cadavers were placed in the prone position. The curve connecting the acromion and lateral epicondyle of the humerus close to the skin was designed as the longitudinal reference line (L), and the curve connecting the lateral and the medial epicondyle of the humerus was designed as the horizontal reference line (H). Sihler's staining was used to visualize the dense intramuscular nerve region of the triceps brachii muscle. The abundance of muscle spindle was calculated after hematoxylin and eosin stain. CHRMSA was labelled by barium sulphate, and spiral computed tomography scanning and three- dimensional reconstruction were performed. Using the Syngo system, the projection points of CHRMSA on the posterior and anterior arm surface (P and P' points), the position of P points projected to the L and H lines (PL and PH points), and the depth of CHRMSA were determined. The PL of the CHRMSA of the long, medial, and lateral heads of the triceps brachii muscle were located at 34.83 %, 75.63 %, and 63.93 % of the L line, respectively, and the PH was located at 63.46 %, 69.62 %, and 56.07 % of the H line, respectively. In addition, the depth was located at 34.73 %, 35.48 %, and 35.85 % of the PP' line, respectively. These percentage values are all the means. These body surface locations and depths are suggested to be the optimal blocking targets for botulinum toxin A in the treatment of triceps brachii muscle spasticity.

RESUMEN: Este estudio tuvo como objetivo localizar con precisión la ubicación y la profundidad del centro de la región más alta del huso muscular (CHRMSA) del músculo tríceps braquial. Se colocaron veinticuatro cadáveres adultos en posición prona y se designó la curva que conecta el acromion y el epicóndilo lateral del húmero cerca de la piel como la línea de referencia longitudinal (L), y la curva que conecta los epicóndilos lateral y medial del húmero fue designada como la línea de referencia horizontal (H). Se usó la tinción de Sihler para visualizar la región nerviosa intramuscular densa del músculo tríceps braquial. La abundancia de huso muscular se calculó después de la tinción con hematoxilina y eosina. CHRMSA se marcó con sulfato de bario y se realizó una tomografía computarizada espiral y una reconstrucción tridimensional. Usando el sistema Syngo, fueron determinados los puntos de proyección de CHRMSA en la superficie posterior y anterior del brazo (puntos P y P'), la posición de los puntos P pro- yectados en las líneas L y H (puntos PL y PH) y la profundidad de CHRMSA. Los PL de la CHRMSA de las cabezas larga, medial y lateral del músculo tríceps braquial se ubicaron en el 34,83 %, 75,63 % y 63,93 % de la línea L, respectivamente, y el PH se ubicó en el 63,46 %, 69,62 %, y 56,07 % de la línea H, respectivamente. La profundidad se ubicó en el 34,73 %, 35,48 % y 35,85 % de la línea PP', respectivamente. Estos valores porcentuales son todas las medias. Se sugiere que estas ubicaciones y profundidades de la superficie corporal son los objetivos de bloqueo óptimos para la toxina botulínica A en el tratamiento de la espasticidad del músculo tríceps braquial.

Cichoric acid from extracted Echinacea purpurea induces the proliferation and apoptosis of peripheral blood mononuclear cells from yaks

BACKGROUND: Cichoric acid (CA) is extracted from Echinacea purpurea. It is well known and widely used for its immunological function. However, the effect of CA on peripheral blood mononuclear cells (PBMCs) from yaks is still unclear. This study investigated the potential influences of CA on the proliferation, cytokine induction, and apoptosis of PBMCs from Datong yak in vivo, and aimed to provide a basis for exploring the pharmacological activities of CA on yaks. RESULTS: In this study, CA promoted PBMCs proliferation by combining concanavalin A (Con A) and exhibited a dose-dependent effect as demonstrated by a Cell Counting Kit-8. The concentration of 60 µg/ml CA was the best and promoted the transformation from the G0/G1 phase to the S and G2/M phases with Con A. Furthermore, 60 µg/ml CA significantly increased IL-2, IL-6, and IFN-γ levels and PCNA, CDK4 and Bcl-2 expression levels, but it significantly inhibited the TP53, Bax, and Caspase-3 expression levels. Transcriptome analysis revealed a total of 6807 differentially expressed genes (DEGs) between the CA treatment and control groups. Of these genes, 3788 were significantly upregulated and 3019 were downregulated. Gene Ontology and pathway analysis revealed that DEGs were enriched in cell proliferation and immune function signaling pathways. The expression level of some transcription factors (BTB, Ras, RRM_1, and zf-C2H2) and genes (CCNF, CCND1, and CDK4) related to PBMCs proliferation in yaks were significantly promoted after CA treatment. By contrast, anti-proliferation-associated genes (TP53 and CDKN1A) were inhibited. CONCLUSIONS: In summary, CA could regulate the immune function of yaks by promoting proliferation and inhibiting inflammation and apoptosis of PBMCs.

Hypoxia-Inducible Factor-2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin-6.

BACKGROUND AND AIMS: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions. APPROACH AND RESULTS: We observed that APAP challenge caused stabilization of hypoxia-inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particularly HIF-2α. Genetic deletion of the HIF-2α gene in myeloid cells (HIF-2αmye/- ) markedly exacerbated APAP-induced liver injury (AILI) without affecting APAP bioactivation and detoxification. In contrast, hepatic and serum levels of the hepatoprotective cytokine interleukin 6 (IL-6), its downstream signal transducer and transcription factor 3 activation in hepatocytes, as well as hepatic MΦ IL-6 expression were markedly reduced in HIF-2αmye/- mice compared to wild-type mice post-APAP challenge. In vitro experiments revealed that hypoxia induced IL-6 production in hepatic MΦs and that such induction was abolished in HIF-2α-deleted hepatic MΦs. Restoration of IL-6 by administration of exogenous IL-6 ameliorated AILI in HIF-2αmye/- mice. Finally, IL-6-mediated hepatoprotection against AILI was abolished in hepatocyte-specific IL-6 receptor knockout mice. CONCLUSIONS: The data demonstrate that APAP treatment leads to HIF-2α stabilization in hepatic MΦs and that HIF-2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL-6, thereby ameliorating AILI.

Spider venom peptides as potential drug candidates due to their anticancer and antinociceptive activities.

Spider venoms are known to contain proteins and polypeptides that perform various functions including antimicrobial, neurotoxic, analgesic, cytotoxic, necrotic, and hemagglutinic activities. Currently, several classes of natural molecules from spider venoms are potential sources of chemotherapeutics against tumor cells. Some of the spider peptide toxins produce lethal effects on tumor cells by regulating the cell cycle, activating caspase pathway or inactivating mitochondria. Some of them also target the various types of ion channels (including voltage-gated calcium channels, voltage-gated sodium channels, and acid-sensing ion channels) among other pain-related targets. Herein we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against the pathophysiological conditions including cancer and pain.

Spider venom peptides as potential drug candidates due to their anticancer and antinociceptive activities

Spider venoms are known to contain proteins and polypeptides that perform various functions including antimicrobial, neurotoxic, analgesic, cytotoxic, necrotic, and hemagglutinic activities. Currently, several classes of natural molecules from spider venoms are potential sources of chemotherapeutics against tumor cells. Some of the spider peptide toxins produce lethal effects on tumor cells by regulating the cell cycle, activating caspase pathway or inactivating mitochondria. Some of them also target the various types of ion channels (including voltage-gated calcium channels, voltage-gated sodium channels, and acid-sensing ion channels) among other pain-related targets. Herein we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against the pathophysiological conditions including cancer and pain.(AU)

Spider venom peptides as potential drug candidates due to their anticancer and antinociceptive activities

Spider venoms are known to contain proteins and polypeptides that perform various functions including antimicrobial, neurotoxic, analgesic, cytotoxic, necrotic, and hemagglutinic activities. Currently, several classes of natural molecules from spider venoms are potential sources of chemotherapeutics against tumor cells. Some of the spider peptide toxins produce lethal effects on tumor cells by regulating the cell cycle, activating caspase pathway or inactivating mitochondria. Some of them also target the various types of ion channels (including voltage-gated calcium channels, voltage-gated sodium channels, and acid-sensing ion channels) among other pain-related targets. Herein we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against the pathophysiological conditions including cancer and pain.(AU)

Localization of the nerve entry points of thigh adductor muscles by spiral computed tomography: a novel anatomical guide for chemical neurolysis in treating muscle spasticity / Localización de los puntos de entrada del nervio de los músculos aductores del muslo mediante tomografía computarizada espiral: una nueva guía anatómica para la neurolosis química en el tratamiento de la espasticidad muscular

The nerve entry points (NEPs) cannot yet be accurately localized for the treatment of thigh adductor muscles spasticity in chemical neurolysis. The aim of this study was to identify the location and depth of the NEPs of thigh adductor muscles by spiral computed tomography (CT) and bony landmarks. Forty lower limbs of twenty adult cadavers were dissected in supine position. A curved line on skin surface from the tip of greater trochanter of femur to the center of pubic tubercle was designated as the horizontal reference line (H). Another curved line from the tip of great trochanter to the lateral epicondyle of femur was designated as the longitudinal reference line (L). Following dissection, the NEPs were labeled with barium sulfate, and their body surface projection points (P) were determined by spiral CT. Projection of NEP in the opposite direction was designated as P'. The percentage location of the intersections (PH and PL) of P with the H and L and the percentage depth of NEPs were determined with the Syngo system. The PH for the NEP of pectineus, gracilis, adductor longus, adductor brevis and adductor magnus muscles branch were located at 76.41±0.71 %, 93.85±2.07 %, 92.05±2.15 %, 80.75±1.20 % and 88.08±1.09 % of the H, respectively. The PLwere at 1.64±0.04 %, 29.89±1.90 %, 16.06±1.32 %, 11.66±0.11 % and 22.94±0.90 % of the L, respectively. The depth of NEP from P points were at 17.52±0.52 %, 38.38±2.75 %, 20.88±0.79 %, 20.35±0.82 % and 39.52±0.67 % of PP', respectively. These results help to carry out more precise localization of the NEPs. It should provide a novel anatomical guide for improving the efficacy and efficiency of chemical neurolysis in treating thigh adductor muscle spasticity.

Aún no se pueden localizar con precisión los puntos de entrada del nervio (PEN) para el tratamiento de la espasticidad de los músculos aductores del muslo a través de la neurólisis química. El objetivo de este estudio fue identificar la ubicación y la profundidad de los PEN de los músculos aductores del muslo mediante tomografía computarizada espiral (TC) y puntos de referencia óseos. Se disecaron loa miembros inferiores de 20 cadáveres adultos en posición supina. Se trazó una línea curva en la superficie de la piel desdeel ápice del trocánter mayor del fémur hasta el centro del tubérculo púbico y se designó como línea de referencia horizontal (H). Otra línea curva desde el ápice del trocánter mayor hasta el epicóndilo lateral del fémur se designó como línea de referencia longitudinal (L). Después de la disección, los PEN se marcaron con sulfato de bario y sus puntos de proyección de la superficie del cuerpo (P) se determinaron mediante TC helicoidal. La proyección de PEN en la dirección opuesta se designó como P '. El porcentaje de ubicación de las intersecciones (PH y PL) de P con H y L y la profundidad porcentual de los PEN se determinaron con el sistema Syngo. Los PH para los PEN de los músculos pectineus, gracilis, adductor longus, aductor brevis y rama aductora del músculo aductor magnus se localizaron en 76,41±0,71 %, 93,85±2,07 %, 92,05±2,15 %, 80,75±1,20 % y 88,08±1,09 % de H, respectivamente. Los PL estuvieron en 1,64±0,04 %, 29,89±1,90 %, 16,06±1,32 %, 11,66±0,11 % y 22,94±0,90 % de la L, respectivamente. La profundidad de PEN de P puntos fue de 17,52±0,52 %, 38,38±2,75 %, 20,88±0,79 %, 20,35±0,82 % y 39,52±0,67 % de PP ', respectivamente. Estos resultados ayudan a realizar una localización más precisa de los PEN. Se debe proponer una nueva guía anatómica para mejorar la eficacia y la eficiencia de la neurólisis química en el tratamiento de la espasticidad del músculo aductor del muslo.

Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects

ABSTRACT Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects.

Prenatal Docosahexaenoic Acid Supplementation and Offspring Development at 18 Months: Randomized Controlled Trial.

OBJECTIVE: We evaluated the effects of prenatal docosahexaenoic acid (DHA) supplementation on offspring development at 18 months of age. DESIGN: Randomized placebo double-blind controlled trial. SETTINGS: Cuernavaca, Mexico. PARTICIPANTS AND METHODS: We followed up offspring (n = 730; 75% of the birth cohort) of women in Mexico who participated in a trial of DHA supplementation during the latter half of pregnancy. We assessed the effect of the intervention on child development and the potential modifying effects of gravidity, gender, SES, and quality of the home environment. INTERVENTIONS OR MAIN EXPOSURES: 400 mg/day of algal DHA. OUTCOME MEASURES: Child development at 18 months of age measured using the Spanish version of the Bayley Scales of Infant Development-II. We calculated standardized psychomotor and mental development indices, and behavior rating scale scores. RESULTS: Intent-to-treat differences (DHA-control) were: Psychomotor Developmental Index -0.90 (95% CI: -2.35, 0.56), Mental Developmental Index -0.26 (95% CI: -1.63, 1.10) and Behavior Rating Scale -0.01 (95% CI: -0.95, 0.94). Prenatal DHA intake attenuated the positive association between home environment and psychomotor development index observed in the control group (p for interaction = 0.03) suggesting potential benefits for children living in home environments characterized by reduced caregiver interactions and opportunities for early childhood stimulation. CONCLUSIONS: Prenatal DHA supplementation in a population with low intakes of DHA had no effects on offspring development at 18 months of age although there may be some benefit for infants from poor quality home environments. TRIAL REGISTRATION: Clinicaltrials.gov NCT00646360.

Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers

L-3-n-butylphthalide (L-NBP) is a naturally occurring antioxidant, which can be used for the treatment of acute ischemic stroke and vascular dementia. This study evaluated the safety, tolerability and pharmacokinetics of L-NBP tablets in healthy Chinese volunteers. This was a single-center, randomized, double-blind, placebo-controlled, single- and multiple-dose study. Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12). Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of L-NBP were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration; AEs in this study occurred less frequently and more mildly than AEs listed for the DL-NBP soft capsule. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 1 h, and the mean t1/2 was approximately 13.76 h. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, the steady-state was reached within 3 days with slight accumulation. In summary, the L-NBP tablet was well tolerated in healthy Chinese subjects. Slight accumulation appeared after repeated doses.

L-3-n-butilftalida (L-NMP) é um antioxidante natural, que pode ser utilizado para o tratamento do acidente isquêmico agudo e demência vascular. Este estudo avaliou segurança, tolerância e farmacocinética de comprimidos de L-NBP em chineses voluntários sadios. Este foi um estudo monocêntrico, randomizado, duplo cego, com controle por placebo e doses única e múltipla. Os indivíduos receberam dose única de comprimido de L-NBP de 80, 160, 320 ou 480 mg (n=40) e doses múltiplas de 160 mg duas vezes ao dia, por sete dias (n=12). Amostras de plasma foram analisadas com LC-MS/MS. Os parâmetros farmacocinéticos do L-NBP foram calculados utilizando análise não compartimental, com o programa WinNonlin. A análise estatística foi realizada utilizando-se o programa SPSS. Todos os eventos adversos (EAs) foram moderados e de duração limitada. EAs nesse estudo ocorreram menos frequentemente e mais moderadamente do que os EAs relacionados para cápsulas moles de DL-NBP. Não se observaram eventos adversos graves (EAG), morte ou abandono do estudo. Com dose única, atingiu-se o Cmax em cerca de 1 hora e o t1/2 médio foi de, aproximadamente, 13,76 h. A área sob a curva (ASC) e o Cmax aumentaram com o aumento da dose, mas não se observou proporcionalidade na faixa acima de 160 a 480 mg. No estudo de dose múltipla, o equilíbrio foi alcançado em três dias, com pequeno acúmulo. Em resumo, o comprimido de L-NMP foi bem tolerado em indivíduos chineses saudáveis. O acúmulo pequeno apareceu após doses repetidas.

Processing of fear and anger facial expressions: the role of spatial frequency.

Spatial frequency (SF) components encode a portion of the affective value expressed in face images. The aim of this study was to estimate the relative weight of specific frequency spectrum bandwidth on the discrimination of anger and fear facial expressions. The general paradigm was a classification of the expression of faces morphed at varying proportions between anger and fear images in which SF adaptation and SF subtraction are expected to shift classification of facial emotion. A series of three experiments was conducted. In Experiment 1 subjects classified morphed face images that were unfiltered or filtered to remove either low (<8 cycles/face), middle (12-28 cycles/face), or high (>32 cycles/face) SF components. In Experiment 2 subjects were adapted to unfiltered or filtered prototypical (non-morphed) fear face images and subsequently classified morphed face images. In Experiment 3 subjects were adapted to unfiltered or filtered prototypical fear face images with the phase component randomized before classifying morphed face images. Removing mid frequency components from the target images shifted classification toward fear. The same shift was observed under adaptation condition to unfiltered and low- and middle-range filtered fear images. However, when the phase spectrum of the same adaptation stimuli was randomized, no adaptation effect was observed. These results suggest that medium SF components support the perception of fear more than anger at both low and high level of processing. They also suggest that the effect at high-level processing stage is related more to high-level featural and/or configural information than to the low-level frequency spectrum.

Auditory- and visual-evoked potentials in Mexican infants are not affected by maternal supplementation with 400 mg/d docosahexaenoic acid in the second half of pregnancy.

The evidence relating prenatal supplementation with DHA to offspring neurological development is limited. We investigated the effect of prenatal DHA supplementation on infant brainstem auditory-evoked responses and visual- evoked potentials in a double-blind, randomized controlled trial in Cuernavaca, Mexico. Pregnant women were supplemented daily with 400 mg DHA or placebo from gestation wk 18-22 through delivery. DHA and placebo groups did not differ in maternal characteristics at randomization or infant characteristics at birth. Brainstem auditory-evoked responses were measured at 1 and 3 mo in 749 and 664 infants, respectively, and visual-evoked potentials were measured at 3 and 6 mo in 679 and 817 infants, respectively. Left-right brainstem auditory-evoked potentials were moderately correlated (range, 0.26-0.43; all P < 0.001) and left-right visual-evoked potentials were strongly correlated (range, 0.79-0.94; all P < 0.001) within any assessment. Correlations across visits were modest to moderate (range, 0.09-0.38; all P < 0.01). The offspring of DHA-supplemented women did not differ from those of control women with respect to any outcome measure (all comparisons P > 0.10). We conclude that DHA supplementation during pregnancy did not influence brainstem auditory-evoked responses at 1 and 3 mo or visual-evoked potentials at 3 and 6 mo.

Dietary intakes of polyunsaturated fatty acids among pregnant Mexican women.

Nutritional demands for docosahexaenoic acid (DHA) are high during pregnancy. Diets low in DHA and long-chain polyunsaturated fatty-acids (LC-PUFA) in pregnancy are associated with poorer DHA status and slower reestablishment of maternal stores. To assess intakes of LC-PUFA among urban pregnant women in Central Mexico, we conducted a cross-sectional survey in Prenatal Clinic at the General Hospital No. 1 of the Mexican Society Security Institute, Cuernavaca, Morelos, Mexico. We ascertained intakes over past three months of 110 food items using a food frequency questionnaire developed for this population. Among 1364 pregnant women 18-35 years of age (mean age 26.2 ± 4.7 years) who were interviewed at 18-22 weeks gestation, median (inter-quartile range) daily intakes of linoleic acid, alpha-linolenic acid (LA), arachidonic acid, eicosapentaenoic acid and DHA were 17.6 (13.6; 22.2) g, 1.4 (1.0; 2.0) g, 137 (102; 174) mg, 18 (10; 38) mg, and 55 (37; 99) mg respectively. The median ratio of n-6 to n-3 PUFA was 11.8:1. The main dietary contributions to DHA intake were eggs, chicken, and fresh canned fish. Intakes of PUFAs were higher among women who had completed high school (p<0.01). We conclude that intakes of DHA were much lower than recommended values; the high n-6 to n-3 ratio suggests a suboptimal balance of these PUFAs. Very few sources of DHA are commonly eaten.

Growth to age 18 months following prenatal supplementation with docosahexaenoic acid differs by maternal gravidity in Mexico.

Little is known about the long-term effects of DHA intake during pregnancy. Offspring of primagravid Mexican women who received 400 mg/d DHA from wk 20 of gestation through delivery were heavier and had larger head circumferences at birth than children whose mothers received placebo; no effect was observed in offspring of multigravidae. We have followed these children (n = 739; 76% of the birth cohort), measuring length, weight, and head circumference at 1, 3, 6, 9, 12, and 18 mo. At 18 mo, intent-to-treat differences between placebo and DHA, adjusted for maternal height and child sex and age at measurement, were: length, -0.21 cm (95% CI = -0.58, 0.15); weight, -0.03 kg (95% CI =-0.19, 0.13); and head circumference, 0.02 cm (95% CI = -0.18, 0.21) (all P > 0.05). There was heterogeneity of associations by maternal gravidity for weight (P < 0.08), length (P < 0.02), and head circumference (P < 0.05). Among offspring of primagravid women, length at 18 mo was increased by 0.72 cm (95% CI = 0.11, 1.33) following DHA supplementation, representing 0.26 length-for-age Z-score units; among offspring of multigravidae, the estimate was -0.13 cm (95% CI = -0.59, 0.32) (P > 0.5). Maternal DHA supplementation during the second half of gestation may enhance growth through 18 mo of children born to primagravid women.