Our observations confirm that uncontrolled acromegaly increases mortality compared to the general population and that mortality rates similar to the general population are restored once remission is induced.

This large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool. The risk of bacterial meningitis is very low (0.1%) in patients with none of the criteria. The Bacterial Meningitis Score may be helpful to guide clinical decision making for the management of children presenting to emergency departments with CSF pleocytosis.

Background: Cardiovascular disease (CVD) is the leading cause of mortality in type 1 diabetes (T1D) and relates strongly to insulin resistance (IR). Lean and obese T1D adolescents have marked IR. Metformin improves surrogate markers of IR in T1D, but its effect on directly-measured IR and vascular health in T1D youth is unclear. We hypothesized that 1) T1D adolescents have impaired vascular function, and 2) metformin improves this IR and vascular dysfunction. Methods: T1D adolescents and controls underwent MRI of the ascending (AA) and descending aorta (DA) to assess pulse wave velocity (PWV), relative area change (RAC), maximal (WSSMAX) and time-averaged wall shear stress (WSSTA). T1D participants also underwent assessment of carotid intima-media thickness (cIMT) by ultrasound, brachial distensibility (BrachD) by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate/insulin, [M/I]). T1D adolescents were randomized 1:1 to 3 months of 2000 mg metformin or placebo daily, after which baseline measures were repeated. Results: Forty-eight T1D adolescents ages 12–21 years (40% BMI ≥ 90th%ile; 56% female) and twenty-four nondiabetic controls of similar age, BMI and sex distribution were enrolled. T1D adolescents demonstrated impaired aortic health vs. controls, including elevated AA and DA PWV, reduced AA and DA RAC and elevated AA and DA WSSMAX and WSSTA. T1D adolescents in the metformin vs. placebo group had improved M/I (12.2±3.2 vs. −2.4±3.6 [mg/kg/min]/uIU/uL, p=0.005; 18.6±4.8 vs. −3.4±5.6 [mg/lean kg/min]/uIU/uL, p=0.005) and reduced weight (−0.5±0.5 vs. 1.6±0.5 kg, p=0.004), BMI (−0.2±0.15 vs. 0.4±0.15 kg/m2, p=0.005) and fat mass (−0.7±0.3 vs. 0.6±0.4 kg, p=0.01). M/I also improved in normal-weight participants (11.8±4.4 vs. −4.5±4.4 [mg/kg/min]/uIU/uL, p=0.02, 17.6±6.7 vs. −7.0±6.7 [mg/lean kg/min]/uIU/uL, p=0.02). The metformin group had reduced AA WSSMAX (−0.3±0.4 vs. 1.5±0.5 dyne/cm2, p=0.03), AA PWV, (−1.1±1.20 vs. 4.1±1.6 m/s, p=0.04) and far-wall diastolic cIMT (−0.04±0.01 vs. −0.00±0.01 mm, p=0.049) vs. placebo. Conclusions: T1D adolescents demonstrate IR and impaired vascular health vs. controls. Metformin improves IR, regardless of baseline BMI, and BMI, weight, fat mass, insulin dose, aortic and carotid health in T1D adolescents. Metformin may hold promise as a cardioprotective intervention in T1D.

In patients with bacterial meningitis, antibiotic pretreatment is associated with higher cerebrospinal fluid glucose levels and lower cerebrospinal fluid protein levels, although pretreatment does not modify cerebrospinal fluid white blood cell count or absolute neutrophil count results.

CD40͞CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways. C D40 is a member of the pleiotropic tumor necrosis factor receptor (TNFR) superfamily, which also includes such functionally diverse molecules as CD27, CD30, OX40, RANK, LT-␤R, the p75 low-affinity nerve growth factor receptor, Fas, and members of the death receptor family as well as TNFR1 and TNFR2 (1). CD40 stimulation activates B cells and promotes various aspects of a functional humoral immune response, including enhancement of survival and proliferation (2). Like many TNFR family members, CD40 activates the JNK͞SAPK and NF-B pathways (3, 4). Both of these pathways involve serine͞threonine kinases that regulate gene expression through activation of AP1 and Rel transcription factors, respectively. Another stress-responsive pathway that has also been reported to be activated by CD40 (5) is the p38 kinase pathway, which leads to the phosphorylation and activation of transcription factors such as ATF2 (6). Previous work has also linked CD40 to the activation of the extracellular signal-regulated kinase (ERK)͞mitogen-activated protein kinase (MAPK) pathway (7).In addition to serine͞threonine kinases, a link between CD40 signaling and tyrosine kinase activation has been suggested (8).One pathway shown to be activated by CD40 and to play an important role in CD40 signaling is that initiated by PI-3 kinase (PI-3K) (8-10). PI-3K phosphorylates membrane phospholipids (11), which can recruit and activate pleckstrin homology domaincontaining molecules such as the kinase protein kinase B. This kinase may then regulate the activity of forkhead-related transcription factors (12, 13).In each of the above pathways, one of the major final ...