A novel adenine-based diruthenium(III) complex: Synthesis, crystal structure, electrochemical properties and evaluation of the anticancer activity.

Metal complexes based on purine nucleobases can be a very useful tool in the diagnosis and treatment of some diseases as well as in other biomedical applications. We have prepared and characterized a novel dinuclear ruthenium(III) complex based on the nucleobase adenine of formula [{Ru(µ-Cl)(µ-Hade)}2Cl4]Cl2·2H2O (1) [Hade = protonated adenine]. Complex 1 was characterized through Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy and energy dispersive X-ray analysis (SEM-EDX), magnetometer (SQUID) and cyclic voltammetry (CV) techniques. The crystal structure of 1 was determined by single-crystal X-ray diffraction. 1 crystallizes in the monoclinic system with space group P21/n. Each ruthenium(III) ion is six-coordinate and bonded to four Cl atoms [the average value of the RuIII-Cl bonds lengths is ca. 2.329(1) Å] and two N atoms (N3 and N9) from two adenine molecules, the N1 atom being protonated in both of them. The anticancer activity was evaluated through cell viability assays performed on a colon cancer (HCT116) and a gastric cancer cell lines (AGS), 1 showing an incipient anticancer effect on the AGS cell line at the highest concentration used in the study.

Uso de probióticos en la prevención de enterocolitis necrotizante / Use of probiotics in the prevention of necrotizing enterocolitis

INTRODUCCIÓN: La enterocolitis necrotizante (ECN) es una patología inflamatoria del sistema digestivo, potencialmente mortal, que afecta a los recién nacidos. Ocurre con mayor frecuencia en recién nacidos prematuros y en especial en aquellos con muy bajo peso de nacimiento (RNMBPN) y extremo bajo peso de nacimiento (RNEBPN). Su fisiopatología es multifactorial, sin embargo, se postula disbiosis intestinal es un factor patogénico importante en su desarrollo. Por consiguiente, se ha propuesto que la administración de probióticos podría tener un rol en la prevención de la ECN en pacientes con alto riesgo. OBJETIVO: Realizar una búsqueda bibliográfica con el objetivo de conocer la evidencia existente en relación al efecto de los probióticos en recién nacidos. RESULTADOS: Los resultados de las revisiones sistemáticas y metanálisis revisados indican que la administración de probióticos reduce el riesgo de ECN, muerte y sepsis tardía en los RNMBPN, no obstante, en el grupo de RNEBPN aun hacen falta estudios. Los estudios que comparan diferentes estrategias de administración de probióticos señalan que los esquemas que incluyen la administración de una mezcla de 2 o más probióticos obtienen los mejores resultados en la prevención de ECN y muerte. Adicionalmente, algunos artículos sugieren un mejor efecto si los esquemas probióticos a utilizar, incluyen especies de los géneros Bifidobacterium y Lactobacillus. CONCLUSIÓN: Existe evidencia en la literatura especializada que apoya el uso de los probióticos en la prevención de ECN y otros desenlaces adversos en los recién nacido prematuros.

Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease of the digestive system that affects newborns. It occurs most frequently in preterm infants and especially in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. Its pathophysiology is multifactorial; however, intestinal dysbiosis is postulated to be an important pathogenic factor in its development. Therefore, it has been proposed that the administration of probiotics may have a role in the prevention of NEC in high-risk patients. This update presents a brief overview of the evidence regarding the effect of probiotics in neonates. The results of the systematic reviews and meta-analyses reviewed indicate that probiotic administration reduces the risk of NEC, death and late sepsis in VLBW infants, however, studies are still lacking in the ELBW group. Studies comparing different probiotic administration strategies indicate that schemes that include the administration of a mixture of 2 or more probiotics obtain the best results in the prevention of NEC and death. Additionally, there is some evidence to favor schemes that include species of the genera Bifidobacterium and Lactobacillus. CONCLUSION: There is evidence in the specialized literature that supports probiotic administration may reduces the risk of NEC and other adverse outcomes in preterm infants.

El contacto piel a piel como promotor de la lactancia materna, y su posible relación con la disminución de la hiperbilirrubinemia / Skin-to-skin contact as a promoter of breastfeeding, and its possible relationship with the reduction of hyperbilirubinemia

INTRODUCCIÓN: El contacto piel a piel (CPP) postparto es una práctica de atención de salud fuertemente aconsejada por la OMS, por los beneficios a largo y a corto plazo que conlleva tanto para la salud de la madre como para la del recién nacido. OBJETIVO: Realizar una búsqueda bibliográfica con el objetivo de determinar los beneficios que tiene la CPP durante el periodo del postparto inmediato sobre la lactancia materna (LM) y la ictericia neonatal (IN). RESULTADOS: Los resultados muestran que el CPP aumenta diversos indicadores de éxito de lactancia materna, dentro de los cuales destacan: aumento en la efectividad de la primera lactancia, mayor probabilidad de mantener la LM a 4 meses, aumento del periodo de LM en promedio, mayor probabilidad de LM exclusiva a 6 meses. No se encontraron mayores beneficios al iniciar el CPP antes de los 10 minutos, ni al prolongarlo más de 60 minutos. Además, el CPP indirectamente disminuye la probabilidad de presentar IN, debido a que aumenta la frecuencia de LM, indicador que se asocia de manera indirecta a los niveles de bilirrubina en el recién nacido. CONCLUSIÓN: La revisión de la literatura especializada nos permite concluir que el contacto temprano entre la madre y su hijo en sala de partos, piel a piel, tiene efectos significativamente positivos en la lactancia materna y puede llegar a representar un factor protector de la hiperbilirrubinemia no conjugada en el RN.

Postpartum skin-to-skin contact (SSC) is a health care practice strongly advised by the WHO because of the long- and short-term benefits for both maternal and newborn health. This update summarizes the main findings supporting the recommendation to perform SSC during the immediate postpartum period, specifically the benefits on breastfeeding (BF) and neonatal jaundice (NI). The results show that SSC increases several indicators of breastfeeding success, including: increased effectiveness of the first breastfeeding, greater probability of maintaining BF at 4 months, increased BF period on average, greater probability of exclusive BF at 6 months. No greater benefits were found when initiating SSC before 10 minutes, nor when prolonging it for more than 60 minutes. In addition, SSC indirectly decreases the probability of presenting NI, because it increases the frequency of BF, an indicator that is indirectly associated with bilirubin levels in the newborn. CONCLUSION: A review of the specialized literature allows us to conclude that postpartum skin-to-skin contact (SSC) has significantly positive effects on breastfeeding and may represent benefits in bilirubin levels in the newborn.

Functionality of tRNAs encoded in a mobile genetic element from an acidophilic bacterium.

The genome of the acidophilic, bioleaching bacterium Acidithiobacillus ferrooxidans, strain ATCC 23270, contains 95 predicted tRNA genes. Thirty-six of these genes (all 20 species) are clustered within an actively excising integrative-conjugative element (ICEAfe1). We speculated that these tRNA genes might have a role in adapting the bacterial tRNA pool to the codon usage of ICEAfe1 genes. To answer this question, we performed theoretical calculations of the global tRNA adaptation index to the entire A. ferrooxidans genome with and without the ICEAfe1 encoded tRNA genes. Based on these calculations, we observed that tRNAs encoded in ICEAfe1 negatively contribute to adapt the tRNA pool to the codon use in A. ferrooxidans. Although some of the tRNAs encoded in ICEAfe1 are functional in aminoacylation or protein synthesis, we found that they are expressed at low levels. These findings, along with the identification of a tRNA-like RNA encoded in the same cluster, led us to speculate that tRNA genes encoded in the mobile genetic element ICEAfe1 might have acquired mutations that would result in either inactivation or the acquisition of new functions.

Nuclear DNA replication and repair in parasites of the genus Leishmania: Exploiting differences to develop innovative therapeutic approaches.

Leishmaniasis is a common tropical disease that affects mainly poor people in underdeveloped and developing countries. This largely neglected infection is caused by Leishmania spp, a parasite from the Trypanosomatidae family. This parasitic disease has different clinical manifestations, ranging from localized cutaneous to more harmful visceral forms. The main limitations of the current treatments are their high cost, toxicity, lack of specificity, and long duration. Efforts to improve treatments are necessary to deal with this infectious disease. Many approved drugs to combat diseases as diverse as cancer, bacterial, or viral infections take advantage of specific features of the causing agent or of the disease. Recent evidence indicates that the specific characteristics of the Trypanosomatidae replication and repair machineries could be used as possible targets for the development of new treatments. Here, we review in detail the molecular mechanisms of DNA replication and repair regulation in trypanosomatids of the genus Leishmania and the drugs that could be useful against this disease.

Are leukotriene inhibitors useful for bronchiolitis? / ¿Tienen utilidad los inhibidores de leucotrienos en bronquiolitis?

Bronchiolitis is a prevalent disease in children under two years of age, which carries significant morbidity and mortality. However, there is controversy regarding the optimal therapeutic management. Leukotriene inhibitors have been proposed as an alternative, although its efficacy is not clear yet. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified two systematic reviews comprising six trials addressing the question of this article. We extracted data, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded leukotriene inhibitors might not decrease mortality levels on bronchiolitis patients and it is not clear whether they decrease length of hospital stay. They might reduce recurrent wheezing, but the certainty of the evidence is low, and they increase adverse effects.

Benefits of Regular Exercise on Inflammatory and Cardiovascular Risk Markers in Normal Weight, Overweight and Obese Adults.

Obesity is a worldwide epidemic that increases the risk of several well-known co-morbidities. There is a complicated relationship between adipokines and low-grade inflammation in obesity and cardiovascular disease (CVD). Physical activity practices have beneficial health effects on obesity and related disorders such as hypertension and dyslipidemia. We investigated the effects of 6 and 12 months of moderate physical training on the levels of adipokines and CVD markers in normal weight, overweight and obese volunteers. The 143 participants were followed up at baseline and after six and twelfth months of moderate regular exercise, 2 times a week, for 12 months. The volunteers were distributed into 3 groups: Normal Weight Group (NWG,), Overweight Group (OVG) and Obese Group (OBG). We evaluated blood pressure, resting heart rate, anthropometric parameters, body composition, fitness capacity (VO2max and isometric back strength), cardiovascular markers (CRP, total cholesterol, LDL-c, HDL-c, homocysteine) and adipokine levels (leptin, adiponectin, resistin, IL-6 and TNF-alpha). There were no significant changes in anthropometric parameters and body composition in any of the groups following 6 and 12 months of exercise training. Leptin, IL-6 levels and systolic blood pressure were significantly elevated in OBG before the training. Regular exercise decreased HDL-c, leptin, adiponectin and resistin levels and diastolic blood pressure in OVG. In OBG, exercise diminished HDL-c, homocysteine, leptin, resistin, IL-6, adiponectin. Moderate exercise had no effect on the body composition; however, exercise did promote beneficial effects on the low-grade inflammatory state and CVD clinical markers in overweight and obese individuals.

Niveles de aluminio sérico en un grupo de pacientes con enfermedad de Alzheimer / Serum levels of aluminum in a group of patients with Alzheimer's disease / Níveis séricos de alumínio em um grupo de pacientes com doença de Alzheimer

La Enfermedad de Alzheimer (EA) es una patología neurodegenerativa frecuente en la población senil. Clínicamente se caracteriza por la pérdida progresiva de la memoria y otras habilidades cognitivas. Se han propuesto diversas causas como desencadenantes de la EA, entre las cuales se encuentran factores ambientales como malnutrición, lesiones a nivel craneal y exposición al aluminio (Al), debido a que este metal es una sustancia neurotóxica. El objetivo del presente estudio fue evaluar los niveles de aluminio sérico en pacientes con enfermedad de Alzheimer, internados en un geriátrico en el municipio Veroes, Estado Yaracuy, durante el período mayo-junio de 2013. La muestra estuvo conformada por 22 pacientes con EA, y el grupo control estuvo representado por 12 pacientes sin EA. Las concentraciones de aluminio sérico fueron determinadas por Espectrofotometría de Absorción Atómica Electrotérmica (ETAAS) con horno de grafito. Se obtuvieron valores de la mediana de aluminio sérico de 2,15 mg/L, con un máximo de elevación de 3,0 mg/L para el grupo con EA, mientras que el control fue de 1,60 mg/L, con un máximo de 3,30 mg/L. Ninguno de los pacientes presentaron niveles de Al sérico por encima del límite permisible. Se observaron cifras superiores de este metal en los pacientes con EA en comparación con el grupo control, además de ser significativamente mayores en el género femenino y en aquellos que consumían antiácidos.

Alzheimer's disease (AD) is a common neurodegenerative disorder in the elderly population. It is clinically characterized by progressive loss of memory and other cognitive skills. There are several proposed AD causes as triggers, among which are environmental factors including malnutrition, cranial injuries and exposure level aluminum (Al), because this metal is a neurotoxic substance. The aim of this study was to evaluate serum aluminum levels in patients with Alzheimer's disease, institutionalized in Veroes town, Yaracuy state during May-June 2013 period. The sample consisted of 22 patients with AD and the control group was represented by 12 patients without AD. Serum aluminum concentrations were determined by Electrothermal Atomic Absorption Spectrophotometry (ETAAS) with graphite furnace. Median values of serum aluminum of 2.15 mg/L, with a maximum height of 3.0 mg/L for the AD group were obtained, while the control was 1.60 mg/L, with a maximum of 3.30 mg/L. None of the patients had serum Al levels above the allowable limit. Higher figures of this metal were observed in patients with AD compared with the control group, as well as being significantly higher in females and in those eating antacids.

A doença de Alzheimer (DA) é uma desordem neurodegenerativa frequente na população idosa. Clinicamente caracteriza-se pela perda progressiva da memória e outras habilidades cognitivas. Várias causas têm sido propostas como gatilhos para DA, incluindo fatores ambientais tais como a desnutrição, lesões cranianas e exposição de alumínio (Al), devido a que este metal é uma substância neurotóxica. O objetivo deste estudo foi avaliar os níveis de alumínio sérico em pacientes com doença de Alzheimer, hospitalizados na cidade Veroes, Estado Yaracuy, durante o período maio-junho de 2013. A mostra consistiu de 22 pacientes com DA e o grupo controle foi representado por 12 pacientes sem DA. Concentrações de alumínio sérico foram determinadas por Espectrofotometria de Absorção Atômica Eletrotérmica (ETAAS) com forno de grafite. Os valores da mediana de alumínio sérico de 2,15 mg/L, com uma altura máxima de 3,0 mg/L para o grupo DA foram obtidos, enquanto que para o grupo controle foi de 1,60 mg/L, com um máximo de 3,30 mg/L. Nenhum dos pacientes tinha níveis séricos de Al acima do limite permitido. Foram observados valores mais elevados deste metal nos pacientes com DA em comparação com o grupo controle, além de ser significativamente maior no sexo feminino e nas pessoas que consumiam antiácidos.

Niveles de aluminio sérico en un grupo de pacientes con enfermedad de Alzheimer / Serum levels of aluminum in a group of patients with Alzheimers disease / Níveis séricos de alumínio em um grupo de pacientes com doenþa de Alzheimer

La Enfermedad de Alzheimer (EA) es una patología neurodegenerativa frecuente en la población senil. Clínicamente se caracteriza por la pérdida progresiva de la memoria y otras habilidades cognitivas. Se han propuesto diversas causas como desencadenantes de la EA, entre las cuales se encuentran factores ambientales como malnutrición, lesiones a nivel craneal y exposición al aluminio (Al), debido a que este metal es una sustancia neurotóxica. El objetivo del presente estudio fue evaluar los niveles de aluminio sérico en pacientes con enfermedad de Alzheimer, internados en un geriátrico en el municipio Veroes, Estado Yaracuy, durante el período mayo-junio de 2013. La muestra estuvo conformada por 22 pacientes con EA, y el grupo control estuvo representado por 12 pacientes sin EA. Las concentraciones de aluminio sérico fueron determinadas por Espectrofotometría de Absorción Atómica Electrotérmica (ETAAS) con horno de grafito. Se obtuvieron valores de la mediana de aluminio sérico de 2,15 mg/L, con un máximo de elevación de 3,0 mg/L para el grupo con EA, mientras que el control fue de 1,60 mg/L, con un máximo de 3,30 mg/L. Ninguno de los pacientes presentaron niveles de Al sérico por encima del límite permisible. Se observaron cifras superiores de este metal en los pacientes con EA en comparación con el grupo control, además de ser significativamente mayores en el género femenino y en aquellos que consumían antiácidos.(AU)

Alzheimers disease (AD) is a common neurodegenerative disorder in the elderly population. It is clinically characterized by progressive loss of memory and other cognitive skills. There are several proposed AD causes as triggers, among which are environmental factors including malnutrition, cranial injuries and exposure level aluminum (Al), because this metal is a neurotoxic substance. The aim of this study was to evaluate serum aluminum levels in patients with Alzheimers disease, institutionalized in Veroes town, Yaracuy state during May-June 2013 period. The sample consisted of 22 patients with AD and the control group was represented by 12 patients without AD. Serum aluminum concentrations were determined by Electrothermal Atomic Absorption Spectrophotometry (ETAAS) with graphite furnace. Median values of serum aluminum of 2.15 mg/L, with a maximum height of 3.0 mg/L for the AD group were obtained, while the control was 1.60 mg/L, with a maximum of 3.30 mg/L. None of the patients had serum Al levels above the allowable limit. Higher figures of this metal were observed in patients with AD compared with the control group, as well as being significantly higher in females and in those eating antacids.(AU)

A doenþa de Alzheimer (DA) é uma desordem neurodegenerativa frequente na populaþÒo idosa. Clinicamente caracteriza-se pela perda progressiva da memória e outras habilidades cognitivas. Várias causas tÛm sido propostas como gatilhos para DA, incluindo fatores ambientais tais como a desnutriþÒo, les§es cranianas e exposiþÒo de alumínio (Al), devido a que este metal é uma substÔncia neurotóxica. O objetivo deste estudo foi avaliar os níveis de alumínio sérico em pacientes com doenþa de Alzheimer, hospitalizados na cidade Veroes, Estado Yaracuy, durante o período maio-junho de 2013. A mostra consistiu de 22 pacientes com DA e o grupo controle foi representado por 12 pacientes sem DA. Concentraþ§es de alumínio sérico foram determinadas por Espectrofotometria de AbsorþÒo At¶mica Eletrotérmica (ETAAS) com forno de grafite. Os valores da mediana de alumínio sérico de 2,15 mg/L, com uma altura máxima de 3,0 mg/L para o grupo DA foram obtidos, enquanto que para o grupo controle foi de 1,60 mg/L, com um máximo de 3,30 mg/L. Nenhum dos pacientes tinha níveis séricos de Al acima do limite permitido. Foram observados valores mais elevados deste metal nos pacientes com DA em comparaþÒo com o grupo controle, além de ser significativamente maior no sexo feminino e nas pessoas que consumiam antiácidos.(AU)

Removal of Cu(II) ions from aqueous streams using poly(acrylic acid-co-acrylamide) hydrogels.

The adsorption of Cu(II) ions from aqueous solutions onto poly(acrylic acid-co-acrylamide) hydrogels was investigated. The hydrogels were prepared via free-radical solution polymerization using Irgacure 754 as a photoinitiator and ethylene glycol dimethacrylate as a cross-linking agent. Loading of acrylamide/acrylic acid moieties on the surfaces of hydrogels and the amount of cross-linking agent were varied to determine the maximum metal uptake. Polymerization kinetics was investigated by (1)H NMR. The physicochemical properties of hydrogels were investigated by nitrogen sorption measurements, elemental analysis, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). The (1)H NMR results demonstrated that the polymerization reaction was carried out almost to completion and confirmed the absence of residual monomers. Swelling results indicated that, by appropriate selection of cross-linking agent amount and monomer ratio, hydrogels can be swollen up to 70,000%. Further characterization of the hydrogels showed rapid adsorption kinetics and equilibrium Cu(II) adsorption capacities of 121 mg g(-1). Cu(II) adsorption kinetic data followed pseudo-first-order kinetics. Adsorption equilibrium data were better fitted by a Langmuir isotherm. FTIR and XPS results indicated the presence of a tetradentate copper complex on the surfaces of hydrogels. The copper uptake achieved suggests the potential use of hydrogels to extract toxic metals from industrial aqueous streams.

Capacidad respiratoria, niveles de vitamina C y malonilaldehído en estudiantes de bioanálisis fumadores y no fumadores / Respiratory capacity, vitamin C and malonilaldehyde levels in smokers and non smokers students of bioanalysis

Diversos autores señalan las implicaciones de fumar en la alteración de la capacidad respiratoria y del sistema oxida ción/an - tioxidación y la importancia de la detección de las mismas para contribuir en la prevención de diversas patologías. La presente investigación plantea evaluar la capacidad respiratoria y los niveles de vitamina C (VC) y malonilaldehído (MDA) de fumadores y no fumadores. Participaron 50 estudiantes de Bioanálisis de ambos sexos, clasificados según la Organización Mundial de la Salud en fumadores diarios (FD), fumadores ocasionales (FO) y no fumadores (NF). Los parámetros evaluados fueron: volumen espiratorio forzado en el primer segundo (VEF1) y la capacidad vital forzada (CVF), niveles de VC y MDA. Los resultados presentados como X +/- DS y porcentajes y analizados por ANOVA, fueron: El 69,2% y 84,6% de los estudiantes (FD, FO) presentaron valores normales de CVF y VEF, sin diferencias estadísticamente significativas con los NF. Los niveles de VC (mg/dl.) fueron 1,19 ± 0,30 (NF) con 1,12 ± 0,09 (FO) sin diferencias significativas entre ellos y el MDA (µm/l) mostró un aumento estadísticamente significativo (p < 0,05) en los F.O. (1,56 ± 0,5) con respecto a los NF (0,99 ± 0,60). Se concluye que los valores de MDA mostraron un aumento significativo en los FO, que se corresponden con manifestaciones de estrés oxidativo. Sin embargo, los niveles de vitamina C, aunque se mostraron más bajos en el grupo FO, no evidenciaron diferencias significativas al igual que los índices espirométricos.

Several authors have shown the implications of smoking in the alteration of respiratory capacity and oxidation / antioxidation system and the importance of screening them for help in preventing various diseases. In the present investigation was to assess respiratory capacity and vitamin C (VC) and malondialdehyde (MDA) levels of smokers and non smokers. Partici - pated 50 bioanalysis students both sexes, classified by the World Health Organization in daily smokers (DF), occasional smokers (OF) and non-smokers (NF). The evaluated parameters were: forced expiratory volume in first second (FEV1) and forced vital capacity (FVC), levels of VC and malonilaldehyde. Results presented as X ± SD and percentages and statistically analyzed by ANOVA, were 69,2% and 84,6% of students (DF, OF) had normal values of FVC and FEV, respectively, without differences significant height. VC levels (mg/dl) Were 1.19 ± 0.30 (NF) with 1.12 ± 0.09 (OF) without significant differences between them and the MDA (ìm/l) showed a statistically significant increase (p<0.05) their values in OF (1.56 ± 0.5) with res pect to NF (0.99 ± 0.60). We conclude that the values of MDA showed a significant increase in OF, which correspond to manifestations of oxidative stress. However, vitamin C levels, though were lower in FO group, showed no significant differences as well as spirometry.

CD8+ cell noncytotoxic anti-HIV response: restoration by HAART in the late stage of infection.

Highly active antiretroviral therapy (HAART) is currently the best HIV infection management strategy. However, its effects on the CD8+ T cell noncytotoxic anti-HIV response (CNAR) are not well known. We investigated if HAART has different effects on CNAR in patients at the intermediate and late stages of HIV infection. Untreated healthy HIV-infected subjects with a mean CD4+ T cell count of 606 cells/microl were examined as a reference group. Plasma viral load, CD4+ T cell count, and CNAR activity were measured at baseline and regular intervals for at least 48 weeks following initiation of HAART. Baseline CNAR activity in all subjects correlated inversely with viral load and directly with CD4 T+ cell counts. The level of CNAR in the latestage group was significantly lower than in the intermediate-stage and the healthy reference group (p < 0.01). Following initiation of HAART, substantial increases in CD4+ T cell counts and decreases in viral loads were observed in both groups, indicating treatment success. CNAR activity was found to be increased significantly during HAART, but only in the late-stage group (p < 0.01). This increase in CD8+ cell function was seen within 4 weeks of treatment initiation and resulted in levels of CNAR activity almost equal to those observed in the healthy reference subjects. Our findings suggest a beneficial effect on CNAR in those individuals with reduced activity, typically in late-stage infection.