Murmur identification and outcome prediction in phonocardiograms using deep features based on Stockwell transform.

Traditionally, heart murmurs are diagnosed through cardiac auscultation, which requires specialized training and experience. The purpose of this study is to predict patients' clinical outcomes (normal or abnormal) and identify the presence or absence of heart murmurs using phonocardiograms (PCGs) obtained at different auscultation points. A semi-supervised model tailored to PCG classification is introduced in this study, with the goal of improving performance using time-frequency deep features. The study begins by investigating the behavior of PCGs in the time-frequency domain, utilizing the Stockwell transform to convert the PCG signal into two-dimensional time-frequency maps (TFMs). A deep network named AlexNet is then used to derive deep feature sets from these TFMs. In feature reduction, redundancy is eliminated and the number of deep features is reduced to streamline the feature set. The effectiveness of the extracted features is evaluated using three different classifiers using the CinC/Physionet challenge 2022 dataset. For Task I, which focuses on heart murmur detection, the proposed approach achieved an average accuracy of 93%, sensitivity of 91%, and F1-score of 91%. According to Task II of the CinC/Physionet challenge 2022, the approach showed a clinical outcome cost of 5290, exceeding the benchmark set by leading methods in the challenge.

CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration.

BACKGROUND: Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells obtained from D-galactosamine-treated livers promotes SHPC expansion, thereby accelerating liver regeneration. Extracellular vesicles (EVs) secreted by Thy1+ cells induce sinusoidal endothelial cells (SECs) and Kupffer cells (KCs) to secrete IL17B and IL25, respectively, thereby activating SHPCs through IL17 receptor B (RB) signaling. This study aimed to identify the inducers of IL17RB signaling and growth factors for SHPC proliferation in EVs secreted by Thy1+ cells (Thy1-EVs). METHODS: Thy1+ cells isolated from the livers of rats treated with D-galactosamine were cultured. Although some liver stem/progenitor cells (LSPCs) proliferated to form colonies, others remained as mesenchymal cells (MCs). Thy1-MCs or Thy1-LSPCs were transplanted into Ret/PH-treated livers to examine their effects on SHPCs. EVs were isolated from the conditioned medium (CM) of Thy1-MCs and Thy1-LSPCs. Small hepatocytes (SHs) isolated from adult rat livers were used to identify factors regulating cell growth in Thy1-EVs. RESULTS: The size of SHPC clusters transplanted with Thy1-MCs was significantly larger than that of SHPC clusters transplanted with Thy1-LSPCs (p = 0.02). A comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, cytokine-induced neutrophil chemoattractant-2 (CINC-2), and monocyte chemotactic protein 1 (MCP-1) were candidates for promoting SHPC growth. Additionally, miR-199a-5p mimics promoted the growth of SHs (p = 0.02), whereas CINC-2 and MCP-1 did not. SECs treated with CINC-2 induced Il17b expression. KCs treated with Thy1-EVs induced the expression of CINC-2, Il25, and miR-199a-5p. CM derived from SECs treated with CINC-2 accelerated the growth of SHs (p = 0.03). Similarly, CM derived from KCs treated with Thy1-EVs and miR-199a-5p mimics accelerated the growth of SHs (p = 0.007). In addition, although miR-199a-overexpressing EVs could not enhance SHPC proliferation, transplantation of miR-199a-overexpressing Thy1-MCs could promote the expansion of SHPC clusters. CONCLUSION: Thy1-MC transplantation may accelerate liver regeneration owing to SHPC expansion, which is induced by CINC-2/IL17RB signaling and miR-199a-5p via SEC and KC activation.

Efeito prolongado da toxina botulínica associada à suplementação com zinco e fitase / Prolonged effect of botulinum toxin associated with zinc and phytase supplementation / Efecto prolongado de la toxina de botulino asociada con el suplemento de zinc y la fitasa

A toxina botulínica é produzida naturalmente pela bactéria anaeróbia gram- positiva Clostridium botulinum, sendo considerada uma neurotoxina com efeitos capazes de reduzir atividades do sistema nervoso parassimpático, principalmente em relação as desordens de movimentos. A alta efetividade e o resultado do efeito de bloqueio na contração da musculatura facial justificam sua aplicação regular na estética, atuando no tratamento e prevenção das rugas e linhas de expressão. Entretanto, para a ação da toxina botulínica é necessário que o Zinco (Zn) exerça a ação no bloqueio da contração muscular através do mecanismo da clivagem no receptor SNAP-25. O objetivo deste trabalho é investigar a correlação do mecanismo de ação da toxina botulínica no bloqueio da contração muscular associado com a suplementação via oral de cápsulas de zinco e fitase, para comprovar a efetividade na durabilidade de bloqueio muscular com TBA. A pesquisa foi realizada através da aplicação de um questionário aleatório para participantes da pesquisa que fazem aplicação de TBA na musculatura facial de ambos os gêneros, com idade acima de 18 anos e que realizam a suplementação prévia de Zn e Fitase para aumentar a durabilidade do efeito da neurotoxina. Em relação aos resultados encontrados observou-se uma mudança significativa na duração do efeito da TBA quando associado a suplementação prévia de Zn e fitase. Dos 44 participantes da pesquisa 22,7% responderam que ficaram satisfeitos com os efeitos da TBA sem suplementação prévia, enquanto 93,2% afirmaram no questionário uma duração maior do bloqueio muscular quando suplementaram previamente com Zn e Fitase. Conclui-se que a suplementação de Zn e fitase previamente a aplicação da TBA tem resultado positivo na durabilidade do bloqueio da contração da musculatura facial, o que desperta grande interesse na área da estética aplicada, sugerindo novas terapias complementares que possam assegurar a satisfação dos pacientes que são adeptos a este procedimento estético.

Botulinum toxin is produced naturally by the anaerobic gram-positive bacterium Clostridium botulinum, being considered a neurotoxin with effects capable of reducing activities of the parasympathetic nervous system, mainly in relation to movement disorders. The high effectiveness and the result of the blocking effect in the contraction of the facial musculature justify its regular application in aesthetics, acting in the treatment and prevention of wrinkles and lines of expression. However, for the action of botulinum toxin it is necessary that Zinc (Zn) exerts the action in blocking muscle contraction through the cleavage mechanism in the SNAP-25 receptor. The objective of this work is to investigate the correlation of the mechanism of action of botulinum toxin in the blocking of muscle contraction associated with oral supplementation of zinc capsules and phytase, to prove the effectiveness in the durability of muscle block with TBA.The research was carried out by applying a random questionnaire to research participants who apply TBA in the facial musculature of both genders, aged over 18 years and who perform the previous Zn and Fitase supplementation to increase the durability of the effect of neurotoxin. In relation to the results found, a significant change in the duration of the effect of TBA was observed when associated with previous Zn and phytase supplementation. Of the 44 participants in the survey, 22.7% responded that they were satisfied with the effects of ABR without prior supplementation, while 93.2% stated in the questionnaire a longer duration of muscle block when they had previously supplemented with Zn and Fitase. It is concluded that the Zn and phytase supplementation prior to the application of the TBA has positive result in the durability of the blockage of the contraction of the facial musculature, which arouses great interest in the area of applied aesthetics, suggesting new complementary therapies that can ensure the satisfaction of patients who are adherents to this aesthetic procedure.

La toxina botulínica es producida naturalmente por la bacteria anaeróbica Gram-positiva Clostridium botulinum y se considera una neurotoxina con efectos capaces de reducir las actividades del sistema nervioso parasiinfático, principalmente en relación con los trastornos del movimiento. La alta eficacia y el resultado del efecto bloqueante sobre la contracción de los músculos faciales justifican su aplicación regular en estética, actuando en el tratamiento y prevención de arrugas y líneas de expresión. Mientras tanto, para la acción de la toxina botulínica, es necesario que Zinc (Zn) ejerza la acción de bloqueo de la contracción muscular por el mecanismo de escisión del receptor SNAP-25. El objetivo de este trabajo es investigar la correlación del mecanismo de acción de la toxina botulínica en el bloqueo de la contracción muscular asociada a la suplementación oral de cápsulas de zinc y fitasa, para probar la eficacia de la durabilidad del bloqueo muscular con TBA. La investigación se realizó aplicando un cuestionario aleatorio a los participantes en la investigación que aplican TBA a los músculos faciales de ambos géneros mayores de 18 años y que realizan el suplemento previo de Zn y Fitase para aumentar la durabilidad del efecto neurotoxina. En relación con los resultados hallados, se observó un cambio significativo en la duración del efecto del TBA cuando se asoció con el suplemento de Zn y fitasa. De los 44 participantes en la investigación, el 22,7% respondió que estaban satisfechos con los efectos de la TBA sin suplementos previos, mientras que el 93,2% declaró en el cuestionario una larga duración del bloqueo muscular cuando se les había suplementado previamente con Zn y Fitase. Se concluye que la suplementación con Zn y fitasa previa a la aplicación del TBA ha producido un resultado positivo en la durabilidad del bloqueo de contracción muscular facial, que despierta gran interés en el área de estética aplicada, sugiriendo nuevas terapias complementarias que puedan garantizar la satisfacción de los pacientes que son adeptivos a este procedimiento estético.

Efeito prolongado da toxina botulínica associada à suplementação com zinco e fitase / Prolonged effect of botulinum toxin associated with zinc and phytase supplementation / Efecto prolongado de la toxina de botulino asociada con el suplemento de zinc y la fitasa

A toxina botulínica é produzida naturalmente pela bactéria anaeróbia gram- positiva Clostridium botulinum, sendo considerada uma neurotoxina com efeitos capazes de reduzir atividades do sistema nervoso parassimpático, principalmente em relação as desordens de movimentos. A alta efetividade e o resultado do efeito de bloqueio na contração da musculatura facial justificam sua aplicação regular na estética, atuando no tratamento e prevenção das rugas e linhas de expressão. Entretanto, para a ação da toxina botulínica é necessário que o Zinco (Zn) exerça a ação no bloqueio da contração muscular através do mecanismo da clivagem no receptor SNAP-25. O objetivo deste trabalho é investigar a correlação do mecanismo de ação da toxina botulínica no bloqueio da contração muscular associado com a suplementação via oral de cápsulas de zinco e fitase, para comprovar a efetividade na durabilidade de bloqueio muscular com TBA. A pesquisa foi realizada através da aplicação de um questionário aleatório para participantes da pesquisa que fazem aplicação de TBA na musculatura facial de ambos os gêneros, com idade acima de 18 anos e que realizam a suplementação prévia de Zn e Fitase para aumentar a durabilidade do efeito da neurotoxina. Em relação aos resultados encontrados observou-se uma mudança significativa na duração do efeito da TBA quando associado a suplementação prévia de Zn e fitase. Dos 44 participantes da pesquisa 22,7% responderam que ficaram satisfeitos com os efeitos da TBA sem suplementação prévia, enquanto 93,2% afirmaram no questionário uma duração maior do bloqueio muscular quando suplementaram previamente com Zn e Fitase. Conclui-se que a suplementação de Zn e fitase previamente a aplicação da TBA tem resultado positivo na durabilidade do bloqueio da contração da musculatura facial, o que desperta grande interesse na área da estética aplicada, sugerindo novas terapias complementares que possam assegurar a satisfação dos pacientes que são adeptos a este procedimento estético.

Botulinum toxin is produced naturally by the gram-positive anaerobic bacterium Clostridium botulinum, and is considered a neurotoxin with effects capable of reducing activities of the parasympathetic nervous system, especially in relation to movement disorders. The high effectiveness and the result of the blocking effect on the contraction of facial muscles justify its regular application in aesthetics, acting in the treatment and prevention of wrinkles and expression lines. However, for the action of botulinum toxin it is necessary that the Zinc (Zn) exerts the action of blocking muscle contraction through the cleavage mechanism in the SNAP-25 receptor. The objective of this study is to investigate the correlation of the mechanism of action of botulinum toxin in blocking muscle contraction associated with oral supplementation of zinc capsules and phytase, to prove the effectiveness in the durability of muscle blockade with TBA. The research was carried out by applying a randomized questionnaire to research participants who apply TBA to the facial muscles of both genders, over 18 years of age, and who perform prior supplementation of Zn and Phytase to increase the durability of the neurotoxin effect. In relation to the results found it was observed a significant change in the duration of the effect of TBA when associated with prior supplementation of Zn and phytase. Of the 44 research participants 22.7% responded that they were satisfied with the effects of TBA without prior supplementation, while 93.2% stated in the questionnaire a longer duration of muscle blockade when previously supplemented with Zn and Phytase. We conclude that the supplementation of Zn and phytase previously to the application of TBA has a positive result in the durability of the blockade of facial muscle contraction, which arouses great interest in the area of applied esthetics, suggesting new complementary therapies that can ensure the satisfaction of patients who are adept at this esthetic procedure.

La toxina botulínica es producida naturalmente por la bacteria anaeróbica Gram-positiva Clostridium botulinum y se considera una neurotoxina con efectos capaces de reducir las actividades del sistema nervioso parasiinfático, principalmente en relación con los trastornos del movimiento. La alta eficacia y el resultado del efecto bloqueante sobre la contracción de los músculos faciales justifican su aplicación regular en estética, actuando en el tratamiento y prevención de arrugas y líneas de expresión. Mientras tanto, para la acción de la toxina botulínica, es necesario que Zinc (Zn) ejerza la acción de bloqueo de la contracción muscular por el mecanismo de escisión del receptor SNAP-25. El objetivo de este trabajo es investigar la correlación del mecanismo de acción de la toxina botulínica en el bloqueo de la contracción muscular asociada a la suplementación oral de cápsulas de zinc y fitasa, para probar la eficacia de la durabilidad del bloqueo muscular con TBA. La investigación se realizó aplicando un cuestionario aleatorio a los participantes en la investigación que aplican TBA a los músculos faciales de ambos géneros mayores de 18 años y que realizan el suplemento previo de Zn y Fitase para aumentar la durabilidad del efecto neurotoxina. En relación con los resultados hallados, se observó un cambio significativo en la duración del efecto del TBA cuando se asoció con el suplemento de Zn y fitasa. De los 44 participantes en la investigación, el 22,7% respondió que estaban satisfechos con los efectos de la TBA sin suplementos previos, mientras que el 93,2% declaró en el cuestionario una larga duración del bloqueo muscular cuando se les había suplementado previamente con Zn y Fitase. Se concluye que la suplementación con Zn y fitasa previa a la aplicación del TBA ha producido un resultado positivo en la durabilidad del bloqueo de contracción muscular facial, que despierta gran interés en el área de estética aplicada, sugiriendo nuevas terapias complementarias que puedan garantizar la satisfacción de los pacientes que son adeptivos a este procedimiento estético.

Atrioventricular Synchronization for Detection of Atrial Fibrillation and Flutter in One to Twelve ECG Leads Using a Dense Neural Network Classifier.

This study investigates the use of atrioventricular (AV) synchronization as an important diagnostic criterion for atrial fibrillation and flutter (AF) using one to twelve ECG leads. Heart rate, lead-specific AV conduction time, and P-/f-wave amplitude were evaluated by three representative ECG metrics (mean value, standard deviation), namely RR-interval (RRi-mean, RRi-std), PQ-interval (PQi-mean, PQI-std), and PQ-amplitude (PQa-mean, PQa-std), in 71,545 standard 12-lead ECG records from the six largest PhysioNet CinC Challenge 2021 databases. Two rhythm classes were considered (AF, non-AF), randomly assigning records into training (70%), validation (20%), and test (10%) datasets. In a grid search of 19, 55, and 83 dense neural network (DenseNet) architectures and five independent training runs, we optimized models for one-lead, six-lead (chest or limb), and twelve-lead input features. Lead-set performance and SHapley Additive exPlanations (SHAP) input feature importance were evaluated on the test set. Optimal DenseNet architectures with the number of neurons in sequential [1st, 2nd, 3rd] hidden layers were assessed for sensitivity and specificity: DenseNet [16,16,0] with primary leads (I or II) had 87.9-88.3 and 90.5-91.5%; DenseNet [32,32,32] with six limb leads had 90.7 and 94.2%; DenseNet [32,32,4] with six chest leads had 92.1 and 93.2%; and DenseNet [128,8,8] with all 12 leads had 91.8 and 95.8%, indicating sensitivity and specificity values, respectively. Mean SHAP values on the entire test set highlighted the importance of RRi-mean (100%), RR-std (84%), and atrial synchronization (40-60%) for the PQa-mean (aVR, I), PQi-std (V2, aVF, II), and PQi-mean (aVL, aVR). Our focus on finding the strongest AV synchronization predictors of AF in 12-lead ECGs would lead to a comprehensive understanding of the decision-making process in advanced neural network classifiers. DenseNet self-learned to rely on a few ECG behavioral characteristics: first, characteristics usually associated with AF conduction such as rapid heart rate, enhanced heart rate variability, and large PQ-interval deviation in V2 and inferior leads (aVF, II); second, characteristics related to a typical P-wave pattern in sinus rhythm, which is best distinguished from AF by the earliest negative P-peak deflection of the right atrium in the lead (aVR) and late positive left atrial deflection in lateral leads (I, aVL). Our results on lead-selection and feature-selection practices for AF detection should be considered for one- to twelve-lead ECG signal processing settings, particularly those measuring heart rate, AV conduction times, and P-/f-wave amplitudes. Performances are limited to the AF diagnostic potential of these three metrics. SHAP value importance can be used in combination with a human expert's ECG interpretation to change the focus from a broad observation of 12-lead ECG morphology to focusing on the few AV synchronization findings strongly predictive of AF or non-AF arrhythmias. Our results are representative of AV synchronization findings across a broad taxonomy of cardiac arrhythmias in large 12-lead ECG databases.

The Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Oral Cavity and Abdominal Organs.

CXCL1 is a CXC chemokine, CXCR2 ligand and chemotactic factor for neutrophils. In this paper, we present a review of the role of the chemokine CXCL1 in physiology and in selected major non-cancer diseases of the oral cavity and abdominal organs (gingiva, salivary glands, stomach, liver, pancreas, intestines, and kidneys). We focus on the importance of CXCL1 on implantation and placentation as well as on human pluripotent stem cells. We also show the significance of CXCL1 in selected diseases of the abdominal organs, including the gastrointestinal tract and oral cavity (periodontal diseases, periodontitis, Sjögren syndrome, Helicobacter pylori infection, diabetes, liver cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), HBV and HCV infection, liver ischemia and reperfusion injury, inflammatory bowel disease (Crohn's disease and ulcerative colitis), obesity and overweight, kidney transplantation and ischemic-reperfusion injury, endometriosis and adenomyosis).

The Importance of CXCL1 in Physiology and Noncancerous Diseases of Bone, Bone Marrow, Muscle and the Nervous System.

This review describes the role of CXCL1, a chemokine crucial in inflammation as a chemoattractant for neutrophils, in physiology and in selected major non-cancer diseases. Due to the vast amount of available information, we focus on the role CXCL1 plays in the physiology of bones, bone marrow, muscle and the nervous system. For this reason, we describe its effects on hematopoietic stem cells, myoblasts, oligodendrocyte progenitors and osteoclast precursors. We also present the involvement of CXCL1 in diseases of selected tissues and organs including Alzheimer's disease, epilepsy, herpes simplex virus type 1 (HSV-1) encephalitis, ischemic stroke, major depression, multiple sclerosis, neuromyelitis optica, neuropathic pain, osteoporosis, prion diseases, rheumatoid arthritis, tick-borne encephalitis (TBE), traumatic spinal cord injury and West Nile fever.

The Potential Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Cardiovascular System, Respiratory System and Skin.

In this paper, we present a literature review of the role of CXC motif chemokine ligand 1 (CXCL1) in physiology, and in selected major non-cancer diseases of the cardiovascular system, respiratory system and skin. CXCL1, a cytokine belonging to the CXC sub-family of chemokines with CXC motif chemokine receptor 2 (CXCR2) as its main receptor, causes the migration and infiltration of neutrophils to the sites of high expression. This implicates CXCL1 in many adverse conditions associated with inflammation and the accumulation of neutrophils. The aim of this study was to describe the significance of CXCL1 in selected diseases of the cardiovascular system (atherosclerosis, atrial fibrillation, chronic ischemic heart disease, hypertension, sepsis including sepsis-associated encephalopathy and sepsis-associated acute kidney injury), the respiratory system (asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, coronavirus disease 2019 (COVID-19), influenza, lung transplantation and ischemic-reperfusion injury and tuberculosis) and the skin (wound healing, psoriasis, sunburn and xeroderma pigmentosum). Additionally, the significance of CXCL1 is described in vascular physiology, such as the effects of CXCL1 on angiogenesis and arteriogenesis.

Study protocol for a two-center test of a nurse-implemented chronotherapeutic restoring bundle in critically ill children: RESTORE Resilience (R2).

Often, pediatric intensive care environments are not conducive to healing the sick. Critically ill children experience disruptions in their circadian rhythms, which can contribute to delayed recovery and poor outcomes. We aim to test the hypothesis that children managed via RESTORE Resilience (R2), a nurse-implemented chronotherapeutic bundle, will experience restorative circadian rhythms compared to children receiving usual care. In this two-phased, prospective cohort study, two separate pediatric intensive care units in the United Sates will enroll a total of 20 baseline subjects followed by 40 intervention subjects, 6 months to less than 18 years of age, requiring invasive mechanical ventilation. During the intervention phase, we will implement the R2 bundle, which includes: (1) a focused effort to replicate the child's pre-hospitalization daily routine, (2) cycled day-night lighting and sound modulation, (3) minimal yet effective sedation (RESTORE), (4) nighttime fasting with bolus enteral daytime feedings, (5) early progressive mobility (PICU Up!), (6) continuity in nursing care, and (7) parent diaries. Our primary outcome is circadian activity ratio post-extubation. We hypothesize that children receiving R2 will experience restored circadian rhythms as evidenced by decreased nighttime activity while in the PICU. Our exploratory outcomes include salivary melatonin levels; electroencephalogram (EEG) slow-wave activity; R2 feasibility, adherence, and system barriers; levels of patient comfort; exposure to sedative medications; time to physiological stability; and parent perception of being well cared for. This paper describes the design, rationale, and implementation of R2. CLINICALTRIALSGOV IDENTIFIER: NCT04695392.

Deficiencia de cinc en mujeres en edad reproductiva, La Habana, Cuba / Zinc deficiency in childbearing-aged women, Havana, Cuba

Introducción: La deficiencia de cinc se considera un problema de salud global. Existe escasa información sobre el estado nutricional del cinc en mujeres cubanas en edad reproductiva. Objetivo: Identificar deficiencia de cinc y cobre sérico en mujeres en edad reproductiva, según factores relacionados, como la anemia, inflamación, exceso de peso y adiposidad abdominal. Métodos: Se estudiaron 104 mujeres de 18 a 40 años de edad, de La Habana, aparentemente sanas. Se realizó un estudio transversal descriptivo. Se realizó la determinación de cinc, cobre, hemoglobina, ferritina, proteína C reactiva, alfa 1 glicoproteína, peso, talla y circunferencia mínima de la cintura, se calculó el índice de masa corporal. Se utilizaron puntos de corte internacionales para la evaluación. Resultados: La prevalencia de deficiencia de hierro, estimada por ferritina sérica, cinc y cobre sérico fueron 66,3 por ciento (67/102), 36,2 por ciento (34/94) y 19,1 por ciento (18/94), respectivamente. De las mujeres 23,5 por ciento (24/102) tenían anemia e inflamación 8,8 por ciento (9/102) y 13 por ciento (13/102) estimada por CRP y AGP. Predominaron mujeres con exceso de peso 52,9 por ciento (54/102) y adiposidad abdominal 61,8 por ciento (60/97). Conclusiones: El riesgo de deficiencia de cinc en la muestra es elevado, la prevalencia del Zn sérico disminuido supera el 20 por ciento. No existe criterio para evaluar el riesgo de deficiencia de cobre como problema de salud pública. Las deficiencias de cinc y cobre no parecen estar asociadas a la anemia, la inflamación y el estado nutricional general. Se requiere realizar pesquisas adicionales para identificar la magnitud de las deficiencias de cinc y cobre y sus posibles causas(AU)

Introduction: Zinc deficiency is considered a global health problem. There is scarce information on zinc's nutritional state in Cuban childbearing-aged women. Objective: Identify zinc and serum copper deficiency in childbearing-aged women, based on related factors, such as anemia, inflammation, excess weight and abdominal adiposity. Methods: 104 seemingly healthy women from Havana, aged 18 to 40 were studied. A descriptive cross-sectional study was conducted. The determination of zinc, copper, hemoglobin, ferritin, C-reactive protein, alpha 1 glycoprotein, weight, size and minimum waist circumference was made, and the body mass index was calculated. International breakpoints were used for evaluation. Results: The prevalence of iron deficiency, estimated by serum ferritin, zinc and serum copper was 66.3 percent (67/101), 36.2 percent (34/94) and 19.1 percent (18/94), respectively. Of women, 23.5 percent (24/102) had anemia, and 8.8 percent had inflammation (9/102) and 13 percent (13/100) estimated by CRP and AGP. Women with overweight 52.9 percent (54/102) and abdominal adiposity 61.8% (60/97) predominated. Conclusions: The risk of zinc deficiency in the sample is high, the prevalence of decreased serum Zn exceeds 20 percent. There is no criterion for assessing the risk of copper deficiency as a public health problem. Zinc and copper deficiencies do not appear to be associated with anemia, inflammation and overall nutritional status. Additional tests are required to identify the magnitude of zinc and copper deficiencies and their possible causes(AU)

Assessment of Cytokine-Induced Neutrophil Chemoattractants as Biomarkers for Prediction of Pulmonary Toxicity of Nanomaterials.

This work determines whether cytokine-induced neutrophil chemoattractants (CINC)-1, CINC-2 and CINC-3 can be markers for predicting high or low pulmonary toxicity of nanomaterials (NMs). We classified NMs of nickel oxide (NiO) and cerium dioxide (CeO2) into high toxicity and NMs of two types of titanium dioxides (TiO2 (P90 and rutile)) and zinc oxide (ZnO) into low toxicity, and we analyzed previous data of CINCs in bronchoalveolar lavage fluid (BALF) of rats from three days to six months after intratracheal instillation (0.2 and 1.0 mg) and inhalation exposure (0.32-10.4 mg/m3) of materials (NiO, CeO2, TiO2 (P90 and rutile), ZnO NMs and micron-particles of crystalline silica (SiO2)). The concentration of CINC-1 and CINC-2 in BALF had different increase tendency between high and low pulmonary toxicity of NMs and correlated with the other inflammatory markers in BALF. However, CINC-3 increased only slightly in a dose-dependent manner compared with CINC-1 and CINC-2. Analysis of receiver operating characteristics for the toxicity of NMs by CINC-1 and CINC-2 showed the most accuracy of discrimination of the toxicity at one week or one month after exposure and CINC-1 and CINC-2 in BALF following intratracheal instillation of SiO2 as a high toxicity could accurately predict the toxicity at more than one month after exposure. These data suggest that CINC-1 and CINC-2 may be useful biomarkers for the prediction of pulmonary toxicity of NMs relatively early in both intratracheal instillation and inhalation exposure.

Swimming Physical Training Prevented the Onset of Acute Muscle Pain by a Mechanism Dependent of PPARγ Receptors and CINC-1.

Regular physical exercise has been described as a good strategy for prevention or reduction of musculoskeletal pain. The Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) has been investigated as a promising target for the control of inflammatory pain. Therefore, the aim of this study was to evaluate whether activation of PPARγ receptors is involved in the reduction of acute muscle pain by chronic exercise and, in this case, whether this process is modulated by inflammatory cytokines. To this end, Wistar rats were submitted to swimming physical training for a period of 10 weeks, 5 days per week, 40 min/day, in an intensity of 4% of the body mass. Muscle hyperalgesia was measured by Randall Selitto test and pro-inflammatory cytokines were quantified by ELISA. The results showed that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia and the increase in muscle levels of Cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by carrageenan into gastrocnemius muscle. In addition, local pre-treatment with the selective PPARγ receptors antagonist GW9662 reversed the mechanical muscle hypoalgesia and the modulation of CINC-1 levels induced by swimming physical training. These data suggest that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia by a mechanism dependent of PPARγ receptors, which seems to contribute to this process by modulation of the pro-inflammatory cytokine CINC-1, and highlight the potential of PPARγ receptors as a target to control musculoskeletal pain and to potentiate the reduction of musculoskeletal pain induced by exercise.

Role of CINC-1 and CXCR2 receptors on LPS-induced fever in rats.

The classic model of fever induction is based on the administration of lipopolysaccharide (LPS) from Gram-negative bacteria in experimental animals. LPS-induced fever results in the synthesis/release of many mediators that assemble an LPS-fever cascade. We have previously demonstrated that cytokine-induced neutrophil chemoattractant (CINC)-1, a Glu-Leu-Arg (ELR) + chemokine, centrally administered to rats, induces fever and increases prostaglandin E2 in the cerebrospinal fluid. We now attempt to investigate the involvement of CINC-1 and its functional receptor CXCR2 on the fever induced by exogenous and endogenous pyrogens in rats. We also investigated the effect of reparixin, an allosteric inhibitor of CXCR1/CXCR2 receptors, on fever induced by either systemic administration of LPS or intracerebroventricular injection of CINC-1, as well as TNF-α, IL-1ß, IL-6, or ET-1, known mediators of febrile response. Our results show increased CINC-1 mRNA expression in the liver, hypothalamus, CSF, and plasma following LPS injection. Moreover, reparixin administered right before CINC-1 or LPS abolished the fever induced by CINC-1 and significantly reduced the response induced by LPS. In spite of these results, reparixin does not modify the fever induced by IL-1ß, TNF-α, and IL-6, but significantly reduces ET-1-induced fever. Therefore, it is plausible to suggest that CINC-1 might contribute to LPS-induced fever in rats by activating CXCR2 receptor on the CNS. Moreover, it can be hypothesized that CINC-1 is placed upstream TNF-α, IL-1ß, and IL-6 among the prostaglandin-dependent fever-mediator cascade and amidst the prostaglandin-independent synthesis pathway of fever.

Suppression of Intestinal Epithelial Cell Chemokine Production by Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0389 Is Mediated by Secreted Bioactive Molecules.

Host intestinal epithelial cells (IEC) present at the gastrointestinal interface are exposed to pathogenic and non-pathogenic bacteria and their products. Certain probiotic lactic acid bacteria (LAB) have been associated with a range of host-immune modulatory activities including down-regulation of pro-inflammatory gene expression and cytokine production by IEC, with growing evidence suggesting that these bacteria secrete bioactive molecules with immunomodulatory activity. The aim of this study was to determine whether two lactobacilli with immunomodulatory activity [Lactobacillus rhamnosus R0011 (Lr) and Lactobacillus helveticus R0389 (Lh)], produce soluble mediators able to influence IEC responses to Pattern Recognition Receptor (PRR) ligands and pro-inflammatory cytokines [Tumor Necrosis Factor α (TNFα), Interleukin-1ß (IL-1ß)], signals inducing IEC chemokine production during infection. To this end, the effects of cell-free supernatants (CFS) from Lr and Lh on IEC production of the pro-inflammatory chemokines interleukin (IL)-8 and cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by a range of host- or pathogen-derived pro-inflammatory stimuli were determined, and the impact on human HT-29 IEC and a primary IEC line (rat IEC-6) was compared. The Lr-CFS and Lh-CFS did not significantly modulate basal IL-8 production from HT-29 IECs or CINC-1 production from IEC-6 cells. However, both Lr-CFS and Lh-CFS significantly down-regulated IL-8 production from HT-29 IECs challenged with varied PRR ligands. Lr-CFS and Lh-CFS had differential effects on PRR-induced CINC-1 production by rat IEC-6 IECs, with no significant down-regulation of CINC-1 observed from IEC-6 IECs cultured with Lh-CFS. Further analysis of the Lr-CFS revealed down-regulation of IL-8 production induced by the pro-inflammatory cytokines IL-1ß and TNFα Preliminary characterization of the bioactive constituent(s) of the Lr-CFS indicates that it is resistant to treatment with DNase, RNase, and an acidic protease, but is sensitive to alterations in pH. Taken together, these results indicate that these lactobacilli secrete bioactive molecules of low molecular weight that may modulate host innate immune activity through interactions with IEC.

Elimination half-lives of interleukin-6 and cytokine-induced neutrophil chemoattractant-1 synthesized in response to inflammatory stimulation in rats.

The elimination half-lives of in Interleukin-6 (IL-6) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) in rats after inflammatory stimulation were investigated. Five male Sprague-Dawley rats were used (age, 9 weeks; body weight, 235-375 g). Turpentine oil was intramuscularly injected at a dose of 2 mL/kg body weight to induce acute inflammation. Blood was collected pre-injection and 6, 12, 24, 36, 48, 60, 72, 84, and 96 h after the turpentine oil injection. Serum concentrations of IL-6, CINC-1, and α2-macroglobulin (α2M) were measured by enzyme-linked immunosorbent assay. Half-lives were calculated as 0.693/elimination rate constant. The serum concentration of α2M peaked at 48 h after turpentine oil injection. Serum concentrations of IL-6 and CINC-1 increased and peaked at 12 and 24 h, respectively. The terminal elimination half-lives of IL-6 and CINC-1 were 15.5 and 29.9 h, respectively. The half-life of CINC-1 was significantly longer than that of IL-6 (P=0.006). These results suggested that these cytokines synthesized in response to inflammatory stimulation were rapidly eliminated in rats. The serum concentrations of these cytokines should be measured at an early stage if these cytokines will be used as surrogate inflammatory markers instead of acute-phase proteins.

The ß2-adrenoceptor agonist clenbuterol reduces the neuroinflammatory response, neutrophil infiltration and apoptosis following intra-striatal IL-1ß administration to rats.

OBJECTIVES: Clenbuterol is a brain penetrant ß2-adrenoceptor agonist with anti-inflammatory and putative neuroprotective properties. In the present investigation, the effect of clenbuterol was assessed in a rat model of acute brain injury induced by intra-striatal administration of the pro-inflammatory cytokine IL-1ß. METHODS: Clenbuterol (0.5 mg/kg; i.p.) was administered one hour prior to stereotactically delivered IL-1ß (100 ng) into the striatum. Four hours postinjection, rats were anesthetized, blood samples were collected for circulating cytokine and chemokine analysis, and the ipsilateral striatum and liver tissue were harvested for mRNA expression analysis of target genes. RESULTS: Intrastriatal IL-1ß provoked an inflammatory response with increased expression of IL-1ß and the pro-inflammatory cytokine TNF-α. TNF-α expression was also increased in the liver and circulating concentrations of the chemokine cytokine-induced neutrophil chemoattractant 1 (CINC-1) were raised in response to intrastriatal IL-1ß administration. The striatal response was accompanied by NFκB activation and 24 hours postinjection, increased immunoreactivity of the neutrophil marker MBS-2, indicative of cell infiltration and increased TUNEL staining, a cell marker of apoptosis. Treatment with clenbuterol attenuated all IL-1ß-induced changes in the striatum including MBS-2 immunoreactivity and TUNEL + staining. Clenbuterol also attenuated IL-1ß-induced expression of TNF-α in the liver and the increase in circulating CINC-1 concentrations. CONCLUSIONS: The results provide evidence that clenbuterol elicits anti-inflammatory effects, suppresses the peripheral acute phase response and reduces the infiltration of neutrophils and apoptotic response to acute IL-1ß-induced brain injury. Suppression of both the central and peripheral response following clenbuterol administration may contribute to its protective properties following brain injury.

Elimination half-lives of interleukin-6 and cytokine-induced neutrophil chemoattractant-1 synthesized in response to inflammatory stimulation in rats / 한국실험동물학회지

The elimination half-lives of in Interleukin-6 (IL-6) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) in rats after inflammatory stimulation were investigated. Five male Sprague-Dawley rats were used (age, 9 weeks; body weight, 235–375 g). Turpentine oil was intramuscularly injected at a dose of 2 mL/kg body weight to induce acute inflammation. Blood was collected pre-injection and 6, 12, 24, 36, 48, 60, 72, 84, and 96 h after the turpentine oil injection. Serum concentrations of IL-6, CINC-1, and α₂-macroglobulin (α2M) were measured by enzyme-linked immunosorbent assay. Half-lives were calculated as 0.693/elimination rate constant. The serum concentration of α2M peaked at 48 h after turpentine oil injection. Serum concentrations of IL-6 and CINC-1 increased and peaked at 12 and 24 h, respectively. The terminal elimination half-lives of IL-6 and CINC-1 were 15.5 and 29.9 h, respectively. The half-life of CINC-1 was significantly longer than that of IL-6 (P=0.006). These results suggested that these cytokines synthesized in response to inflammatory stimulation were rapidly eliminated in rats. The serum concentrations of these cytokines should be measured at an early stage if these cytokines will be used as surrogate inflammatory markers instead of acute-phase proteins.

Anti-inflammatory and antioxidant effect of cerium dioxide nanoparticles immobilized on the surface of silica nanoparticles in rat experimental pneumonia.

A massage with the potent counter-inflammatory material, cerium dioxide nanoparticles, is promising and the antioxidant properties of CeO2 are considered the main, if not the only, mechanism of this action. Nevertheless, the elimination of ceria nano-particles from the organism is very slow and there is a strong concern for toxic effect of ceria due to its accumulation. To overcome this problem, we engineered a combined material in which cerium nanoparticles were immobilized on the surface of silica nanoparticles (CeO2 NP), which is shown to be easily removed from an organism and could be used as carriers for nano-ceria. In our study particle size was 220±5nm, Zeta-potential -4.5mV (in water), surface charge density -17.22µC/cm2 (at pH 7). Thirty-six male Wistar rats, 5 months old and 250-290g were divided into four groups: 1) control; 2) CeO2 NP treatment; 3) experimental pneumonia (i/p LPS injection, 1mg/kg); and 4) experimental pneumonia treated with CeO2 NP (4 times during the study in dosage of 0.6mg/kg with an orogastric catheter). Gas exchange and pulmonary ventilation were measured four times: 0, 1, 3 and 24h after LPS injection in both untreated and CeO2 NP-treated animals. The mRNA of TNF-α, Il-6, and CxCL2 were determined by RT-PCR. ROS-generation in blood plasma and lung tissue homogenates were measured by means of lucigenin- and luminol-enhanced chemiluminescence. Endotoxemia in the acute phase was associated with: (1) pathological changes in lung morphology; (2) increase of ROS generation; (3) enhanced expression of CxCL2; and (4) a gradual decrease of VO2 and VE. CeO2 NP treatment of intact animals did not make any changes in all studied parameters except for a significant augmentation of VO2 and VE. CeO2 NP treatment of rats with pneumonia created positive changes in diminishing lung tissue injury, decreasing ROS generation in blood and lung tissue and decreasing pro-inflammatory cytokine expression (TNF-α, Il-6 and CxCL2). Oxygen consumption in this group was increased compared to the LPS pneumonia group. In our study we have shown anti-inflammatory and antioxidant effects of CeO2 NP. In addition, this paper is the first to report that CeO2 NP stimulates oxygen consumption in both healthy rats, and rats with pneumonia. We propose the key in understanding the mechanisms behind the phenomena lies in the property of CeO2 NP to scavenge ROS and the influence of this potent antioxidant on mitochondrial function. The study of biodistribution and elimination of СеО2NP is the purpose of our ongoing study.

Aging increases the expression of lung CINCs and MCP-1 in senile patients with pneumonia.

OBJECTIVE: To explore the relationship between aging and the expression of monocyte chemoattractant protein (MCP) and cytokine-induced neutrophil chemoattractant (CINCs) in patients with pneumonia. RESULTS: Bacteria counts in senile group were significantly higher than non-senile group, and while white blood cell and neutrophil counts in senile group were observably lower than non-senile group. The concentration of MCP-1 was significantly higher in senile group compared with the non-senile group, and the expression of CINC-1 and CINC-2α was also higher in senile group. In all patients with different pathogens, expression of all the factors was significantly higher in senile group compared with the non-senile group. What's more, expression of MCP-1, CINC-1 and CINC-2α showed significant difference in some patients with different pathogens. CINC-2ß and CINC-3 expression was not detected in both groups. MATERIALS AND METHODS: The present study included 800 patients with pneumonia who were hospitalized to the Department of Respiratory Medicine in Tongji Hospital during the period from December of 2014 to June of 2016. All patients were divided into two groups: senile pneumonia and non-senile pneumonia group. Bacteria, white blood cell and neutrophil counts were determined by automatic blood cell analyzer. The expression of MCP-1, CINC-1, CINC-2α, CINC-2ß and CINC-3 was determined by ELISA assay. CONCLUSIONS: Aging can increase the expression of MCP-1,CINC-1 and CINC-2α in patients with pneumonia, which may lead to increased risk of pneumonia in the elderly.