The cardio-renal axis. Non ST-segment elevation myocardial infarction risk stratification according to renal dysfunction

Background: Chronic kidney disease (CKD) is one of the strongest risk factor for myocardial infarction (MI) and mortality. The aim of this study was to assess the association between renal dysfunction severity, short-term outcomes and the use of in-hospital evidence-based therapies among patients with non–ST-segment elevation myocardial infarction (NSTEMI). Methods: We examined data on 320 patients presenting with NSTEMI to Maggiore’s Emergency Department from 1st Jan 2010 to 31st December 2011. The study patients were classified into two groups according to their baseline glomerular filtration rate (GFR): renal dysfunction (RD) (GFR<60) and non-RD (GFR≥60 ml/min). Patients were then classified into four groups according to their CKD stage (GFR≥60, GFR 59-30, GFR 29-15, GFR <15). Results: Of the 320 patients, 155 (48,4%) had a GFR<60 ml/min at baseline. Compared with patients with a GFR≥60 ml/min, this group was, more likely to be female, to have hypertension, a previous myocardial infarction, stroke or TIA, had higher levels of uric acid and C-reactive protein. They were less likely to receive immediate (first 24 hours) evidence-based therapies. The GFR of RD patients treated appropriately increases on average by 5.5 ml/min/1.73 m2. The length of stay (mean, SD) increased with increasing CKD stage, respectively 5,3 (4,1), 7.0 (6.1), 7.8 (7.0), 9.2 (5.8) (global p <.0001). Females had on average a longer hospitalization than males, regardless of RD. In hospital mortality was higher in RD group (3,25%). Conclusions: The in-hospital mortality not was statically difference among the patients with a GFR value ≥60 ml/min, and patients with a GFR value <60 ml/min. The length of stay increased with increasing CKD stages. Despite patients with RD have more comorbidities then without RD less frequently receive guideline –recommended therapy. The GFR of RD patients treated appropriately improves during hospitalization, but not a level as we expected.

Shikonin directly targets mitochondria and causes mitochondrial dysfunction in cancer cells

Chemotherapy is a mainstay of cancer treatment. Due to increased drug resistance and the severe side effects of currently used therapeutics, new candidate compounds are required for improvement of therapy success. Shikonin, a natural naphthoquinone, was used in traditional Chinese medicine for the treatment of different inflammatory diseases and recent studies revealed the anticancer activities of shikonin. We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines. Transcriptome-wide mRNA expression studies showed that shikonin induced genetic pathways regulating cell cycle, mitochondrial function, levels of reactive oxygen species, and cytoskeletal formation. Taking advantage of the inherent fluorescence of shikonin, we analyzed its uptake and distribution in live cells with high spatial and temporal resolution using flow cytometry and confocal microscopy. Shikonin was specifically accumulated in the mitochondria, and this accumulation was associated with a shikonin-dependent deregulation of cellular Ca(2+) and ROS levels. This deregulation led to a breakdown of the mitochondrial membrane potential, dysfunction of microtubules, cell-cycle arrest, and ultimately induction of apoptosis. Seeing as both the metabolism and the structure of mitochondria show marked differences between cancer cells and normal cells, shikonin is a promising candidate for the next generation of chemotherapy.

Relationship between aetiology and left ventricular systolic dysfunction in hypertrophic cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a common cardiac disease caused by a range of genetic and acquired disorders. The most common cause is genetic variation in sarcomeric proteins genes. Current ESC guidelines suggest that particular clinical features (‘red flags’) assist in differential diagnosis. Aims: To test the hypothesis that left ventricular (LV) systolic dysfunction in the presence of increased wall thickness is an age-specific ‘red flag’ for aetiological diagnosis and to determine long-term outcomes in adult patients with various types of HCM. Methods: A cohort of 1697 adult patients with HCM followed at two European referral centres were studied. Aetiological diagnosis was based on clinical examination, cardiac imaging and targeted genetic and biochemical testing. Main outcomes were: all-cause mortality or heart transplantation (HTx) and heart failure (HF) related-death. All-cause mortality included sudden cardiac death or equivalents, HF and stroke-related death and non-cardiovascular death. Results: Prevalence of different aetiologies was as follows: sarcomeric HCM 1288 (76%); AL amyloidosis 115 (7%), hereditary TTR amyloidosis 86 (5%), Anderson-Fabry disease 85 (5%), wild-type TTR amyloidosis 48 (3%), Noonan syndrome 15 (0.9%), mitochondrial disease 23 (1%), Friedreich’s ataxia 11 (0.6%), glycogen storage disease 16 (0.9%), LEOPARD syndrome 7 (0.4%), FHL1 2 (0.1%) and CPT II deficiency 1 (0.1%). Systolic dysfunction at first evaluation was significantly more frequent in phenocopies than sarcomeric HCM [105/409 (26%) versus 40/1288 (3%), (p<0.0001)]. All-cause mortality/HTx and HF-related death were higher in phenocopies compared to sarcomeric HCM (p<0.001, respectively). When considering specific aetiologies, all-cause mortality and HF-related death were higher in cardiac amyloidosis (p<0.001, respectively). Conclusion: Systolic dysfunction at first evaluation is more common in phenocopies compared to sarcomeric HCM representing an age-specific ‘red flag’ for differential diagnosis. Long-term prognosis was more severe in phenocopies compared to sarcomeric HCM and when comparing specific aetiologies, cardiac amyloidosis showed the worse outcomes.

Muscle membrane dysfunction in critical illness myopathy assessed by velocity recovery cycles

To test the hypothesis that muscle fibers are depolarized in patients with critical illness myopathy by measuring velocity recovery cycles (VRCs) of muscle action potentials.

Carcinoma ex pleomorphic adenoma in a minor salivary gland: report of a case

BACKGROUND: Carcinoma ex pleomorphic adenoma is exceedingly rare in minor salivary glands of the oral cavity. We present a case of carcinoma ex pleomorphic adenoma (CEPA) of the buccal mucosa in a 47-year-old Turkish patient. The buccal mass was of a size of 1.5 cm located in the left cheek. Pleomorphic adenoma was the tentative diagnosis. METHODS: The tumor was removed under local anesthesia. Histopathologic evaluation revealed a preexisting pleomorphic adenoma associated with adenoid tumor component with tubulo-cystic and papillary or pseudopapillary structures; CEPA was diagnosed. Capsular integrity was incomplete with infiltration by islands of metaplastic/dysplastic epithelium. RESULTS: Secondary surgery of the site was performed. No tumor tissue could be detected in the resection specimen. The patient is free of recurrence since 9 months.

Toll-like receptor-3-induced mitochondrial dysfunction in cultured human hepatocytes

Several studies have shown the presence of liver mitochondrial dysfunction during sepsis. TLR3 recognizes viral double-stranded RNA and host endogenous cellular mRNA released from damaged cells. TLR3 ligand amplifies the systemic hyperinflammatory response observed during sepsis and in sepsis RNA escaping from damaged tissues/cells may serve as an endogenous ligand for TLR3 thereby modulating immune responses. This study addressed the hypothesis that TLR3 might regulate mitochondrial function in cultured human hepatocytes. HepG2 cells were exposed to TLR-3 ligand (dsRNA--polyinosine-polycytidylic acid; Poly I:C) and mitochondrial respiration was measured. Poly I:C induced a reduction in maximal mitochondrial respiration of human hepatocytes which was prevented partially by preincubation with cyclosporine A (a mitochondrial permeability transition pore-opening inhibitor). Poly-I:C induced activation of NF-κB, and the mitochondrial dysfunction was accompanied by caspase-8 but not caspase-3 activation and by no major alterations in cellular or mitochondrial ultrastructure.

[Myocardial dysfunction in sepsis]

Myocardial dysfunction appears in 25% of patients with severe sepsis and in 50% of patients with septic shock, even in the presence of hyper dynamic states. It is characterized by a reduction in left ventricle ejection fraction, that reverts at the seventh to tenth day of evolution. Right ventricular dysfunction and diastolic left ventricular dysfunction can also appear. There is no consensus if an increase in end diastolic volume is part of the syndrome. High troponin or brain natriuretic peptide levels are associated with myocardial dysfunction and a higher mortality. The pathogenesis of myocardial dysfunction is related to micro and macro circulatory changes, inflammatory response, oxidative stress, intracellular calcium management disturbances, metabolic changes, autonomic dysfunction, activation of apoptosis, mitochondrial abnormalities and a derangement in catecholaminergic stimulation. Since there is no specific treatment for myocardial dysfunction, its management requires an adequate multi systemic support to maintain perfusion pressures and systemic flows sufficient for the regional and global demands.

Influenza A(H1N1) infection and severe cardiac dysfunction in adults: A case series

BACKGROUND: While viral myocarditis and heart failure are recognized and feared complications of seasonal influenza A infection, only limited information is available for 2009 influenza A(H1N1)-induced heart failure. METHODS AND MAIN FINDINGS: This case series summarizes the disease course of four patients with 2009 influenza A(H1N1) infection who were treated at our institution from November 2009 until September 2010. All patients presented with severe cardiac dysfunction (acute heart failure, cardiogenic shock or cardiac arrest due to ventricular fibrillation) as the leading symptom of influenza A(H1N1) infection. Two patients most likely had pre-existent cardiac pathologies, and three required catecholamine therapy to maintain hemodynamic function. Except for one patient who died before influenza A(H1N1) infection had been diagnosed, all patients received antiviral therapy with oseltamivir and supportive critical care. Acute respiratory distress syndrome due to influenza A(H1N1) infection developed in one patient. Heart function normalized in two of the three surviving patients but remained impaired in the other one at hospital discharge. CONCLUSIONS: Influenza A(H1N1) infection may be associated with severe cardiac dysfunction which can even be the leading clinical symptom at presentation. During an influenza pandemic, a thorough history may reveal flu-like symptoms and should indicate testing for H1N1 infection also in critically ill patients with acute heart failure.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia

Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem.

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

The mammary gland vasculature revisited

Concomitant with the extensive growth and differentiation of the mammary epithelium during pregnancy and lactation, and epithelial involution after weaning, the vasculature of the mammary gland undergoes repeated cycles of expansion and regression. Vascular expansion is effected by sprouting angiogenesis, intussusception and conceivably also vasculogenesis. The capacity of the epithelial cells to stimulate vascular growth and differentiation is dependent on the constellation of systemic and local hormones and growth factors as well as the changing demands for oxygenation and nutrient supply. This results in the release of angiogenic factors which stimulate endothelial cell growth and regulate vascular architecture. In contrast to the angiogenic phase of the mammary gland cycle, little is known about the control of vascular regression although this would possibly offer new insights into therapeutic possibilities against breast cancer. In this review we summarize knowledge regarding the mechanisms regulating the vasculature of the mammary gland and delineate the importance of the vasculature in the attainment of organ function. In addition, we discuss the angiogenic mechanisms observed during mammary carcinogenesis and their consequences for breast cancer therapy.

Sacral neuromodulation for neurogenic lower urinary tract dysfunction: systematic review and meta-analysis

Context Treatment of neurogenic lower urinary tract dysfunction (LUTD) is a challenge, because conventional therapies often fail. Sacral neuromodulation (SNM) has become a well-established therapy for refractory non-neurogenic LUTD, but its value in patients with a neurologic cause is unclear. Objective To assess the efficacy and safety of SNM for neurogenic LUTD. Evidence acquisition Studies were identified by electronic search of PubMed, EMBASE, and ScienceDirect (on 15 April 2010) and hand search of reference lists and review articles. SNM articles were included if they reported on efficacy and/or safety of tested and/or permanently implanted patients suffering from neurogenic LUTD. Two reviewers independently selected studies and extracted data. Study estimates were pooled using Bayesian random-effects meta-analysis. Evidence synthesis Of the 26 independent studies (357 patients) included, the evidence level ranged from 2b to 4 according to the Oxford Centre for Evidence-Based Medicine. Half (n = 13) of the included studies reported data on both test phase and permanent SNM; the remaining studies were confined to test phase (n = 4) or permanent SNM (n = 9). The pooled success rate was 68% for the test phase (95% credibility interval [CrI], 50–87) and 92% (95% CrI, 81–98%) for permanent SNM, with a mean follow-up of 26 mo. The pooled adverse event rate was 0% (95% CrI, 0–2%) for the test phase and 24% (95% CrI, 6–48%) for permanent SNM. Conclusions There is evidence indicating that SNM may be effective and safe for the treatment of patients with neurogenic LUTD. However, the number of investigated patients is low with high between-study heterogeneity, and there is a lack of randomised, controlled trials. Thus, well-designed, adequately powered studies are urgently needed before more widespread use of SNM for neurogenic LUTD can be recommended.

The prevalence of endothelial dysfunction in patients with and without coronary artery disease

Endothelial dysfunction (ED) is frequently present in patients presenting with acute or stable coronary artery disease (CAD), but it is also found in patients presenting with chest pain without angiographic coronary lesions.

Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1

Episodic ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K(+) channel subunit K(v)1.1. Episodic ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, K(v)1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed episodic ataxia type 1 to characterize the effects of K(v)1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of episodic ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with episodic ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify K(v)1.1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity.