Citations

Background: Nerve involvement developed in a patient with granuloma annulare, as evidenced by a perineural infiltrate of histiocytes in the dermis. The histopathologic pattern was suggestive of leprosy. No mycobacteria were observed, and neurologic testing was normal. Objective: To determine whether inflammation of the nerves or perineural tissue is common in granuloma annulare, we studied the cutaneous nerves in skin biopsy specimens from 14 patients with granuloma annulare. Methods: Sections were stained with hematoxylin-eosin to highlight inflammatory cells and with S-100 to identify cutaneous nerves. Results: No inflammation around nerves was found in 12 specimens, abutting granulomatous inflammation was found in 1 specimen, and enveloping granulomatous inflammation was found in 1 specimen. No nerves were infiltrated by inflammatory cells. Conclusion: Perineural granulomatous inflammation resembling the perineural infiltrate of leprosy appears to be an uncommon characteristic of granuloma annulare. Clinical correlation and acid-fast stains can assist in establishing the correct diagnosis. Contexte: Une atteinte nerveuse est apparue chez un patient atteint de granulome annulaire, comme en témoignait un infiltrat périneural d'histiocytes dans le derme. Les signes histopathologiques étaient évocateurs de la lèpre, mais aucune mycobactérie n'a été observée, et l'examen neurologique était normal. Objectif: L'étude visait à déterminer si l'inflammation des nerfs ou du tissu périneural est fréquente dans le granulome annulaire; pour ce faire, nous avons examiné les nerfs cutanés dans des prélèvements biopsiques de la peau, effectués sur 14 patients atteints de granulome annulaire. Méthodes: Les coupes ont été colorées à l'hématoxyline-éosine pour mettre en évidence des cellules inflammatoires, ainsi qu'au S-100 pour repérer les nerfs cutanés. Résultats: Aucune inflammation autour des nerfs n'a été observée sur 12 prélèvements, mais il y avait présence d'inflammation granulomateuse contiguë sur un prélèvement et d'inflammation granulomateuse enveloppante, sur un autre prélèvement. Les nerfs n'ont pas été infiltrés par les cellules inflammatoires. Conclusion: L'inflammation granulomateuse périneurale qui ressemble à l'infiltration périneurale observée dans la lèpre semble un signe peu fréquent du granulome annulaire. L'établissement de corrélations cliniques et des colorations résistantes à l'acide peuvent faciliter la pose du bon diagnostic.

AbstractWe performed a retrospective review of outcomes after heart transplantation during long‐term follow‐up of a surgical cohort of 1138 Fontan patients who were followed at the Mayo Clinic. Follow‐up information was obtained from medical records and a clinical questionnaire that was mailed to patients not known to be deceased at the initiation of the study. Forty‐four of 1138 Fontan patients with initial or subsequent evaluation at Mayo had cardiac transplantation between 1988 and 2014 (mean age at transplantation was 23.2 ± 12 yr, median was 19.8 yr; mean interval between Fontan and transplantation was 13.0 ± 7.7 yr, median was 13.1 yr). Two patients had combined organ transplantation (one heart–lung, one heart–liver). Twelve of the 44 (27%) patients had PLE prior to transplantation. There was no difference in post‐bypass Fontan pressures or incidence of late reoperations for AVV repair/replacement between transplanted and non‐transplanted patients. There were 16 (36%) deaths in the transplantation cohort; seven occurred within 30 days of transplantation. Overall one, five, 10, and 15 yr post‐transplantation survival was 80%, 72%, 69%, and 55%, respectively. Although this is a challenging group of patients, intermediate‐term results suggest that cardiac transplantation remains a reasonable option for patients with a failed Fontan circulation.

Background— In asymptomatic patients with severe aortic stenosis, guidelines recommend left ventricular ejection fraction (LVEF) of <50% as the threshold for referral for aortic valve replacement. We investigated the importance of LVEF on long-term outcome after aortic valve replacement in symptomatic and asymptomatic patients with severe aortic stenosis. Methods and Results— We retrospectively identified 2017 patients with severe aortic stenosis (aortic valve area<1 cm 2 , mean gradient≥40 mm Hg, or indexed aortic valve area<0.6 cm 2 /m 2 ) who underwent surgical aortic valve replacement from January 1995 to June 2009. Patients were divided into 4 groups depending on preoperative LVEF (<50% in 300 [15%] patients, 50%–59% in 331 [17%], 60%–69% in 908 [45%], and ≥70% in 478 [24%]). During follow-up of 5.3±4.4 years, 1056 (52%) patients died. A decrease in mortality was observed with increasing LVEF, P <0.0001; 5-year mortality estimates (95% confidence interval) were 0.41 (0.35–0.47), LVEF<50%; 0.35 (0.29–0.41), LVEF 50% to 59%; 0.26 (0.23–0.29), LVEF 60% to 69%; and 0.22 (0.18–0.26), LVEF≥70%. Compared with patients with LVEF≥60%, patients with LVEF 50% to 59% had increased mortality (hazard ratio [HR], 1.58; P <0.001), with similar risk increase in both symptomatic (HR, 1.56; P <0.001) and asymptomatic patients (HR, 1.58; P =0.006). Correcting for risk factors, LV mass index, aortic valve area, and stroke volume index, LVEF was independently predictive of mortality (HR, 0.88 per 10%; P <0.001). When this analysis was repeated in the subset of 1333 patients without history of coronary artery disease, LVEF remained associated with mortality (HR, 0.90 per 10%; P =0.009). Conclusions— LVEF is a powerful predictor of outcome in patients with severe aortic stenosis undergoing aortic valve replacement, independent of the presence of valve-related symptoms.

Background— In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients. Methods and Results— In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction ≥50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72±10 versus 76±12 years of age; P =0.002), presented less often with atrial fibrillation (13% versus 24%; P =0.05) and chronic obstructive pulmonary disease (2% versus 19%; P <0.001), and had a lower prevalence of hypertension (73% versus 40%; P <0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120±39 versus 95±25 g/m 2 ; P <0.0001), increased relative wall thickness (0.61±0.15 versus 0.50±0.11; P <0.0001), shorter mitral deceleration time (199±58 versus 268±62 ms; P <0.0001), and increased left atrial volume index (49±18 versus 42±15 mL/m 2 ; P =0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms. Conclusions— The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00294775.

Background Plasma fibulin‐1 levels have been associated with N‐terminal pro–B‐type natriuretic peptide levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues. Methods and Results One hundred twenty‐five patients with severe aortic stenosis who were scheduled for aortic valve replacement ( AVR ) were evaluated with preoperative echocardiography and their plasma fibulin‐1 levels were determined with ELISA . The cohort was followed for a median of 4 years after AVR . Increased restrictive left ventricular ( LV ) filling pattern was observed with increased plasma fibulin‐1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin‐1 tertile groups, P =0.004). Likewise, reduced longitudinal systolic LV function (6.6±1.1 versus 6.1±1.3 versus 5.7±1.5 cm/s, P =0.05) and increased LV filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin‐1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13±4 versus 15±5 versus 16±6 in the fibulin‐1 tertile groups, P =0.04). Conclusions In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin‐1 is associated with restrictive filling of the LV , decreased longitudinal systolic function of the LV , and increased LV filling pressures. Clinical Trial Registration URL: www.clinicaltrial.gov with Identifier: NCT00294775

SummaryStem cells live long lives, renew themselves, and differentiate into more mature, less potent, specialized cells, such as epidermal keratinocytes and dermal fibroblasts. Stem cells can be embryonic, if derived from an embryo, or adult/somatic if derived from postembryonic tissue. By producing new skin cells, stem cell division and differentiation can potentially rejuvenate skin and restore hair. To reproduce, stem cells can undergo symmetric nondifferentiative or differentiative divisions, or asymmetric differentiative divisions. Asymmetric divisions reproduce the stem cell and provide a more differentiated, but less potent transient amplifying cell. Divisions and differentiation of transient amplifying cells regenerate tissues by producing cells of a specific lineage, for example, keratinocytes. Epidermal stem cells lie in niches in the interfollicular epidermis, sebaceous gland, and in the bulge regions of hair follicles. These epidermal stem cells renew the epidermis, the sebaceous glands, and hair follicles after mature cells die. Dermal stem cells lie in the hair papillae, around pericytes, and elsewhere among other dermal cells. These form pericytes, myoblasts, fibroblasts, chondrocytes, and other specialized dermal cells. Along with other signaling pathways, the Wnt signaling pathway controls stem cell fate. Wnt signals enlist two functionally and chemically different gene coactivators to direct the time and type of replicative divisions. Stem cells may help to heal wounds, repair damaged tissues, regenerate aged skin, and reinvigorate growth of skin, hair, nails, and mucous membranes.

Background— Global longitudinal systolic strain (GLS) is often reduced in aortic stenosis despite normal ejection fraction. The importance of reduced preoperative GLS on long-term outcome after aortic valve replacement is unknown. Methods and Results— A total of 125 patients with severe aortic stenosis and ejection fraction >40% scheduled for aortic valve replacement were evaluated preoperatively and divided into 4 groups according to GLS quartiles. Patients were followed up for 4 years. The primary end points were major adverse cardiac events (MACEs) defined as cardiovascular mortality and cardiac hospitalization because of worsening of heart failure; the secondary end point was cardiovascular mortality. MACE and cardiac mortality were significantly increased in patients with lower GLS. Estimated 5-year MACE was increased: first quartile 19% (n=6) / second quartile 20% (n=6) / third quartile 35% (n=11) / fourth quartile 49% (n=15); P =0.04. Patients with increased age, left ventricular hypertrophy, and left atrial dilatation were at increased risk. In Cox regression analysis, after correcting for standard risk factors and ejection fraction, GLS was found to be significantly associated with cardiac morbidity and mortality. In a stepwise Cox model with forward selection, GLS was the sole independent predictor: hazard ratio=1.13 (95% confidence interval, 1.02–1.25), P =0.04. Comparing the overall log likelihood χ 2 of the predictive power of the multivariable model containing GLS was statistically superior to models based on EuroScore, history with ischemic heart disease, and ejection fraction. Conclusions— In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS provides important prognostic information beyond standard risk factors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00294775.

Abstract Background: Based upon preclinical synergy and prior phase 1 study results, the clinical efficacy of flavopiridol combined with cisplatin was assessed in patients with recurrent ovarian and primary peritoneal cancers. Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) followed by flavopiridol (100 mg/m2 IV, 24 h continuous infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant ovarian/primary peritoneal cancers (defined by disease progression &gt; vs. &lt;6 months following platin-based therapy). Measurable disease (RECIST criteria) – or evaluable disease plus CA125 &gt;2X the post-treatment nadir – was required, as was ECOG performance &lt;2 and exposure to only one prior treatment regimen. Results: Forty-five patients were enrolled between April 20, 2004 and March 4, 2010 – 40 platin-resistant patients (Group 1), and 5 platin-sensitive patients (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12); 39 of the 40 eligible patients have now discontinued treatment. While only 10% of all patients incurred grade 4 toxicities, grade 3 toxicities were seen in the majority (65%). The most frequent grade 3 and 4 toxicities were neutropenia (all grade 3, 17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Sensory neuropathy, grade 1 or 2, was observed in 75% of all patients – with grade 3 and 4 neuropathy not observed primarily due to pre-specified aggressive dose reductions. Six patients (15%) in Group 1 achieved a confirmed response (1 CR, 5 PR), with a median response duration of 119 days (range 84-212). Ten additional Group 1 patients (32.5%) experienced maintained stable disease. Median Group 1 overall time to progression was 3.7 months; overall survival was 17.2 months. Pilot assessment of attained ascites flavopiridol level and sensitivity of patient ascitic tumor cells to flavopiridol confirmed that patient flavopiridol levels were consistent with observed clinical antitumor efficacy. In Group 2, although 2 of 5 patients also responded (40%; 2 PR), the cohort was closed due to poor accrual. Conclusions: The combination of flavopiridol and cisplatin has promising clinical activity in both platin-sensitive and platin-resistant ovarian and primary peritoneal cancers. Supported in part by NCI CA097129, CA15083 and CM62205; clinicaltrials.gov identifier NCT00083122 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2011-4712