Comparison of an insulin analog,insulin aspart,and regular human insulin with no insulin in gestational diabetes mellitus

OBJECTIVE: To assess the short-term efficacy of insulin aspart in comparison with regular human insulin in women with gestational diabetes mellitus (GDM) during standardized meal tests. RESEARCH DESIGN AND METHODS: The study included 15 women with GDM who had inadequate diabetes control with diet alone. On 3 consecutive days, breakfast meal tests were performed-the first with no exogenous insulin and the other two after the injection of either regular insulin or insulin aspart. RESULTS: The peak insulin concentration was higher and the peak glucose and C-peptide concentrations were lower with both insulin preparations than with no exogenous insulin. Glucose areas under the curve above baseline were significantly lower with insulin aspart (180-min area, 7.1 mg. h. dl(-1); P = 0.018), but not with regular insulin (30.2 mg. h. dl(-1); P = 0.997), than with no insulin (29.4 mg. h. dl(-1)). CONCLUSIONS: This study demonstrates that effective postprandial glycemic control in women with GDM who required insulin was brought about by insulin aspart through higher insulin peak and lower demand on endogenous insulin secretion.     

Free-breathing 3D whole-heart black-blood imaging with motion sensitized driven equilibrium

Purpose:

To automatically analyze the time course of collateralization in a rat hindlimb ischemia model based on signal intensity distribution (SID).

Materials and Methods:

Time‐of‐flight magnetic resonance angiograms (TOF‐MRA) were acquired in eight rats at 2, 7, and 21 days after unilateral femoral artery ligation. Analysis was performed on maximum intensity projections filtered with multiscale vessel enhancement filter. Differences in SID between ligated limb and a reference region were monitored over time and compared to manual collateral artery identification.

Results:

The differences in SID correlated well with the number of collateral arteries found with manual quantification. The time courses of ultrasmall (diameter ?0.5 mm) and small (diameter ≈0.5 mm) collateral artery development could be differentiated, revealing that maturation of the collaterals and enlargement of their feeding arteries occurred mainly after the first week postligation.

Conclusion:

SID analysis performed on axial maximum intensity projections is easy to implement, fast, and objective and provides more insight in the time course of arteriogenesis than manual identification. J. Magn. Reson. Imaging 2012;379‐386. © 2011 Wiley Periodicals, Inc.

     

The epidemiology of osteoporosis and fractures in geriatric medicine

Several conclusions can be drawn from this article, the most important of which are as follows: 1. Low bone mass is widely prevalent among older men and women and is associated with important fracture consequences. 2. The prevalence of osteoporosis and fracture is projected to increase over the next several decades. 3. Although Caucasian women are at greatest risk, substantial numbers of men and women of non-Caucasian heritage are also affected. 4. The population burden of disease consequences, including mortality, morbidity, and social and personal cost, is anticipated to increase as well. 5. In the group at greatest risk (Caucasian women), osteoporosis and fracture have well-established risk factors, many of which are modifiable. 6. Relevance of these risk factors for groups other than Caucasian women appears likely but requires further investigation. 7. Personal and societal costs associated with osteoporosis are enormous; as such, identification of persons at risk and prevention and treatment of this disease should be public health priorities.     

Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities

Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.     

Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.     

A novel serine protease of the mammalian HtrA family is up-regulated in mouse uterus coinciding with placentation

This paper characterizes a novel gene, previously identified as uniquely regulated at implantation in mouse uterus. We cloned its full mRNA sequence encoding a serine protease possessing an IGF-binding domain and named it pregnancy-related serine protease (PRSP). PRSP is structurally similar to mammalian HtrA1 (56% amino acid similarity). Northern analysis revealed that the expression of PRSP mRNA was low before pregnancy, but it was increased at implantation and markedly up-regulated post-implantation. In-situ hybridization localized low levels of mRNA expression to the epithelium and stroma during very early pregnancy, but high expression to the decidual cells on day 8.5, primarily at the mesometrial pole where the placenta was forming. By day 10.5, PRSP mRNA was detected in the placenta. We also cloned an alternatively spliced PRSP mRNA that is expressed at a very low level. We located PRSP gene on chromosome 5 and established its intron/exon structure, which unambiguously explains how the two mRNA variants are produced through alternative splicing. Based on PRSP protein domain structure and its unique expression during pregnancy, we propose that PRSP plays an important role in the formation/function of the placenta.     

Clinical and Economic Outcomes for Patients with Health Care-Associated Staphylococcus aureus Pneumonia

While the increasing importance of methicillin-resistant Staphylococcus aureus (MRSA) as a pathogen in health care-associated S. aureus pneumonia has been documented widely, information on the clinical and economic consequences of such infections is limited. We retrospectively identified all patients admitted to a large U.S. urban teaching hospital between January 2005 and May 2008 with pneumonia and positive blood or respiratory cultures for S. aureus within 48 h of admission. Among these patients, those with suspected health care-associated pneumonia (HCAP) were identified using established criteria (e.g., recent hospitalization, admission from nursing home, or hemodialysis). Subjects were designated as having methicillin-resistant (MRSA) or methicillin-susceptible (MSSA) HCAP, based on initial S. aureus isolates. Initial therapy was designated “appropriate” versus “inappropriate” based on the expected susceptibility of the organism to the regimen received. We identified 142 patients with evidence of S. aureus HCAP. Their mean (standard deviation [SD]) age was 64.5 (17) years. Eighty-seven patients (61%) had initial cultures that were positive for MRSA. Most (∼90%) patients received appropriate initial antibiotic therapy (86% for MRSA versus 91% for MSSA; P = 0.783). There were no significant differences between MRSA and MSSA HCAP patients in mortality (29% versus 20%, respectively), surgery for pneumonia (22% versus 20%), receipt of mechanical ventilation (60% versus 58%), or admission to the intensive care unit (79% versus 76%). Mean (SD) total charges per admission were universally high ($98,170 [$94,707] for MRSA versus $104,121 [$91,314]) for MSSA [P = 0.712]). Almost two-thirds of patients admitted to hospital with S. aureus HCAP have evidence of MRSA infection. S. aureus HCAP, irrespective of MRSA versus MSSA status, is associated with significant mortality and high health care costs, despite appropriate initial antibiotic therapy.Traditionally, infections have been categorized as either community associated or nosocomial in origin. The theory supporting this dichotomy arose from observations that pathogens causing these two types of infections were distinct. However, with the spread of health care delivery beyond the confines of acute-care hospitals, patients increasingly may present to emergency departments (ED) with infections caused by organisms such as methicillin-resistant Staphylococcus aureus (MRSA). This trend has led to the evolution of the concept of health care-associated infection (HCAI). Recent studies have validated the concept of HCAI for a number of types of infection, ranging from endocarditis to pneumonia (1, 4, 10, 12). Many such reports, however, have provided scant microbiologic information and have focused more on distinctions in patient types and risk factors for resistant infection. The situation regarding limited microbiologic data is particularly acute with respect to S. aureus. Although Fridkin and colleagues, in an assessment of the national burden of MRSA, underscored the growing prevalence of this pathogen in health care-associated pneumonia (HCAP) (3), they presented little information regarding outcomes of such infections.S. aureus in general—and MRSA in particular—remains a growing challenge for both hospitals and physicians. Good infection prevention practices necessitate isolation precautions for patients with MRSA, which has made early identification of these persons a time-sensitive endeavor. Beyond infection prevention issues, which may complicate the care of patients at risk for MRSA HCAP, patients with HCAP due to either methicillin-sensitive S. aureus (MSSA) or MRSA may consume substantial resources. Further complicating management of HCAP due to S. aureus is the shift in strain types and antimicrobial resistance implicated in pneumonia (3). The USA300 strain of MRSA, for example, may produce significant toxins and may not respond well to anti-MRSA antimicrobials that are routinely employed (11). Because of these issues, physicians require data regarding the microbiology, epidemiology, and outcomes associated with HCAP due to S. aureus (both MSSA and MRSA).To address these issues, we conducted a retrospective observational study of patients in a large urban hospital with HCAP due to culture-proven S. aureus. Our aims were to describe outcomes and resource utilization among patients with S. aureus HCAP and to understand possible differences between patients with MSSA versus MRSA pneumonia. We also sought to examine differences in outcomes and resource utilization as a function of pathogen susceptibility to vancomycin and the specific strain type involved.(Preliminary findings from this study were presented at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC]-Infectious Diseases Society of America [IDSA] 46th Annual Meeting and the 2008 annual meeting of the American College of Chest Physicians [ACCP] [1a, 10a, 11a].)