Disturbances in the microcirculation can lead to secondary lymphedema, a common pathological condition that, despite its frequency, still lacks a cure. Lymphedema is clinically well described, but while the genetic underpinnings that cause lymphatic malformations and primary lymphedema are being discovered, the pathophysiology and pathobiology of secondary lymphedema remain poorly understood, partly due to the lack of well-described experimental models. Here, we provide a detailed characterization of secondary lymphedema in the mouse tail and correlate the evolution of tissue swelling to changes in tissue architecture, infiltration of immune cells, deposition of lipids, and proliferation and morphology of the lymphatic vessels. We show that sustained swelling leads to lymphatic hyperplasia and upregulation of vascular endothelial growth factor (VEGF)-C, which may exacerbate the edema because the hyperplastic vessels are poorly functional. The onset of lymphatic hyperplasia occurred prior to the onset of lipid accumulation and peak VEGF-C expression. Langerhans dendritic cells were seen in the dermis migrating from the epidermis to the lymphatic capillaries in edematous tissue. Furthermore, these results were consistent between two different normal mouse strains, but swelling was significantly greater in a matrix metalloproteinase (MMP)-9 null strain. Thus, by characterizing this highly reproducible model of secondary lymphedema, we conclude that VEGF-C upregulation and lymphatic hyperplasia resulting from dermal lymphatic ligation and lymphedema leads to decreased drainage function and that MMP-9 may be important in counteracting tissue swelling.

Relative to other lung transplant indications, our SSc group experienced comparable survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates, despite the high prevalence of severe esophageal dysfunction. Esophageal dysfunction rarely precluded active listing for lung transplantation.

Background Cocaine is a major cause of acute coronary syndrome (ACS), especially in young adults; however, the mechanistic underpinning of cocaine-induced ACS remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking. Methods and Results We used myocardial contrast echocardiography (MCE) to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low non-intoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naïve young men (median age 32 years). Post-destruction time-intensity MCE kinetic data were fit to the equation: y = A(1-e- β t) to quantify functional capillary blood volume (A), microvascular flow velocity (β), and myocardial perfusion (A × β). Heart rate (HR), mean arterial pressure (MAP), and LV work (two-dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased MAP (+14±2 mmHg; mean ± SE), HR (+8±3 beats/min), and LV work (+50±18 mmHg·mL-1·bpm-1). Despite increasing these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7±9.8 to 75.9±10.8 a.u/s, p<0.01) due mainly to decreased capillary blood volume (133.9±5.1 to 111.7±7.7 a.u., p<.05) with no significant change in microvascular flow velocity (0.8±0.1 to 0.7±0.1 a.u.). Conclusions In healthy cocaine-naïve young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries.

Awake bronchoscopic intubation supported with a noninvasive positive pressure delivery systems may be feasible alternative to standard direct laryngoscopy approach. Further studies are needed to better assess its safety and applicability.

Cardiovascular disease (CVD) is the leading cause of death for American women. Women share many of the same risk factors (RFs) for CVD as men, and in both, women and men, these RFs are associated with age. Additionally, the prevalence of multiple RFs increases with age. Though menopause has been thought to increase CVD risk in women, the association between menopause and age obfuscates a causal relationship. While men's CVD mortality has decreased since the 1980s, women's CVD mortality has climbed until 2000. This has resulted in a sex-related CVD mortality gap, with women having higher mortality than men since 1984. Contributing to this female-majority CVD mortality gap is a lack of awareness of CVD risk among women and their physicians. Awareness campaigns, such as the Heart Truth and the Red Dress symbol, appear to have improved recognition of CVD risk in women. Further, female-specific guidelines have been developed to prevent and reduce CVD in women. Though the current understanding of the role of menopause in CVD is controversial, studies suggest that menopause does not exacerbate CVD independent of aging, and hormone replacement therapy is not effective for secondary prevention of CVD.

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Loss of sarcolemmal nitric oxide synthase (nNOS) engenders ischemia of exercising dystrophin‐deficient muscles of mdx mice and boys with Duchenne muscular dystrophy. We tested if muscle ischemia also occurs in Becker muscular dystrophy (BMD), a milder disease often caused by dystrophin mutations involving the nNOS binding site, and is improved by tadalafil, a phosphodiesterase (PDE5A) inhibitor that enhances cGMP/NO signaling. We measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] during lower body negative pressure [LBNP]) at rest and during rhythmic handgrip (HG) in 5 male controls (Ctrls) and 10 men with BMD who underwent a placebo‐controlled cross‐over trial of single‐dose (20 mg) tadalafil. At baseline, HG greatly attenuated vasoconstriction in Ctrls (ΔHb02:−393±89 vs. −91±40 units, p<.01; rest vs. HG) but caused no attenuation in BMD (−381±45 vs. − 374±46). Tadalafil markedly improved ischemia in BMD (ΔHb02:− 439±70 vs. −230±54, rest vs. HG; p=0.014) whereas placebo had no effect. These data provide the first evidence in man that PDE5A inhibition can improve blood flow regulation in dystrophin‐deficient skeletal muscle. Funded by MDA 201149.

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