Validation of DNA test for hip dysplasia failed in Danish Labrador Retrievers.

Canine hip dysplasia is characterized by poor hip joint conformation and laxity. The disease is a complex trait influenced by both genetics and environment. Diagnosis and quantification of hip dysplasia are performed by radiographic examination of the hip joint and the diagnosis is used for making breeding decisions in many breeds. A prognostic genetic test (the Dysgen test) based on seven associated SNPs has been developed in a study based on Spanish Labrador Retrievers. In our study this test has been evaluated in 39 Danish Labrador Retrievers with known radiographic hip score: 14 with hip dysplasia (grade D or E) and 25 without hip dysplasia (grade A or B). There was no significant correlation between the Dysgen test results and the radiographic hip status (P = 0.3203) in these dogs, indicating that Dysgen test results obtained for Danish Labrador Retrievers have no prognostic value.

Erectile dysfunction as a harbinger for increased cardiometabolic risk.

In August 2003, the Minority Health Institute (MHI) convened an Expert Advisory Panel of cardiologists and urologists to design a new practice model algorithm that uses erectile dysfunction (ED) as a clinical tool for early identification of men with systemic vascular disease. The MHI algorithm noted ED as a marker for the presence of cardiovascular disease and suggested that ED may well be a cardiovascular risk equivalent warranting aggressive secondary prevention management strategies, even in the absence of other cardiac or peripheral vascular symptoms. The MHI algorithm stipulates that all men 25 years of age and older should be asked about ED as a routine part of the cardiovascular history during any office visit. The presence of ED should prompt an aggressive assessment for occult vascular disease; many men with erectile difficulty would benefit from early, aggressive management of cardiovascular risk factors with both lifestyle modification and pharmacotherapy to achieve optimal target goals under the existing treatment guidelines. Since publication of the algorithm in 2005, additional research studies have further supported the advisory panel recommendations.

Relation of C-reactive protein and other cardiovascular risk factors to penile vascular disease in men with erectile dysfunction.

Erectile dysfunction (ED) may be an early sign or symptom of cardiovascular disease (CVD). We examined the relation of traditional and emerging risk factors for CVD to the severity of penile vascular disease in men with ED and without clinical coronary artery disease (CAD). In total, 137 men with ED were evaluated for penile vascular disease severity by penile Doppler ultrasound. These men were divided into the following groups based on ultrasound results: normal, cavernous venous occlusive disease, mild arterial insufficiency, and severe arterial insufficiency. Traditional (fasting lipid panel, fasting glucose, age, BMI, smoking, Framingham coronary artery disease risk score) and emerging (C-reactive protein, Lp(a), homocysteine) risk factors for CVD were correlated to severity of penile vascular disease in men with ED and without clinical CAD. Using univariate analysis, penile Doppler groups showed significant positive correlation to CRP (r=0.21; < or = 0.05) and age (r=0.30; < or = 0.01). For CRP, this correlation remained significant even when adjusted for age (< or = 0.05). Men displaying evidence of penile arterial disease (mild and severe arterial insufficiency) were characterized by elevated CRP levels (0.17 mg/dl) compared to men with no evidence of arterial abnormalities in the penis (0.04 mg/dl). CRP levels correlate significantly with increasing severity of penile vascular disease as measured by penile Doppler.

Arterial distensibility and physical activity in the ARIC study.

PURPOSE: Arterial distensibility decreases with age. This decrease may be associated with the initiation and/or progression of hypertension and atherosclerosis and may be attenuated by positive lifestyle habits, including habitual physical activity. We tested the hypothesis that self-reported sport, leisure, and work physical activity is associated with greater arterial distensibility (i.e., carotid artery pulsatile diameter changes). METHODS: The Atherosclerosis Risk in Communities (ARIC) study assessed left common carotid arterial diameters and intimal-medial wall thickness (IMT) using B-mode ultrasound techniques, in 10,644 African-American and white men and women aged 45-64 yr and free of cardiovascular disease. RESULTS: Work activity, but not sports or leisure activity, was weakly associated with greater arterial distensibility in an ANCOVA model adjusted for blood pressure and other covariates (diastolic arterial diameter, pulse pressure, pulse pressure squared, age, race, sex, smoking, dietary fat intake, height, education, and clinical center) (P for linear trend = 0.03). Vigorous sports activity was weakly positively associated with arterial distensibility (arterial diameter change (mean +/- SE in mm) 0.42 +/- 0.004 vs 0.41 +/- 0.002 for the 12.7% of participants reporting any vs no vigorous activity, P = 0.02), and this association was not attenuated by adjustment for IMT, body mass index, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or diabetes. Repeated analyses with traditional arterial stiffness indices showed similar findings for vigorous but not work activity. CONCLUSION: In contrast to several smaller studies, these findings do not support the hypothesis that habitual physical activity has a strong, consistent positive effect on arterial distensibility.

Brachial artery elastic mechanics in patients with heart failure.

Studies of arterial elasticity in patients with heart failure (HF) have produced varying results. In addition, the direct effects of smooth muscle relaxation on arterial wall mechanics in these patients have not been well characterized. Nineteen patients with New York Heart Association class II to IV HF and 17 age- and size-matched normal subjects were studied by using a recently validated technique for measuring brachial arterial wall mechanics over a wide pressure range. The left brachial artery was imaged through a water-filled blood pressure cuff by use of an ultrasound wall-tracking system at baseline and after 0.4 mg sublingual nitroglycerin (NTG). Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Baseline area, compliance, and pulse wave velocity versus TP curves were similar in the normal subjects and the patients with HF. The incremental elastic modulus versus TP curve tended to be lower in the patients with HF. The wall-to-lumen ratio was increased in HF (P=0.05). NTG significantly shifted the area versus TP (P<0.001) and compliance versus TP (P<0.05) curves upward and the pulse wave velocity versus TP (P<0.05) curve downward in both groups. NTG also significantly (P<0.001) shifted the stress versus strain curve to the right in both groups but did not alter the incremental elastic modulus versus TP curve. We conclude that the brachial arterial wall-to-lumen ratio is increased in HF. This finding occurs together with a trend toward reduced arterial stiffness such that overall mechanical behavior of the brachial artery is preserved. Smooth muscle relaxation with NTG produces similar improvements in brachial arterial wall mechanics in normal subjects and in patients with HF.

Atherosclerotic plaque rupture: a fatigue process?

The mechanism of atherosclerotic plaque rupture is not known. Current theories focus on the acute triggers of plaque rupture and myocardial infarction such as increased shear or circumferential stress, rupture of the vasa vasorum and vasospasm. We hypothesize that a critical mechanism causing plaque rupture is fatigue failure, the catastrophic rupture of a material following exposure to high-cycle, low-amplitude repetitive stress. Comparisons between material fatigue and plaque rupture demonstrate that this hypothesis is consistent with known physiologic and epidemiologic data on plaque rupture.

Partial aortic valve fusion induced by left ventricular assist device.

BACKGROUND: Left ventricular assist devices (LVADs) may be used (1) as a bridging device to cardiac transplantation, (2) for permanent replacement of left ventricular function, and (3) as a bridge to recovery of ventricular function, for example, in recoverable myocardial disease. In this third group of patients, it is important that the LVAD does not produce changes in the heart that will have a deleterious effect on cardiac function once the device is removed. Furthermore, if the LVAD fails, survival depends on optimal function of the diseased heart. METHODS: All hearts with LVADs encountered as surgical specimens following heart transplantation or at autopsy at the Fairview-University of Minnesota Medical Center during the 5-month period August 1998 to January 1999 were examined for native valvular heart disease. The nature and extent of commissural fusion was noted and measured. Light microscopy was performed on any valve lesions. RESULTS: Four of 6 patients with HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) LVADs showed evidence of commissural fusion (acquired aortic stenosis). In 1 patient, this condition was caused by an organizing thrombus uniting a 14-mm length of the commissural region of the right coronary and noncoronary cusps of the aortic valve. Fibrous commissural fusion due to totally organized thrombus in the other 3 patients affected one aortic commissure (2 patients, 2 mm and 4 mm, respectively) and two commissures (1 patient, 2 mm and 5 mm). Partial cuspal fusion in each case was due to permanent closure of the native aortic valve induced by the LVAD's operating in its automatic setting. Mean length of commissural fusion was 5.4 mm (range, 2 to 14 mm; standard deviation [SDI = +/-5.0 mm). Mean duration of implantation of the six LVADs was 180.3 days (range, 26 to 689 days; SD = +/-253.8 days). The LVADs of the 3 patients with fibrous fusion of the commissures had been implanted for an average of 252.3 days (range, 26 to 689 days; SD = +/-378.2 days). CONCLUSIONS: Normal function of the LVAD produces permanent closure of the native aortic valve. Stasis on the ventricular aspect of the aortic valve, combined with a low level of anticoagulation, favors thrombosis at this site. Thrombus organization leads to aortic stenosis of variable severity. This previously unsuspected complication was not detected clinically in any of our patients. Aortic stenosis may hold serious implications for patients in whom the LVAD acts as a bridge to recovery or in those in whom the LVAD fails. Prevention may be achieved by intermittently reducing LVAD pumping action. A built-in venting cycle would be of value in long-term implants. Thrombi on the aortic valve may also predispose patients to infective endocarditis, because bloodstream infection is common in patients with LVADs.

An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells.

We have previously described a SWI/SNF-related protein complex (PYR complex) that is restricted to definitive (adult-type) hematopoietic cells and that specifically binds DNA sequences containing long stretches of pyrimidines. Deletion of an intergenic DNA-binding site for this complex from a human beta-globin locus construct results in delayed human gamma- to beta-globin switching in transgenic mice, suggesting that the PYR complex acts to facilitate the switch. We now show that PYR complex DNA-binding activity also copurifies with subunits of a second type of chromatin-remodeling complex, nucleosome-remodeling deacetylase (NuRD), that has been shown to have both nucleosome-remodeling and histone deacetylase activities. Gel supershift assays using antibodies to the ATPase-helicase subunit of the NuRD complex, Mi-2 (CHD4), confirm that Mi-2 is a component of the PYR complex. In addition, we show that the hematopoietic cell-restricted zinc finger protein Ikaros copurifies with PYR complex DNA-binding activity and that antibodies to Ikaros also supershift the complex. We also show that NuRD and SWI/SNF components coimmunopurify with each other as well as with Ikaros. Competition gel shift experiments using partially purified PYR complex and recombinant Ikaros protein indicate that Ikaros functions as a DNA-binding subunit of the PYR complex. Our results suggest that Ikaros targets two types of chromatin-remodeling factors-activators (SWI/SNF) and repressors (NuRD)-in a single complex (PYR complex) to the beta-globin locus in adult erythroid cells. At the time of the switch from fetal to adult globin production, the PYR complex is assembled and may function to repress gamma-globin gene expression and facilitate gamma- to beta-globin switching.

Transcatheter closure of post-infarction ventricular septal defect with the Amplatzer Septal Occluder device.

There is an 80-90% mortality rate within the first 2 months of the occurrence of a post-infarction ventricular septal defect (VSD) with medical treatment alone. The muscular VSD presents a technical problem for the surgeon. Surgical treatment was unsuccessful in two patients. They were treated successfully using the Amplatzer Septal Occluder, with improvement in their condition.

Expanded normative data for the Mattis Dementia Rating Scale for use with urban, elderly medical patients.

Normative data for the Mattis Dementia Rating Scale (MDRS), stratified by age and education, are provided for use with older adults (ages 61-94) in urban medical settings. Age and education accounted for the greatest amount of variance in MDRS performance. Gender and race were also associated with total MDRS scores, though to a lesser extent. The present normative data are more appropriate for use with older patients seen in urban medical settings than normative data obtained from samples of better-educated, relatively healthy, Caucasian adults. This study provides additional evidence of the significant influence of age and education on MDRS total score (MDRS-T) performance, and highlights the importance of matching an examinee's demographic background to the normative sample with which his or her test score is being compared. Careful consideration of this match is likely to lead to more accurate diagnostic conclusions and potentially improved patient care.

Effects of left ventricular assist devices on outcomes in patients undergoing heart transplantation.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly being used to "bridge" patients to heart transplantation. METHODS: Data from 40 consecutive status 1 heart transplantation patients treated with intravenous inotrope therapy (n = 20) or the HeartMate LVAD (n = 20) were retrospectively analyzed. RESULTS: Baseline clinical characteristics were similar in the two groups. At the time of transplantation, LVAD patients had significantly higher blood pressure and sodium with significantly lower blood urea nitrogen and creatinine. After transplantation, renal failure (52.6% versus 16.7%) and right heart failure (31.6% versus 5.6%) occurred more frequently (p < 0.05) in the inotrope group. Six-month survival after transplantation did not significantly differ in the inotrope or LVAD groups (73.7% versus 88.9%) but event-free survival was significantly (p < 0.05) lower in the inotrope group (15.8% versus 55.6%). Total hospital charges were significantly lower in the inotrope group ($213,860 +/- $107,560 versus $342,620 +/- $104,420), but average daily hospital charges were not different ($3,990 +/- $1,300 versus $4,130 +/- $2,050). CONCLUSIONS: Status 1 heart transplant patients treated with an LVAD as opposed to inotrope therapy have improved clinical and metabolic function at the time of transplant and improved survival to 6 months after transplant without major complications. Total costs are higher in the LVAD patients but average daily costs are similar.

Decreased health care use among patients with silent myocardial ischemia: support for a generalized rather than cardiac-specific silence.

OBJECTIVE: The absence of angina among patients with silent myocardial ischemia (SMI) may be a cardiac phenomenon or may reflect a generalized lack of bodily awareness and symptom reporting. We tested the hypothesis that the silence is generalized, and, therefore, that patients with SMI would make fewer health care visits for noncardiac/chest-pain problems than patients with symptomatic ischemia. METHODS: We counted all out-patient visits to our medical system for the prior 18 months for 95 patients who demonstrated ischemia during treadmill exercise testing and subsequent nuclear scanning: 62 of the patients had SMI during exercise, and 33 of the patients had symptomatic ischemia. RESULTS: Patients with SMI made were significantly less likely to have sought emergency care or primary care and had significantly fewer primary care visits than patients with symptomatic ischemia. Group differences remained after controlling for demographics and health status variables. The two groups did not differ on utilization of specialty care. CONCLUSION: The reduced use of emergency and primary care among patients with SMI suggests that they have a generalized rather than cardiac-specific reduction in somatic awareness and/or symptom reporting.

Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells.

Pre-clinical studies indicate that efficient retrovirus-mediated gene transfer into hematopoietic stem cells and progenitor cells can be achieved by co-localizing retroviral particles and target cells on specific adhesion domains of fibronectin. In this pilot study, we used this technique to transfer the human multidrug resistance 1 gene into stem and progenitor cells of patients with germ cell tumors undergoing autologous transplantation. There was efficient gene transfer into stem and progenitor cells in the presence of recombinant fibronectin fragment CH-296. The infusion of these cells was associated with no harmful effects and led to prompt hematopoietic recovery. There was in vivo vector expression, but it may have been limited by the high rate of aberrant splicing of the multidrug resistance 1 gene in the vector. Gene marking has persisted more than a year at levels higher than previously reported in humans.

Left ventricular assist device bridge therapy for acute myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction (AMI) complicated by cardiogenic shock have a high mortality rate. Current treatment modalities remain suboptimal for these patients. METHODS: From April 1995 to March 1998, 7 patients were identified as having AMI associated with cardiogenic shock. All received intraaortic balloon pump assistance, in addition to maximal inotropic support. RESULTS: The mean preoperative cardiac index was 2.0+/-0.3 L/min/m2 and pulmonary capillary wedge pressure was 23+/-6 mm Hg. Three patients received thrombolytic therapy and 4 patients underwent percutaneous transluminal coronary angioplasty without success. Left ventricular assist devices (LVADs) were implanted as bridge therapy to heart transplantation. One patient died from recurrence of a ventricular septal defect during LVAD support. Six patients were transplanted successfully after mean LVAD support of 59+/-33 days. Five patients are alive and well at a mean follow-up of 898+/-447 days. One patient died 3 days after transplantation from acute allograft dysfunction. CONCLUSIONS: Timely application of LVADs as bridge therapy to heart transplantation in these critically ill patients can be lifesaving, and should be investigated further.

Endothelial dysfunction in patients with heart failure: relationship to disease severity.

BACKGROUND: Heart failure is associated with abnormal endothelium-dependent vasodilation. However, the relationship of this abnormality to heart failure severity has not been well defined. METHODS AND RESULTS: We used strain-gauge plethysmography to assess forearm blood flow (FBF) responses to endothelium-dependent, endothelium-independent, and reactive hyperemic stimuli in normal subjects (n = 29) and in patients with mild (n = 26) and severe (n = 41) heart failure. FBF responses to intra-arterial methacholine (0.3, 1.5, 3.0 microg/min) were significantly (P < .005) and similarly reduced in patients with mild (2.8 +/- 0.4, 5.9 +/- 0.7, and 7.7 +/- 1.1 mL/min/dL) and severe (2.7 +/- 0.4, 5.4 +/- 0.7, and 6.9 +/- 0.9) heart failure compared with normal subjects (4.5 +/- 0.4, 9.4 +/- 1.0, and 12.0 +/- 1.1). FBF responses to nitroprusside (1, 5, 10 microg/min) were significantly reduced in mild (2.4 +/- 0.3, 6.7 +/- 1.1, and 11.9 +/- 2.0, P < .05) and severe (1.9 +/- 0.2, 5.1 +/- 0.5, and 7.3 +/- 0.9, P < .001) heart failure groups compared with normal subjects (3.8 +/- 0.5, 10.8 +/- 1.2, and 14.9 +/- 1.2). However, FBF responses were reduced to a greater extent (P < .001) in mild heart failure compared with severe heart failure. Peak reactive hyperemia was significantly impaired only in severe heart failure. There was no correlation between methacholine responses and ejection fraction, maximum oxygen consumption, wedge pressure, or serum norepinephrine. CONCLUSION: Impaired endothelium-dependent vasodilation is present and near maximum in mild heart failure. Endothelial dysfunction may be an early finding in human heart failure.

Vascular ATP-dependent potassium channels, nitric oxide, and human forearm reactive hyperemia.

Vascular ATP-dependent potassium (K+ATP) channels open and contribute to reactive hyperemia (RH) in animals. The contribution of K+ATP channels to ischemic vasolidation during RH and interactions with endothelium-derived nitric oxide have not been well characterized in human subjects. RH blood flow responses (mL/dL) following 5 minutes of cuff occlusion were measured using strain-gauge plethysmography in 22 normal human subjects age 42 +/- 2 years. Measurements were obtained at baseline and following intra-arterial administration of the K+ATP channel closer glibenclamide, the nitric oxide synthase inhibitor L-N-monomethyl arginine (L-NMMA), or both drugs simultaneously. Glibenclamide (100 micrograms/min) did not change basal flow (2.7 +/- 0.3 to 2.7 +/- 0.3 mL/min/dL), but L-NMMA (8 mumol/min) and combined glibenclamide and L-NMMA significantly (p < 0.05) decreased basal flow (3.0 +/- 0.5 to 2.0 +/- 0.2 and 3.3 +/- 0.5 to 2.5 +/- 0.3, respectively). Glibenclamide significantly (p < 0.01) decreased RH flow (18.2 +/- 1.3 to 14.8 +/- 1.3) and excess flow (5.3 +/- 1.2 to 1.3 +/- 1.3). L-NMMA significantly (p < 0.05) decreased RH flow (21.2 +/- 1.8 to 18.9 +/- 1.9) and tended to decrease excess flow (6.1 +/- 2.2 to 3.9 +/- 2.5). Combined drug infusion significantly (p < 0.1) decreased RH flow (21.6 +/- 2.2 to 18.0 +/- 2.4) and excess flow (6.3 +/- 1.6 to 1.6 +/- 1.6), with reductions in RH and excess flow similar to those following glibenclamide infusion alone. We conclude that forearm vascular K+ATP channels are closed at baseline. They open and contribute to RH vasodilation. The addition of nitric oxide inhibition to K+ATP channel blockade does not result in additive or synergistic inhibition of RH.

HemT-3, an alternative transcript of mouse gene HemT specific to male germ cells.

A number of genes are known to be expressed primarily in hematopoietic cells and testis and are thought to function in the control of both blood cell and male germ cell differentiation. We have recently identified a mouse gene, HemT, that encodes two alternatively spliced transcripts specific to hematopoietic cells (HemT-1 and HemT-2) and kidney (HemT-2). We have now isolated a third HemT transcript, HemT-3, that is found only in testis by Northern blot analysis and RT-PCR. HemT-3 is alternatively spliced and may be initiated differently from HemT-1 and HemT-2. RNA in-situ hybridization of testis from wild-type and germ-cell-deficient adult mice, as well as from mice at different developmental stages, indicates that HemT-3 is expressed only in early spermatocytes. HemT-3 cDNA has a major open reading frame related to a human glycosylphosphatidylinositol (GPI)-anchored protein, GML. Using an antibody generated against a peptide derived from the HemT-3 open reading frame, we have detected a testis-specific 22kDa protein by Western blot analysis.