mRNA expression, functional profiling and multivariate classification of colon biopsy specimen by cDNA overall glass microarray

INTRODUCTION mRNA expression array analysis is usually performed on high volume surgery or blood samples. However, evaluation of routine biopsy specimens could yield information, as to how the local pathological processes differ from healthy counterparts.…     

Activation of intracellular signaling systems by high-density lipoproteins

The proteosome of high-density lipoprotein particles is quite complex and consists of up to 75 different proteins and enzymes. The specific protein cargo of HDL particles regulates their functionality. In addition to their documented capacity to engage in reverse cholesterol transport, reduce oxidized lipid, and function as apoprotein donors, HDL particles can activate a variety of signaling systems in endothelial cells, smooth muscle cells, and platelets. The HDLs can deliver sphingolipids to the surface of these cell types and activate sphingosine phosphate receptors. Sphingosine phosphate receptors are coupled to numerous different intracellular signaling cascades exerting roles in vasodilatation, inflammation, cell migration and apoptosis, inhibition of platelet activation, and endothelial adhesion molecule expression, among other functions. The ability of HDL to influence such a diverse array of cellular functions lends biological plausibility to the substantial epidemiological and clinical evidence suggesting that the HDLs are unique among lipoproteins in that they are vasculoprotective and antiatherogenic.     

Automated virtual microscopy of gastric biopsies

BACKGROUND: Automated virtual microscopy of specimens from gastrointestinal biopsies is based on cytometric parameters of digitized histological sections. To our knowledge, cytometric parameters of gastritis and of adenocarcinoma have yet to be fully characterized. Our objective was to classify gastritis and adenocarcinoma based on cytometric parameters. We hypothesized that automated virtual microscopy using this novel classification can reliably diagnose gastritis and adenocarcinoma. METHODS: Routinely processed hematoxylin-and-eosin-stained histological sections from specimens that showed normal mucosa (14 cases), gastritis (35 cases), and adenocarcinoma (30 cases) diagnosed by conventional optical microscopy were scanned and digitized at high resolution. Thirty-eight cytometric parameters based on density and morphometry were applied to glands and superficial epithelium. Twelve cytometric parameters based on cytologic detail were applied to individual cells. RESULTS: Statistically significant differences in cytometric parameters for normal mucosa, gastritis, and adenocarcinoma were found. The most discriminatory parameter was the ratio of the total number of cells to the number of interstitial cells. These differences correctly classified adenocarcinoma at 100% accuracy and overall correctness was 86%. CONCLUSIONS: We describe a novel method of analyzing gastric mucosal histology based on cytometric parameters. Automated virtual microscopy can be used to classify gastric mucosa as normal, gastritis, or adenocarcinoma with reasonable accuracy. Further research is necessary to determine whether automated virtual microscopy can subclassify gastric mucosal histology in greater detail.     

Successful use of adalimumab for treating fistulizing Crohn's disease with pyoderma gangrenosum: Two birds with one stone

Crohn's disease (CD) is a chronic relapsing and remitting autoinflammatory disorder of the gastrointestinal tract that has many intestinal and extraintestinal complications. The purpose of treatment is long-term remission, reduction of complications, and improvement of patients' quality of life. In many cases, this can be quite challenging and it is necessary to have a well thought out management strategy. We present the case of a 38-year-old woman with fistulizing CD that manifested as diffuse abdominal pain and bloody diarrhea accompanied by arthralgia. In addition, there were ulcerative lesions surrounded by cutaneous inflammation and erythema on her extremities, indicative of pyoderma gangrenosum. The patient was treated with high doses of parenteral methylprednisolone without any improvement and was started on adalimumab. A positive response to adalimumab therapy was observed: after 2 mo of therapy, the ulcerative skin lesion healed completely and the enterogastric fistula was closed after 5 mo adalimumab treatment. Adalimumab might be a suitable initial as well as maintenance therapy in patients with complicated CD.     

Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels

The glial water channel aquaporin-4 (AQP4) has been hypothesized to modulate water and potassium fluxes associated with neuronal activity. In this study, we examined the seizure phenotype of AQP4 -/- mice using in vivo electrical stimulation and electroencephalographic (EEG) recording. AQP4 -/- mice were found to have dramatically prolonged stimulation-evoked seizures after hippocampal stimulation compared to wild-type controls (33 +/- 2 s vs. 13 +/- 2 s). In addition, AQP4 -/- mice were found to have a higher seizure threshold (167 +/- 17 microA vs. 114 +/- 10 microA). To assess a potential effect of AQP4 on potassium kinetics, we used in vivo recording with potassium-sensitive microelectrodes after direct cortical stimulation. Although there was no significant difference in baseline or peak [K(+)](o), the rise time to peak [K(+)](o) (t(1/2), 2.3 +/- 0.5 s) as well as the recovery to baseline [K(+)](o) (t(1/2), 15.6 +/- 1.5 s) were slowed in AQP4 -/- mice compared to WT mice (t(1/2), 0.5 +/- 0.1 and 6.6 +/- 0.7 s, respectively). These results implicate AQP4 in the expression and termination of seizure activity and support the hypothesis that AQP4 is coupled to potassium homeostasis in vivo.     

Postinjury Abdominal Compartment Syndrome: Are We Winning the Battle?

Postinjury (primary) abdominal compartment syndrome (ACS) was described more than 15 years ago as severe abdominal distension with high peak airway pressures, CO₂ retention, and oliguria, which led to unplanned re-exploration after damage-control laparotomy. Later, a more elusive type of ACS was recognized, which develops without abdominal injuries (secondary ACS). Both syndromes were recently characterized, their independent predictors were identified, and preventive strategies were developed to reduce their incidence. Once viewed as a syndrome with almost uniform mortality, systematic preventative strategies and therapeutic efforts have reduced the prevalence, morbidity, and mortality of the syndrome. This review was designed to summarize the recent advances in the management of ACS, to classify the currently available evidence, and to identify future directions of research and clinical care.     

Humanized anti-CD2 monoclonal antibody treatment of plaque psoriasis: efficacy and pharmacodynamic results of two randomized,double-blind,placebo-controlled studies of intravenous and subcutaneous siplizumab

New biologic therapies focused primarily on cytokine pathways, some targeting T cell-mediated immune responses, are being developed for the treatment of psoriasis. Siplizumab is a humanized anti-CD2 monoclonal antibody that interferes with costimulation necessary for T cell activation and proliferation. We assessed the biological activity, serum concentrations, and pharmacodynamic effects of siplizumab in patients with plaque psoriasis. Two multicenter, phase II randomized, double-blind, placebo-controlled studies were conducted: one study randomized 124 patients to one of two intravenous (IV) doses (0.012 and 0.04 mg/kg) of siplizumab, given every 2 weeks × 8 doses; the other study randomized 420 patients to one of three subcutaneous (SC) dose regimens of siplizumab given weekly (5 mg for 12 weeks, 5 mg for 6 weeks, and 7 mg for 4 weeks) or placebo for 12 weeks. Adults with plaque psoriasis involving ≥10% of the body surface area and who were not receiving psoriasis therapy were eligible. Treatment with siplizumab resulted in reductions in psoriasis severity, but most of the effects were not statistically significant compared with placebo. Statistically significant differences among IV siplizumab-treated and placebo groups were observed at study day 28, with greater psoriasis area and severity index (PASI) score reductions from baseline in the siplizumab groups. The difference in PASI50 response rates between the 0.04 mg/kg siplizumab and placebo groups was also statistically significant at day 28. A trend toward clinical improvement was observed in SC siplizumab-treated groups. Significant reductions in circulating absolute lymphocyte counts and CD2⁺ (CD3⁺, CD8⁺, and CD16⁺/56⁺), but not CD2⁻ (CD19⁺ and CD14⁺), lymphocyte populations were observed. These changes were not accompanied by concomitant reductions in infiltrating CD3⁺ lymphocytes in psoriatic lesions, epidermal thickness, or keratin 16 (K16) and intercellular adhesion molecule (ICAM) expression. The effect of siplizumab did not differentially affect CD45RO⁺ and CD45RA⁺ lymphocytes. Low or undetectable mean trough serum concentrations of siplizumab following IV or SC treatment were observed. Pharmacokinetic data coupled with higher-than-expected placebo clinical response rates may partly explain siplizumab’s marginal clinical activity. Higher doses of siplizumab may be required to detect significant improvements in psoriasis; however, further development of this agent was not planned.     

Centric Relation Registration Using an Anterior Deprogrammer in Dentate Patients

A technique is described for registering centric relation in dentate patients using an anterior deprogrammer to prevent muscle splinting. Properly executed, the patient is able to close into centric relation unassisted, eliminating the possibility of operator-induced error associated with commonly accepted manipulative techniques. Verification is possible visually when articulating casts by confirming the precise alignment of the mandibular incisors with occlusal markings on the deprogrammer attached to the maxillary cast.