Multiple Clinical Conditions Research Articles

TLR2 modulates antibodies required for intestinal ischemia/reperfusion-induced damage and inflammation.

In multiple clinical conditions, including trauma and hemorrhage, reperfusion magnifies ischemic tissue damage. Ischemia induces expression of multiple neoantigens, including lipid alterations that are recognized by the serum protein, β2-glycoprotein I (β2-GPI). During reperfusion, binding of β2-GPI by naturally occurring Abs results in an excessive inflammatory response that may lead to death. As β2-GPI is critical for intestinal ischemia/reperfusion (IR)-induced tissue damage and TLR2 is one of the proposed receptors for β2-GPI, we hypothesized that IR-induced intestinal damage and inflammation require TLR2. Using TLR2(-/-) mice, we demonstrate that TLR2 is required for IR-induced mucosal damage, as well as complement activation and proinflammatory cytokine production. In response to IR, TLR2(-/-) mice have increased serum β2-GPI compared with wild-type mice, but β2-GPI is not deposited on ischemic intestinal tissue. In addition, TLR2(-/-) mice also did not express other novel Ags, suggesting a sequential response. Unlike other TLRs, TLR2(-/-) mice lacked the appropriate Ab repertoire to induce intestinal IR tissue damage or inflammation. Together, these data suggest that, in addition to the inflammatory response, IR-induced injury requires TLR2 for naturally occurring Ab production.

Multisystemic Side Effects of an Indispensable Old Drug: A Case Report of Chronic Lithium Use (A Patient with Multiple Side Effects of Lithium)

Presented here is a case of long-term lithium use, with multiple emerging lithium-associated side effects. An 82-year-old woman was brought into the emergency department because of loss of consciousness. According to the physical examination and laboratory analyses, patient was diagnosed with lithium-associated hypercalcemia, hyperparathyroidism, nephrogenic diabetes insipidus (NDI), symptomatic sinus bradycardia, and thyroid dysfunction. In the literature, there is a limited number of case reports with lithium induced multiple clinical conditions. Multiple clinical manifestations due to the side effects of chronic lithium use might be seen. Health care professionals should keep in mind that lithium-related side effects might trigger or exacerbate each other. To avoid toxicity, close follow-up and clinical supervision are important for the early diagnosis and treatment of these side effects, due to the narrow therapeutic index and obscure clinical signs and symptoms of toxicity.

Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis.

SummaryInsulin resistance is a sine qua non of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, aging, and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumor necrosis factor-α (TNF) or by the steroid dexamethasone (Dex) to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.

Price elasticity and medication use: cost sharing across multiple clinical conditions.

To address the impact that out-of-pocket prices may have on medication use, it is vital to understand how the demand for medications may be affected when patients are faced with changes in the price to acquire treatment and how price responsiveness differs across medication classes. To examine the impact of cost-sharing changes on the demand for 8 classes of prescription medications. This was a retrospective database analysis of 11,550,363 commercially insured enrollees within the 2005-2009 MarketScan Database. Patient cost sharing, expressed as a price index for each medication class, was the main explanatory variable to examine the price elasticity of demand. Negative binomial fixed effect models were estimated to examine medication fills. The elasticity estimates reflect how use changes over time as a function of changes in copayments. Model estimates revealed that price elasticity of demand ranged from -0.015 to -0.157 within the 8 categories of medications (P less than 0.01 for 7 of 8 categories). The price elasticity of demand for smoking deterrents was largest (-0.157, P less than 0.0001), while demand for antiplatelet agents was not responsive to price (P greater than 0.05). The price elasticity of demand varied considerably by medication class, suggesting that the influence of cost sharing on medication use may be related to characteristics inherent to each medication class or underlying condition.

Evaluation and management of thrombocytopenic neonates in the intensive care unit

Thrombocytopenia is a very frequent problem among sick neonates, affecting up to 35% of all infants admitted to the neonatal intensive care unit (NICU), and serves as an important indicator of multiple clinical conditions. The cause of the thrombocytopenia is unclear in up to 60% of affected neonates. A clinical classification of thrombocytopenia is based on the time of presentation, early (≤72 hours of life) vs. late (>72 hours of life). Early thrombocytopenia is commonly associated with feto-maternal conditions, is most commonly caused by disorders associated with placental insufficiency, and is generally mild to moderate and resolves spontaneously within 7-10 days without any intervention. In contrast, neonates who develop late-onset thrombocytopenia frequently have bacterial sepsis or necrotizing enterocolitis. It is often severe (platelets <50,000/μL), prolonged and frequently requires multiple platelet transfusions. Platelet transfusions represent the only specific therapy currently available for most thrombocytopenic neonates, even though much evidence suggests that platelet transfusions are not benign. Many of the prophylactic platelet transfusions currently given to NICU patients are unnecessary, convey no benefits, and carry known and unknown risks. For this reason, pharmacological alternatives have been investigated as potential therapies for thrombocytopenia, but they still have limited use treating the common varieties of neonatal thrombocytopenia.

Adipocyte induced arterial calcification is prevented with sodium thiosulfate

BackgroundCalcification can occur in fat in multiple clinical conditions including in the dermis, breasts and in the abdomen in calciphylaxis. All of these are more common in patients with advanced kidney disease. Clinically, hyperphosphatemia and obesity are risk factors. Thus we tested the hypothesis that adipocytes can calcify in the presence of elevated phosphorus and/or that adipocytes exposed to phosphorus can induce vascular smooth muscle cell (VSMC) calcification. Methods3T3-L1 preadipocytes were induced into mature adipocytes and then treated with media containing high phosphorus. Calcification was assessed biochemically and PCR performed to determine the expression of genes for osteoblast and adipocyte differentiation. Adipocytes were also co-cultured with bovine VSMC to determine paracrine effects, and the efficacy of sodium thiosulfate was determined. ResultsThe results demonstrated that high phosphorus induced the calcification of differentiated adipocytes with increased expression of osteopontin, the osteoblast transcription factor Runx2 and decreased expression of adipocyte transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (CEBPα), indicating that high phosphorus led to a phenotypic switch of adipocytes to an osteoblast like phenotype. Sodium thiosulfate, dose dependently decreased adipocyte calcification and inhibited adipocyte induced increase of VSMC calcification. Co-culture studies demonstrated that adipocytes facilitated VSMC calcification partially mediated by changes of secretion of leptin and vascular endothelial growth factor (VEGF) from adipocytes. ConclusionHigh phosphorus induced calcification of mature adipocytes, and adipocytes exposed to elevated phosphorus can induce calcification of VSMC in a paracrine manner. Sodium thiosulfate inhibited this calcification and decreased the secretin of leptin and VEGF from adipocytes. These results suggest that adipocyte exposure to elevated phosphorus may be a pathogenic factor in calcification observed in the skin in calciphylaxis and other diseases.

Pseudotumor Cerebri Associated with Vitamin B12 Deficiency

Pseudotumor cerebri, also named idiopathic intracranial hypertension, is a condition of raised intracranial pressure in the absence of a mass lesion or cerebral edema. It is rare in childhood and often associated with multiple clinical conditions. In this report, we presented a case with peudotumor cerebri associated with megaloblastic anemia due to vitamin B12 deficiency.

Activation of Mu Opioid Receptors Sensitizes Transient Receptor Potential Vanilloid Type 1 (TRPV1) via β-Arrestin-2-Mediated Cross-Talk

The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in β-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates β-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven β-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.

Subarachnoid Hemorrhage: Beyond Aneurysms

Spontaneous subarachnoid hemorrhage (SAH) typically prompts a search for an underlying ruptured saccular aneurysm, which is the most common nontraumatic cause. Depending on the clinical presentation and pattern of SAH, the differential diagnosis may include a diverse group of causes other than aneurysm rupture. For the purposes of this review, we classify SAH into three main patterns, defined by the distribution of blood on unenhanced CT: diffuse, perimesencephalic, and convexal. The epicenter of the hemorrhage further refines the differential diagnosis and guides subsequent imaging. Additionally, we review multiple clinical conditions that can simulate the appearance of SAH on CT or MRI, an imaging artifact known as pseudo-SAH.

Congenital cryptorchidism - its anatomical aspects, embryogenesis and clinical consequences

The testes are a pair of male reproductive organs. The testicular variations are unusual and can result in multiple clinical conditions. Congenital cryptorchidism is a condition in which one or both the testes have not passed down the scrotal sac. During a routine cadaveric dissection of a middle aged male cadaver, in the left side of the pelvic part of the abdomen an unusual undescended testis was noted near the deep inguinal ring. Additional to this we also noted a thick band of ligament connecting the epididymis of testis to the fascia transversalis, close to the deep inguinal ring. As per our knowledge such congenital testicular variations has not been cited in the recent medical literature. The anatomical aspects, embryogenesis and clinical consequences of these congenital variations have been discussed in detail. Proper knowledge and awareness of such testicular variations is clinically essential in operative procedures and necessary treatment for monarchism, which improves fertility and endocrine functions.

The effects of quality of care on costs: a conceptual framework.

The quality of health care and the financial costs affected by receiving care represent two fundamental dimensions for judging health care performance. No existing conceptual framework appears to have described how quality influences costs. We developed the Quality-Cost Framework, drawing from the work of Donabedian, the RAND/UCLA Appropriateness Method, reports by the Institute of Medicine, and other sources. The Quality-Cost Framework describes how health-related quality of care (aspects of quality that influence health status) affects health care and other costs. Structure influences process, which, in turn, affects proximate and ultimate outcomes. Within structure, subdomains include general structural characteristics, circumstance-specific (e.g., disease-specific) structural characteristics, and quality-improvement systems. Process subdomains include appropriateness of care and medical errors. Proximate outcomes consist of disease progression, disease complications, and care complications. Each of the preceding subdomains influences health care costs. For example, quality improvement systems often create costs associated with monitoring and feedback. Providing appropriate care frequently requires additional physician visits and medications. Care complications may result in costly hospitalizations or procedures. Ultimate outcomes include functional status as well as length and quality of life; the economic value of these outcomes can be measured in terms of health utility or health-status-related costs. We illustrate our framework using examples related to glycemic control for type 2 diabetes mellitus or the appropriateness of care for low back pain. The Quality-Cost Framework describes the mechanisms by which health-related quality of care affects health care and health status-related costs. Additional work will need to validate the framework by applying it to multiple clinical conditions. Applicability could be assessed by using the framework to classify the measures of quality and cost reported in published studies. Usefulness could be demonstrated by employing the framework to identify design flaws in published cost analyses, such as omitting the costs attributable to a relevant subdomain of quality.

TLR2 initiates intestinal ischemia/reperfusion induced tissue damage (P4003)

Abstract Reperfusion (the return of blood flow) significantly magnifies ischemia (lack of blood flow) induced tissue damage in multiple clinical conditions including trauma and hemorrhage. During reperfusion, naturally occurring antibodies recognize endogenous damage-associated molecular patterns (DAMP), followed by an excessive complement activation, neutrophil infiltration and inflammatory response which frequently results in an excessive systemic inflammatory response which may lead to death. TLRs recognize DAMP and TLR4 is required for intestinal ischemia-reperfusion (IR). As TLR2 has been proposed to be the receptor for at least one DAMP, the serum protein, β2-glycoprotein I (β2-GPI) which is critical in intestinal ischemia reperfusion (IR), we hypothesized that IR-induced intestinal damage requires TLR2 for subsequent inflammation and tissue damage. Using TLR2-/- mice, we demonstrate that TLR2 is required for excessive IR-induced complement activation and pro-inflammatory cytokine production. TLR2-/- mice not only lacked the appropriate antibody repertoire to induce intestinal IR but treatment with wildtype antibodies was not sufficient to induce tissue damage or inflammation. Compared to wildtype mice, TLR2-/- mice have increased serum β2-GPI but β2-GPI is not deposited on ischemic intestinal tissue. Our data suggest that TLR2 interacts with β2-GPI and is required for neo-antigen expression and initiation of the systemic inflammatory response during intestinal IR.

Interventions to Improve Adherence to Self-administered Medications for Chronic Diseases in the United States

Suboptimum medication adherence is common in the United States and leads to serious negative health consequences but may respond to intervention. To assess the comparative effectiveness of patient, provider, systems, and policy interventions that aim to improve medication adherence for chronic health conditions in the United States. Eligible peer-reviewed publications from MEDLINE and the Cochrane Library indexed through 4 June 2012 and additional studies from reference lists and technical experts. Randomized, controlled trials of patient, provider, or systems interventions to improve adherence to long-term medications and nonrandomized studies of policy interventions to improve medication adherence. Two investigators independently selected, extracted data from, and rated the risk of bias of relevant studies. The evidence was synthesized separately for each clinical condition; within each condition, the type of intervention was synthesized. Two reviewers graded the strength of evidence by using established criteria. From 4124 eligible abstracts, 62 trials of patient-, provider-, or systems-level interventions evaluated 18 types of interventions; another 4 observational studies and 1 trial of policy interventions evaluated the effect of reduced medication copayments or improved prescription drug coverage. Clinical conditions amenable to multiple approaches to improving adherence include hypertension, heart failure, depression, and asthma. Interventions that improve adherence across multiple clinical conditions include policy interventions to reduce copayments or improve prescription drug coverage, systems interventions to offer case management, and patient-level educational interventions with behavioral support. Studies were limited to adults with chronic conditions (excluding HIV, AIDS, severe mental illness, and substance abuse) in the United States. Clinical and methodological heterogeneity hindered quantitative data pooling. Reduced out-of-pocket expenses, case management, and patient education with behavioral support all improved medication adherence for more than 1 condition. Evidence is limited on whether these approaches are broadly applicable or affect longterm medication adherence and health outcomes. Agency for Healthcare Research and Quality.

AKI in the ICU: definition, epidemiology, risk stratification, and outcomes

Acute kidney injury (AKI) has emerged as a major public health problem that affects millions of patients worldwide and leads to decreased survival and increased progression of underlying chronic kidney disease (CKD). Recent consensus criteria for definition and classification of AKI have provided more consistent estimates of AKI epidemiology. Patients, in particular those in the ICU, are dying of AKI and not just simply with AKI. Even small changes in serum creatinine concentrations are associated with a substantial increase in the risk of death. AKI is not a single disease but rather a syndrome comprising multiple clinical conditions. Outcomes from AKI depend on the underlying disease, the severity and duration of renal impairment, and the patient's renal baseline condition. The development of AKI is the consequence of complex interactions between the actual insult and subsequent activation of inflammation and coagulation. Contrary to the conventional view, recent experimental and clinical data argue against renal ischemia-reperfusion as a sine qua non condition for the development of AKI. Loss of renal function can occur without histological signs of tubular damage or even necrosis. The detrimental effects of AKI are not limited to classical well-known symptoms such as fluid overload and electrolyte abnormalities. AKI can also lead to problems that are not readily appreciated at the bedside and can extend well beyond the ICU stay, including progression of CKD and impaired innate immunity. Experimental and small observational studies provide evidence that AKI impairs (innate) immunity and is associated with higher infection rates.

Creatine Phosphate: Pharmacological and Clinical Perspectives

Since the 1970s, extensive experimental and clinical research has demonstrated that relevant reductions of creatine phosphate (CrP) or phosphocreatine availability occur in a wide spectrum of pathophysiological situations. A decrease in intracellular concentrations of creatine (Cr) and CrP results in a hypodynamic state of cardiac and skeletal muscle pathology. Many experimental and clinical studies have evaluated the possibility to improve cardiac and skeletal muscle performance by exogenous administration of CrP. Furthermore, many experimental studies have shown that CrP may play two important roles in the regulation of muscle energetics and work. First, CrP maintains local adenosine triphosphate pools and stabilizes cellular membranes due to electrostatic interactions with phospholipids. The second mechanism decreases the production of lysophosphoglycerides in hypoxic hearts, protects the sarcolemma of cardiac cells against ischemic damage, decreases the frequency of arrhythmias, and increases post-ischemic recovery of contractile function. Recent research on CrP has demonstrated positive therapeutic results in various clinical applications. These benefits have been applied in several pathological conditions, such as heart failure, acute myocardial ischemia, chronic ischemic heart disease, cardiac surgery, skeletal muscle hypotonotrophy, and cerebral ischemia. This review describes the CrP shuttle, pathophysiological basis of the supplementation of CrP, and its therapeutic effects in multiple clinical conditions. The major aim is to summarize results of the intense research carried out over 40 years to provide evidence to support the adjunctive use of CrP in many pathological conditions that may target cellular energy impairment; thus, increasing energy metabolism.

The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

Molecular identification and characterization of Mycobacterium avium subspecies paratuberculosis in free living non-human primate (Rhesus macaques) from North India

In recent years, Mycobacterium avium subspecies paratuberculosis (MAP) has emerged as major animal pathogen with significant zoonotic concerns, worldwide. MAP infection is endemic in domestic and wild ruminant population in India. However, information on MAP infection in free ranging animal species and non human primates is limited. Present study aimed to estimate the status of MAP infection in free living Rhesus macaques suffering with multiple clinical conditions (coughing and loose stool). A total of 25 stool samples were collected from six colonies of Rhesus macaques from Mathura region (North India) and screened for the presence of MAP, using microscopic examination and IS900 PCR, directly from stool samples. PCR positive DNA samples were further genotyped using IS1311 PCR-restriction enzyme analysis. Of the 25 stool samples, 10 (40.0%) and 2 (8.0%) were positive for MAP using microscopic examination and direct IS900 PCR, respectively. IS900 PCR positive DNA samples were genotyped as 'Indian Bison type', which is a major MAP genotype infecting domestic and wild ruminant species and human beings in India. Prevalence of MAP in Rhesus macaques (Indian monkeys) was moderately high and confirmed interspecies sharing of MAP between domestic livestock and non-human primates. Presence of MAP in non-human primates, support the etiological role of MAP in inflammatory bowel disease patients. Indian monkeys may serve as model for understanding the role of non-human primates in sustenance, transmission and pathogenesis of MAP infection.

Accessory muscle in the forearm: a clinical and embryological approach

Muscular variations of the flexor compartment of forearm are usual and can result in multiple clinical conditions limiting the functions of forearm and hand. The variations of the muscles, especially accessory muscles may simulate soft tissue tumors and can result in nerve compressions. During a routine dissection of the anterior region of the forearm and hand, an unusual muscle was observed on the left side of a 65-year-old male cadaver. The anomalous muscle belly arose from the medial epicondyle approxiamately 1 cm posterolateral to origin of normal flexor carpi ulnaris muscle (FCU), and from proximal part of the flexor digitorum superficialis muscle. It inserted to the triquetral, hamate bones and flexor retinaculum. Passive traction on the tendon of accessory muscle resulted in flexion of radiocarpal junction. The FCU which had one head, inserted to the pisiform bone hook of hamate and palmar aponeurosis. Its contiguous muscles displayed normal morphology. Knowledge of the existence of muscle anomalies as well as the location of compression is useful in determining the pathology and appropriate treatment for compressive neuropathies. In this study, a rare accessory muscle has been described.

Multiple Diseases Discriminated by Quantitation of Blood Transcriptome

The steady circulation and physiologically interactive nature of blood ensures that this dynamic system encounters, transmits, and responds to a wide range of biological signals. In this context, we hypothesized that quantitative measurement of the blood transcriptome can enable the identification and validation of RNA transcripts that are specifically associated with the presence of a particular disease or clinical condition. In the present study, we have used 631 blood RNA expression profiling in conjunction with microarray technology to generate highly discriminative panels of 10 pairs of probe sets for each of four separate clinical conditions (gender, colorectal cancer, prostate cancer and osteoarthritis). The robust training set performance for each disease or condition-specific multi-gene panel was corroborated with an independent test set, with areas under the receiver-operating characteristic curves ranging from 0.87 to 0.93 for each of the four conditions in the test set population. This study demonstrates that quantitative measurement of the blood transcriptome, in conjunction with microarray technology, can be used to generate highly discriminative multi-gene panels for many clinical conditions. This approach has great potential to enable the simultaneous monitoring of multiple disease states or clinical conditions from a single blood sample.

Update on pulmonary hypertension complicating chronic obstructive pulmonary disease

Pulmonary hypertension (PH) is the hemodynamic manifestation of various pathological processes that result in elevated pulmonary artery pressures (PAP). The National Institutes of Health Registry defined pulmonary arterial hypertension as the mean PAP of more than 25 mm Hg with a pulmonary capillary wedge pressure or left atrial pressure equal to or less than 15 mm Hg. This definition remains the currently accepted definition of PH that is used to define PH related to multiple clinical conditions including chronic obstructive pulmonary disease (COPD). The estimated US prevalence of COPD by the National Health Survey in 2002 in people aged >25 was 12.1 million. There is a lack of large population-based studies in COPD to document the correct prevalence of PH and outcome. The major cause of PH in COPD is hypoxemia leading to vascular remodeling. Echocardiogram is the initial screening tool of choice for PH. This simple noninvasive test can provide an estimate of right ventricular systolic and right atrial pressures. Right heart catheterization remains the gold standard to diagnose PH. It provides accurate measurement of mean PAP and pulmonary capillary wedge pressure. Oxygen therapy remains the cornerstone therapeutic for hypoxemia in COPD patients. Anecdotal reports suggest utility of PDE5-inhibitors and prostacyclin to treat COPD-related PH. Large randomized clinical trials are needed before the use of these drugs can be recommended.