The influence of association between aging and reduced protein intake on some immunomodulatory aspects of bone marrow mesenchymal stem cells: an experimental study.

PURPOSE: Dietary protein deficiency is common in the elderly, compromising hematopoiesis and the immune response, and may cause a greater susceptibility to infections. Mesenchymal stem cells (MSCs) have immunomodulatory properties and are essential to hematopoiesis. Therefore, this study aimed to investigate, in an aging model subjected to malnutrition due a reduced protein intake, aspects related to the immunomodulatory capacity of MSCs. METHODS: Male C57BL/6 mice from young and elderly groups were fed with normoproteic or hypoproteic diets (12% and 2% of protein, respectively) and nutritional, biochemical and hematological parameters were evaluated. MSCs from bone marrow were isolated, characterized and their secretory parameters evaluated, along with gene expression. Additionally, the effects of aging and protein malnutrition on MSC immunomodulatory properties were assessed. RESULTS: Malnourished mice lost weight and demonstrated anemia, leukopenia, and bone marrow hypoplasia. MSCs from elderly animals from both groups showed reduced CD73 expression and higher senescence rate; also, the malnourished state affected CD73 expression in young animals. The production of IL-1ß and IL-6 by MSCs was affected by aging and malnutrition, but the IL-10 production not. Aging also increased the expression of NFκB, reducing the expression of STAT-3. However, MSCs from malnourished groups, regardless of age, showed decreased TGF-ß and PGE2 production. Evaluation of the immunomodulatory capacity of MSCs revealed that aging and malnutrition affected, mainly in lymphocytes, the production of IFN-γ and IL-10. CONCLUSION: Aging and reduced protein intake are factors that, alone or together, influence the immunomodulatory properties of MSCs and provide basic knowledge that can be further investigated to explore whether MSCs' therapeutic potential may be affected.

OsYUCCA2 deficiency in rice growth and development / Influência da deficiência de OsYUCCA2 no crescimento e desenvolvimento do arroz

YUCCA (YUC) proteins have critical roles in plant growth and development through their involvement in auxin production. Rice (Oryza sativa L. cv Nipponbare) has 14 OsYUC proteins, but little is known regarding their functional redundancy. In this study, transgenic rice seedlings expressing GUS-tagged antisense-OsYUC2 under the control of the ubiquitin promoter were used to investigate the effects of OsYUC2 deficiency on seedling growth and development. GUS staining showed that antisense-OsYUC2 was expressed primarily in rapidly dividing cells in callus, vegetative, and reproductive tissues. Phenotypic analysis showed that callus differentiation was compromised in OsYUC2 antisense rice. Adverse vegetative effects were observed in shoot height and embryonic, adventitious, and lateral root numbers. Reproductive tissues were also impacted, with reductions in panicle length, flower number, seed setting number, seed setting rate, and grain weight. Auxin analysis showed that indole-3-acetic acid (IAA) levels were reduced in OsYUC2 antisense rice, and exogenous addition of 3-indolebutyric acid (IBA, an analogue of IAA) partially rescued defective growth phenotypes. Taken together, these results indicated that deficiency of OsYUC2 impairs auxin biosynthesis, thereby affecting rice growth and development.

As proteínas YUCCA (YUC) possuem importantes papéis no crescimento e desenvolvimento das plantas por meio de seu envolvimento na produção de auxinas. O arroz (Oryza sativa L. cv Nipponbare) possui 14 proteínas OsYUC, no entanto, pouco se sabe a respeito da sua redundância funcional. No presente estudo, mudas de arroz transgênico expressando OsYUC2 anti-senso com tag-GUS sob o controle do promotor de ubiquitina foram utilizadas para investigar os efeitos da deficiência de OsYUC2 no crescimento e desenvolvimento de mudas. As manchas de GUS indicaram que OsYUC2 anti-senso foi expressado primordialmente em células que se dividem rapidamente através de calos, tecidos vegetativos e reprodutivos. A análise fenotípica indicou que a diferenciação do calo foi comprometida no arroz OsYUC2 anti-senso. Os efeitos vegetativos adversos foram observados na altura do rebento e no número de raízes embrionárias, adventícias e laterais. Os tecidos reprodutivos também foram impactados, com reduções no comprimento da panícula, número de flores, número de sementes, proporção de sementes e peso de grão. A análise de auxina ilustrou que os níveis de ácido indol-3-acético (IAA) foram reduzidos no arroz anti-senso OsYUC2 e a adição exógena de ácido 3-indolbutírico (IBA, um análogo de IAA) resgatou parcialmente os fenótipos de crescimento defeituosos. Em conjunto, tais resultados indicam que a deficiência de OsYUC2 prejudica a biossíntese de auxina, afetando o crescimento e o desenvolvimento do arroz.

Proteinemia as a Prognostic Factor in Colorectal Cancers beyond Surgery and Chemotherapy

Background: Globally, 1,096,601, 704,376, and 48,541 new colon, rectum, and anus cancer cases were recorded in 2018, respectively. Besides, 551,269, 310,394 and 19,129 cases of colon, rectum, and anus cancer deaths occurred in the same year. As a result, these cancers ranked in the third level of cancer incidence, and in the second level of cancer mortality. As it is known, all cancer patients are subjected to cancerinduced and therapy-induced nutritional deficiencies (mainly of proteins and calories). The present study aimed to assess proteins level in colorectal cancer (CRC) patients who underwent surgery and chemotherapy. Methods: A combined retrospective and prospective study was performed. The present study enrolled 100 CRC patients with their data on surgical procedures and chemotherapy management. Assessments of the studied samples were conducted as a baseline before receiving chemotherapy and preoperatively as P0, while the period after that was termed as P1. The serum samples were collected to measure protein concentration. Total Protein Kit, Micro was used. Results: The mean age of the patients was 50.7±12.88 years old. Only 8% had a positive CRC family history. Rectosigmoid cancer represented the most frequent site, figured in 41% of the cases, followed by rectum cancer. Multiple sites of CRC metastasis were recorded in 15% of the patients. All patients received chemoradiation. Folinic acid (leucovorin), 5-FU, and oxaliplatin (FOLFOX) was the most used regimen, administered in 40% of the patients. Oxaliplatin and capecitabine (also called Xeloda) (XELOX) were administered in 14% of the patients. Folinic acid (leucovorin), 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI) were administered in 16% of the patients. Single-agent oxaliplatin or carboplatin were administered in 6% of the patients, each. 5-FU plus leucovorin was administered to 12% of the patients. Three patients received irinotecan, and oxaliplatin (IROX). One patient received folinic acid (leucovorin), 5-FU and irinotecan (FOLFIRI). Also, Gemzar was administered to two patients only. A total of 80% of the patients underwent several surgical procedures. Anterior perineal resection (APR) and total mesorectal excision (TME) were the most common two surgeries, performed in 20 and in 30% of the patients, respectively. In P0 status, 44% of the patients suffered from low protein levels, and 13% of the patients were within the normal level. These findings were statistically different (p=0.03). After CRC management (i.e., P1 status), 70% of the patients had protein deficiency. These results have strong significant differences (p=0.000). The mean of protein concentration declined gradually after management, from 8.82±0.9 μg/L to 6.210.78 μg/L, with a strong association between a reduction in proteins levels towards deficiency and surgical procedures and chemotherapy protocols (p=0.000). Conclusion: The incidence of CRC is increasing annually, and the chance of being diagnosed with this type of cancer has risen in recent years. In the present study, the male to female ratio was 1:1.5, and the 5th decade of life was themost common age for the diagnosis of CRC. A negative family history and bowel inflammatory diseases (IBD) history did not exclude people from exposure to the incidence of CRC. Colorectal cancer with localized and moderately differentiated adenocarcinoma were the most common types in the present work. Tumor distance from the anal verge seems to be very important and plays a significant role in the choosing of surgical intervention types and chemoradiation protocols. Colorectal cancer acts as a complex condition and, in addition to its management, nutritional state influences it in different mechanisms. Most patients suffered from hypoproteinemia after surgery and chemoradiation. As a result, alteration in the treatment outcomes, delaying in wound healing, and an increase in postoperative complications may occur. (AU)

Protein restriction during puberty alters nutritional parameters and affects ovarian and uterine histomorphometry in adulthood in rats.

In a large part of the population inefficient ingestion of proteins, whether for cultural, aesthetic or economic reasons, is a global concern. Low-protein diets can cause severe functional complications, mainly during the development and maturation of organs and systems, including the female reproductive system. The present study investigated the effect of nutritional protein restriction during puberty on the oestrous cycle and expression of sex steroid receptors (AR, ERα e ERß) in ovarian and uterine tissues of adult rats. Protein restriction promoted lower body weight gain, feed efficiency and higher caloric intake. There was an increase in the oestrus phase arrest without changing the total length of the oestrous cycle. The consumption of low-protein diet also reduced the thickness of the uterine endometrium (uterine epithelium and endometrial stroma) in addition to increasing the number of primary and atretic follicles in the ovaries. Furthermore, the low-protein diet reduced the levels of androgen receptor (AR) and increased the oestrogen receptor ß (ERß) in the ovary, while no significant changes were observed in the uterus. Our study reinforces the importance of adequate protein intake during puberty, since physiological changes in this developmental period interfere with the histomorphometry of the ovaries and uteri, possibly resulting in impaired folliculogenesis and fertility in the reproductive period.

Effects of protein malnutrition on hematopoietic regulatory activity of bone marrow mesenchymal stem cells.

Protein malnutrition causes anemia and leukopenia as it reduces hematopoietic precursors and impairs the production of mediators that regulate hematopoiesis. Hematopoiesis occurs in distinct bone marrow niches that modulate the processes of differentiation, proliferation and self-renewal of hematopoietic stem cells (HSCs). Mesenchymal stem cells (MSCs) contribute to the biochemical composition of bone marrow niches by the secretion of several growth factors and cytokines, and they play an important role in the regulation of HSCs and hematopoietic progenitors. In this study, we investigated the effect of protein malnutrition on the hematopoietic regulatory function of MSCs. C57BL/6NTaq mice were divided into control and protein malnutrition groups, which received, respectively, a normal protein diet (12% casein) and a low protein diet (2% casein). The results showed that protein malnutrition altered the synthesis of SCF, TFG-ß, Angpt-1, CXCL-12, and G-CSF by MSCs. Additionally, MSCs from the protein malnutrition group were not able to maintain the lymphoid, granulocytic and megakaryocytic-erythroid differentiation capacity compared to the MSCs of the control group. In this way, the comprehension of the role of MSCs on the regulation of the hematopoietic cells, in protein malnutrition states, is for the first time showed. Therefore, we infer that hematopoietic alterations caused by protein malnutrition are due to multifactorial alterations and, at least in part, the MSCs' contribution to hematological impairment.

Protein deficiency during Trichinella spiralis infection impairs lung immunity against newborn larvae.

The goal of this study was to analyse the effects of a protein-deficient (PD) diet on antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro against newborn larvae (NBL) of Trichinella spiralis in the lungs of infected rats. Two groups of weaning Wistar rats received a PD diet (6.5% casein) and other two received a control diet (C, 20% casein). After ten days, one group of each diet was infected (PDI and CI ) with muscle larvae. Lung tissue extracts (LTE) and lung cell suspension (LCS) were obtained. PDI had lower titres of anti-NBL antibodies in LTE than CI . In ADCC assays using control cells, NBL mortality percentage was lower with LTE from PDI than LTE from CI (P < .01). In assays using control cytotoxic sera, ADCC was exerted by LCS from CI at all days post-infection (p.i.), but only by LCS from 13 days p.i. from PDI . ADCC assays combining LTE and LCS from the same group showed a lower response for PDI than for CI (P < .0001). LCS from PDI contained lower numbers of neutrophils, eosinophils and FcεRI+ cells than CI . PD may diminish ADCC activity against T spiralis NBL in lungs through alterations in specific antibodies and effector cells.

Taurine treatment reverses protein malnutrition-induced endothelial dysfunction of the pancreatic vasculature: The role of hydrogen sulfide.

BACKGROUND: Protein malnutrition in childhood predisposes individuals to vascular and pancreatic endocrine dysfunction, thus increasing the risk of diabetes and hypertension. Because taurine may reduce cardiometabolic risk, we hypothesized that taurine treatment has a beneficial effect on the pancreatic vasculature during protein restriction. METHODS AND RESULTS: Weaned mice were fed a normal or a low-protein diet and were treated with or without taurine for 3 months. The lieno-pancreatic artery (LPA) from low-protein diet-treated mice exhibited impaired endothelium-dependent relaxation to acetylcholine that was associated with decreased endothelium-derived hyperpolarization (EDH), hydrogen sulfide (H2S) production, and H2S-synthesizing CBS expression and impaired vasorelaxation to an H2S-donor, NaHS. These changes were prevented by taurine treatment. We compared the effects of taurine with the effects of the direct vasodilator hydralazine and found that both normalized blood pressure and the endothelial vasodilator function of the LPA in the mice fed a protein-restricted diet. However, only taurine restored the CBS expression in the LPA and insulin secretion in response to high glucose. The LPA supplies the pancreas and shares morphometry with the mesenteric resistance artery (MRA). However, in the MRA, low-protein diet-induced endothelial dysfunction is driven by impaired NOS-derived NO with no changes in H2S signaling. CONCLUSIONS: The results suggest that taurine protects against protein malnutrition-induced endothelial dysfunction in the LPA by upregulating the CBS-H2S pathway. Considering the importance of the pancreatic vasculature for endocrine islet activity, taurine may be a potential therapy for the vascular and metabolic dysfunction associated with malnutrition and comorbidities.

Desgaste proteico energético en pacientes con enfermedad renal crónica en estadios III a IV en Caldas, Colombia / Protein Energy Wasting in Patients with Chronic Renal Disease in Stage III to IV Caldas (Colombia)

Resumen Introducción: la enfermedad renal crónica (ERC) es un problema de salud mundial con una prevalencia aproximada del 7,2 % en países desarrollados y del 10 % en todo el mundo; además, es un factor independiente de morbilidad y riesgo cardiovascular que se caracteriza por la pérdida progresiva de la función renal. Objetivo: evaluar la frecuencia de desgaste proteico energético (DPE) en pacientes con ERC en estadios III a IV. Materiales y métodos: estudio descriptivo y de corte transversal. Se realizó una evaluación de los registros de las base de datos de la Sociedad Internacional de Nutrición y Metabolismo Renal sobre pacientes con ERC que contaran con variables sociodemográficas, bioquímicas, valoración global subjetiva (VGS) y medidas antropométricas para el diagnóstico de DPE. Resultados: de 200 pacientes revisados en consulta externa de Nefrología, 60 cumplieron con los criterios de inclusión. El promedio de edad fue de 68,4 años, con una media de tasa de filtración glomerular (TFG) de 47,1 mL/min. Respecto a la ERC, el 61,66 % (n=37) de los participantes fue clasificado en estadio IIIa; el 31,6 % (n=19), en estadio IIIb, y el 6,66 % (n=4), en estadio IV. Ninguno de los pacientes cumplió con los criterios para el DPE. La evaluación de la VGS mostró que el 53,33 % (n=32) de los pacientes estaba en categoría VGS-A (bien nutridos), el 45 % (n=27) en VGS-B (malnutrición moderada) y solo un paciente en VGS-C (malnutrición grave). La mayor proporción de pacientes con bajos niveles de albúmina y colesterol estuvo en pacientes con ERC en estadio IIIb, y los pacientes con índice de masa corporal <23, en estadios IIIb y IV. Conclusión: según los criterios de la Sociedad Internacional de Nutrición y Metabolismo Renal, ningún paciente presentó DPE.

Abstract Introduction: Chronic kidney disease (CKD) is a condition that is recognized as a global health problem and has an approximate prevalence of 7.2% in developed countries, and 10% in the world population, it is also an independent factor of cardiovascular morbidity and risk characterized by progressive loss of kidney function. Objective: To evaluate the frequency of DPE in patients with CKD stages III to IV. Methods: Descriptive, cross-sectional study. Evaluation of a database of patients with CKD, which will have sociodemographic, biochemical variables, Subjective Global Assessment (VGS), and anthropometric measures, for the diagnosis of DPE of the International Society for Nutrition and Renal Metabolism. Results: Of 200 reviewed patients from the Nephrology outpatient clinic, 60 met the inclusion criteria. The average age was 68.4 years, with a mean glomerular filtration rate (GFR) of 47.1ml / min. Regarding CKD, 61.66% (37) of the patients classified in stage IIIa, 31.6% (19) in stage IIIb, and 6.66% (4) in stage IV. None of the patients met the criteria for DPE. The VGS evaluation showed that 53.33% (32) of the patients were in the VGS A category (well nourished), 45% (27) VGS B (moderate malnutrition) and only one patient was classified as VGS C (severe malnutrition). The highest proportion of patients with low levels of albumin and cholesterol was in patients with CKD stage IIIb, and patients with BMI less than 23 in stages IIIb and IV. Conclusion: According to the criteria of the International Society for Renal Nutrition and Metabolism, no patient had DPE. outpatient clinic in Caldas, with CKD stages III to IV-. METHODS: Descriptive, cross-sectional study. Evaluation of a database of patients with CKD, which will have sociodemographic, biochemical variables, Subjective Global Assessment (SGA), and anthropometric measures, for the diagnosis of PEW of the International Society for Nutrition and Renal Metabolism. RESULTS: Of200 reviewed patients from the Nephrology outpatient clinic, 60 met the inclusion criteria. The average age was 68.4 years, with a mean glomerular filtration rate (GFR) of 47.1ml / min. Regarding CKD, 61.66% (37) of the patients were classified in stage IIIa, 31.6% (19) in stage IIIb, and 6.66% (4) in stage IV. None of the patients met the criteria for PEW. The SGA evaluation showed that 53.33% (32) of the patients were in SGAA category (well nourished), 45% (27) SGA B (moderate malnutrition) and only one patient was classified as SGA C (severe malnutrition). The highest proportion of patients with low albumin and cholesterol levels was in patients with CKD in stage IIIb, and patients with BMI less than 23 in stages IIIb and IV. Conclusion: According to the criteria of the International Society for Nutrition and Renal Metabolism, no patient had PEW.

History and Design of the INCAP Longitudinal Study (1969-1977) and Its Impact in Early Childhood.

The Institute of Nutrition of Central America and Panama (INCAP) longitudinal study of 1969 to 1977 was a community randomized trial in which 2 pairs of matched villages received either a protein-rich gruel (atole) or a nonprotein, low-energy drink (fresco). Both contained equal amounts of micronutrients by volume. I review the history and design of the study and impact on dietary intakes and physical growth. The design dates from the 1960s when protein was seen as the main dietary deficiency. During the 1970s, emphasis shifted to energy deficiency and this influenced early analyses. Energy from the 2 drinks during pregnancy was associated with improved birthweights and whether protein was also provided along with energy appeared to make no difference. These analyses, observational in nature, were possible because there was substantial overlap in energy intakes from the supplements during pregnancy across village types. In children, analyses initially focused on energy but eventually relied on the original experimental design. Exposure to the atole compared to fresco was associated with improved physical growth at 3 years of age but not from 3 to 7 years. Consumption of the fresco in the first 3 years of life was low such that there was little overlap in energy intakes from the supplements, not allowing for the type of analyses done for pregnancy. Diets in atole villages were greater from 15 to 36 months in protein, energy, and micronutrients, making attribution of impact on growth to a specific nutrient impossible. The atole improved linear growth, arm, and calf circumferences at 3 years but not skinfold thicknesses.

Spinal anesthesia for c-section in patients with protein S deficiency: case report and literature review / Anestesia espinal para cesárea en paciente con deficiencia de proteína S: informe de caso y revisión de la literatura

Abstract Introduction: Congenital protein S deficiency is a very rare disease in the population. In pregnant women it is associated with spontaneous abortion and fetal death, among other complications. Case presentation: We present the case of a 32-year-old multigravida with a 36-week pregnancy, with thromboprophylaxis with enoxaparin from the 4th week of gestation and with a diagnosis of thrombophilia-due to functional protein S deficiency-which was intervened with elective c-section under spinal anesthesia. In addition, a review of the relevant literature was conducted. Discussion: The risk of venous thromboembolism is approximately 4 to 5 times greater during gestation, and the recommendation of thromboprophylaxis in low-risk thrombophilia is based on the presence of associated risk factors. In patients receiving low molecular weight heparin (LMWH) as thromboprophylaxis, an interval of at least 12 hours after the last dose of LMWH before neuropsy and restarting the next dose after at least 4hours of spinal technique use is recommended. Conclusion: Neuroaxial techniques should be individualized and receive pre and postpartum thromboprophylaxis. In addition, non-pharmacological thromboprophylaxis measures in the perioperative period should be considered. Spinal anesthesia was effective and safe in this patient.

Resumen Introducción: La deficiencia congénita de proteína S es una enfermedad muy rara en la población. En gestantes está asociada a aborto espontáneo y muerte fetal, entre otras complicaciones. Presentación del caso: Presentamos el caso de una multigesta de 32 años con embarazo de 36 semanas, con tromboprofilaxis con enoxaparina desde la semana cuarta de gestación y con diagnóstico de trombofilia -por deficiencia de proteína S funcional-, la cual fue intervenida con cesárea electiva bajo anestesia espinal. Además, se realizó revisión de la literatura al respecto. Discusión: El riesgo de tromboembolismo venoso es aproximadamente 4 a 5 veces mayor durante la gestación, y la recomendación de tromboprofilaxis en trombofilias de bajo riesgo se basa en la presencia de factores de riesgo asociados. En pacientes que reciben Heparinas de Bajo Peso Molecular (HBPM) como tromboprofilaxis, se recomienda un intervalo de al menos 12 horas después de la última dosis de HBPM antes de la punción del neuroeje, y reiniciar la siguiente dosis después de al menos 4 horas de uso de la técnica espinal. Conclusión: Las técnicas neuroaxiales deben ser individualizadas y recibir tromboprofilaxis pre y posparto. Además, se deben tener en cuenta las medidas de tromboprofilaxis no farmacológicas en el periodo perioperatorio. La anestesia espinal fue efectiva y segura en esta paciente.

Maternal protein malnutrition prolongs sickness behavior in male offspring.

Female rats were fed a normal or hypoproteic diet during the phases of gestation and lactation. The male offspring of these rats were grown to adulthood and used to study the effects of maternal protein malnutrition on progeny. The adult male rats were pretreated with either saline or LPS and subjected to behavioral tests 2 and 6 h after administration. Tumor necrosis factor (TNF-α), corticosterone and body temperature were the parameters used for assessment. Two hours after LPS administration, sickness behavior was developed in all the animals, regardless of maternal protein malnutrition. After 6 h of LPS administration, sickness behavior was more pronounced in the rats that had been subjected to maternal protein malnutrition. Only the rats with maternal protein malnutrition expressed an increase in the plasma levels of TNF-α and corticosterone. Maternal protein malnutrition prolongs sickness behaviors in offspring.

Protein malnutrition impairs bone marrow endothelial cells affecting hematopoiesis.

BACKGROUND & AIMS: Protein malnutrition (PM) affects hematopoiesis leading to bone marrow (BM) hypoplasia and arrests hematopoietic stem cells (HSC) in G0/G1 cell cycle phases, which cause anemia and leukopenia. Hematopoiesis is mainly regulated by BM niches where endothelial cells (EC) present a key regulatory role. Thus, our objective is to evaluate whether PM affects the modulatory capacity of EC on hematopoiesis. METHODS: C57BL/6 male mice received for 5 weeks a normal protein diet (12% casein) or a low protein diet (2% casein). MSC were isolated and differentiated in vitro into EC and the synthesis of SCF, Ang-1, CXCL-12, IL-11, TGF-ß and G-CSF were evaluated. The HSC and hematopoietic progenitors were quantified and the EC capacity to modulate the hematopoietic system was also evaluated. Moreover, the ability of PM bone marrow to support hematopoieisis was assessed by proliferation of infused leukemic myelo-monoblasts cells. RESULTS: PM decreases HSC and hematopoietic progenitor pool and promotes cell cycle arrest and a lower proliferation rate of leukemic myelo-monoblasts. PM also committed hematopoietic regulatory characteristics from EC, resulting in the modification of both cell cycle pattern and hematopoietic differentiation. CONCLUSION: BM microenvironment is compromised in PM, and since PM disturbs EC, it becomes one of the factors responsible for the hematopoietic cell cycle arrest and impairment of HSC differentiation.

Impairment of G-CSF receptor on granulocytic progenitor cells causes neutropenia in protein malnutrition.

OBJECTIVE: It is well known that protein malnutrition (PM) states can affect hematopoiesis, leading to severe leukopenia and reduced number of granulocytes, which act as the first line of defense, and are important to the innate immune response. The aim of this study was to elucidate some of the mechanisms involved in the impairment of granulopoiesis in PM. METHODS: Male C57BL/6 mice were submitted to PM with a low-protein diet containing 2% protein. Control mice were fed a 12% protein-containing diet. Bone marrow histology and the percentage of granulocytic progenitors were evaluated after in vivo granulocyte-colony stimulating factor (G-CSF) stimulus. Cell proliferation, STAT3 signaling, and the expression of G-CSF receptor were evaluated in hematopoietic progenitor cells. RESULTS: Malnourished animals presented with leukopenia associated with reduced number of granulocytes and reduced percentage of granulocytic progenitors; however, no differences were observed in the regulatory granulopoietic cytokine G-CSF. Additionally, the malnourished group presented with impaired response to in vivo G-CSF stimulus compared with control animals. PM was implicated in decreased ability of c-Kit+ cells to differentiate into myeloid progenitor cells and downregulated STAT3 signaling. Furthermore, the malnourished group exhibited reduced expression of G-CSF receptor on granule-monocytic progenitors. This reduced expression was not completely reversible with G-CSF treatment. CONCLUSIONS: This study implies that PM promotes intrinsic alterations to hematopoietic precursors, which result in hematologic changes, mainly neutropenia, observed in peripheral blood in PM states.

Protein C and S deficiency as a cause of mesenteric thrombosis: Differential diagnosis of systemic vasculitis / Deficiencia de proteínas C y S como causa de trombosis mesentérica: diagnóstico diferencial de las vasculitis sistémicas

ABSTRACT Acute mesenteric ischemia is a medical emergency that accounts for less than 1/1000 hospital admissions. The disease affects adults older than 50 years predominantly with cardiac compromise, in whom the presence of acute abdominal pain is the cardinal manifestation, and should make the clinician suspect this entity. Its presentation in adolescents is unusual; therefore, in these cases, the possibility of an underlying thrombophilia should be part of the differential diagnosis. The case is presented here of a young female with a protein C and S deficiency as the cause of mesenteric thrombosis.

RESUMEN La isquemia mesentérica aguda es una urgencia médica que se presenta en menos de 1/1.000 ingresos hospitalarios. Es una entidad clínica infrecuente, predominante en adultos mayores de 50 arios con afectación cardíaca, en quienes la presencia de dolor abdominal agudo es la manifestación cardinal y debería hacer sospechar dicho diagnóstico. La presentación en adolescentes es inusual, por lo que, en estos casos, la posibilidad de una trombofilia subyacente debe formar parte del diagnóstico diferencial. Presentamos el caso de una paciente joven con deficiencia de proteínas C y S como agente causal de trombosis mesentérica.

Centros de recuperación nutricional: 1984-2011 / Nutritional Recovery Centers: 1984-2011

Los centros de recuperación nutricional (CRN) fueron creados por el Dr. José María Bengoa en Venezuela. En el presente estudio se realizó una revisión sistemática cualitativa, de 1984 al 2011, que permitió analizar las modalidades de funcionamiento de los diferentes CRN en el mundo, mediante indicadores de: criterios de admisión, parámetros utilizados en estos centros, así como las modalidades de tratamiento, tiempo de estancia y criterios de alta. Se encontraron diecisiete artículos que describen algunos o todos estos indicadores. El uso de los CRN se encontró en cuatro países de África (Etiopía, Kenia, Malawi y Nigeria), cuatro de América (Bolivia, Brasil, Chile y Nicaragua) y dos en Asia (India y Nepal). Los resultados reflejan la importancia de los CRN en el tratamiento de la desnutrición, sobre todo si se acompaña con la educación de las madres sobre la alimentación, prácticas higiénicas, etc., para un mejor cuidado en el hogar. Nuevas evidencias en el tratamiento de la desnutrición han motivado la evolución de los centros, pero aún así, sus limitaciones persisten. No obstante, las ventajas de su uso son excepcionales. Se propone, de acuerdo con los diferentes tipos de centros, y en base a las deficiencias o limitaciones observadas en su conceptualización y designación, redefinir las NRC bajo el concepto de Centros Globales de Nutrición (GloNuCen) basados en la comunidad y la personalización nutricional, los cuales podrían ser centros fijos en el caso de hospitales y servicios ambulatorios, e instalaciones móviles para situaciones de emergencia que, si duran con el tiempo, puedan convertirse en centros fijos(AU)

The Nutritional Recovery Centers (NRC) were created by Dr. Jose María Bengoa in Venezuela. In the present study a qualitative systematic review was carried out, from 1984 to 2011, allowing us to analyze the operating modalities of the different CRNs in the world, by means of indicators of: admission criteria, parameters used in these centers, as well as their treatment modalities, time of stay and discharge criteria. Seventeen articles have been found that describe some or all of these indicators. The use of NRCs was found in four African countries (Ethiopia, Kenya, Malawi and Nigeria), four in America (Bolivia, Brazil, Chile and Nicaragua) and two in Asia (India and Nepal). The results reflect the importance of NRC in the treatment of malnutrition, especially if it is reinforced with mothers' education about food, hygiene practices, etc., for better home care. New evidence in the treatment of malnutrition has motivated the evolution of the centers, but still, their limitations persist. Nonetheless, the advantages of their use are exceptional. It is proposed, according to the different types of centers, and based on the deficiencies or limitations observed in their conceptualization and designation, to redefine the NRCs under the concept of Global Nutrition Centers (GloNuCen) based on the community and nutritional customization, which could be fixed centers in the case of hospitals and outpatient services, and mobile facilities for emergency situations that, if they last over time, could turn into fixed centers(AU)

Protein malnutrition mitigates the effects of a high-fat diet on glucose homeostasis in mice.

Nutrient malnutrition, during the early stages of development, may facilitate the onset of metabolic diseases later in life. However, the consequences of nutritional insults, such as a high-fat diet (HFD) after protein restriction, are still controversial. We assessed overall glucose homeostasis and molecular markers of mitochondrial function in the gastrocnemius muscle of protein-restricted mice fed an HFD until early adulthood. Male C57BL/6 mice were fed a control (14% protein-control diet) or a protein-restricted (6% protein-restricted diet) diet for 6 weeks. Afterward, mice received an HFD or not for 8 weeks (mice fed a control diet and HFD [CH] and mice fed a protein-restricted diet and HFD [RH]). RH mice showed lower weight gain and fat accumulation and did not show an increase in fasting plasma glucose and insulin levels compared with CH mice. RH mice showed higher energy expenditure, increased citrate synthase, peroxisome-proliferator-activated receptor gamma coactivator 1-alpha protein content, and higher levels of malate and α-ketoglutarate compared with CH mice. Moreover, RH mice showed increased AMPc-dependent kinase and acetyl coenzyme-A (CoA) carboxylase phosphorylation, lower intramuscular triacylglycerol content, and similar malonyl-CoA levels. In conclusion, protein undernourishment after weaning does not potentiate fat accumulation and insulin resistance in adult young mice fed an HFD. This outcome seems to be associated with increased skeletal muscle mitochondrial oxidative capacity and reduced lipids accumulation.

Maternal protein malnutrition induces autism-like symptoms in rat offspring.

Objective: We tested the correlation between maternal protein malnutrition and autistic-like symptoms using behavioral tests in rodents that measure main behavioral characteristics observed in humans with autism spectrum disorder (ASD). Methods: Pregnant female rats were fed a normal diet or a hypoproteic diet during gestation and lactation periods. The litters were weighed every 3 days during lactation, and the offspring were tested in behavioral tasks during infancy (postnatal day (PND) 5: quantification of ultrasonic vocalizations; PND 13: homing behavior test) and adolescence (PND 30-32: open field, hole-board, play social behavior, and object recognition tests) in order to capture the prevalence of some of the core and associated symptoms of ASD. Results: Litters of the hypoproteic diet group had a lesser weight gain during lactation. In addition, pups of dams fed with a hypoproteic diet vocalized less compared to those fed with a normal diet, and they showed impaired social discrimination abilities in the homing behavior test. In adolescence, both male and female offspring of the hypoproteic diet group showed no impairment in locomotor activity; however, they exhibited stereotypic behavior in the hole-board test and a decrease in social play behaviors. Male offspring showed increased interest in exploring a familiar object rather than a novel object. Conclusion: Our results show that maternal protein malnutrition in rats causes offspring behaviors that resemble core and associated ASD symptoms.

Hydroalcoholic extract of Brazilian green propolis modulates inflammatory process in mice submitted to a low protein diet.

The occurrence of inflammation and protein malnutrition is an aggravating risk factor for morbidity and mortality in the clinical setting. The green propolis, a natural product made by Apis mellifera bees from Baccharis dracunculifolia resin, has therapeutic potential to modulate chronic inflammation. However, its effect on inflammation in an impaired nutritional status is not known. The aim of this study was to characterize the effects of the administration of the hydroalcoholic extract of the green propolis in the chronic inflammatory process of mice submitted to a low-protein diet. For this, we used the subcutaneous implantation of sponge disks as an inflammatory model and the animals were distributed in the following groups: standard protein diet (12% protein content), control treatment; standard protein diet, propolis treatment; low-protein diet (3% protein content), control treatment; low-protein diet, propolis treatment. Propolis was given daily at a dose of 500 mg/kg (p.o.) during a period of 7 or 15 days. Our main findings show that animals fed with standard protein diet and treated with propolis had low levels of red blood cells, hemoglobin, and hematocrit, with the subsequent reestablishment of these levels, in addition to monocyte count elevation and higher TNF levels after one week of treatment. In the low-protein diet group, the propolis treatment provided a significant recovery in weight and maintenance of total serum protein levels at the end of two weeks of treatment. Histological analysis showed propolis reduced the inflammatory infiltrate in the sponges of both standard and low-protein diet groups. In addition, the propolis extract presented antiangiogenic effect in both groups. Therefore, our data suggests that the hydroalcoholic extract of the green propolis promotes weight recovery and avoid the reduction of protein levels, in addition to inhibit inflammation and angiogenesis in animals fed with a low-protein diet.

Protein malnutrition effects of perivascular bone marrow microenvironment on the regulation of hematopoiesis / Efeitos da desnutrição proteica sobre o microambiente perivascular medular na regulação da hematopoese

Protein malnutrition (PM) causes anemia and leukopenia by reduction of hematopoietic precursors and impaired production of mediators that induce hematopoiesis, as well as structural and ultrastructural changes in the bone marrow (BM) extracellular matrix. Hematopoiesis occurs in the bone marrow (BM) in distinct regions called niches, which modulate the processes of differentiation, proliferation and self-renewal of the hematopoietic stem cell (HSC). The perivascular niche, composed mainly by mesenchymal stem cells (MSC) and endothelial cells (EC), is the major modulator of HSC and its function extends to the migration of mature hematopoietic cells into the peripheral blood through the production of cytokines and growth factors. Thus, our hypothesis is that PM changes the perivascular niche and our objective is to evaluate whether PM affects the modulatory capacity of MSC and EC on hematopoiesis. C57BL/6 male mice were divided into Control and Malnourished groups, which received for 5 weeks, respectively, a normal protein diet (12% casein) and a low protein diet (2% casein). After this period, animals were euthanized, nutritional and hematological evaluations were performed, featuring the PM. We performed leukemic myelo-monoblasts cells transplantation and observed that these cells have a lower proliferation rate and are rather in the cell cycle G0/G1 phases in malnourished mice, indicating that the BM microenvironment is compromised in PM. MSC were isolated, characterized and differentiated in vitro into EC cells, which were evidenced by CD31 and CD144 markers. We performed the quantification of HSC and hematopoietic progenitors, as well as some regulators of proliferation and differentiation, ex vivo and after cultures with MSC or EC. We observed that PM reduces HSC and hematopoietic progenitors ex vivo. In PM, MSC promote increase in HSC and suppress hematopoietic differentiation, whereas ECs induce cell cycle arrest. Additionally, we verified that PM affects granulopoesis by decreasing the expression of G-CSFr in granule-monocytic progenitors. Thus, we conclude that PD compromises hematopoiesis due to intrinsic alterations in HSC, as well as alterations in the medullary perivascular niche

A desnutrição proteica (DP) provoca anemia e leucopenia decorrente da redução de precursores hematopoéticos e comprometimento da produção de mediadores indutores da hematopoese. A hematopoese ocorre na medula óssea (MO) em regiões distintas chamadas de nichos, que modulam os processos de diferenciação, proliferação e auto renovação da célula tronco hematopoiética (CTH). O microambiente perivascular, composto principalmente por células tronco mesenquimais (CTM) e células endoteliais (CE), é o principal modulador das CTH e sua função se estende até a migração das células hematopoiéticas maduras para o sangue periférico, através da produção de citocinas e fatores de crescimento. Dessa forma, nossa hipótese é que a DP altera o microambiente perivascular e objetivamos avaliar se a DP afeta a capacidade modulatória das CTM e CE sobre a hematopoese. Utilizamos camundongos C57BL/6 machos, divididos em grupos Controle e Desnutrido, sendo que o grupo Controle recebeu ração normoproteica (12% caseína) e o grupo Desnutrido recebeu ração hipoproteica (2% caseína), ambos durante 5 semanas. Após este período, os animais foram eutanasiados, foi realizada a avaliação nutricional e hematológica, caracterizando a DP. Realizamos transplantes de mielomonoblastos leucêmicos e observamos que estas células apresentam menor taxa de proliferação e se encontram em maior quantidade nas fases G0/G1 do ciclo celular em camundongos desnutridos, indicando que o microambiente medular está comprometido. Isolamos CTM, que foram caracterizadas e diferenciadas in vitro em CE, o que foi evidenciado pelos marcadores CD31 e CD144. Quantificamos CTH e progenitores hematopoéticos, bem como reguladores de proliferação e diferenciação, ex vivo e após culturas com CTM ou CE. Observamos que a DP reduz CTH e progenitores hematopoéticos ex vivo. Na DP, as CTM promovem incremento de CTH e suprimem a diferenciação hematopoética, enquanto que as CE induzem parada no ciclo celular. Adicionalmente, observamos que a DP afeta a granulopoese por diminuição da expressão de G-CSFr nos progenitores grânulo-monocíticos. Dessa forma, concluímos que a DP compromete a hematopoese por alterações intrínsecas na CTH, como também por alterações ocasionadas no microambiente perivascular medular

Influence of protein malnutrition on cutaneous wound healing in rats / Impacto da desnutrição proteica na cicatrização de feridas cutâneas em ratos

ABSTRACT Objective Investigate histological changes related to inflammatory response and collagen expression during wound healing in rats with protein malnutrition. Methods Twenty male Wistar rats underwent cutaneous surgery and were divided into two experimental groups: Malnourished (8% casein diet); Nourished (17% casein diet). Animals were euthanized after 5th and 10th days, descriptive and quantitative analyses were performed on sections stained with hematoxylin-eosin and sirius red, respectively. Statistical analysis of data using nonparametric Fisher's exact test with p<0.05 was carried out. Results At five days, increased fibroblast proliferation (p<0.01) and collagen expression (p<0.05) was observed in N5 group. After ten days, N10 and MN10 animals showed higher amount of granulation tissue and edema/inflammatory infiltrate independent of nutritional status (p>0.05), only N10 group showed fibroblast proliferation (p<0.01) and increased collagen expression (p<0.01). Conclusion Protein malnutrition seems not to influence inflammatory phase of healing, whereas it negatively effects fibroblast proliferation and collagen synthesis.

RESUMO Objetivo Investigar as alterações histológicas relacionadas à resposta inflamatória e à expressão de colágeno durante a cicatrização em ratos com desnutrição protéica. Métodos Vinte ratos Wistar machos foram submetidos à cirurgia cutânea e divididos em dois grupos experimentais: Desnutridos (dieta com caseína a 8%); Nutridos (17% de dieta com caseína). Animais foram eutanasiados após 5 e 10 dias, análises descritivas e quantitativas foram realizadas em cortes corados com hematoxilina-eosina e sirius vermelho, respectivamente. Análise estatística dos dados utilizando teste exato não paramétrico de Fisher com p<0,05 foi realizada. Resultados Aos cinco dias, observou-se aumento da proliferação fibroblástica (p<0,01) e expressão de colágeno (p<0,05) no grupo N5. Após 10 dias, animais N10 e MN10 apresentaram maior quantidade de tecido de granulação e edema/infiltrado inflamatório independente do estado nutricional (p>0,05), apenas grupo N10 apresentou proliferação fibroblástica (p<0,01) e aumento da expressão de colágeno (p<0,01). Conclusão A desnutrição protéica parece não influenciar na fase inflamatória da cicatrização, porém afeta negativamente a proliferação de fibroblastos e a síntese de colágeno.