Severe Disease States Research Articles

Abstract 624: Lower Than Expected Morbidity Of Transgenic Mice Expressing Rat Tonin After Myocardial Infarction.

Alternative angiotensin II (AngII) formation pathways have been identified. The tonin, capable to act on angiotensinogen (Agt) to form AngII, seems to have a key role in pathophysiological processes resulting from the deleterious effects of AngII. Study with transgenic animals [TGM(rTon’)] over expressing tonin in the brain, heart, kidneys and adrenal glands showed smaller heart weight to body weight index in cardiac hypertrophy, suggesting some cardioprotective state. This unexpected result goes in disagreement with AngII effects. It was seen that other transgenic mice (ACE, renin transgenics) with anticipated increase of AngII level respond with a more severe disease state to any experimental pathophysiological stress. Thus, the aim of this study was to evaluate whether the smaller cardiac index could also mean better functional state. We assessed this question by studying the hemodynamic and neuro-humoral response of TGM(rTon’) mice to 4 months of myocardial ischemia (MI). Before MI, TGM(rTon’) mice had similar HR and BP variability, 68% of higher sympathetic-vagal balance, 203% increased of adrenal catecholamine concentration and 77% reduced of AngII to Ang1-7 index compared to control group. After the MI, control and TGM(rTon’) animals showed similar infarction area. However, while the MI-control group reduced 62% of its HR variability and increased 27% of its BP variability, the MI-transgenic group did alter neither HR nor BP variability. Catecholamine profile showed 11% increased in the MI-control group while 41% decreased in the MI-transgenic group. The Ang II to Ang-(1-7) ratio was 40% lower in the MI-transgenic group compared to the MI-control. The TGM(rTon’) group respond to myocardial infarction with maintenance of its HR and BP variability indicating a lower prognostic index of morbidity compared to control group. Unchanged variability may be a reflection of counterbalancing processes recruitment, such as increased formation of Ang-(1-7), as seen in the heart.

Endotoxin-Induced Monocytic Microparticles Have Contrasting Effects on Endothelial Inflammatory Responses

Septic shock is a severe disease state characterised by the body's life threatening response to infection. Complex interactions between endothelial cells and circulating monocytes are responsible for microvasculature dysfunction contributing to the pathogenesis of this syndrome. Here, we intended to determine whether microparticles derived from activated monocytes contribute towards inflammatory processes and notably vascular permeability. We found that endotoxin stimulation of human monocytes enhances the release of microparticles of varying phenotypes and mRNA contents. Elevated numbers of LPS-induced monocytic microparticles (mMP) expressed CD54 and contained higher levels of transcripts for pro-inflammatory cytokines such as TNF, IL-6 and IL-8. Using a prothrombin time assay, a greater reduction in plasma coagulation time was observed with LPS-induced mMP than with non-stimulated mMP. Co-incubation of mMP with the human brain endothelial cell line hCMEC/D3 triggered their time-dependent uptake and significantly enhanced endothelial microparticle release. Unexpectedly, mMP also modified signalling pathways by diminishing pSrc (tyr416) expression and promoted endothelial monolayer tightness, as demonstrated by endothelial impedance and permeability assays. Altogether, these data strongly suggest that LPS-induced mMP have contrasting effects on the intercellular communication network and display a dual potential: enhanced pro-inflammatory and procoagulant properties, together with protective function of the endothelium.

Metabolism of cartilage proteoglycans in health and disease.

Cartilage proteoglycans are extracellular macromolecules with complex structure, composed of a core protein onto which a variable number of glycosaminoglycan chains are attached. Their biosynthesis at the glycosaminoglycan level involves a great number of sugar transferases well-orchestrated in Golgi apparatus. Similarly, their degradation, either extracellular or intracellular in lysosomes, involves a large number of hydrolases. A deficiency or malfunction of any of the enzymes participating in cartilage proteoglycan metabolism may lead to severe disease state. This review summarizes the findings regarding this topic.

The haemodynamic cascade

The haemodynamic cascade

Endoscopic Sinus Surgery Provides Effective Relief as Demonstrated by Pre‐ and Post‐operative Healthcare Use

Objectives: Analyze the impact of endoscopic sinus surgery (ESS) on overall healthcare use for treatment of chronic rhinosinusitis (CRS), and evaluate the effectiveness of ESS based on pre- and post-operative healthcare use. Methods: A retrospective database analysis was conducted using Marketscan. All patients with ESS (CPT 31254-31288) in 2008 and at least 5 years continuous medical and drug plan enrollment were included (n=8,827). In- and outpatient medical history including prescriptions but excluding pain medication (potentially less disease-specific) for all sinonasal procedures or diagnoses was analyzed. All costs were determined on a per-patient, per-quarter basis, from 4 quarters pre-surgery to 8 quarters post-surgery. Results: During the 4th quarter pre-surgery (9-12 months pre-operative), healthcare use included ~1.95 prescriptions (95% confidence interval [CI] 1.89-2.00), 1.92 visits or procedures per patient (95%CI: 1.83-2.01), and total average cost of US$ 399.10 (95%CI: US$391.24-US$406.96). These costs increased significantly within 2 months pre-operatively to $1,523.41, including 3.75 prescriptions (95%CI: 3.68-3.81). The cost of ESS and related medical care for 90-day post-op averaged $8,521.87 (95%CI: $8,505.16-$8,538.58). By the 15th month post-operative, healthcare costs dropped to $363.68 (95%CI: $355.77-371.59), with 1.98 prescriptions (95% CI: 1.93-2.04) and remained flat for the remainder of the follow-up period. Cost of all drug categories declined post-operatively, except for leukotriene modifiers. Conclusions: Immediately prior to ESS, patients’ healthcare needs increased approximately 4-fold. Within 15 months post-surgery, however, costs were statistically lower than observed 12 months pre-surgery. These findings suggest that ESS may have provided timely management of a severe and unsustainable disease state.

The cost of treatment failure: resource use and costs incurred by hepatitis C virus genotype 1–infected patients who do or do not achieve sustained virological response to therapy

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.

THU0069 Increased rate of diastolic heart failure in rheumatoid arthritis correlates with systemic inflammation and persistent disease activity, independent from treatment strategy

BackgroundIncreased prevalence of chronic heart failure is observed in patients with rheumatoid arthritis (RA) and heart failure with normal ejection fraction (HFNEF) is the predominant type. Although traditional cardiovascular risk...

Tolerability and safety profile of risperidone in a sample of children and adolescents

The aim of this prospective observational study was to verify the tolerability and safety profile of risperidone in a sample of antipsychotic-naive children/adolescent patients having a different psychiatric diagnosis. Twenty-two (mean age of 12±3.2) antipsychotic-naive patients who started therapy with risperidone were recruited. The assessment involved anthropometric data (weight, height, BMI, BMI z-score and BMI percentile), cardiovascular parameters (blood pressure and QTc interval) and blood tests (levels of glucose, triglycerides, total cholesterol, glutamic oxaloacetic and pyruvic transaminases, γ-glutamyl transferase, prolactin, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, thyroglobulin, antithyroid peroxidase and antithyroglobulin). After an average follow-up of 6 months of risperidone therapy, a statistically significant increase in weight and body composition was observed. Furthermore, an increase in serum levels of prolactin was observed in 50% of patients. No other significant changes in metabolic and cardiovascular parameters were found. Although an increase in these parameters was detected, it remained in the normal range. This study suggests the use of specific protocols for monitoring children/adolescents treated with second-generation antipsychotics to manage the metabolic long-term complications and progression to more severe disease states.

Guillain-Barré Syndrome

Acute Inflammatory polyneuropathies are an important group of neuromuscular disorders and are referred to collectively as Guillain-Barré syndrome (GBS). Our knowledge regarding pathogenesis, diagnosis and management continues to expand, resulting in improved opportunities for identification and treatment. These autoimmune processes cause neuropathy by affecting various structures (myelin or axons), at different locations (nerve root, nerve cell bodies or peripheral nerve) with a variety of patterns. Most clinical neurologists will be involved in the management of patients with these disorders, and there are now a variety of reasonable therapies available for acquired demyelinating neuropathies. In this report, we review the distinctive clinical, laboratory and electro-diagnostic features that aid in their diagnosis, with emphasis on clinical characteristics that are of paramount importance in diagnosing specific conditions and determining the most appropriate therapies, and helpful in determining long-term prognosis.

New Drugs and Strategies for Management of Clostridium difficile Colitis

Approaches for management of Clostridium difficile infection continually evolve as research reveals shifts in epidemiology, microbial pathogenesis, disease severity states, and response to therapy. These new discoveries significantly impact diagnostic and therapeutic strategies, given the high morbidity associated with this common nosocomial infectious diarrhea. Critically ill patients are at an increased risk of developing diarrheal illness like C. difficile and succumbing to potentially fatal complications of this infection. Early diagnosis of severe disease state may improve patient outcomes. In this article, we review treatment strategies and new approaches for the management of C. difficile in critically ill patients.

Increased Nitroxidative Stress Promotes Mitochondrial Dysfunction in Alcoholic and Nonalcoholic Fatty Liver Disease

Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins. Persistent mitochondrial dysfunction sensitizes the target cells/organs to other pathological risk factors and thus ultimately contributes to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease. The incidences of nonalcoholic fatty liver disease continuously increase due to high prevalence of metabolic syndrome including hyperlipidemia, hypercholesterolemia, obesity, insulin resistance, and diabetes. Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion. To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease. The aims of this paper are to briefly describe the mechanisms, functional consequences, and detection methods of mitochondrial dysfunction. We also describe advantages and limitations of the Cys-targeted redox proteomics method with alternative approaches. Finally, we discuss various applications of this method in studying oxidatively modified mitochondrial proteins in extrahepatic tissues or different subcellular organelles and translational research.

Chronic stress increases bone resorption in apical periodontitis stress and endodontic disease in rats

Introduction It is estimated that a large portion of the population suffers from stress. It seems that even small problems day to day are capable of producing severe disease states if they are not well managed [1]. This emotional state is capable of providing an interaction between the central nervous system (CNS),

High-tailing it to the apical surface. Focus on “Apical targeting of the P2Y4 receptor is directed by hydrophobic and basic residues in the cytoplasmic tail”

epithelial cell function requires the generation and maintenance of polarized apical and basolateral membrane domains with distinct protein and lipid compositions. This asymmetry in membrane composition is essential for myriad cell functions that include substratum adhesion, cell-cell communication

An update on purple urine bag syndrome

Purple urine bag syndrome is characterized by the urinary drainage bag turning purple in patients on prolonged urinary catheterization, especially those in the bedridden state. It is associated with bacterial urinary tract infections caused by indigo-producing and indirubin-producing bacteria, usually affects women, and is associated with alkaline urine, constipation, and a high bacterial load in the urine. Almost all patients with purple urine bag syndrome are catheterized due to significant disability, and the urinary pH is 7.0 or more. In general, intensive treatment with antibiotics is not recommended. Purple urine bag syndrome per se almost always appears to be asymptomatic and harmless. However, caution is needed, because some cases have been reported to show progression to severe disease states, so further research into the morbidity and mortality of this infection is warranted.

Plasmablast frequency and trafficking receptor expression are altered in pediatric ulcerative colitis

The incidence of pediatric ulcerative colitis (UC), a chronic autoinflammatory disease of the colon, is on the rise. Although an increased infiltration of B cells from the peripheral blood into the colon occurs in UC, B-cell trafficking is understudied. We hypothesized that the frequency of circulating plasmablasts (PBs) and their trafficking receptor (TR) expression may be indicative of the location and degree of pathology in pediatric UC. We conducted multicolor flow cytometry analyses of circulating IgA(+/-) PBs and IgA(+) memory B cells (MBCs) in pediatric UC patients with remission, mild, moderate, and severe state of disease (n = 12), and healthy pediatric (n = 2) and adult donors (n = 11). Compared to healthy donors the average frequency of PBs among total peripheral blood lymphocytes is increased 30-fold during severe UC activity, and positively correlates with Pediatric Ulcerative Colitis Activity Index score, C-reactive protein level, and erythrocyte sedimentation rate. A greater percent of PBs in severe patients express the gut-homing receptors α4β7 and CCR10, and the inflammatory homing molecule P-selectin ligand (P-sel lig). The percent of IgA(+) MBCs expressing α4β7, however, is reduced. Furthermore, expression of the small intestine TR CCR9 is decreased on α4β7(high) PBs, and on α4β7(high) /CCR10(high) PBs and MBCs in these patients, consistent with preferential cell targeting to the colon. Peripheral blood PBs with a colon-homing phenotype (α4β7/CCR10/P-sel lig) are elevated in children with severe UC. Screening this B-cell subset may provide a complementary approach in monitoring disease activity or therapeutic efficacy in pediatric UC.

Pharmacoeconomics of Alzheimer’s disease (AD) treatment with cholinesterase inhibitors

Until more effective and especially disease-modifying treatments for Alzheimer's disease (AD) are available, the therapeutic arsenal consists of cholinesterase inhibitors for mild to moderate dementia and memantine for moderate to severe dementia. Health economic data make an important contribution to the planning of healthcare services and the estimation of the cost of drug reimbursement. As such, for cholinesterase inhibitors it is claimed that the direct cost of the drug itself is eclipsed by the cost savings associated with delaying institutionalisation or delaying the time of progression into a more severe disease state. The present manuscript reviews several factors contributing to the costs of AD, gives an overview of available studies claiming the cost-effectiveness of current AD treatments, highlights strengths and weaknesses of the aforementioned studies, and discusses the impact of (early) identification and treatment of AD. It is concluded that there still is a need for long-term follow-up data from prospective cohort studies before the cost-effectiveness of cholinesterase inhibitors for AD can be confirmed.

Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma

Osteosarcoma, a common malignancy primarily affecting children, generally has a poor prognosis. Novel diagnostic, prognostic and therapeutic markers are required to ameliorate the negative outcomes of this disease. We investigated two potential markers, WNT-5a and ROR2, which are hypothesized to dysregulate WNT signaling pathways to promote tumorigenesis in other types of cancer. We investigated WNT-5a and ROR2 expression using immunohistochemistry in 42 osteosarcoma and 12 osteochondroma specimens, and compared the expression of these proteins with one another as well as with clinicopathological parameters. WNT-5a was detected in 34/42 (81.0%) cases and ROR2 was detected in 31/42 (73.8%) cases, significantly higher than in osteochondroma (16.7 and 25.0%, respectively; both P<0.05). Expression of these proteins was positively correlated (r=0.552, P<0.05). Furthermore, expression of WNT-5a and ROR2 was both correlated with Enneking surgical stage and tumor metastasis (P<0.05), but not with patient gender, age or pathological type. Thus, WNT-5a and ROR2 were more highly expressed in more severe disease states, and therefore may play a coordinated role in the occurrence and progression of osteosarcoma.

Nitric Oxide Synthase Encapsulation in Liposomes: a Potential Delivery Platform to (Nitric Oxide)‐Deficient Targets

AbstractNitric oxide (NO) is a freely diffusible, gaseous free radical, associated with many physiological and pathological processes: such as neuronal signaling, immune response and inflammatory response. In mammalian organisms, NO is produced from L‐arginine in an NADPH‐dependent reaction catalyzed by a family of nitric oxide synthase (NOS) enzymes. Typically, large NO fluctuations in biological systems under/over a critical limit is associated with problems that range from transient dysfunctions to severe chronic disease states. In this regard, we explore the development of a potential delivery and release method of nitric oxide to NO‐deficient sites using liposomes as vehicles. Liposomes have already been used as effective nano‐carriers. In this short communication, we report on the preparation and characterization of liposomes carrying a recombinant NOS enzyme. We report on the efficacy of using liposomes to carry NOS enzymes, and on the extent of preservation of native NOS structure and function. In addition to the characterization of liposome stability and recovery of enzymatic activity after encapsulation in liposomes, we also measured the NO production upon NOS stimulation. The NO release was monitored with a nitric oxide ultrasensitive electrochemical microsensor placed near NOS‐carrying liposomes. This method of NOS‐carrying liposomes shows the promise of potential development as a platform for targeted NO‐delivery.

Epidemiology and clinical features of pediatric psoriasis in tertiary referral psoriasis clinic

Few epidemiological studies of pediatric patients with moderate to severe psoriasis have been available despite there being no approved systemic therapy for these patients. The aim of the present study was to elucidate clinical features of pediatric psoriasis in a tertiary referral psoriasis clinic. We analyzed the clinical data of 358 patients under 18 years of age referred to our clinic from other private clinics and medical centers. Our data showed a male :female ratio of 1.06:1 and a peak age of onset of 10-11 years. Of the patients, 32.4% had a positive family history. The most prevalent phenotype was plaque type (67.3%) and the mean Psoriasis Area and Severity Index score was 17.2 ± 12.7. The most frequently affected body part was the trunk (69.5%), followed by the legs (65.3%). Exposure to sunlight and summer season improved psoriatic lesions, while stress and winter season aggravated the clinical course. Only 26.0% of patients received systemic therapy or phototherapy during the therapeutic course. Oral acitretin (11.2%) was most frequently used followed by ultraviolet B phototherapy (7.3%). The childhood group (<13 years) showed higher prevalence of guttate and generalized pustular phenotypes and more severe clinical course compared with the adolescent group (13-18 years). In conclusion, our patients showed distinctive features in clinical phenotypes, disease severity and affected body parts compared with previous reports. We also found that clinical application of systemic therapies were limited considering the severe disease state of our patients, demanding a need for more research on treatment of pediatric psoriasis.

Biomarkers in neurocritical care.

The gold standard for assessing neurological function is the bedside clinical examination. However, in neurocritical patients, the signs and symptoms related to the severity of illness can often be ambiguous. It can be hard to distinguish between a severe but stable disease state and one that is dynamic and in a critical decline. Clinicians and family members alike may struggle with the uncertainty of functional outcome prediction. Intermediate biomarkers of brain injury can assist with ongoing clinical management of patients, and in some circumstances can guide prognosis. Used in the right setting, biomarkers in neurocritical care can also aid with decisions to intensify treatment or avoid prolonged and unnecessary therapy. The term biomarker is used in various ways, and here we use it to refer to 3 general types: 1) circulating blood macromolecules, 2) brain imaging, and 3) continuous invasive monitors. Despite its promise, biomarkers have several limitations and should be interpreted in the context of the overall clinical assessment.