CD98: a type II transmembrane glycoprotein expressed from the beginning of primitive and definitive hematopoiesis may play a critical role in the development of hematopoietic cells

In our search for cell surface markers expressed on hematopoietic stem cells and/or very early progenitor cells we found that the Joro 177 monoclonal antibody (MoAb) bound to most hematopoietic cells in day 8/8.5 yolk sac, day 12 fetal liver, and day 13 fetal thymocytes; it stained hematopoietic stem cells and less immature lymphoid, myeloid, and erythroid-lineage cells, but not most thymocytes and splenic lymphocytes in adult mice. Joro 177 MoAb stimulated tyrosine phosphorylation of an integral of 124-kD protein and induced homotypic aggregation of lymphoid progenitor cells. Importantly, Joro 177 MoAb inhibited cell survival/growth and consequently the generation of lymphoid, myeloid, and erythroid lineage cells in vitro from early Lin- hematopoietic precursors. Joro 177 MoAb induced apoptosis of hematopoietic progenitor cells. Molecular cloning and expression indicated that Joro 177 MoAb recognizes a type II transmembrane protein, which is the mouse homologue of the human CD98 heavy chain gene. We suggest that CD98 is a cell membrane receptor involved in the control of cell survival/death of hematopoietic cells.     

Pharmacodynamics of β-lactamase inhibition by NXL104 in combination with ceftaroline: examining organisms with multiple types of β-lactamases

New broad-spectrum β-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of β-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-β-lactam β-lactamase inhibitor. In this evaluation, we examined organisms carrying defined β-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of Klebsiella pneumoniae and one isolate of Enterobacter cloacae. K. pneumoniae 27-908M carried KPC-2, SHV-27, and TEM-1 β-lactamases. Its isogenic mutant, K. pneumoniae 4207J, was "cured" of the plasmid expressing the KPC-2 enzyme. K. pneumoniae 24-1318A carried a CTX-M-15 enzyme, and E. cloacae 2-77C expressed a stably derepressed AmpC chromosomal β-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that "time > threshold" was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.     

Factors predicting the age when type 2 diabetes is diagnosed in Hong Kong Chinese subjects

OBJECTIVE: To examine the factors predicting age at diagnosis of type 2 diabetes in Hong Kong Chinese. RESEARCH DESIGN AND METHODS: The relationships between age at diagnosis and parental history of diabetes as well as an array of clinical and metabolic factors were examined using a hospital clinic-based diabetes registry involving 3,414 index patients with type 2 diabetes Patterns of age at diagnosis in successive generations were also examined using 21 affected child-parent pairs and 7 affected child-parent-grandparent trios. RESULTS: Approximately 29% of the index patients were diagnosed with type 2 diabetes at < or = 35 years of age (hereby defined as early-onset). Compared with the patients diagnosed at >35 years of age (hereby defined as late-onset) the early-onset patients had higher rates of positive paternal (16 vs. 5%) and maternal (22 vs. 12%) history of diabetes (both at P < 0.01) and had poorer metabolic profiles. In the overall index patients, male sex, higher HbA1c waist-to-hip ratio (WHR), and systolic blood pressure (sBP); lower HDL cholesterol level; and a positive paternal was well as maternal history of diabetes predicted younger age at diagnosis. More senior age and higher BMI and diastolic blood pressure predicted olderq age at diagnosis. Predictors for younger age at diagnosis in the male patients were higher HbA1c and sBP and a positive paternal history of diabetes Predictors for younger age at diagnosis in the female patients were higher HbA1c WHR, and sBP and a paternal as well as maternal history of diabetes. In the affected child parent pairs and clild-parent-grandparent trios there was a decrease in age at diagnosis in successive generations. CONCLUSIONS: Our data indicate that both familial (possibly genetic) and metabolic factors affect the age of onset of type 2 diabetes in the Chinese population. The results also suggest an onset and progression pattern of the disease that is compatible with the phenomenon of anticipation.     

Regulation of natural antibiotic expression by inflammatory mediators and mimics of infection in human endometrial epithelial cells

The natural antibiotic molecules, beta-defensins 1 and 2 (HBD1/2) and secretory leukocyte protease inhibitor (SLPI), have an important role in mucosal defence and are present in the uterus. This study details their regulation in primary endometrial epithelial cells and in two endometrial cell lines (MFE/HES). Cells were treated with proinflammatory molecules and mimics of infection [lipopolysaccharide (LPS) and lipoteichoic acid (LTA)]. mRNA for HBD1, HBD2 and SLPI was detected in primary endometrial epithelial cells using real-time quantitative PCR. HBD1 mRNA was present at very low levels preventing conclusive study of its regulation. However, HBD2 mRNA expression was increased by interferon-gamma, interleukin (IL)-1beta alone and IL-1beta+tumour necrosis factor (TNF)-alpha. SLPI mRNA was not affected by proinflammatory mediators, although protein levels fell in the presence of IL-1beta+TNFalpha. LPS had little effect on antimicrobial expression. However, there was a trend towards increased expression with LTA treatment for 4-8 h. Antimicrobial expression in endometrial cell lines was similar to that in primary cells, although SLPI was increased by IL-1beta+TNFalpha treatment. These results suggest that in endometrium some natural antibiotics (e.g. SLPI) may be constitutively expressed providing a basal level of protection, while others (e.g. HBD2) are inducible allowing maximal antimicrobial activity during infection. Natural antimicrobials will have an important role in endometrium in protecting against infection.     

Regret and its avoidance: a neuroimaging study of choice behavior

Human decisions can be shaped by predictions of emotions that ensue after choosing advantageously or disadvantageously. Indeed, anticipating regret is a powerful predictor of future choices. We measured brain activity using functional magnetic resonance imaging (fMRI) while subjects selected between two gambles wherein regret was induced by providing information about the outcome of the unchosen gamble. Increasing regret enhanced activity in the medial orbitofrontal region, the anterior cingulate cortex and the hippocampus. Notably, across the experiment, subjects became increasingly regret-aversive, a cumulative effect reflected in enhanced activity within medial orbitofrontal cortex and amygdala. This pattern of activity reoccurred just before making a choice, suggesting that the same neural circuitry mediates direct experience of regret and its anticipation. These results demonstrate that medial orbitofrontal cortex modulates the gain of adaptive emotions in a manner that may provide a substrate for the influence of high-level emotions on decision making.     

Neural systems supporting interoceptive awareness

Influential theories of human emotion argue that subjective feeling states involve representation of bodily responses elicited by emotional events. Within this framework, individual differences in intensity of emotional experience reflect variation in sensitivity to internal bodily responses. We measured regional brain activity by functional magnetic resonance imaging (fMRI) during an interoceptive task wherein subjects judged the timing of their own heartbeats. We observed enhanced activity in insula, somatomotor and cingulate cortices. In right anterior insular/opercular cortex, neural activity predicted subjects' accuracy in the heartbeat detection task. Furthermore, local gray matter volume in the same region correlated with both interoceptive accuracy and subjective ratings of visceral awareness. Indices of negative emotional experience correlated with interoceptive accuracy across subjects. These findings indicate that right anterior insula supports a representation of visceral responses accessible to awareness, providing a substrate for subjective feeling states.     

Optimal use of antibiotic resistance surveillance systems

Increasing concern about the emergence of resistance in clinically important pathogens has led to the establishment of a number of surveillance programmes to monitor the true extent of resistance at the local, regional and national levels. Although some programmes have been operating for several years, their true usefulness is only now being realised. This review describes some of the major surveillance initiatives and the way in which the data have been used in a number of different settings. In the hospital, surveillance data have been used to monitor local antibiograms and determine infection control strategies and antibiotic usage policies. In the community, surveillance data have been used to monitor public health threats, such as infectious disease outbreaks involving resistant pathogens and the effects of bioterrorism countermeasures, by following the effects of prophylactic use of different antibiotics on resistance. Initially, the pharmaceutical industry sponsored surveillance programmes to monitor the susceptibility of clinical isolates to marketed products. However, in the era of burgeoning resistance, many developers of antimicrobial agents find surveillance data useful for defining new drug discovery and development strategies, in that they assist with the identification of new medical needs, allow modelling of future resistance trends, and identify high-profile isolates for screening the activity of new agents. Many companies now conduct pre-launch surveillance of new products to benchmark activity so that changes in resistance can be monitored following clinical use. Surveillance data also represent an integral component of regulatory submissions for new agents and, together with clinical trial data, are used to determine breakpoints. It is clear that antibiotic resistance surveillance systems will continue to provide valuable data to health care providers, university researchers, pharmaceutical companies, and government and regulatory agencies.     

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.