M2/M4 muscarinic receptor binding in the anterior cingulate cortex in schizophrenia and mood disorders

We have previously shown a decrease in [(3)H]pirenzepine binding to M1/M4 muscarinic receptors in the anterior cingulate cortex in schizophrenia but not in major depression or bipolar disorder. The present study aimed to extend these findings by examining the binding of [(3)H]AF-DX 384 to M2/M4 receptors in the same cohort of subjects. Using quantitative autoradiography we measured [(3)H]AF-DX 384 binding in the anterior cingulate cortex of 15 schizophrenia, 15 bipolar, 15 major depression and 15 control cases. Post-mortem tissue was obtained from the Stanley Foundation Brain Bank. [(3)H]AF-DX 384 binding had a homogenous distribution amongst the layers of the anterior cingulate cortex, was higher in males than in females and declined with prolonged storage of tissue. An inverse correlation between [(3)H]AF-DX384 binding and age of onset of the disease was observed in the schizophrenia group suggesting that the earlier the age at onset the higher the binding was. In the depression group, there was a significant effect of gender on [(3)H]AF-DX 384 binding with females having lower binding in comparison to males. In the bipolar group, there was a significant inverse correlation between antipsychotic medication and [(3)H]AF-DX 384 binding, suggesting that the higher the dose of medication the lower the binding was. No differences in [(3)H]AF-DX 384 binding were seen between the four groups. The present results provide no evidence of M2/M4 receptor alterations in the anterior cingulate cortex in schizophrenia and affective disorders and extend the body of evidence implicating cortical M1 but not M2 involvement in the pathology and pharmacotherapy of schizophrenia.     

High-resolution computed tomography features of nonspecific interstitial pneumonia and usual interstitial pneumonia

OBJECTIVE: To assess the accuracy of high-resolution computed tomography (HRCT) in the diagnosis of nonspecific interstitial pneumonia (NSIP). We hypothesized that the computed tomography (CT) features of NSIP could be distinguished from those of usual interstitial pneumonia (UIP). METHODS: The HRCT images of 47 patients with surgical lung biopsy-proven NSIP (n = 25) and UIP (n = 22) were independently reviewed by 2 thoracic radiologists. Predominant imaging patterns, most likely diagnosis, and diagnostic level of confidence were recorded. A confident HRCT diagnosis of NSIP was based on the presence of spatially uniform, bilateral, basal-predominant ground-glass and/or reticular opacities with little if any honeycombing, whereas UIP was confidently diagnosed if a spatially inhomogeneous, bilateral, peripheral, basal-predominant pattern of reticular opacities and honeycombing with little if any ground-glass attenuation was identified. RESULTS: A predominant pattern of ground-glass and/or reticular opacity with minimal to no honeycombing was demonstrated in 48 (96%) of 50 readings in patients with NSIP. Conversely, the presence of honeycombing as a predominant feature had a predictive value of 90% for UIP (P < 0.001). Usual interstitial pneumonia was more likely than NSIP to be subpleural and patchy (P < 0.001). A confident CT diagnosis of NSIP and UIP was correct in 73% and 88% of cases, respectively. The correctness of a CT diagnosis made at intermediate or high confidence was 68% and 88%, respectively. The kappa value for distinction of NSIP from UIP was 0.72. CONCLUSION: In contrast to previous reports, NSIP can be separated from UIP in most cases. The presence of honeycombing as a predominant imaging finding is highly specific for UIP and can be used to differentiate it from NSIP, particularly when the distribution is patchy and subpleural predominant. The presence of predominant ground-glass and reticular opacity is highly characteristic of NSIP, but there is a subset of patients with UIP who have this pattern and may require biopsy for differentiation from NSIP.     

Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development

Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.     

Clinical evaluation of a compomer and an amalgam primary teeth class II restorations: a 2-year comparative study

PURPOSE: This study was performed to compare the clinical performance between the compomer F2000 and amalgam Dispersalloy in Class II restorations in primary molars over a 2-year period. METHODS: Seventy-five amalgam and 75 compomer restorations were placed in 75 children based on a split-mouth design. The restorations were evaluated after 1 week and after 6, 12, 18, and 24 months of oral function. The evaluation consisted of a clinical assessment according to modified Ryge criteria, a radiographic examination using bite-wing radiographs, and an observation of epoxy casts under scanning electron microscopy. RESULTS: The results showed statistically significant differences in the marginal adaptation and anatomic form between amalgam and compomer restorations. A higher number of compomer restorations were rated as Bravo, while a higher number of amalgam restorations were rated as Alpha at 24 months. Significant differences in the failure of the restoration and development of secondary caries were not found between the materials. CONCLUSIONS: The use of compomer F2000 in Class II resorations in primary molars, although it presents a significantly higher number of restorations rated as Bravo regarding the marginal adaptation and anatomic form vs the amalgam, does not increase the risks of developing secondary caries and failure of the restoration over a period of 2 years.     

Greek Orthodox fasting rituals: a hidden characteristic of the Mediterranean diet of Crete

The longevity and excellent health status of the population of Crete has been attributed to its lifestyle and dietary habits. The impact of Greek Orthodox Christian Church fasting on these dietary habits has never been studied. One hundred and twenty Greek Orthodox Christians living in Crete participated in a 1-year prospective study. One half of the subjects, who fasted regularly (fasters), and sixty non-faster controls were followed longitudinally for the three main fasting periods over 1 year; Christmas (40 d), Lent (48 d) and the Assumption (15 d). Pre- and end-holy days measurements were performed in each fasting period including: 24 h dietary recall, blood collection and anthropometric measurements. Based on the 24 h recall, fasters as compared with controls had lower intakes of end-holy days dietary cholesterol, total fat, saturated fatty acids, trans-fatty acids and protein (P < 0.001). Fasters presented a decrease of 753 kJ (180 kcal) in end-holy days energy intake (P < 0.05) compared with an increase of 573 kJ (137 kcal) in the controls (P < 0.05). Fasters had a decrease in end-holy days Ca intake (P < 0.001) and an increase in end-holy days total dietary fibre (P < 0.001) and folate (P < 0.05), attributed to their higher consumption of fruit and vegetables in end-holy periods (P < 0.001). There were no differences for other vitamins or minerals between pre- and end-holy periods in both groups except for vitamin B2. The Orthodox Christian dietary regulations are an important component of the Mediterranean diet of Crete characterised by low levels of dietary saturated fatty acids, high levels of fibre and folate, and a high consumption of fruit, vegetables and legumes.     

'Designer' tumors in mice

We have developed and tested successfully a general method based on Cre-mediated recombination that can be used for ubiquitous or tissue-specific expression of protein products, including tumor-inducing oncoproteins. Depending on the specificity of a chosen promoter driving cre expression, tumors develop by design in bitransgenic mouse progeny derived by crossing Cre-producing mice with partners carrying a dormant oncogenic transgene (targeted into the 3' noncoding region of the cytoplasmic beta-actin locus) that becomes functional after excision of a 'floxed' DNA segment. To provide proof-of-principle, we have used as models transgenes encoding the polyomavirus middle T antigen (PVMT) and the T antigens of the SV40 early region (SVER). Cre-dependent activation of widespread SVER expression resulted in hyperplasias or invasive tumors affecting particular visceral smooth muscles, whereas Cre-dependent, mammary gland-specific expression of PVMT-induced adenocarcinomas, according to plan. Unexpectedly, we also encountered spontaneous (Cre-independent) oncogene expression occurring as a rare event, which simulates the initiation of sporadic tumors and leads to PVMT-induced hemangiomas and mammary carcinomas or SVER-induced disseminated sarcomas, thus, revealing particular tissue susceptibilities to the actions of these oncoproteins.     

Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier

The endothelial cells (EC) of the microvasculature in the brain form the anatomical basis of the blood-brain barrier (BBB). In the present study, the effects of agents that modify the permeability of a well-established in vitro model of the human BBB were studied. The monolayers formed by confluent human brain microvessel endothelial cell (HBMEC) cultures are impermeable to the macromolecule tracer horseradish peroxidase (HRP) and have high electrical resistance. Exposure of HBMEC to various cytokines including TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS) decreased transendothelial electrical resistance (TEER) mainly by increasing the permeability of the tight junctions. Primary cultures of HBMEC express endothelial nitric oxide synthase (eNOS) and produce low levels of NO. Treatment with the NO donors sodium nitroprusside (SNP) and DETA NONOate or the cGMP agonist 8-Br-cGMP significantly increased monolayer resistance. Conversely, inhibition of soluble guanylyl cyclase with ODQ rapidly decreased the resistance, and pretreatment of HBMEC with Rp-8-CPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, partially prevented the 8-Br-cGMP-induced increase in resistance. Furthermore, NO donors and 8-Br-cGMP could also reverse the increased permeability of the monolayers induced by IL-1beta, IFN-gamma, and LPS. These results indicate that NO can decrease the permeability of the human BBB through a mechanism at least partly dependent on cGMP production and cGMP-dependent protein kinase activation.     

Effect of maltose-containing sports drinks on exercise performance

This study examined the effect of maltose-containing sports drinks on exercise performance. Ten subjects completed 4 trials. Each trial consisted of a glycogen depletion protocol, followed by a 15-min refueling, after which subjects performed an 1-h performance test while consuming one of the experimental drinks (HGlu, glucose; HMal, maltose; MalMix, sucrose, maltose, and maltodextrin; Plac, placebo). Drinks provided 0.65 g/kg body weight carbohydrates during refueling and 0.2 g/kg every 15 min during the performance test. Although no significant differences were found in performance (HGlu: 67.2 +/- 2.0; HMal: 68.6 +/- 1.7; MalMix: 66.7 +/- 2.0; Plac: 69.4 +/- 3.0 min, P> 0.05), subjects completed the MalMix trial 3.9%; faster than the Plac. Carbohydrate drinks caused comparable plasma glucose values that were significantly higher during refueling and at the end of exercise, compared to Plac. The data suggest that although carbohydrate drinks help to maintain plasma glucose at a higher level, no differences in performance could be detected after glycogen-depleting exercise.