Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro-B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. METHODS AND RESULTS Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). CONCLUSIONS vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Symptoms before periapical surgery related to histologic diagnosis and postoperative healing at 12 months for 178 periapical lesions

To compare the preoperative signs and symptoms with the histologic diagnosis and postoperative healing at 12 months for 178 periapical lesions.

Na(+), K(+), Cl(-), acid-base or H2O homeostasis in children with urinary tract infections: a narrative review.

Guidelines on the diagnosis and management of urinary tract infections in childhood do not address the issue of abnormalities in Na(+), K(+), Cl(-) and acid-base balance. We have conducted a narrative review of the literature with the aim to describe the underlying mechanisms of these abnormalities and to suggest therapeutic maneuvers. Abnormalities in Na(+), K(+), Cl(-) and acid-base balance are common in newborns and infants and uncommon in children of more than 3 years of age. Such abnormalities may result from factitious laboratory results, from signs and symptoms (such as excessive sweating, poor fluid intake, vomiting and passage of loose stools) of the infection itself, from a renal dysfunction, from improper parenteral fluid management or from the prescribed antimicrobials. In addition, two transient renal tubular dysfunctions may occur in infants with infectious renal parenchymal involvement: a reduced capacity to concentrate urine and pseudohypoaldosteronism secondary to renal tubular unresponsiveness to aldosterone that presents with hyponatremia, hyperkalemia and acidosis. In addition to antimicrobials, volume resuscitation with an isotonic solution is required in these children. In secondary pseudohypoaldosteronism, isotonic solutions (such as 0.9 % saline or lactated Ringer) correct not only the volume depletion but also the hyperkalemia and acidosis. In conclusion, our review suggests that in infants with infectious renal parenchymal involvement, non-renal and renal causes concur to cause fluid volume depletion and abnormalities in electrolyte and acid-base balance, most frequently hyponatremia.

Survival and relapse in patients with thrombotic thrombocytopenic purpura

Survival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

Reduced endurance of the cervical flexor muscles in patients with concurrent temporomandibular disorders and neck disability

Subjects with temporomandibular disorders (TMDs) have been found to have clinical signs and symptoms of cervical dysfunction. Although many studies have investigated the relationship between the cervical spine and TMD, no study has evaluated the endurance capacity of the cervical muscles in patients with TMD. Thus the objective of this study was to determine whether patients with TMD had a reduced endurance of the cervical flexor muscles at any level of muscular contraction when compared with healthy subjects. One hundred and forty-nine participants provided data for this study (49 subjects were healthy, 54 had myogenous TMD, and 46 had mixed TMD). There was a significant difference in holding time at 25% MVC between subjects with mixed TMD when compared to subjects with myogenous TMD and healthy subjects. This implies that subjects with mixed TMD had less endurance capacity at a lower level of contraction (25% MVC) than healthy subjects and subjects with myogenous TMD. No significant associations between neck disability, jaw disability, clinical variables and neck flexor endurance test were found.

Clinical features and practical diagnosis of bullous pemphigoid

Bullous pemphigoid (BP) represents the most common autoimmune subepidermal blistering disease. BP typically affects the elderly and is associated with significant morbidity. It has usually a chronic course with spontaneous exacerbations. The cutaneous manifestations of BP can be extremely protean. While diagnosis of BP in the bullous stage is straightforward, in the non-bullous stage or in atypical variants of BP signs and symptoms are frequently non-specific with eg, only itchy excoriated, eczematous, papular and/or urticarial lesions that may persist for several weeks or months. Diagnosis of BP critically relies on immunopathologic examinations including direct immunofluorescence microscopy and detection of serum autoantibodies by indirect immunofluorescence microscopy or BP180-ELISA.

Clinical features and practical diagnosis of bullous pemphigoid

Bullous pemphigoid (BP) represents the most common autoimmune subepidermal blistering disease. BP typically affects the elderly and is associated with significant morbidity. It has usually a chronic course with spontaneous exacerbations. The cutaneous manifestations of BP can be extremely protean. While diagnosis of BP in the bullous stage is straightforward, in the non-bullous stage or in atypical variants of BP signs and symptoms are frequently non-specific with eg, only itchy excoriated, eczematous, papular and/or urticarial lesions that may persist for several weeks or months. Diagnosis of BP critically relies on immunopathologic examinations including direct immunofluorescence microscopy and detection of serum autoantibodies by indirect immunofluorescence microscopy or BP180-ELISA.

Etiology and symptoms of severe hypokalemia in emergency department patients

To investigate the prevalence, etiology, and symptoms of severe hypokalemia in patients presenting to the emergency department.

Inhibition of IL-1, IL-6, and TNF-alpha in immune-mediated inflammatory diseases

Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-alpha), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-alpha, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-alpha is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.

[The nasopalatine duct cyst--epidemiology, diagnosis and therapy]

The nasopalatine duct cyst is the most frequent nonodontogenic cyst of the jaws. The cyst originates from epithelial remanents from the nasopalatine duct. The cells may be activated spontaneously during life, or are eventually stimulated by the irritating action of various agents (infection, etc.). Generally, patients present without clinical signs and symptoms. Therefore, the tentative diagnosis "nasopalatine duct cyst" is often based on a coincidental radiological finding on a routine panoramic view or occlusal radiograph. The definite diagnosis should be based on clinical, radiological and histopathologic findings. The therapy of nasopalatine duct cysts consists of an enucleation of the cystic tissue, only in rare cases a marsupialization needs to be performed. The present review of the literature presents and discusses the epidemiology, etiology, diagnostic work-up, differential diagnostic aspects, histopatholgy, and therapeutic strategies for nasopalatine duct cysts.

Acute pancreatitis and thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) has multiple clinical manifestations and risk factors, but the events that actually trigger acute episodes of TTP are often unclear. We describe the case of a 56-year-old woman who presented with clinical signs and symptoms of TTP and acute pancreatitis. We discuss whether pancreatitis was due to ischemic pancreatic damage caused by microvascular platelet clumping in the frame of TTP, or whether acute pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP.

Experimental arthritis: effect on growth parameters and total skeletal calcium

Aim of the study was to investigate the possible mechanisms leading to stunted growth and osteoporosis in experimental arthritis. Fourty-two female rats of 7-8 weeks of age were randomly assigned to three groups of 14 animals each: (a) controls; (b) adjuvant-inoculated (AA); and (c) adjuvant-inoculated rats receiving 10 mg cyclosporin A (CsA) orally for 30 days. Biological parameters studied were: hindpaw swelling; vertebral length progression expressed as Delta increments between days 1 and 30 as a parameter of skeletal growth, and estimation of total skeletal mineral content by dual energy X-ray absorptiometry (n=10 each group) on day 30. Endocrine parameters measured were pulsatile release of growth hormone (rGH) on day 30 following jugular cannulation and measurement of insulin-like growth factor (IGF-1) in pooled plasma from rGH profiles. Results can be summarized as follows: Untreated AA rats exhibited local signs of inflammation in comparison with controls (hindpaw diameter 8.1-8.9 mm vs. 5.3-5.6 mm in controls). Treatment with CsA normalized this parameter (4.9-5.6 mm). Vertebral growth was significantly retarded in AA rats in comparison with controls (214+/-32 vs. 473+/-33 microm; p<0.001). Administration of CsA normalized vertebral size increment with a clear tendency to overgrowth (523+/-43 microm, n.s.). There was also a marked reduction in total skeletal mineral content in diseased (AA) rats as compared to controls (5.8+/-0.1 vs. 7.5+/-0.1g [OH-apatite]; p<0.001), and a moderate but significant increment above controls in the group receiving CsA (8.0+/-0.1 vs. 7.5+/-0.1g [OH-appatite]; p<0.04). Integrated rGH profiles exhibited a significant fall in arthritic rats and were completely restored to normal under CsA treatment. A trend toward higher rGH values was observed in the latter group (2908+/-554 in AA vs. 8317+/-1492 ng/ml/240 min in controls; p<0.001, and 10940+/-222 ng/ml/240 min, n.s. in the CsA group). There was a good correlation between skeletal growth and rGH pulsatility (r=0.81; p<0.001). IGF-1 followed a similar pattern (630+/-44 in AA vs. 752+/-30 ng/ml in controls; p<0.04, and 769+/-59 ng/ml in the CsA group, n.s. vs. controls). Thus, a clear tendency to skeletal overgrowth following treatment was observed in agreement with the hormonal data. It can therefore be concluded that, in experimental arthritis, attenuated GH-spiking and reduced circulating IGF-1 appear to be causally related to growth retardation, probably mimicking signs and symptoms observed in juvenile arthritis. Therapy with CsA is followed by normalization of hormonal and biological parameters accompanied by a catch up phenomenon in skeletal growth which is also observed clinically in juvenile arthritis. Generalized osteopenia is a prominent feature seemingly connected with the growth abnormalities as they parallel each other during the evolution of the disease and respond equally to therapy.

Management of infusion reactions in clinical trials and beyond: the US and EU perspectives

Monoclonal antibodies have expanded our cancer-fighting armamentarium in both the United States and Europe. While in general, monoclonal antibodies are well tolerated and do not have significant overlapping side effects with traditional cytotoxic agents, severe infusion reactions (IRs)--sometimes severe enough to be life threatening--have been reported. The pathophysiology of severe infusion reactions associated with monoclonal antibodies is poorly understood, but mechanisms are beginning to be elucidated. Geographic differences in the incidence of IRs have become apparent. Understanding the risk, recognizing the signs and symptoms, and being ready to promptly manage severe IRs are key for the clinician to avoid unnecessarily discontinuing these effective anticancer agents and prevent potentially tragic consequences for their patients. To date, clinical trials have incorporated monoclonal antibodies into combinations with standard cytotoxic regimens; it is expected that in time clinical trials will be testing promising new combinations utilizing multiple targeted agents, resulting in improved toxicity profiles and efficacy for cancer patients.

Correlations between severity of clinical signs and histopathological changes in 60 dogs with spinal cord injury associated with acute thoracolumbar intervertebral disc disease

The outcome of spinal surgery in dogs with absent voluntary motor function and nociception following intervertebral disc (IVD) herniation is highly variable, which likely attests to differences in the severity of spinal cord damage. This retrospective study evaluated the extent to which neurological signs correlated with histologically detected spinal cord damage in 60 dogs that were euthanased because of thoracolumbar IVD herniation. Clinical neurological grades correlated significantly with the extent of white matter damage (P<0.001). However, loss of nociception also occurred in 6/31 (19%) dogs with relatively mild histological changes. The duration of clinical signs, Schiff-Sherrington posture, loss of reflexes and pain on spinal palpation were not significantly associated with the severity of spinal cord damage. Although clinical-pathological correlation was generally good, some clinical signs frequently thought to indicate severe cord injury did not always correlate with the degree of cord damage, suggesting functional rather than structural impairment in some cases.