Multiple Patient Studies Research Articles

Infiltrating immune cells in the kidney in salt-sensitive hypertension and renal injury.

The importance of the immune system in hypertension, vascular disease, and renal disease has been appreciated for over 50 years. Recent experimental advances have led to a greater appreciation of the mechanisms whereby inflammation and immunity participate in cardiovascular disease. In addition to the experimental data, multiple studies in patients have demonstrated a strong correlation between the observations made in animals and humans. Of great interest is the development of salt-sensitive hypertension in humans with the concurrent increase in albumin excretion rate. Experiments in our laboratory have demonstrated that feeding a high-NaCl diet to Dahl salt-sensitive (SS) rats results in a significant infiltration of T lymphocytes into the kidney that is accompanied by the development of hypertension and renal disease. The development of disease in the Dahl SS closely resembles observations made in patients; studies were therefore performed to investigate the pathological role of infiltrating immune cells in the kidney in hypertension and renal disease. Pharmacological and genetic studies indicate that immune cell infiltration into the kidney amplifies the disease process. Further experiments demonstrated that infiltrating T cells may accentuate the Dahl SS phenotype by increasing intrarenal ANG II and oxidative stress. From these and other data, we hypothesize that infiltrating immune cells, which surround the blood vessels and tubules, can serve as a local source of bioactive molecules which mediate vascular constriction, increase tubular sodium reabsorption, and mediate the retention of sodium and water to amplify sodium-sensitive hypertension. Multiple experiments remain to be performed to refine and clarify this hypothesis.

Assessing neurocognitive function in psychiatric disorders: A roadmap for enhancing consensus

It has been challenging to identify core neurocognitive deficits that are consistent across multiple studies in patients with Obsessive Compulsive Disorder (OCD). In turn, this leads to difficulty in translating findings from human studies into animal models to dissect pathophysiology. In this article, we use primary data from a working memory task in OCD patients to illustrate this issue.Working memory deficiencies have been proposed as an explanatory model for the evolution of checking compulsions in a subset of OCD patients. However, findings have been mixed due to variability in task design, examination of spatial vs. verbal working memory, and heterogeneity in patient populations. Two major questions therefore remain: first, do OCD patients have disturbances in working memory? Second, if there are working memory deficits in OCD, do they cause checking compulsions?In order to investigate these questions, we tested 19 unmedicated OCD patients and 23 matched healthy controls using a verbal working memory task that has increased difficulty/task-load compared to classic digit-span tasks. OCD patients did not significantly differ in their performance on this task compared to healthy controls, regardless of the outcome measure used (i.e. reaction time or accuracy). Exploratory analyses suggest that a subset of patients with predominant doubt/checking symptoms may have decreased memory confidence despite normal performance on trials with the highest working memory load.These results suggest that other etiologic factors for checking compulsions should be considered. In addition, they serve as a touchstone for discussion, and therefore help us to generate a roadmap for increasing consensus in the assessment of neurocognitive function in psychiatric disorders.

Theoretical Analysis of Vascular Regulatory Mechanisms Contributing to Retinal Blood Flow Autoregulation

To study whether impaired retinal autoregulation is a risk factor for glaucoma, the relationship between vascular regulatory mechanisms and glaucoma progression needs to be investigated. In this study, a vascular wall mechanics model is used to predict the relative importance of regulatory mechanisms in achieving retinal autoregulation. Resistance vessels are assumed to respond to changes in pressure, shear stress, carbon dioxide (CO2), and the downstream metabolic state communicated via conducted responses. Model parameters governing wall tension are fit to pressure and diameter data from porcine retinal arterioles. The autoregulation pressure range for control and elevated levels of IOP is predicted. The factor by which flow changes as the blood pressure exiting the central retinal artery is varied between 28 and 40 mm Hg is used to indicate the degree of autoregulation (1 indicates perfect autoregulation). In the presence of only the myogenic response mechanism, the factor is 2.06. In the presence of the myogenic and CO2 responses, the factor is 1.22. The combination of myogenic, shear, CO2, and metabolic responses yields the best autoregulation (factor of 1.10). Model results are compared with flow and pressure data from multiple patient studies, and the combined effects of the metabolic and CO2 responses are predicted to be critical for achieving retinal autoregulation. When IOP is elevated, the model predicts a decrease in the autoregulation range toward low perfusion pressure, which is consistent with observations that glaucoma is associated with decreased perfusion pressure.

Safety of tumor necrosis factor inhibitors use for rheumatoid arthritis and ankylosing spondylitis in Africa, the Middle East, and Asia: focus on severe infections and tuberculosis

Multiple studies of patients in Western countries with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have indicated increased risk for active tuberculosis (TB) and other infections among these individuals. It has also been consistently reported that patients receiving tumor necrosis factor (TNF) inhibitors for these conditions have higher rates of active TB and other infections than RA or AS patients not receiving these medications. These issues have been studied less extensively in the Asia and Africa-Middle East regions, and information from these regions is important because of higher rates of TB in the general population. This paper reviews studies of RA and AS patients from Asia, Africa, and the Middle East who received TNF inhibitors. A literature search was conducted using http://www.ncbi.nlm.nih.gov/pubmed to collect and report these data. The years included in the PubMed literature search ranged from January 2000 to October 2011. Additionally, information from the China Hospital Knowledge Database was used to report data from Chinese patients with RA and AS treated with TNF inhibitors. Results from these studies indicate that the risk for active TB and other infections in AS and RA patients from Asia, Africa, and the Middle East are increased in patients receiving TNF inhibitors and that the risk is higher among those treated with monoclonal antibodies versus soluble TNF receptor.

Development of a statistical model of knee kinetics for applications in pre-clinical testing

Pre-clinical computational testing of total knee replacements (TKRs) often only considers a single patient model with simplified applied loads. In studies of multiple patients, most only take into account geometric differences, especially in studies on the knee. Limited availability of kinetic data means that it is difficult to account for inter-patient variability. Principal component analysis (PCA) based statistical models have been used to capture the variation of a set of data and generate new instances of the data. This study presents a method to create a statistical model of kinetic waveform data. A PCA based statistical model was created of the tibiofemoral joint loads for level gait of preoperative TKR patients using data predicted from a musculoskeletal model. A reconstruction test showed that, using principal components (PCs) representing 95% variance, the median root-mean-squared (RMS) error was <0.1 body weight (BW) for the forces and <0.001BWm for the moments. Leave-one-out tests were also performed and although the median RMS error increased for each load in comparison to the reconstruction error (maximum was 0.2BW for the axial force and 0.012BWm for the varus–valgus moment) these were considered within an acceptable limit. The purpose of creating a statistical model is to be able to sample a large set of data representing a population from a small set of clinical data. Such models can potentially be used in population based studies of TKRs incorporating inter-patient variability.

Viscosupplementation with hylan G-F 20 in patients with osteoarthrosis of the knee

Viscosupplementation (VIS) is one of several treatment modalities for osteoarthritis of the knee. It is useful in the treatment of osteoarthritis when other methods of conservative care have failed and it may be a safer method of treatment than oral chemical therapy which can have significant side effects with even short-term usage. The biochemical effects of hyaluronic acid are incompletely understood, however there are several accepted modes of action which result in a positive clinical effect on the function of the knee joint. There is some evidence that hyaluronic acid preparations with a higher molecular weight may be more beneficial to the patient. It is commonly used after arthroscopic meniscectomy and or debridement of the knee in a patient with chondral disease. The clinical effects have been well documented in multiple studies in patients with mild to moderate osteoarthritis in study groups before or after arthroscopic surgery of the knee. Adverse events do occur and are easily treated with only rare case reports of systemic effects. Furthermore, there is some evidence that VIS can prolong the need for total knee arthroplasty in the older patient as well.

Understanding Stroke in Women

See related article, pages 909–914. “The pure and simple truth is rarely pure and never simple”. —Oscar Wilde Sex differences in clinical care and outcomes have been documented in multiple studies of patients with coronary artery disease, with research showing differences in presentation, disparities in diagnosis and management, and worse clinical outcomes in women compared to men.1,2 There has been concern that similar sex differences exist in the care and outcomes of patients with stroke, given the parallels in patient populations and risk factors in individuals with cardiac and cerebrovascular disease. To date, however, the research on the interaction between gender and stroke has been limited and results have been inconsistent. Thus, any new information on this topic is welcome. In this issue of Stroke , Eriksson et al3 report on an analysis of 24 633 stroke events in 2006 from the large, well-designed, population-based Swedish National Quality Register (RIKS-Stroke). They found that compared to men, women were older (mean age difference 4.8 years) and were more often unconscious on presentation. No differences were found in processes of care such as administration of thrombolysis or discharge on anticoagulants. Women were more likely to develop deep venous thromboses and fractures, whereas men …

Colonic Polyps in the “Esophagus”

Purpose: Esophageal atresia is a condition in which the proximal and distal portions of the esophagus do not communicate. Etiologies of these anomalies are still largely unknown; however, vascular insufficiency, genetic factors, vitamin deficiencies, drug and alcohol exposure, viral, chemical, and physical events have all been linked to embryologic developmental aberrancy. Our patient is a 32 y.o. male with esophageal and duodenal atresia corrected by gastrojejunal anastomosis and colonic interposition as an infant. He presented with nausea, melena, hematemesis, and a syncopal episode. His medical history was remarkable for dysphagia and recurrent pneumonias. On admission, UGI and SBS revealed colonic interposition with segments of the jejunum anastomosed to the stomach, proximal duodenum, and biliary system. Gastric varices, an ulcer in the fundus, and inflammatory changes in the duodenal bulb were suspected. Upper endoscopy however, revealed a non-bleeding 1.5 cm neo-esophageal /gastric ulcer at the anastomosis site, and a 1 cm sessile polyp in the proximal neo-esophageal transposed colon. This was removed via snare cautery polypectomy and was later histologically confirmed as a juvenile retention polyp. Multiple studies of patients with interposition report post-operative complications such as motility problems, gastroesophageal reflux, and respiratory complications.7 The endoscopic findings and history of recurrent pneumonia in our patient confirm these findings. Cases of adenomatous polyps and adenocarcinoma in transposed colonic segments to correct esophageal atresia have also been reported. This illustrates the need and re-emphasizes the importance of colon cancer screening wherever colonic tissue is found. 1. Deurloo et al, “Esophageal function after correction of esophageal atresia: follow-up after more than 18 years.” Eur J Gastroenterol Hepatol. 2005; 17(1): A27.[figure1][figure2]FigureFigure

Cine CT for Attenuation Correction in Cardiac PET/CT

In dual-modality PET/CT systems, the CT scan provides the attenuation map for PET attenuation correction. The current clinical practice of obtaining a single helical CT scan provides only a snapshot of the respiratory cycle, whereas PET occurs over multiple respiratory cycles. Misalignment of the attenuation map and emission image because of respiratory motion causes errors in the attenuation correction factors and artifacts in the attenuation-corrected PET image. To rectify this problem, we evaluated the use of cine CT, which acquires multiple low-dose CT images during a respiratory cycle. We evaluated the average and the intensity-maximum image of cine CT for cardiac PET attenuation correction. Cine CT data and cardiac PET data were acquired from a cardiac phantom and from multiple patient studies. The conventional helical CT, cine CT, and PET data of an axially translating phantom were evaluated with and without respiratory motion. For the patient studies, we acquired 2 cine CT studies for each PET acquisition in a rest-stress (13)N-ammonia protocol. Three readers visually evaluated the alignment of 74 attenuation image sets versus the corresponding emission image and determined whether the alignment provided acceptable or unacceptable attenuation-corrected PET images. In the phantom study, the attenuation correction from helical CT caused a major artifactual defect in the lateral wall on the PET image. The attenuation correction from the average and from the intensity-maximum cine CT images reduced the defect by 20% and 60%, respectively. In the patient studies, 77% of the cases using the average of the cine CT images had acceptable alignment and 88% of the cases using the intensity maximum of the cine CT images had acceptable alignment. Cine CT offers an alternative to helical CT for compensating for respiratory motion in the attenuation correction of cardiac PET studies. Phantom studies suggest that the average and the intensity maximum of the cine CT images can reduce potential respiration-induced misalignment errors in attenuation correction. Patient studies reveal that cine CT provides acceptable alignment in most cases and suggest that the intensity-maximum cine image offers a more robust alternative to the average cine image.

VZV vasculopathy and postherpetic neuralgia

Two serious complications of varicella-zoster virus (VZV) reactivation are vasculopathy and postherpetic neuralgia (PHN). Clinical-virologic analyses have proven that VZV vasculopathy is caused by chronic active virus infection in cerebral arteries. Conclusive evidence that PHN is caused by persistent or productive VZV infection is less compelling because human ganglia are not accessible during life for pathologic and virologic examination. However, the notion that PHN may reflect a smoldering VZV ganglionitis is supported by 1) the detection of VZV DNA and proteins in peripheral blood mononuclear cells of many patients with PHN; 2) studies of multiple patients with zoster sine herpete, which indicate a productive VZV ganglionitis; and 3) a favorable response of some patients with zoster sine herpete and PHN to antiviral treatment. Few studies have used antiviral therapy to manage PHN with conflicting results. Larger, double-blind studies, which give IV antiviral drug, are needed.

Efficacy of cyclooxygenase-2–specific inhibitors

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The clinical efficacy of NSAIDs is primarily related to the inhibition of COX-2 activity, whereas much of the toxicity, particularly gastrointestinal toxicity, is related to COX-1 inhibition. In vitro and in vivo assays indicate that both COX-2–specific inhibitors and conventional NSAIDs are equally effective in inhibiting COX-2, suggesting that the clinical efficacy of COX-2–specific inhibitors should be similar to that of conventional NSAIDs. Multiple studies in patients with osteoarthritis, rheumatoid arthritis, and acute pain have now confirmed that the clinical efficacy of COX-2–specific inhibitors is similar to that of conventional NSAIDs.

Applied potential tomography: a new noninvasive technique for assessing gastric function

Applied potential tomography is a new, non-invasive technique that yields sequential images of the resistivity of gastric contents after subjects have ingested a liquid or semi-solid meal. This study validates the technique as a means of measuring gastric emptying. Experiments in vitro showed an excellent correlation between measurements of resistivity and either the square of the radius of a glass rod or the volume of water in a spherical balloon when both were placed in an oval tank containing saline. Altering the lateral position of the rod in the tank did not alter the values obtained. Images of abdominal resistivity were also directly correlated with the volume of air in a gastric balloon. Profiles of gastric emptying of liquid meals obtained using APT were very similar to those obtained using scintigraphy or dye dilution techniques provided that acid secretion was inhibited by cimetidine. Profiles of emptying of a mashed potato meal using APT were also very similar to those obtained by scintigraphy. Measurements of the emptying of a liquid meal from the stomach were reproducible if acid secretion was inhibited by cimetidine. Thus, APT is an accurate and reproducible method of measuring gastric emptying of liquids and particulate food. It is inexpensive, well tolerated, easy to use and ideally suited for multiple studies in patients, even those who are pregnant. A preliminary study is also presented that assesses the technique as a means of measuring gastric acid secretion. Comparison of resistivity changes with measured acid secretion following the injection of pentagastrin shows good correlations. APT might offer a non-invasive alternative to the use of a nasogastric tube and acid collection.

Applied Potential Tomography: A New Noninvasive Technique for Measuring Gastric Emptying

Applied potential tomography is a new, noninvasive technique that yields sequential images of the resistivity of gastric contents after subjects have ingested a liquid or semisolid meal. This study validates the technique as a means of measuring gastric emptying. Experiments in vitro showed an excellent correlation between measurements of resistivity and either the square of the radius of a glass rod or the volume of water in a spherical balloon when both were placed in an oval tank containing saline. Altering the lateral position of the rod in the tank did not alter the values obtained. Images of abdominal resistivity were also directly correlated with the volume of air in a gastric balloon. Profiles of gastric emptying of liquid meals obtained using applied potential tomography were very similar to those obtained using scintigraphy or dye dilution techniques, provided that acid secretion was inhibited by cimetidine. Profiles of emptying of a mashed potato meal using applied potential tomography were also very similar to those obtained by scintigraphy. Measurements of the emptying of a liquid meal from the stomach were reproducible i f acid secretion was inhibited by cimetidine. Thus, applied potential tomography is an accurate and reproducible method of measuring gastric emptying of liquids and particulate food. It is inexpensive, well tolerated, easy to use, and ideally suited for multiple studies in patients, even those who are pregnant.