Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease

Contains fulltext : 109282.pdf (publisher's version ) (Open Access)BACKGROUND: A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. METHODS/DESIGN: This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, alpha1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. DISCUSSION: We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. TRIAL REGISTRATION NUMBER: Clinical trials.gov NCT01354405

Late-onset erythromelalgia in a previously healthy young woman: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Erythromelalgia is a rare disorder characterized by episodic erythema and burning pain, which commonly involves the extremities. We present a case of late onset erythromelalgia in a previously healthy young woman and briefly review the literature. Our patient's case also has additional uncommon features not reported previously.</p> <p>Case presentation</p> <p>A 33-year-old previously healthy Caucasian woman presented with complaints of episodic burning pain and flushing occurring in a central distribution involving her face, ears, upper chest and, occasionally, her upper extremities. Her symptoms were triggered by lying down or warm temperature exposure and were relieved by cooling measures. Extensive diagnostic work-up looking for secondary causes for the symptoms was negative and the diagnosis of erythromelalgia was made based on details provided in her clinical history supported by raised temperature in the affected area measured by thermography during a symptomatic episode. The patient did not respond to pharmacological therapy or surgical sympathectomy. She was advised on lifestyle modification to avoid activities which triggered her symptoms. She was hypothermic with a core temperature between 92 and 95°F. She also had premature ovarian failure, which had not previously been reported.</p> <p>Conclusion</p> <p>Erythromelalgia is a rare disorder of unknown cause. There is no confirmatory diagnostic test; diagnosis is based on details provided in the patient's medical history and physical examination during the episodes. For those affected, this disorder leads to significant long-term morbidity and unfortunately, to date, no definitive therapy is available except for lifestyle modification.</p

Comparison of outcomes of percutaneous coronary intervention on proximal versus non-proximal left anterior descending coronary artery, proximal left circumflex, and proximal right coronary artery: A cross-sectional study

BACKGROUND: Previous studies have shown that lesions in proximal left anterior descending coronary artery (LAD) may develop more restenosis after balloon angioplasty than lesions in other coronary segments. However, stenting seems to have reduced this gap. In this study, we compared outcomes of percutaneous coronary intervention (PCI) on proximal LAD versus proximal left circumflex (LCX) or right coronary artery (RCA) and proximal versus non-proximal LAD. METHODS: From 1737 patients undergoing PCI between March 2004 and 2005, those with cardiogenic shock, primary PCI, total occlusions, and multivessel or multi-lesion PCI were excluded. Baseline characteristics and in-hospital outcomes were compared in 408 patients with PCI on proximal LAD versus 133 patients with PCI on proximal LCX/RCA (study I) and 244 patients with PCI on non-proximal LAD (study II). From our study populations, 449 patients in study I and 549 patients in study II participated in complete follow-up programs, and long-term PCI outcomes were compared within these groups. The statistical methods included Chi-square or Fisher's exact test, student's t-test, stratification methods, multivariate logistic regression and Cox proportional hazards model. RESULTS: In the proximal LAD vs. proximal LCX/RCA groups, smoking and multivessel disease were less frequent and drug-eluting stents were used more often (p = 0.01, p < 0.001, and p < 0.001, respectively). Patients had longer and smaller-diameter stents (p = 0.009, p < 0.001, respectively). In the proximal vs. non-proximal LAD groups, multivessel disease was less frequent (p = 0.05). Patients had larger reference vessel diameters (p < 0.001) and were more frequently treated with stents, especially direct stenting technique (p < 0.001). Angiographic success rate was higher in the proximal LAD versus proximal LCX/RCA and non-proximal LAD groups (p = 0.004 and p = 0.05, respectively). In long-term follow-up, major adverse cardiac events showed no difference. After statistical adjustment for significant demographic, angiographic or procedural characteristics, long-term PCI outcomes were still similar in the proximal LAD versus proximal LCX/RCA and non-proximal LAD groups. CONCLUSION: Despite the known worse prognosis of proximal LAD lesions, in the era of stenting, our long-term outcomes were similar in patients with PCI on proximal LAD versus proximal LCX/RCA and non-proximal LAD. Furthermore, we had better angiographic success rates in patients with PCI on proximal LAD

Anti-proliferative effect of Rosmarinus officinalis L. extract on human melanoma A375 cells

Rosemary (Rosmarinus officinalis L.) has been used since ancient times in traditional medicine, while nowadays various rosemary formulations are increasingly exploited by alternative medicine to cure or prevent a wide range of health disorders. Rosemary's bioproperties have prompted scientific investigation, which allowed us to ascertain antioxidant, anti-inflammatory, cytostatic, and cytotoxic activities of crude extracts or of pure components. Although there is a growing body of experimental work, information about rosemary's anticancer properties, such as chemoprotective or anti-proliferative effects on cancer cells, is very poor, especially concerning the mechanism of action. Melanoma is a skin tumor whose diffusion is rapidly increasing in the world and whose malignancy is reinforced by its high resistance to cytotoxic agents; hence the availability of new cytotoxic drugs would be very helpful to improve melanoma prognosis. Here we report on the effect of a rosemary hydroalcoholic extract on the viability of the human melanoma A375 cell line. Main components of rosemary extract were identified by liquid chromatography coupled to tandem mass spectrometry (LC/ESI-MS/MS) and the effect of the crude extract or of pure components on the proliferation of cancer cells was tested by MTT and Trypan blue assays. The effect on cell cycle was investigated by using flow cytometry, and the alteration of the cellular redox state was evaluated by intracellular ROS levels and protein carbonylation analysis. Furthermore, in order to get information about the molecular mechanisms of cytotoxicity, a comparative proteomic investigation was performed

A retrospective cohort study on lifestyle habits of cardiovascular patients: how informative are medical records?

Contains fulltext : 79771.pdf (publisher's version ) (Open Access)BACKGROUND: To evaluate the vigilance of medical specialists as to the lifestyle of their cardiovascular outpatients by comparing lifestyle screening as registered in medical records versus a lifestyle questionnaire (LSQ), a study was carried out at the cardiovascular outpatient clinic of the university hospital of Nijmegen, The Netherlands, between June 2004 and June 2005. METHODS: For 209 patients information from medical records on lifestyle habits, physician feedback, and interventions in the past year was compared to data gathered in the last month by a self-report LSQ. RESULTS: Doctors register smoking habits most consistently (90.4%), followed by alcohol use (81.8%), physical activity (50.2%), and eating habits (27.3%). Compared to the LSQ, smoking, unhealthy alcohol use, physical activity, and unhealthy eating habits are underreported in medical records by 31, 83, 54 and 97%, respectively. Feedback, advice or referral was documented in 8% for smoking, 3% for alcohol use, 12% for physical activity, and 26% for eating habits. CONCLUSION: Lifestyle is insufficiently registered or recognized by doctors providing routine care in a cardiovascular outpatient setting. Of the unhealthy lifestyle habits that are registered, few are accompanied by notes on advice or intervention. A lifestyle questionnaire facilitates screening and interventions in target patients and should therefore be incorporated in the cardiovascular setting as a routine patient intake procedure

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Chronic pain is a global problem affecting up to 20% of the world’s population and has a significant economic, social and personal cost to society. Sensory neurons of the dorsal root ganglia (DRG) detect noxious stimuli and transmit this sensory information to regions of the central nervous system (CNS) where activity is perceived as pain. DRG neurons express multiple voltage-gated sodium channels that underlie their excitability. Research over the last 20 years has provided valuable insights into the critical roles that two channels, NaV1.7 and NaV1.9, play in pain signalling in man. Gain of function mutations in NaV1.7 cause painful conditions while loss of function mutations cause complete insensitivity to pain. Only gain of function mutations have been reported for NaV1.9. However, while most NaV1.9 mutations lead to painful conditions, a few are reported to cause insensitivity to pain. The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs

Renal amyloidosis in children

Renal amyloidosis is a detrimental disease caused by the deposition of amyloid fibrils. A child with renal amyloidosis may present with proteinuria or nephrotic syndrome. Chronic renal failure may follow. Amyloid fibrils may deposit in other organs as well. The diagnosis is through the typical appearance on histopathology. Although chronic infections and chronic inflammatory diseases used to be the causes of secondary amyloidosis in children, the most frequent cause is now autoinflammatory diseases. Among this group of diseases, the most frequent one throughout the world is familial Mediterranean fever (FMF). FMF is typically characterized by attacks of clinical inflammation in the form of fever and serositis and high acute-phase reactants. Persisting inflammation in inadequately treated disease is associated with the development of secondary amyloidosis. The main treatment is colchicine. A number of other monogenic autoinflammatory diseases have also been identified. Among them cryopyrin-associated periodic syndrome (CAPS) is outstanding with its clinical features and the predilection to develop secondary amyloidosis in untreated cases. The treatment of secondary amyloidosis mainly depends on the treatment of the disease. However, a number of new treatments for amyloid per se are in the pipeline

Activation of Human Monocytes by Live Borrelia burgdorferi Generates TLR2-Dependent and -Independent Responses Which Include Induction of IFN-β

It is widely believed that innate immune responses to Borrelia burgdorferi (Bb) are primarily triggered by the spirochete's outer membrane lipoproteins signaling through cell surface TLR1/2. We recently challenged this notion by demonstrating that phagocytosis of live Bb by peripheral blood mononuclear cells (PBMCs) elicited greater production of proinflammatory cytokines than did equivalent bacterial lysates. Using whole genome microarrays, we show herein that, compared to lysates, live spirochetes elicited a more intense and much broader transcriptional response involving genes associated with diverse cellular processes; among these were IFN-β and a number of interferon-stimulated genes (ISGs), which are not known to result from TLR2 signaling. Using isolated monocytes, we demonstrated that cell activation signals elicited by live Bb result from cell surface interactions and uptake and degradation of organisms within phagosomes. As with PBCMs, live Bb induced markedly greater transcription and secretion of TNF-α, IL-6, IL-10 and IL-1β in monocytes than did lysates. Secreted IL-18, which, like IL-1β, also requires cleavage by activated caspase-1, was generated only in response to live Bb. Pro-inflammatory cytokine production by TLR2-deficient murine macrophages was only moderately diminished in response to live Bb but was drastically impaired against lysates; TLR2 deficiency had no significant effect on uptake and degradation of spirochetes. As with PBMCs, live Bb was a much more potent inducer of IFN-β and ISGs in isolated monocytes than were lysates or a synthetic TLR2 agonist. Collectively, our results indicate that the enhanced innate immune responses of monocytes following phagocytosis of live Bb have both TLR2-dependent and -independent components and that the latter induce transcription of type I IFNs and ISGs

Principles of Hand Fracture Management

The hand is essential in humans for physical manipulation of their surrounding environment. Allowing the ability to grasp, and differentiated from other animals by an opposing thumb, the main functions include both fine and gross motor skills as well as being a key tool for sensing and understanding the immediate surroundings of their owner