The TLR4 agonist, monophosphoryl lipid A, attenuates the cytokine storm associated with respiratory syncytial virus vaccine-enhanced disease

Formalin-inactivated respiratory syncytial virus vaccine (FI-RSV) induces a poorly understood immunopathological response that leads to disease enhancement upon RSV infection of vaccinees. In the cotton rat model, inclusion of monophosphoryl lipid A (MPL) in the FI-RSV formulation was found to mitigate the lung pathology associated with vaccine-enhanced disease. Here we report that the protective effect of MPL on FI-RSV vaccine-enhanced disease is associated with a dramatic reduction in levels of Th1- and Th2-type cytokines and chemokines normally elicited in response to RSV challenge. Our data illustrate the complexity of proinflammatory response elicited by FI-RSV vaccination and RSV infection and the potential importance of MPL in modifying this response.     

Contamination of mesenchymal stem-cells with fibroblasts accelerates neurodegeneration in an experimental model of Parkinson's disease

Pre-clinical studies have supported the use of mesenchymal stem cells (MSC) to treat highly prevalent neurodegenerative diseases such as Parkinson’s disease (PD) but preliminary trials have reported controversial results. In a rat model of PD induced by MPTP neurotoxin, we first observed a significant bilateral preservation of dopaminergic neurons in the substantia nigra and prevention of motor deficits typically observed in PD such as hypokinesia, catalepsy, and bradykinesia, following intracerebral administration of human umbilical cord-derived MSC (UC-MSC) early after MPTP injury. However, surprisingly, administration of fibroblasts, mesenchymal cells without stem cell properties, as a xenotransplantation control was highly detrimental, causing significant neurodegeneration and motor dysfunction independently of MPTP. This observation prompted us to further investigate the consequences of transplanting a MSC preparation contaminated with fibroblasts, a plausible circumstance in cell therapy since both cell types display similar immunophenotype and can be manipulated in vitro under the same conditions. Here we show for the first time, using the same experimental model and protocol, that transplantation of UC-MSC induced potent neuroprotection in the brain resulting in clinical benefit. However, co-transplantation of UC-MSC with fibroblasts reverted therapeutic efficacy and caused opposite damaging effects, significantly exacerbating neurodegeneration and motor deficits in MPTP-exposed rats. Besides providing a rationale for testing UC-MSC transplantation in early phases of PD aiming at delaying disease progression, our pre-clinical study suggests that fibroblasts may be common cell contaminants affecting purity of MSC preparations and clinical outcome in stem cell therapy protocols, which might also explain discrepant clinical results.     

Utility of immunohistochemistry in detecting alterations of mismatch repair genes of DNA. A series of 48 cases of colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is associated in more than 95% to a germline mutation in the genes of the mismatch repair (MMR) of DNA. The aim of this study was to assess the utility of immunohistochemistry, a simple and fast technique, in the triage of families where HNPCC is suspected. Tumor samples included in this study were from patients with resection for colorectal cancer, examined in our laboratory between 2004 and 2007. For each case, a formalin-fixed paraffin-embedded tissue block containing tumor tissue and normal adjacent mucosa was selected. Tumor specimens were examined with immunohistochemistry for the presence of hMLH1, hMSH2, and hMSH6 proteins. Scoring of the tumor staining was performed without any knowledge of patients' family history. The loss of protein expression was noted in four patients among 48?cases tested: two cases with isolated loss of hMSH2, a case with isolated loss of hMSH6 and one case with combined loss of MSH2/MSH6. No case has shown a suppression of hMLH1 protein. Comparing the immunohistochemical results for clinical has revealed a clear correlation between loss of protein expression demonstrated by immunohistochemistry and clinical data. Indeed, three cases among the four who showed no expression of MMR proteins showed at least one clinical criterion predictive of HNPCC. In conclusion, our study support the potential utility of immunohistochemistry to identify a significant portion of colorectal tumors derived from germline mutation of MMR genes and can be used as an adjunct measure in the identification of HNPCC.     

Development of New Quality Measures for Hospital-Based Care of Suicidal Youth

Objectives

To develop, validate, and test the feasibility of implementation of 4 new quality measures assessing emergency department (ED) and inpatient care for suicidal youth.

Acute septic arthritis in children

Background:  Acute septic arthritis is a health-care problem in growing children. The aim of the present study was to determine the demographic features, clinical presentation, diagnostic evaluation, treatment and outcome of children suffering from acute septic arthritis.
Methods:  Retrospective review of consecutive admissions of children ≤14 years of age with a bacteriologically and/or radiologically confirmed diagnosis of septic arthritis during the 10 year period, January 1997–December 2006 at King Fahad Hospital, King Abdulaziz Medical City was undertaken.
Results:  Sixty-five patients (male : female, 2.4:1), 10 days–14 years of age (mean ± SD: 3.3 ± 3.2 years), met the inclusion criteria. More than half of the patients were under 2 years. The most frequent clinical features were pain (92%), fever (77%), limitation of joint movement (77%) and joint swelling (72%). Joint involvement was monoarticular in 97% of knees, and hips were affected in 75% of patients. Bacteria were isolated from joint aspirate or blood in 28 patients (43%), and Staphylococcus aureus was the most common organism, comprising 39% of the total bacterial isolates. Radiological diagnostic findings were observed in 19 (32%) of 60 patients with plain radiographs, nine (69%) of 16 patients with sonograms of the hip, 36 (80%) of 45 patients with Tc-labeled bone scan and nine (100%) of nine patients with magnetic resonance imaging. The joint infection resolved with no sequelae in 46 patients who were followed up for 6–36 months, but two had bone deformity and 17 were lost to follow up.
Conclusion:  According to the present series, septic arthritis is most common in young infants, mainly monoarticular, and is frequently localized in the knee and hip joints. Early diagnosis and appropriate treatment are associated with excellent outcome.     

Parental psychological distress during pregnancy and childhood cardiovascular development. The Generation R Study

Background

Maternal psychological distress during pregnancy might lead to higher fetal cortisol exposure, which subsequently leads to fetal cardiovascular developmental adaptations and cardiovascular dysfunction in later life.

Aims

We examined whether maternal and paternal psychological distress was associated with the cardiovascular outcome measurements in school age children.

Study design and subjects

In a population-based prospective cohort study among 4831 children, we assessed maternal and paternal psychological distress during pregnancy by questionnaire, using the Brief Symptom Inventory (see Fig. 1).

Outcome measures

At the child age of six years, we performed blood pressure and carotid–femoral pulse wave velocity measurements, and M-mode measurements of left cardiac structures and fractional shortening.

Results

We did not observe associations of high maternal and paternal psychological symptom scores with childhood blood pressure and carotid–femoral pulse wave velocity after adjustment for potential confounders. Maternal overall psychological symptoms were associated with a lower childhood left ventricular mass (difference − 1.10 g (95% confidence interval − 2.13 to − 0.07) between mothers with high scores and normal scores), but not with other cardiac structures and fractional shortening. Paternal overall psychological symptoms showed a similar association with childhood left ventricular mass (difference − 1.34 grams (95% confidence interval − 3.69 to 1.02) between fathers with high scores and normal scores).

Conclusions

Our results do not support the hypothesis that maternal psychological distress affects cardiovascular development in early life. Similar associations of maternal and paternal psychological distress with left ventricular mass suggest that these associations could be due to unmeasured social and environmental factors, rather than direct intra-uterine effects.     

Dietary genistein stimulates anion secretion across female murine intestine

Genistein, a naturally occurring isoflavone, augments in vitro epithelial anion transport via activation of the cystic fibrosis transmembrane conductance regulator chloride channel. In this study, we examined whether chronic dietary exposure to 600 mg/kg genistein (600 G) for 1 mo would stimulate anion secretion across wild-type (Wt, normal) murine intestine. Anion secretion was assessed in freshly excised segments of murine jejuna by measuring short circuit current (I(sc)) and comparing with jejunal segments from mice fed 0 mg/kg genistein (0 G). Basal and forskolin-stimulated anion secretions were augmented (P < 0.05) in female but not in male mice fed 600 G, compared with their counterparts fed 0 G. Serum genistein concentrations were greater in both female and male mice fed 600 G (approximately 3.5-6.9 micromol/L) than those fed 0 G (approximately 100 nmol/L). Anion substitution experiments and bumetanide-sensitivity demonstrated that chloride was the major anion mediating the increased secretion. A smaller bicarbonate component was not augmented by consumption of the genistein diet. These data indicate that chronic exposure to dietary genistein stimulates a sex-dependent increase in basal and forskolin-stimulated chloride secretion across murine intestine.