Diastolic dysfunction of the cardiac allograft and maximal exercise capacity

BACKGROUND: Peak oxygen uptake (peak Vo(2)) is an established integrative measurement of maximal exercise capacity in cardiovascular disease. After heart transplantation (HTx) peak Vo(2) remains reduced despite normal systolic left ventricular function, which highlights the relevance of diastolic function. In this study we aim to characterize the predictive significance of cardiac allograft diastolic function for peak Vo(2). METHODS: Peak Vo(2) was measured using a ramp protocol on a bicycle ergometer. Left ventricular (LV) diastolic function was assessed with tissue Doppler imaging sizing the velocity of the early (Ea) and late (Aa) apical movement of the mitral annulus, and conventional Doppler measuring early (E) and late (A) diastolic transmitral flow propagation. Correlation coefficients were calculated and linear regression models fitted. RESULTS: The post-transplant time interval of the 39 HTxs ranged from 0.4 to 20.1 years. The mean age of the recipients was 55 +/- 14 years and body mass index (BMI) was 25.4 +/- 3.9 kg/m(2). Mean LV ejection fraction was 62 +/- 4%, mean LV mass index 108 +/- 22 g/m(2) and mean peak Vo(2) 20.1 +/- 6.3 ml/kg/min. Peak Vo(2) was reduced in patients with more severe diastolic dysfunction (pseudonormal or restrictive transmitral inflow pattern), or when E/Ea was > or =10. Peak Vo(2) correlated with recipient age (r = -0.643, p < 0.001), peak heart rate (r = 0.616, p < 0.001) and BMI (r = -0.417, p = 0.008). Of all echocardiographic measurements, Ea (r = 0.561, p < 0.001) and Ea/Aa (r = 0.495, p = 0.002) correlated best. Multivariate analysis identified age, heart rate, BMI and Ea/Aa as independent predictors of peak Vo(2). CONCLUSIONS: Diastolic dysfunction is relevant for the limitation of maximal exercise capacity after HTx.

Variation of cell and matrix morphologies in articular cartilage among locations in the adult human knee

OBJECTIVE: Understanding of articular cartilage physiology, remodelling mechanisms, and evaluation of tissue engineering repair methods requires reference information regarding normal structural organization. Our goals were to examine the variation of cartilage cell and matrix morphology in different topographical areas of the adult human knee joint. METHODS: Osteochondral explants were acquired from seven distinct anatomical locations of the knee joints of deceased persons aged 20-40 years and prepared for analysis of cell, matrix and tissue morphology using confocal microscopy and unbiased stereological methods. Differences between locations were identified by statistical analysis. RESULTS: Medial femoral condyle cartilage had relatively high cell surface area per unit tissue volume in the superficial zone. In the transitional zone, meniscus-covered lateral tibia cartilage showed elevated chondrocyte densities compared to the rest of the knee while lateral femoral condyle cartilage exhibited particularly large chondrocytes. Statistical analyses indicated highly uniform morphology throughout the radial zone (lower 80% of cartilage thickness) in the knee, and strong similarities in cell and matrix morphologies among cartilage from the femoral condyles and also in the mediocentral tibial plateau. Throughout the adult human knee, the mean matrix volume per chondron was remarkably constant at approximately 224,000 microm(3), corresponding to approximately 4.6 x 10(6) chondrons per cm(3). CONCLUSIONS: The uniformity of matrix volume per chondron throughout the adult human knee suggests that cell-scale biophysical and metabolic constraints may place limitations on cartilage thickness, mechanical properties, and remodelling mechanisms. Data may also aid the evaluation of cartilage tissue engineering treatments in a site-specific manner. Results indicate that joint locations which perform similar biomechanical functions have similar cell and matrix morphologies; findings may therefore also provide clues to understanding conditions under which focal lesions leading to osteoarthritis may occur.

Early diagnosis of temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot study comparing clinical examination and ultrasound to magnetic resonance imaging

OBJECTIVES: To study the validity of both rheumatological and orthodontic examinations and ultrasound (US) as screening methods for early diagnosis of TMJ arthritis against the gold standard MRI. METHODS: Thirty consecutive juvenile idiopathic arthritis (JIA) patients were included in this pilot study. Rheumatological and orthodontic examinations as well as US were performed within 1 month of the MRI in a blinded fashion. Joint effusion and/or increased contrast enhancement of synovium or bone were considered signs of active arthritis on MRI. RESULTS: A total of 19/30 (63%) patients and 33/60 (55%) joints had signs of TMJ involvement on MRI. This was associated with condylar deformity in 9/19 (47%) patients and 15/33 (45%) joints. Rheumatological, orthodontic and US examinations correctly diagnosed 11 (58%), 9 (47%) and 6 (33%) patients, respectively, with active TMJ arthritis, but misdiagnosed 8 (42%), 10 (53%) and 12 (67%) patients, respectively, as having no signs of inflammation. The best predictor for active arthritis on MRI was a reduced maximum mouth opening. CONCLUSION: None of the methods tested was able to reliably predict the presence or absence of MRI-proven inflammation in the TMJ in our cohort of JIA patients. US was the least useful of all methods tested to exclude active TMJ arthritis.

The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction

The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood-CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood-CNS barriers with focus on CNS autoimmune inflammation.

Impaired verbal memory in Parkinson disease: relationship to prefrontal dysfunction and somatosensory discrimination

OBJECTIVE: To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception. METHODS: Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices. RESULTS: We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients. CONCLUSION: PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.

Neurally adjusted ventilatory assist decreases ventilator-induced lung injury and non-pulmonary organ dysfunction in rabbits with acute lung injury

OBJECTIVE: To determine if neurally adjusted ventilatory assist (NAVA) that delivers pressure in proportion to diaphragm electrical activity is as protective to acutely injured lungs (ALI) and non-pulmonary organs as volume controlled (VC), low tidal volume (Vt), high positive end-expiratory pressure (PEEP) ventilation. DESIGN: Prospective, randomized, laboratory animal study. SUBJECTS: Twenty-seven male New Zealand white rabbits. INTERVENTIONS: Anesthetized rabbits with hydrochloric acid-induced ALI were randomized (n = 9 per group) to 5.5 h NAVA (non-paralyzed), VC (paralyzed; Vt 6-ml/kg), or VC (paralyzed; Vt 15-ml/kg). PEEP was adjusted to hemodynamic goals in NAVA and VC6-ml/kg, and was 1 cmH2O in VC15-ml/kg. MEASUREMENTS AND MAIN RESULTS: PaO2/FiO2; lung wet-to-dry ratio; lung histology; interleukin-8 (IL-8) concentrations in broncho-alveolar-lavage (BAL) fluid, plasma, and non-pulmonary organs; plasminogen activator inhibitor type-1 and tissue factor in BAL fluid and plasma; non-pulmonary organ apoptosis rate; creatinine clearance; echocardiography. PEEP was similar in NAVA and VC6-ml/kg. During NAVA, Vt was lower (3.1 +/- 0.9 ml/kg), whereas PaO2/ FiO2, respiratory rate, and PaCO2 were higher compared to VC6-ml/kg (p<0.05 for all). Variables assessing ventilator-induced lung injury (VILI), IL-8 levels, non-pulmonary organ apoptosis rate, and kidney as well as cardiac performance were similar in NAVA compared to VC6-ml/kg. VILI and non-pulmonary organ dysfunction was attenuated in both groups compared to VC15-ml/kg. CONCLUSIONS: In anesthetized rabbits with early experimental ALI, NAVA is as effective as VC6-ml/kg in preventing VILI, in attenuating excessive systemic and remote organ inflammation, and in preserving cardiac and kidney function.

[Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor-1alpha]

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alpha can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alpha as a therapeutic target.

Efficacy of psychological interventions for sexual dysfunction: a systematic review and meta-analysis

Sexual dysfunction is highly prevalent in the general population and associated with psychological distress and impaired sexual satisfaction. Psychological interventions are promising treatment options, as sexual dysfunction is frequently caused by and deteriorates because of psychological factors. However, research into the efficacy of psychological interventions is rather scarce and an up-to-date review of outcome studies is currently lacking. Therefore, we conducted a systematic review and meta-analysis of all available studies from 1980 to 2009 to examine the efficacy of psychological interventions for patients with sexual dysfunction. A total of 20 randomized controlled studies comparing a psychological intervention with a wait-list were included in the meta-analysis. The overall post-treatment effect size for symptom severity was d = 0.58 (95% CI: 0.40 to 0.77) and for sexual satisfaction d = 0.47 (95% CI: 0.27 to 0.70). Psychological interventions were shown to especially improve symptom severity for women with Hypoactive Sexual Desire Disorder and orgasmic disorder. Our systematic review of 14 studies comparing at least two active interventions head-to-head revealed that very few comparative studies are available with large variability in effect sizes across studies (d between -0.69 and 2.29 for symptom severity and -0.56 and 14.02 for sexual satisfaction). In conclusion, psychological interventions are effective treatment options for sexual dysfunction. However, evidence varies considerably across single disorders. Good evidence exists to date for female hypoactive sexual desire disorder and female orgasmic disorder. Further research is needed on psychological interventions for other sexual dysfunctions, their long-term and comparative effects.

Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span

Children conceived by assisted reproductive technologies (ART) display a level of vascular dysfunction similar to that seen in children of mothers with preeclamspia. The long-term consequences of ART-associated vascular disorders are unknown and difficult to investigate in healthy children. Here, we found that vasculature from mice generated by ART display endothelial dysfunction and increased stiffness, which translated into arterial hypertension in vivo. Progeny of male ART mice also exhibited vascular dysfunction, suggesting underlying epigenetic modifications. ART mice had altered methylation at the promoter of the gene encoding eNOS in the aorta, which correlated with decreased vascular eNOS expression and NO synthesis. Administration of a deacetylase inhibitor to ART mice normalized vascular gene methylation and function and resulted in progeny without vascular dysfunction. The induction of ART-associated vascular and epigenetic alterations appeared to be related to the embryo environment; these alterations were possibly facilitated by the hormonally stimulated ovulation accompanying ART. Finally, ART mice challenged with a high-fat diet had roughly a 25% shorter life span compared with control animals. This study highlights the potential of ART to induce vascular dysfunction and shorten life span and suggests that epigenetic alterations contribute to these problems.

Subclinical thyroid dysfunction and functional capacity among elderly

Background: Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity but with conflicting data. The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. Methods: We included 5182 participants with a mean age of 75.2 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (BI) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944). The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. Results: At baseline, compared to euthyroid participants (BI 19.73±SE 0.06; IADL 13.52±0.02), there was no difference in functional capacity for participants with subclinical hyperthyroidism (BI 19.60±0.09; IADL 13.51±0.12, p>0.05) or subclinical hypothyroidism (BI 19.82±0.06; IADL 13.55±0.08, p>0.05). Over a mean 3.2-year follow-up period, there was no association between thyroid function and annual decline of either BI or IADL (p>0.05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow-up (p>0.05). Results were similar after excluding participants with a maximum BI and/or IADL score at baseline. Conclusion: Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity.

Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

Subclinical thyroid dysfunction and cognitive decline in old age

BACKGROUND Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). METHODS Prospective longitudinal study of men and women aged 70-82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests. RESULTS Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up. CONCLUSION We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.

Combination of Psychological Intervention and Phosphodiesterase-5 Inhibitors for Erectile Dysfunction: A Narrative Review and Meta-Analysis

INTRODUCTION Erectile dysfunction (ED) is an increasing health problem that demands effective treatment. There is evidence that phosphodiesterase-5 inhibitors (PDE5-Is) and psychological intervention (PI) are effective treatment options; however, little is known about their comparative efficacy and the efficacy of combined treatments. AIM The aim of this systematic review and meta-analysis is to evaluate the comparative efficacy of PI, PDE5-Is, and their combination in the treatment of ED. MAIN OUTCOME MEASURES Primary outcome was ED symptoms, and secondary outcome was sexual satisfaction of the patient. METHODS A systematic literature search was conducted in order to identify relevant articles published between 1998 and 2012. We included randomized controlled trials and controlled trials comparing PI with PDE5-I treatment or one of them against a combination of both. RESULTS Eight studies with a total number of 562 patients were included in the meta-analysis. The results of the included studies are inconclusive, though they show a trend towards a larger effect of combined treatment compared with PI or PDE5-I treatment alone. The meta-analysis found that, overall, combined treatment was more efficacious for ED symptoms than PDE5-I treatment or PI alone. Combined treatment was more efficacious than PDE5-I use alone on sexual satisfaction. No differences were found between PDE5-Is and PI as stand-alone treatments. None of the moderators (treatment duration, methodological quality, or researcher allegiance) altered the effects. CONCLUSIONS The combination of PI and PDE5-Is is a promising strategy for a favorable outcome in ED and can be considered as a first-choice option for ED patients. Stronger RCTs are required to confirm this initial finding. Schmidt HM, Munder T, Gerger H, Frühauf S, and Barth J. Combination of psychological intervention and phosphodiesterase-5 inhibitors for erectile dysfunction: A narrative review and meta-analysis. J Sex Med **;**:**-**.

Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats.

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.