Local cerebral glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar depression and in normal controls

We studied 14 patients with obsessive-compulsive disorder (OCD) by positron emission tomography and the fluorodeoxyglucose method, looking for abnormalities in local cerebral metabolic rates for glucose in brain structures that have been hypothesized to function abnormally in OCD. These patients were compared with 14 normal controls and 14 patients with unipolar depression. The patients with unipolar depression and OCD did not differ in levels of anxiety, tension, or depression. In OCD, metabolic rates were significantly increased in the left orbital gyrus and bilaterally in the caudate nuclei. This was apparent on all statistical comparisons with both controls and unipolar depression. The right orbital gyrus showed at least a trend to an increased metabolic rate in all comparisons. The metabolic rate in the left orbital gyrus, relative to that in the ipsilateral hemisphere (orbital gyrus/hemisphere ratio), was significantly elevated compared to controls and subjects with unipolar depression, and stayed high even with successful drug treatment. Though it was in the normal range in the morbid state, with improvement in OCD symptoms after drug treatment, the caudate/hemisphere metabolic ratio increased uniformly and significantly bilaterally. This ratio did not increase in patients who did not respond to treatment. Thus, OCD showed cerebral glucose metabolic patterns that differed from controls in both the symptomatic and recovered states.     

T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens

We show here that T cell cross-reactivity between heterologous viruses influences the immunodominance of virus-specific CD8(+) T cells by two mechanisms. First, T cells specific for cross-reactive epitopes dominate acute responses to viral infections; second, within the memory pool, T cells specific for cross-reactive epitopes are maintained while those specific for non-cross-reactive epitopes are selectively lost. These findings suggest an immunological paradigm in which viral infections shape the available T cell repertoire, causing alterations in the hierarchies of both the primary and memory CD8(+) T cell responses elicited by subsequent viral infections. Thus, immunodominance is a function of the host's previous exposure to unrelated pathogens, and this may have an impact on protective immunity and immunopathology.     

Current status of micro/nanomotors in drug delivery

Abstract

Synthetic micro/nanomotors (MNMs) are novel, self-propelled nano or microscale devices that are widely used in drug transport, cell stimulation and isolation, bio-imaging, diagnostic and monitoring, sensing, photocatalysis and environmental remediation. Various preparation methods and propulsion mechanisms make MNMs “tailormade” nanosystems for the intended purpose or use. As the one of the newest members of nano carriers, MNMs open a new perspective especially for rapid drug transport and gene delivery. Although there exists limited number of in-vivo studies for drug delivery purposes, existence of in-vitro supportive data strongly encourages researchers to move on in this field and benefit from the manoeuvre capability of these novel systems. In this article, we reviewed the preparation and propulsion mechanisms of nanomotors in various fields with special attention to drug delivery systems.     

Comparison of antiproliferative and apoptotic effects of a novel proteasome inhibitor MLN2238 with bortezomib on K562 chronic myeloid leukemia cells

Inhibition of the proteasome has emerged as a clinically effective anticancer therapeutic approach in recent years. Bortezomib (Velcade®) showed extremely high potency against a wide range of cancer cell lines. Ixazomib (MLN9708-MLN2238), the second-generation proteasome inhibitor, selectivity and potency were similar to that of bortezomib, is currently being investigated in phase I studies. It shows superior antitumor activity in hematologic malignancy, especially multiple myelomas. In this study, for the first time, we evaluated and compared the antiproliferative and apoptotic effects of the novel proteasome inhibitor MLN2238 (the active form of MLN9708) with bortezomib using in vitro chronic myeloid leukemia. Cytotoxic and apoptotic effects of MLN2238 and bortezomib were determined by trypan blue dye exclusion assays, WST-1 cell proliferation assay, increased AnnexinV-PI binding capacity, changes in caspase-3 activity and loss of mitochondrial membrane potential (JC-1). Associated with proteasome pathway NFκB1 and c-myc mRNA expression levels were examined by the qRT-PCR method. We observed that cytotoxic and apoptotic effects on K562 cells were started at 5?μm of MLN2238 and 1?μm of bortezomib after 24 and 48?h. Also, MLN2238 and bortezomib downregulated NFκB1 and c-myc mRNA expression at 24?h. Our result revealed that MLN22238 and bortezomib had significant cytotoxic and apoptotic effects on K562 cells. Here, we first demonstrate in vitro data that support the development of MLN2238, by direct comparison with bortezomib on K562 cells.     

Angiopoietin-like 4 Stimulates STAT3-mediated iNOS Expression and Enhances Angiogenesis to Accelerate Wound Healing in Diabetic Mice

Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogenesis. ANGPTL4 expression is markedly elevated upon normal wound injury. In contrast, ANGPTL4 expression remains low throughout the healing period in diabetic wounds. Exogenous ANGPTL4 modulated several regulatory networks involved in cell migration, angiogenesis, and inflammation, as evidenced by an altered gene expression signature. ANGPTL4 influenced the expression profile of endothelial-specific CD31 in diabetic wounds, returning its profile to that observed in wild-type wounds. We showed ANGPTL4-induced nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of inducible nitric oxide synthase (iNOS) expression in wound epithelia, thus revealing a hitherto unknown mechanism by which ANGPTL4 regulated angiogenesis via keratinocyte-to-endothelial-cell communication. These data show that the replacement of ANGPTL4 may be an effective adjunctive or new therapeutic avenue for treating poor healing wounds. The present finding also confirms that therapeutic angiogenesis remains an attractive treatment modality for diabetic wound healing.     

Relationship between Tl-201, Tc-99m (Sn) pyrophosphate and F-18 2-deoxyglucose uptake in ischemically injured dog myocardium

We have previously demonstrated that enhanced glucose utilization in reperfused myocardium as assessed by F-18 2-deoxyglucose (FDG) and positron tomography predicts functional recovery. In this study, we compared segmental uptake of F-18 FDG with that of Tl-201 and Tc-99m (Sn) pyrophosphate (Tc-99m PPi) as conventional markers of tissue viability in seven dogs after a 3-hour intracoronary balloon occlusion and 20 hours of reperfusion. Myocardial blood flow was determined with microspheres. Regional retention fractions were calculated from tracer tissue concentrations, the arterial input function, and blood flow. Ischemic injury was assessed by triphenyltetrazolium chloride (TTC) staining and histologic analysis. At 24 hours, blood flow was 22% lower in reperfused than in control myocardium (p less than 0.05). Uptake of Tl-201 was related linearly to blood flow (r = 0.92), while glucose utilization and Tc-99m PPi were 2.9 (p less than 0.01) and 4.7 (p less than 0.05) times higher in reperfused than in control myocardium. Retention fractions of Tc-99m PPi increased with the degree of ischemic injury, while F-18 FDG uptake was highest in segments with mild cell injury. Thus, in ischemically injured myocardium, Tl-201 primarily reflects blood flow. F-18 FDG as a marker of glucose utilization identifies ischemically injured but viable tissue. The admixture of necrotic cells can be determined with Tc-99m PPi. Our results indicate that a dual tracer approach might best characterize the presence and extent of reversibly and of irreversibly injured tissue in a given myocardial region.     

Cardioangiographic findings in patients with arrhythmogenic right ventricular dysplasia.

The dimension, contractility, and regional wall motion of the right and left ventricles were scored on the angiograms of 13 patients with arrhythmogenic right ventricular dysplasia. In 10 patients the right ventricle was enlarged, in eight the contractility of the right ventricle was reduced, and in all but one patient there were regional wall motion abnormalities of the right ventricle. The most common abnormality of regional wall motion was mild hypokinesia. There were bulging or dyskinetic areas in seven patients. Regional wall motion abnormalities of the left ventricle were found in five patients, two of whom also had bulging or dyskinetic areas. The reproducibility of right ventricular dimension, contractility, and regional wall motion scores was generally fair but varied unexpectedly both within and between two observers (Kendall's Tau 0.38-0.92). The score values of regional wall motion for some of the segments differed considerably within and between observers. One of the observers consistently gave higher scores than the other. These data suggest that a more objective approach is needed for evaluating angiographic changes in arrhythmogenic right ventricular dysplasia.     

Evaluation of the clinical usefulness of mycobacterial skin test antigens in adults with pulmonary mycobacterioses.

A double-blind, multicenter study was conducted to evaluate the usefulness of mycobacterial skin test antigens for the specific diagnosis of adult pulmonary mycobacterial disease. The skin test antigens used were PPD-T (M. bovis) and PPD-B (M. intracellulare), made bioequivalent to 5 TU PPD-S through bioassay in human subjects. Of the 192 adults (18 yr of age or older), those with disease caused by M. tuberculosis (MTB) had significantly larger reactions to PPD-T than did those with disease caused by nontuberculous mycobacteria (NTM) or those with negative culture results (NEG)(13.41 mm versus 4.87 and 4.96 mm, respectively, p less than 0.001). The mean induration to PPD-B in NTM was not different from that in MTB or NEG. Defining a "positive" to be greater than or equal to 10 mm induration and a size difference of greater than or equal to 3 mm between PPD-T and PPD-B, the sensitivity, specificity, and positive predictive value (PPV) for PPD-T in diagnosing MTB versus NTM was 29, 90, and 75%. Corresponding values for PPD-B and NTM disease were 70, 61, and 64%. Dual testing was less useful in distinguishing disease caused by any of the mycobacteria from NEG. Although the sensitivity of PPD-B, made bioequivalent to PPD-S, was high, the specificity and PPV were low. We conclude that this preparation of PPD-B is no more useful in distinguishing adult pulmonary disease caused by NTM than is PPD-T alone.