Publications

Bone formation and remodeling involve coordinated interactions between osteoblasts and osteoclasts through signaling networks involving a variety of molecular pathways. We hypothesized that overexpression of Sonic hedgehog (Shh), a morphogen with a crucial role in skeletal development, would stimulate osteoblastogenesis and bone formation in adult animals in vivo. Systemic administration of adenovirus expressing the N-terminal form of Shh into adult mice resulted in a primary increase in osteoblasts and their precursors. Surprisingly, however, this was associated with altered trabecular morphology, decreased bone volume, and decreased compressive strength in the vertebrae. Whereas no change was detected in the number of osteoclast precursors, bone marrow stromal cells from Shh-treated mice showed enhanced osteoclastogenic potential in vitro. These effects were mediated by the PTH/PTH-related protein (PTHrP) pathway as evidenced by increased sensitivity to PTH stimulation and upregulation of the PTH/PTHrP receptor (PPR). Together, these data show that Shh has stimulatory effects on osteoprogenitors and osteoblasts in adult animals in vivo, which results in bone remodeling and reduced bone strength because of a secondary increase in osteoclastogenesis.

BACKGROUND

Data on the number of individuals eligible for screening, and rates of screening, are necessary to assess national colorectal cancer screening efforts. Such data are sparse for safety-net health systems.

METHODS

A retrospective cohort study of individuals ages 50 to 75 served by a safety-net health system in Tarrant County, TX was conducted to determine (a) the size of the potential screen-eligible population ages 50 to 75, (b) the rate of screening over 5 years among individuals ages 54 to 75, and (c) the potential predictors of screening, including sex, race/ethnicity, insurance status, frequency of outpatient visits, and socioeconomic status.

RESULTS

Of 28,708 potential screen-eligible individuals, 20,416 were ages 54 to 75 and analyzed for screening; 22.0% were screened within the preceding 5 years. Female gender, Hispanic ethnicity, ages 65 to 75, insurance status, and two or more outpatient visits were independently associated with screening. Access to care was an important factor: adjusted odds ratio, 2.57 (95% confidence interval, 2.23-2.98) for any insurance; adjusted odds ratio, 3.53 (95% confidence interval, 3.15-3.97) for two or more outpatient visits.

CONCLUSIONS

The screen-eligible population served by our safety-net health system was large, and the projected deficit in screen rates was substantial. Access to care was the dominant predictor of screening participation. If our results are replicable in similar health systems, the data suggest that screening guidelines and policy efforts must take into account the feasibility of proposed interventions. Strong advocacy for more resources for colorectal cancer screening interventions (including research into the best manner to provide screening for large populations) is needed.

Until recently, most clinical guidelines in the United States were in general agreement about the tests available for colorectal cancer screening, recommending fecal occult blood tests every year, flexible sigmoidoscopy every 5 years, both these tests together, double contrast barium enema every 5 years, or colonoscopy every 10 years. However, the release of two new sets of guidelines in 2008 has made it necessary for primary care physicians to update their knowledge of the recommended screening options. The most influential factor in determining whether a patient is screened is recommendation from a physician. The primary goal of this article is to review and critique the new guidelines for average-risk screening in adults older than 50 years. Armed with this information, primary care physicians will be better educated as to the importance of offering screening to their patients, as well as the strength and weaknesses of each recommended test.

The majority of percutaneous coronary interventions (PCIs) are carried out in nonurgent situations, primarily in patients with stable coronary artery disease. Recent trials have concluded that for patients with stable coronary artery disease, treatment with optimal medical therapy versus optimal medical therapy plus PCI yields equivalent outcomes in terms of morbidity and future risk of myocardial infarction. Since PCI is a procedure with risk, it is important to identify patients for whom the benefit of the procedure outweighs the harms. PCI may be beneficial in certain subgroups, such as patients with moderate-to-severe ischemia on noninvasive testing. Although current guidelines require documentation of ischemia prior to elective PCI and this strategy is cost effective, pre-PCI stress testing appears to be underutilized, potentially leading to PCI being performed in patients who may not derive benefit from the procedure.

BACKGROUND

Transplantation of stem cells from various sources into infarcted hearts has the potential to promote myocardial regeneration. However, the regenerative capacity is limited partly as a result of the low survival rate of the transplanted cells in the ischemic myocardium. In the present study, we tested the hypothesis that combining cell and angiogenic gene therapies would provide additive therapeutic effects via co-injection of bone marrow-derived mesenchymal stem cells (MSCs) with an adeno-associated viral vector (AAV), MLCVEGF, which expresses vascular endothelial growth factor (VEGF) in a cardiac-specific and hypoxia-inducible manner.

METHODS

MSCs isolated from transgenic mice expressing green fluorescent protein and MLCVEGF packaged in AAV serotype 1 capsid were injected into mouse hearts at the border of ischemic area, immediately after occlusion of the left anterior descending coronary, individually or together. Engrafted cells were detected and quantified by real-time polymerase chain reaction and immunostaining. Angiogenesis and infarct size were analyzed on histological and immunohistochemical stained sections. Cardiac function was analyzed by echocardiography.

RESULTS

We found that co-injection of AAV1-MLCVEGF with MSCs reduced cell loss. Although injection of MSCs and AAV1-MLCVEGF individually improved cardiac function and reduced infarct size, co-injection of MSC and AAV1-MLCVEGF resulted in the best improvement in cardiac function as well as the smallest infarct among all groups. Moreover, injection of AAV1-MLCVEGF induced neovasculatures. Nonetheless, injection of MSCs attracted endogenous stem cell homing and increased scar thickness.

CONCLUSIONS

Co-injection of MLCVEGF and MSCs in ischemic hearts can result in better cardiac function and MSC survival, compared to their individual injections, as a result of the additive effects of each therapy.

BACKGROUND

Mutations in the human filaggrin gene (FLG) are associated with atopic dermatitis (AD) and are presumed to provoke a barrier abnormality. Yet additional acquired stressors might be necessary because the same mutations can result in a noninflammatory disorder, ichthyosis vulgaris.

OBJECTIVE

We examined here whether FLG deficiency alone suffices to produce a barrier abnormality, the basis for the putative abnormality, and its proinflammatory consequences.

METHODS

By using the flaky-tail mouse, which lacks processed murine filaggrin because of a frameshift mutation in the gene encoding profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality, further localized the defect, identified its subcellular basis, and assessed thresholds to irritant- and hapten-induced dermatitis.

RESULTS

Flaky-tail mice exhibit low-grade inflammation with increased bidirectional, paracellular permeability of water-soluble xenobiotes caused by impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens at doses that produce no inflammation in wild-type mice, flaky-tail mice experience a severe AD-like dermatosis with a further deterioration in barrier function and features of a T(H)2 immunophenotype (increased CRTH levels plus inflammation, increased serum IgE levels, and reduced antimicrobial peptide [mBD3] expression).

CONCLUSIONS

FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD.

BACKGROUND

Noninfectious nonallergic rhinitis (NINAR) is characterized by self-reported hyperreactivity to nonspecific physical or chemical stimuli. The relationship between these two classes of triggers is not well established, however. We compared NINAR subjects with predominantly physical or chemical triggers versus normal controls with respect to subjective (symptomatic) and objective (obstructive) responses to cold, dry air challenge.

METHODS

We studied 14 NINAR subjects and 10 normal controls. Exposures consisted of 15 minutes of cold dry air (0 degrees C/5% RH) or warm moist air (25 degrees C/50% RH) on two separate days a week apart. Subjects rated symptoms using visual analog scales and had their nasal airway resistance measured at baseline, immediately after, and at 15-minute intervals for 1 hour postexposure.

RESULTS

The majority of NINAR subjects reported physical triggers as more troublesome than chemical. Immediately postprovocation, the mean net proportional change in nasal airway resistance from baseline was +0.18 in NINAR (physical), +0.05 in NINAR (chemical), and -0.01 in control subjects (NS). However, a pooled linear regression by number of physical triggers (0-5) revealed a 7.5% increase in cold air-induced nasal airway resistance per trigger reported (p<0.05). Similarly, raising the criterion number of physical triggers from >or=1 to >or=2 also distinguished NINAR subjects from controls in a bivariate analysis.

CONCLUSION

Either considering self-reported physical triggers as a continuous scale (0-5) or requiring more physical triggers (>or=2 rather than >or=1) to define NINAR successfully predicts objective nasal reactivity to cold air provocation.