The twin arginine translocation system is essential for virulence of Yersinia pseudotuberculosis

Yersinia species pathogenic to humans have been extensively characterized with respect to type III secretion and its essential role in virulence. This study concerns the twin arginine translocation (Tat) pathway utilized by gram-negative bacteria to secrete folded proteins across the bacterial inner membrane into the periplasmic compartment. We have shown that the Yersinia Tat system is functional and required for motility and contributes to acid resistance. A Yersinia pseudotuberculosis mutant strain with a disrupted Tat system (tatC) was, however, not affected in in vitro growth or more susceptible to high osmolarity, oxidative stress, or high temperature, nor was it impaired in type III secretion. Interestingly, the tatC mutant was severely attenuated via both the oral and intraperitoneal routes in the systemic mouse infection model and highly impaired in colonization of lymphoid organs like Peyer's patches and the spleen. Our work highlights that Tat secretion plays a key role in the virulence of Y. pseudotuberculosis.     

The effect of aging on IgD receptor expression by T cells and its functional implications

Summary: Exposure to oligomeric or aggregated (a), but not to mono-merle (m), IgD causes a rapid (within 1 h) upregulation of IgD-R expression on CD4⁺ T cells from young, but not from aged, mice and on both CD4⁺ and CD8⁺ T cells from all young and from =65% of aged humans. In normal young (but not in IgD^−/-) mice, this increase in IgD-R expression is associated with a marked increase in primary and secondary antibody responses, transferable to both aged and young mice with T cells from aIgD pretreated donors. In both species, immunization causes a rise in the IgDR⁺ expression in vivo in the young. In mice, mIgD abolishes both the Induction of IgD-R expression and augmentation of immune responses, suggesting that interaction between IgD-R⁺ T and IgD⁺ B cells is needed. In aged humans, the ability of peripheral blood lymphocytes to exhibit IgD-R expression in response to aIgD in vitro or to influenza vaccine in vivo is strongly correlated to the individual's ability to produce antibody. In T cells from aged mice, but not from aged IgD-non-responder humans, IgD-R are able to come to the cell surface if an additional signal has been supplied, such as by (ionomycin/thapsigargin + aIgD). Agents which induce IgD-R and augmentation of antibody production in aged and young mice include phosphatidylcholine and dehydroepiandrosterone sulfate. The immunoaugmenting effect of pretreatment with these agents appears Indeed due to IgD-R⁺ T cells, because it is abolished by mIgD.     

Perforin and IFN-gamma do not significantly regulate the virus-specific CD8+ T cell response in the absence of antiviral effector activity

Using gene-targeted mice we have investigated whether perforin and/or interferon-gamma exert a direct regulatory effect on the expansion and contraction of antigen-specific CD8(+) T cells following infection with a virus (vesicular stomatitis virus) which is not controlled through these molecular effector systems. Unlike what has been observed when these molecules are essential for pathogen clearance, neither molecule was found to play an important role in regulating the kinetics of the virus-specific CD8(+) T cell response in the absence of antiviral effector activity.     

Optimal care for the child with cancer: A summary statement from the SIOP working committee on psychosocial issues in pediatric oncology

Since its foundation in 1991, the SIOP Working Committee on Psychosocial Issues in Paediatric Oncology 1 has developed and published 12 sets of Guidelines for health‐care professionals treating children with cancer and their families. Those elements considered essential in the process of cure and care of children with cancer are summarized in this document as a formal statement, developed at the 2007 SIOP annual meeting in Mumbai. Elaboration of the concepts with detailed strategies for practice can be found in the referenced guidelines [1–12] and in a companion publication [13]. This article is a summary of what practitioners considered critical elements in the optimal care of the child with cancer, with the goal of stimulating a broader application of these elements throughout the SIOP membership. Pediatr Blood Cancer 2009;52:904–907. © 2009 Wiley‐Liss, Inc.     

Muscle strength, volume and activation following 12-month resistance training in 70-year-old males

In elderly males muscle plantar flexor maximal voluntary contraction (MVC) torque normalised to muscle volume (MVC/VOL) is reduced compared to young males as a result of incomplete muscle activation in the elderly. The aim of the present study was to determine the influence of a 12-month resistance training programme on muscle volume, strength, MVC/VOL, agonist activation and antagonist coactivation of the plantarfexors in elderly males. Thirteen elderly males aged 70 years and over (range 70–82 years), completed a 12-month whole body resistance-training programme (TRN), training three times a week. Another eight males (range 18–30 years), who maintained their habitual physical activity for the same 12-month period as the TRN group acted as controls (CTRL). Isometric plantarflexor maximal voluntary contraction (MVC) torque increased in the TRN group by 20% (P<0.01), from 113.1±22.0 Nm to 141.5±19.2 Nm. Triceps surae volume (TS VOL) assessed using MRI, increased by 12%, from 796.3±78.9 cm³ to 916.8±144.4 cm³ . PF activation, measured using supramaximal double twitch interpolation, increased from 83.6±11.0% pre training, to 92.1±7.6% post training (P<0.05). Dorsiflexion MVC and antagonist coactivation (assessed using surface electromyography) did not change with training. Plantarflexor MVC torque normalized for triceps surae muscle volume (MVC/VOL) was 142.6±32.4 kN m^–2 before training and 157.0± 27.9 kN m^–2 after training (a non-significant increase of 8%). No significant change in any measurement was observed in the CTRL group. This study has shown that the gain in muscle strength in response to long-term (12-month) training in older men is mostly accounted for by an increased muscle volume and activation.     

Neuropsychological profiles of three sisters homozygous for the fragile X premutation

Fragile X syndrome (fraX) is associated with an amplification of a CGG repeat within the fraX mental retardation (FMR-1) gene. We describe an exceptional family in which 3 adult sisters are homozygous for the FMR-1 premutation. Each sister inherited 2 premutation alleles (ca. 80 CGG repeats) from their biologically unrelated parents. The 3 sisters were administered measures of executive function, visual spatial, memory, and verbal skills. Deficiencies in the first 2 of these domains have been reported among females with the full mutation. The sisters' performances were compared with available normative data and with published group means for females affected by fraX. These women did not appear to have verbal or memory difficulties. None of the women demonstrated a global executive function deficit, and none had global deficits in spatial ability. The profiles of these sisters are consistent with reports that the fragile X premutation does not affect cognitive performance. © 1996 Wiley-Liss, Inc.     

Expression of endothelin 2 and localized clear cell renal cell carcinoma

Despite the rising incidence of clear cell renal cell carcinoma, the molecular events that support its development and progression remain unclear. Herein, we evaluate the association of endothelin 2 expression with both clear cell renal cell carcinoma development and progression-free survival. We conducted real-time polymerase chain reaction to determine endothelin 2 expression levels on 238 patients who underwent nephrectomy for localized clear cell renal cell carcinoma, 161 of whom also had adjacent normal kidney samples available for analysis. To evaluate associations with clear cell renal cell carcinoma development, linear mixed models were used to compare differential expression between tumor and a normal kidney as well as to explore interactions with clinicopathologic features. To evaluate associations with prognosis, Cox proportional hazards models were used to assess the association of progression-free survival and endothelin 2 expression in tumor tissue. Overall, endothelin 2 expression was higher in tumor samples versus patient-matched normal kidney samples, with an average fold change of 1.99 (95% confidence interval, 1.48-2.60; P < .0001). This overexpression in tumor versus normal kidney samples was more pronounced in low- compared with high-grade tumors (interaction, P = .0002), in early- compared with late-stage tumors (interaction, P = .001), and in tumors without compared with those with necrosis (interaction, P = .001). Moreover, an increasing endothelin 2 expression in tumors was associated with a longer progression-free survival (hazard ratio, 0.89; 95% confidence interval, 0.80-0.99; P = .03); however, after controlling for known clinicopathologic factors, this association was attenuated (hazard ratio, 0.99; 95% confidence interval, 0.89-1.09; P = .7). Up-regulation of endothelin 2 is a common and early event in localized clear cell renal cell carcinoma. Higher tumor expression of endothelin 2 is associated with a longer progression-free survival but not after adjustment for well-known pathologic indices. Thus, although endothelin 2 does not appear to be an independent prognostic marker, there is evidence of a putative role in clear cell renal cell carcinoma progression. If supportive mechanistic data can be produced, endothelin 2 could represent a potential target for chemopreventive or neoadjuvant therapeutics for clear cell renal cell carcinoma.     

Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting

Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships.