Dietary supplementation of milk fermented with probiotic Lactobacillus fermentum enhances systemic immune response and antioxidant capacity in aging mice

Although probiotics are known to enhance the host immune response, their roles in modulating immunosenescence, resisting infection, and improving redox homeostasis during aging remain unclear. Therefore, the present study was devised in aging mice to assess the antiimmunosenescence potential from the consumption of milk that is fermented with probiotic Lactobacillus fermentum MTCC 5898 (LF). We hypothesized that probiotic supplementation would boost immunity, improve antioxidant capacity, and resist severity of pathogenic infection in aging mice. To test this hypothesis, during a trial period of 2 months, 16-month-old male Swiss mice were kept on 3 experimental diets: basal diet (BD), BD supplemented with skim milk, and BD supplemented with probiotic LF-fermented milk. A concurrent analysis of several immunosenescence markers that include neutrophil functions, interleukins profile, inflammation and antibody responses in the intestine as well as analysis of antioxidant enzymes in the liver and red blood cells was performed. Neutrophil respiratory burst enzymes and phagocytosis increased significantly in probiotic LF-fed groups, whereas no exacerbation in plasma levels of monocyte chemotactic protein 1 and tumor necrosis factor α was observed. Splenocytes registered increased interferon-γ but decreased interleukin 4 and interleukin 10 production, whereas humoral antibodies registered decreases in immunoglobulin G1 (IgG1)/IgG2a ratio and IgE levels in the probiotic-fed groups. Antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in LF-fed groups showed increased activities, which were more pronounced in the liver than in red blood cell. An Escherichia coli–based infection model in aging mice was also designed to validate the protective attributes of LF. Administration of probiotic LF significantly reduced E coli population in organs (intestine, liver, spleen, and peritoneal fluid), as compared with control groups, by enhancing E coli–specific antibodies and inflammatory proteins. Based on these results, it appears that LF supplementation alleviated immunosenescence, enhanced antioxidant enzyme activities, and resisted E coli infection in aging mice; thereby, signifying its potential in augmenting healthy aging.     

Development of chondrosarcoma animal models for assessment of adjuvant therapy

Chondrosarcoma is a primary cancer of bone causing significant morbidity due to local recurrence and limited treatment options. Relatively few chondrosarcoma animal models have been developed, and the only orthotopic model is technically demanding and has limited clinical relevance. The aim of this review is to assess the features of current animal chondrosarcoma models for the purpose of developing new models in which to test adjuvant chondrosarcoma therapy. The available literature on this topic was identified using the PubMed database, and then analysed for relevance to the human chondrosarcoma disease and feasibility in testing new therapeutic agents. Animal‐derived chondrosarcoma models comprise predominantly allograft tumour transplanted into the rat (Swarm rat chondrosarcoma) or the hamster. These types of models are less relevant to the human disease and have been more useful for evaluation of chondrosarcoma growth and histology than in developing novel therapeutic agents. The athymic nude mouse has enabled reliable human xenograft transplantation. A number of human chondrosarcoma cell lines have been successfully used to generate tumours in this species, including OUMS‐27 and HCS‐2/A. Although effective in demonstrating anti‐tumour effects of a number of agents, the lack of a representative orthotopic model diminishes overall clinical relevance. More clinically relevant models of human chondrosarcoma progression are required either through transgenic mice or orthotopic human xenograft models.     

Role of Intraoperative Sentinel Lymph Node Mapping in the Management of Carcinoma of the Esophagus

Background/Aim:

Precise evaluation of lymph node status is one of the most important factors in determining clinical outcome in treating gastro-intestinal (GI) cancer. Sentinel lymph node (SLN) mapping clearly has become highly feasible and accurate in staging GI cancer. This study aims to investigate the feasibility and accuracy of detection of SLN using methylene blue dye in patients with carcinoma of the esophagus and assess its potential role in determining the rational extent of lymphadenectomy in esophageal cancer surgery.

Materials and Methods:

Thirty-two patients of esophageal cancer diagnosed on endoscopic biopsy were enrolled in this prospective study. After laparotomy, patent methylene blue was injected into the subserosal layer adjacent to the tumor. SLNs were defined as blue stained nodes within a period of 5 min. Standard radical esophagogastrectomy with lymphadenectomy was performed in all the patients. All the resected nodes were examined postoperatively by routine hematoxylin and eosin stain for elucidating the presence of metastasis, and the negative SLNs were examined further with cytokeratin immunohistochemical staining.

Results:

SLNs were detected in 26 (81.25%) patients out of 32 patients who were studied. The number of SLNs ranged from 1 to 4 with a mean value of 1.7 per case. The SLNs of esophageal cancer were only found in N1 area in 21 (80.77%) cases, and in N2 or N3 area in only 19.33%. The overall accuracy of the procedure was 75% in predicting nodal metastasis. SLN had a sensitivity of 85.71% in mid esophageal tumors and 93.33% in lower esophageal tumors. The SLN biopsy had sensitivity of 87.5% in the case of squamous cell carcinoma and 92.86% in the cases of adenocarcinoma of the esophagus. The accuracy of the procedure for squamous cell carcinoma and adenocarcinoma was 60% and 76.47%, respectively.

Conclusion:

SLN mapping is an accurate diagnostic procedure for detecting lymph node metastasis in patients with esophageal cancer and may indicate rational extent of lymphadenectomy in these patients. SLN mapping provides “right nodes” to the pathologists for detailed analysis and appropriate staging, thereby helping in individualizing the multi-modal treatment for esophageal cancer.     

Macrophage activation syndrome in malaria

Macrophage activation syndrome (MAS) is a clinical syndrome caused by an excessive proliferation of T lymphocytes and well-differentiated macrophages; an entity distinct from malignant histiocytosis. Although rheumatologic conditions are the common cause of MAS, a wide range of infections are also seen to cause MAS. We report an adolescent with severe Plasmodium falciparum malaria and MAS. He fulfilled six out of eight criteria required to diagnose hemophagocytic lymphohistiocytosis.     

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis.

BACKGROUND: Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE: To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS: Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS: Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION: Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.     

4–1BB signal stimulates the activation,expansion, and effector functions of γδ T cells in mice and humans

We show here that the expression of 4–1BB is rapidly induced in γδ T cells following antigenic stimulation in both mice and humans, and ligation of the newly acquired 4–1BB with an agonistic anti‐4–1BB augments cell division and cytokine production. We further demonstrate that γδ rather than αβ T cells protect mice from Listeria monocytogenes (LM) infection and 4–1BB stimulation enhances the γδ T‐cell activities in the acute phase of LM infection. IFN‐γ produced from γδ T cells was the major soluble factor regulating LM infection. Vγ1⁺ T cells were expanded in LM‐infected mice and 4–1BB signal triggered an exclusive expansion of Vγ1⁺ T cells and induced IFN‐γ in these Vγ1⁺ T cells. Similarly, 4–1BB was induced on human γδ T cells and shown to be fully functional. Combination treatment with human γδ T cells and anti‐hu4–1BB effectively protected against LM infection in human γδ T cell‐transferred NOD‐SCID mice. Taken together, these data provide evidence that the 4–1BB signal is an important regulator of γδ T cells and induces robust host defense against LM infection.     

Dual immunoregulatory pathways of 4-1BB signaling

It is perhaps rare to encounter among the various immunologically competent receptor–ligand pairs that a single cell surface determinant unleashes both a hidden suppressive function and costimulation. 4-1BB, an activation-induced tumor necrosis factor receptor family member chiefly viewed as a powerful T-cell costimulatory molecule, is one such example. Accumulated evidence in recent years uncovered an unknown facet of in vivo 4-1BB signaling (i.e., “active suppression”). Although in vitro signaling via 4-1BB is shown to support both CD4⁺ and CD8⁺ T-cell responses, the same induces a predominant CD8⁺ T-cell response suppressing CD4⁺ T-cell function when applied in vivo. How, when, and why such dual immunoregulatory effect of anti-4-1BB monoclonal antibody (MAB) comes into play is currently the focus of intense research. Existing data, although not complete, uncover several important aspects of in vivo 4-1BB signaling in the amelioration or exacerbation of various immune disorders. Despite minor disagreements, a majority agree that upregulation of interferon (IFN)-γ is critical to anti-4-1BB MAB therapy in addition to immune modulators such as interleukin 2, transforming growth factor β, and indolamine 2,3-dioxygenase⁵, all of which contribute greatly to the success of anti-4-1BB MAB-based immunotherapy. Anti-4-1BB MAB-mediated expansion of novel CD11c⁺CD8⁺ T cells is additional weaponry that appears critical for its in vivo suppressive function. These CD11c⁺CD8⁺ T cells express high levels of IFN-γ, become effective killers, and mediate selective suppression of CD4⁺ T cells. In this review, we discuss the dual nature (costimulatory and suppressive) of 4-1BB-mediated immune regulation, its current status, future direction, and its impact on the immune system, with special reference to its immunotherapy.     

Role of endogenous 4-1BB in the development of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against nuclear antigens including nucleosomes and DNA. To determine the role of T-cell costimulatory molecule 4-1BB in the regulation of SLE, MRL-Fas(lpr) (lpr) mice deficient in 4-1BB (lpr/4-1BB(-/-)) were generated and their disease phenotype was compared to that of control lpr mice. The main finding of this study is that the lpr/4-1BB(-/-) mice had more pronounced skin lesions which appeared earlier, increased lymphadenopathy, increased renal damage, and higher mortality than 4-1BB-intact control lpr mice. The increased severity of lesions in lpr/4-1BB(-/-) mice was closely associated with increases in CD4(+) T, CD3(+) B220(+) double-negative T cells, serum immunoglobulin, anti-dsDNA autoantibodies, and tissue immunoglobulin deposits. These data suggest that the 4-1BB-4-1BB ligand signalling pathway plays an important role in SLE and that deletion of 4-1BB confers susceptibility to lpr mice, leading to accelerated induction of disease and early mortality.     

RET expression does not change with age in the substantia nigra pars compacta of rhesus monkeys

Parkinson's disease is characterized by bradykinesia, rigidity and a resting tremor and the underlying basis for those symptoms is the loss of dopaminergic cells in the nigrostriatal system. Similar to PD, an age-related decrease locomotor activity and the expression of tyrosine hydroxylase immunoreactivity has been observed in rhesus monkeys, but the reason for this decrease in dopaminergic function remains to be elucidated. Trophic factors such as glial cell line derived neurotrophic factor (GDNF) and neurturin sustain the dopaminergic phenotype in midbrain neurons and act through a common receptor tyrosine kinase (RET). Examination of RET expression by immunohistochemistry was performed on sections of tissue containing the substantia nigra pars compacta of young, middle, and old aged rhesus monkeys. Stereological estimates of the number and cellular area of RET-immunoreactive cells found no change with age. Estimation of changes in RET protein using fluorescence intensity measurement was also similar across age groups. The results indicate that the mechanisms of GDNF and neurturin signaling remain intact with age, and therefore these trophic factors may be able to enhance the dopaminergic function of neurons in the nigrostriatal system, when administered to individuals of any age.     

Habitual walking and its correlation to better physical function: implications for prevention of physical disability in older persons

BACKGROUND: Our objective was to determine the association between participation in habitual physical activity (including walking, shopping, and indoor and outdoor activities) and leisure-time or sports activities on physical performance and fitness in older persons. METHODS: In an observational study, 123 predominantly ethnic Chinese participants aged 50 years and older were recruited from a health promotion program. Main outcome measures were bioelectric impedance for body fat composition, peak oxygen consumption (VO(2)max), gait speed, handgrip strength, and chair rise time. RESULTS: The mean age of participants was years. Those with a higher self-reported walking level had a better VO(2)max; every 1 minute per day increase in habitual walking increases VO(2)max by 0.096 (ml/kg)/min (95% confidence interval [CI] 0.027-0.165, p=.007) and is possibly associated with a faster gait speed; (95% CI 0.000-0.005, p=.078). There is an age-related rise in body fat composition, decline in VO(2)max, and slower chair rise time. Men had a lower body fat composition, better VO(2)max, and stronger handgrip. CONCLUSIONS: Habitual walking may impart important health benefits in terms of improvement in physical performance, fitness, and its implications for the prevention of physical disability in older adults. This also reinforces the theory that low- to moderate-intensity activities may improve cardiorespiratory fitness. There is an inevitable physiological age-related decline in physical fitness.