Long term human reconstitution and immune aging in NOD-Rag (−)-γ chain (−) mice

Aging of the human immune system is characterized by a gradual loss of immune function and a skewing of hematopoiesis toward the myeloid lineage, a reduction in the lymphocytic lineage, and progressive increases in senescent memory T cells at the expense of naïve T cells. Both the innate and the adaptive branches of the immune system are affected, including neutrophils, macrophages, dendritic cells and lymphocytes. Mice, the most common research model, although inexpensive, do not necessarily reflect the human immune system in terms of its interaction with infectious agents of human origin or environmental factors. This study analyzed whether a human immune system contained within the NOD-Rag (−)-γ chain (−) mouse model could realistically be used to evaluate the development and therapy of aging-related diseases. To that end lightly irradiated NOD-Rag (−)-γ chain (−) mice were injected intra-hepatically on day 1 of life with purified cord blood-derived CD34⁺ stem and progenitor cells. Multiple mice were constructed from each cord blood donor. Mice were analyzed quarterly for age-related changes in the hematopoietic and immune systems, and followed for periods up to 18–24 months post-transplant. Flow cytometric analyses were performed for hematopoietic and immune reconstitution. It was observed that NOD-Rag (−)-γ chain (−) mice could be “humanized” long-term using cord blood stem cells, and that some evidence of immune aging occurred during the life of the mice.     

Protective effect of (−)clausenamide against Aβ-induced neurotoxicity in differentiated PC12 cells

The neurotoxicity of aggregated β-amyloid (Aβ) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD). In the present study, we investigated the effect of (−)clausenamide ((−)Clau), an aqueous extract of leaves of Clausena lassium (lour) skeel, on the neurotoxicity of Aβ_25–35. The viability of differentiated PC12 cells was determined by MTT assay. Apoptosis was detected by flow cytometry. DCFH-DA was used for assessment of intracellular ROS generation, JC-1 and Rhodamine 123 for measurement of mitochondrial transmembrane potential (MMP). The intracellular calcium was determined with Fluo-3. The phosphorylation of p38 MAPK and the expression of Bcl-2, Bax, P53, Caspase 3 were examined by Western blot. The results showed that (−)Clau significantly elevated cell viability. Furthermore, (−)Clau arrested the apoptotic cascade by reversing overload of calcium, preventing ROS generation, moderated the dissipation of MMP and the misbalance of Bcl-2 and Bax, inhibiting the activation of p38 MAPK and the expression of P53 and cleaved Caspase 3. Our results suggested that (−)Clau may be a therapeutic agent for AD.     

Women in French medicine and psychiatry in the belle époque: A feminist cause?

In France, women's relatively early admission to the medical profession (1868) and to psychiatry (1903) co-existed with a conservative gender discourse concerning women's presumed and pre-determined domestic role. The two women doctors featured in this article (both interns in psychiatry), Madeleine Pelletier and Constance Pascal, illustrate many of the constraints operating on exceptional women in the professions, but each had the capacity to exploit the opportunities for career development in the belle époque, and to negotiate the pitfalls of gender construction.     

Association study between the −1021C/T polymorphism of the dopamine-β-hydroxylase gene promoter and personality traits in healthy subjects

Dopamine and norepinephrine are implicated in the characterization of personality traits. Dopamine-β-hydroxylase (DBH) is the enzyme responsible for conversion of dopamine to norepinephrine, and thus plays an important role in controlling dispositions of these neurotransmitters. Previous studies have shown that the −1021C/T polymorphism of the DBH gene promoter influences plasma DBH activity. Therefore, we examined the association between the −1021C/T DBH polymorphism and personality traits in 627 Japanese healthy volunteers. The DBH genotypes were identified by a PCR-RFLP method, and personality traits were assessed by the Temperament and Character Inventory (TCI). In the two-factor analysis of covariance with the DBH genotype and sex as factors and with age as a covariate, there was no main effect of the DBH genotype on any TCI score, while the interaction between the factors was significant in harm avoidance. In the post hoc analysis, the group with the T allele predictive of lower DBH activity had higher scores of harm avoidance than that without the T allele in females (p = 0.006), but not in males. The present study suggests that the −1021C/T DBH polymorphism affects the personality trait of harm avoidance in healthy females.     

No association between IL-1β −31 C/T polymorphism and the risk of duodenal ulcer: A meta-analysis of 3793 subjects

The aim of this study was to perform a meta-analysis to investigate a more authentic association between IL-1β −31 C/T polymorphism and duodenal ulcer (DU). Systematic searches of electronic databases Embase, PubMed and Web of Science were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were applied. Publication bias was tested by Begg’s funnel plot and Egger’s regression test. A total of 12 studies including 1151 cases and 2642 controls were included in our final meta-analysis. There was no evidence of significant association between IL-1β −31 C/T polymorphism and DU (allelic model: OR = 0.96, 95%CI = 0.86–1.07; additive model: OR = 0.85, 95%CI = 0.67–1.07; dominant model: OR = 0.95, 95%CI = 0.81–1.13; and recessive model: OR = 0.95, 95%CI = 0.79–1.15). Significant association was found in additive model for PB subgroup (OR = 0.65, 95%CI = 0.44–0.96) and recessive model for non-Asian subgroup (OR = 0.72, 95%CI = 0.52–0.99). In conclusion, our meta-analysis suggested that there was no evidence of significant association between IL-1β −31 C/T polymorphism and DU with or without Helicobacter pylori infection in overall population, whereas significant association was found by subgroup analyses which showed protective effect of C/C genotype against DU risk.     

Human cytomegalovirus and Epstein–Barr virus in apical and marginal periodontitis: A role in pathology?

Periodontitis is presumably caused by bacterial infection, but it has been shown recently that affected tissue often contains human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). The present study was initiated to evaluate the role of these viruses in the pathogenesis of periodontitis. HCMV and EBV were quantified in 40 apical and 25 marginal periodontitis samples using real time PCR. In situ hybridization or immunohistochemistry was carried out on apical samples to detect viral presence within cells. A possible association with relevant bacteria was examined. Of the apical periodontitis samples, 50% contained EBV, while none contained HCMV. Of the marginal periodontitis samples, 40% were positive for EBV and 12% for HCMV. With one exception, however, the amount of virus was close to the detection limits. EBV was only detected in 1 out of 15 healthy periodontium samples. Immunohistochemistry and in situ hybridization were all negative. Significant associations were found between periodontal EBV and the presence of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Although there was an obvious association of the virus with clinical samples, it seems unlikely that these viruses play a major role in the pathogenesis of periodontitis of the average patient. Their presence may reflect that the clinical samples contain more blood or saliva compared to controls, or an accumulation of lymphoid cells harboring virus in the inflamed tissue.     

A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?

Stroke is one of the leading causes of death and disability worldwide. Inflammation plays a key role across the time course of stroke, from onset to the post‐injury reparative phase days to months later. Several regulatory molecules are implicated in inflammation, but the most established inflammatory mediator of acute brain injury is the cytokine interleukin‐1. Interleukin‐1 is regulated by large, macromolecular complexes called inflammasomes, which play a central role in cytokine release and cell death. In this review we highlight recent advances in inflammasome research and propose key roles for inflammasome components in the progression of stroke damage.     

The interleukin-6 gene −572C/G promoter polymorphism modifies Alzheimer's risk in APOE ɛ4 carriers

Inflammatory response is involved in the etiopathology of Alzheimer's disease (AD). Interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, was reported to be associated with both increased Aβ aggregation and the appearance of hyperphosphorylated tau in AD brain. To explore the association of genetic variants in the promoter of IL-6 gene with sporadic AD (SAD), a case–control study was conducted in a North Chinese Han population. A systematic screening of IL-6 promoter was performed using direct sequencing and two polymorphisms were obtained including −572C/G (rs1800796) and −384A/T (rs7802308). Definitive genotyping of these markers and apolipoprotein E (APOE) polymorphism were surveyed in 341 SAD patients and 421 controls. The results revealed no significant differences in the distributions of alleles or genotypes between SAD and control groups. However, there was an interaction between −572C/G and APOE genotypes (P = 0.016) using logistic analysis. In the subjects with APOE ?4, there were significant differences in the allele (P = 0.004) and genotype (P = 0.004) distributions of −572C/G polymorphism between SAD and control groups. The −572CC genotype increased risk for AD by 3.301-fold (Wald = 11.093, adjust OR = 3.301, 95% CI = 1.635–6.665, P = 0.001) compared to CG + GG genotype. The present results suggest the −572 polymorphism could modify the risk for SAD in APOE ?4 carriers.     

Involvement of cysteinyl leukotriene receptor 1 in Aβ1–42-induced neurotoxicity in vitro and in vivo

Accumulation of amyloid-β (Aβ) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease, but the mechanisms underlying neurotoxicity triggered by Aβ remain elusive. In the current study, we investigated the roles of cysteinyl leukotriene receptor 1 (CysLT₁R) in Aβ_1–42-induced neurotoxicity in vitro or in vivo. In vitro exposure of mouse primary neurons to Aβ_1–42 caused a gradual increases in CysLT₁R expression. In vivo bilateral intrahippocampal injection of Aβ_1–42 also elicited time-dependent increases of CysLT₁R expression in the hippocampus and cortex of mice. The CysLT₁R antagonist pranlukast not only reversed Aβ_1–42-induced upregulation of CysLT₁R, but also suppressed Aβ_1–42-triggered neurotoxicity evidenced by enhanced nuclear factor-kappa B p65, activated caspase-3, decreased B-cell lymphoma-2 and cell viability and impaired memory. Furthermore, chronic treatment with pranlukast produced similar beneficial effects on memory behavior and hippocampal long-term potentiation to memantine or donepezil in intrahippocampal Aβ_1–42-injected mice. Our data indicate that CysLT₁R is involved in Aβ_1–42-induced neurotoxicity, and that blockade of CysLT₁R, such as application of CysLT₁R antagonist, could be a novel and promising strategy for the treatment of Alzheimer's disease.     

Galactocele and prolactinoma—A pathogenic association?

A galactocele is a rare form of cystic, benign lesion of the breast, appearing when a mammary duct becomes obstructed and over filled with milk. It is usually found in postpartum women, either lactating or not. There are only a few cases reported that are not immediately linked to the lactation, as seen in postmenopausal women or in men. Furthermore, the relationship to overproduction of prolactine, a growth factor for the breast epithelium is not very well defined at this moment. We present such an unusual case of a 37-year-old female patient who has no history of birth or abortion. She was diagnosed with both microprolactinoma and galactocele whose dimensions seemed to be related to the evolution of the pituitary tumor and serum prolactine. Because no other etiology could be found in the young patient for the mammary galactocele, the prolactine excess is the most probable cause. Even considering the rarity of the association it is important to point the hormonal role in changing the anatomy of the breast.     

The Genus Streptococcus – Part II: New Species and Pathogens in the “Miscellaneous” Streptococci and “Viridans” Streptococci Groups

In the second part of this two-part series on an update on the streptococci, new species and emergent human pathogens in the “viridans streptococci” and the “miscellaneous streptococci” groups are discussed. Among the “miscellaneous streptococci,” the most important organism in human infectious diseases is Streptococcus suis. This organism is primarily an agent of disease in swine and other animals and has now emerged as a significant human pathogen, causing bacteremia and meningitis, particularly among populations in Asia and the Far East. While S. suis capsular serotype 2 is the most frequently isolated agent, infections caused by other serotypes are increasingly being reported. In addition, disease caused by S. suis is now being described more frequently in North America in individuals with significant occupational exposure to swine. Among the viridans streptococci, several new species in the mitis-sanguinis group have been described as human pathogens, including Streptococcus pseudopneumoniae, Streptococcus oligofermentans, and Streptococcus tigurinus. Other newly reported viridans group species either comprise part of the human oral microbiome or have been isolated from animals. This article presents information on these bacterial agents, including characteristics for the recognition and identification of the more important clinical isolates in these streptococcal groups.     

Saccadic hypometria in drug‐naïve and drug‐treated schizophrenic patients: A working memory deficit?

In certain conditions patients with schizophrenia make markedly smaller (hypometric) saccades than controls. This hypometria has been thought to reflect dopaminergic blockade as a result of antipsychotic medication. We tested this hypothesis by comparing the performance of an antipsychotic‐naïve group and an antipsychotic‐treated group of first‐episode schizophrenic patients on a predictive saccade paradigm. We explored the possibility that hypometria reflects a spatial working memory deficit by correlating performance on neuropsychological tests of mnemonic function with saccadic accuracy. Both the drug‐naïve and treated schizophrenic patients made hypometric saccades when compared with a group of matched controls. Primary saccade amplitude also correlated significantly with performance on some of the neuropsychological tests. These results are discussed in terms of the roles of cortical dopamine and working memory deficits in schizophrenic patients.     

Polymorphisms of IFN-γ (+874A/T) and IL-12 (+1188A/C) in tuberculosis patients and their household contacts in Hyderabad,India

Several cytokine gene variants have shown to be associated with host susceptibility to infectious diseases including tuberculosis (TB). High rates of transmission were identified within household members of TB patients. In this study, we examined whether single nucleotide polymorphisms of IFN-γ +874A/T and IL-12 +1188A/C affect susceptibility to TB. Genomic DNA from patients with active disease, their household contacts HHC and healthy controls HC was genotyped for IFN-γ +874A/T and IL-12 +1188A/C SNPs by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). IFN-γ +874 AA and AT genotypes were significantly with different frequencies in patients and total HHC as compared to HC (p < 0.0001). In patients IL-12 +1188 AC and CC genotypes were associated with TB (p < 0.003, p < 0.008). In total HHC AC, CC genotypes and both alleles (A&C) were significantly different as compared to HC (p < 0.004, p < 0.001, p < 0.034) and the same result was obtained when HHC were stratified into related (p < 0.02, p < 0.001) and unrelated (p < 0.009, p < 0.017) individuals. Allelic frequencies, however, were significant only in related contacts (p < 0.021). Generalized multifactor dimensionality reduction method (GMDR) testing revealed high risk combinations of several genotypes in IFN-γ & IL-12 genes. Our findings suggest an important role of genetic variations of IFN-γ and IL-12 for susceptibility to TB.     

The Genus Streptococcus – Part I: Emerging Pathogens in the “Pyogenic Cocci” and the “Streptococcus bovis” Groups

In this first part of a two-part update on the streptococci, new and emerging pathogens in the “pyogenic cocci group” and the “Streptococcus bovis group” are addressed. Among the pyogenic cocci, several new species have been described, and some of these are becoming relevant agents of human disease. Streptococcus porcinus and Streptococcus pseudoporcinus are β-hemolytic streptococci that are found in swine and humans, respectively. S. pseudoporcinus has been isolated primarily from the female genital tract and may play a role in genitourinary tract infections, wound infections, and adverse pregnancy outcomes. Streptococcus iniae, Streptococcus hongkongensis, and Streptococcus ictaluri are fish pathogens, and S. iniae, in particular, has been isolated from several human infections in persons who handle raw seafood or experience penetrating injuries from fish spines or crab pincers. Streptococcus gallolyticus subspecies (i.e., the former “S. bovis group”) are well-recognized causes of bacteremia, meningitis, and endocarditis. S. gallolyticus subsp. gallolyticus is known to be associated with colon cancer, and current studies suggest that other S. gallolyticus subspecies (particularly S. gallolyticus subsp. pasteurianus) may also be associated with meningitis and other digestive tract malignancies. In this review, current research on S. gallolyticus subspecies and proposed mechanisms for their involvement in the pathogenesis of colonic carcinoma are also briefly addressed.     

Human β-Defensins and Psoriasin/S100A7 Expression in Salivary Glands

Background

Host defence peptides (HDPs), including human ??-defensins (hBDs) and psoriasin/S100A7, exert antimicrobial and immunoregulatory functions of the innate defense system. In addition to these functions, the search for cancer biomarkers has identified HDPs as playing a potential role in both tumor suppression and oncogenesis. Although HDPs are highly expressed in salivary glands, their role as molecules for potential diagnostic and therapeutic approaches has not yet been analyzed.

Objective

The aim of the present study was to investigate whether expression levels of putative pro- or antioncogenic hBDs, including hBD-1, -2, -3, and psoriasin/S 100A7, are altered in salivary gland tumor tissue as potential targets for molecular-based therapeutic approaches.

Methods

We analyzed the expression levels of hBD-1, -2, -3, and psoriasin/S100A7 by quantitative real-time polymerase chain reaction (qrt-PCR) and immunohistochemistry in a case control study by comparing salivary gland tumor samples relative to healthy control specimens from 58 patients. Expression level analysis of hBD-1, -2, -3, and psoriasin/S 100A7 by qrt-PCR was normalized to the endogenous 18S rRNA expression levels.

Results

The results demonstrate the significant downregulation of hBD-1 (p<0.001), hBD-2 (p = 0.003), hBD-3 (p = 0.002), and psoriasin/S 100A7 (p = 0.003) mRNA in human salivary gland tumors compared with healthy control specimens. Protein expression levels of hBD-1, -2, -3, and psoriasin/S 100A7 in salivary gland tumor tissue were strongly reduced compared with healthy control specimens.

Conclusion

The data indicates a putative role of the innate defense system in salivary gland tumor formation. The identification of immunoregulatory molecules as diagnostic biomarkers or therapeutic targets could provide new approaches for molecular-based diagnostic and therapeutic support to treat salivary gland tumors as well as other malignancies. We suggest that HDPs should be taken into consideration for use in molecular-based therapeutic approaches.     

A clinical,microbiological and immunological comparison between subgingival irrigation with Dentol? and chlorhexidine in advanced periodontitis

Introduction

The purpose of this study was to compare the clinical, microbiological and immunological effects of subgingival irrigation with Dentol^™ and 0.2% chlorhexidine in human advanced periodontitis.

Material and methods

Twenty cases of advanced periodontitis patients were randomly treated either with Dentol^™ (as test) or 0.2% chlorhexidine (as control) every other day for 29 days after primary scaling, root planing and oral hygiene instruction. Pocket depth (PD), bleeding on probing (BOP) and plaque index (PI) were considered as clinical parameters. Total counts of aerobic and anaerobic bacteria were measured in subgingival plaque. At the end, concentrations of TNF-α and IL-1β in gingival crevicular fluid were measured as inflammatory markers.

Results

PD and BOP decreased in both groups on the 29^th day and two weeks afterward. PI did not show any statistical difference either within or among groups (p > 0.05). Results indicate that both chlorhexidine and Dentol^™ diminished total count of subgingival anaerobic bacteria significantly (p < 0.05). Total count of subgingival aerobic bacteria increased in both groups, but the differences between the two groups were statistically significant in favour of Dentol^™ (p < 0.05). The level of IL-1β in the crevicular fluid was reduced in both groups but it was more significant in the test group (p < 0.05). The TNF-a level decreased in both groups but the statistical difference between the two groups was negligible (p > 0.05).

Conclusions

Subgingivally irrigation with Dentol^™, containing 0.02% carvacrol, every other day for 29 days is equally or more effective than 0.2% chlorhexidine in reducing clinical and immunological inflammatory indices.     

Sickle cell anemia and α-thalassemia: A modulating factor in homozygous HbS/S patients in Oman

We report the general phenotype severity and the hematological presentation in a cohort of 125 sickle cell anemia (SCA) patients with identical homozygous HbS/S genotype and categorized by identical β^S haplotype, both with and without alpha thalassemia. No clear general phenotype correlation was found when patients were compared regardless of the haplotype but overall, patients with homozygous alpha thalassemia (α−/α−) had the highest Hb, HCT, RBC and the lowest MCV, MCH and MCHC levels. When patients with identical haplotype were compared, the mildest hematological and clinical conditions were observed in patients of the Asian/Asian haplotype, also known as Arab-Indian haplotype, and carriers of α-thalassemia, suggesting an additional ameliorating effect of alpha thalassemia. In conclusion, our results show that alpha thalassemia improves the hematological conditions but amelioration of the general disease severity is only noticed when compared in cohorts of the same haplotype.