The molecular genetics of schizophrenia: an update

OBJECTIVE: This paper aims to summarise the latest molecular genetic findings in schizophrenia, while providing background information on a number of relevant methodological issues. METHOD: Accumulative genetic data indicate that schizophrenia is a genetically complex disease with an unclear mode of transmission. The development and rapid progression of molecular genetics have provided a wide variety of methods to search for genes predisposing to human disease. The genetic basis for a number of the simpler diseases has been identified and characterised using these methods. More recently, progress has been made in identifying genes predisposing to the genetically more complex diseases such as diabetes mellitus, multiple sclerosis, bipolar disorder and schizophrenia. RESULTS: The latest findings on chromosomes 3, 6, 8, 13, 18 and 22 and on the X chromosome are reviewed. CONCLUSIONS: There is now suggestive support for three susceptibility loci (6p24-22, 8p22-21 and 22q12-q13.1) for schizophrenia, and it is likely that other regions will emerge from studies now in progress. Finding and then characterising genes within these loci will require long-term commitment and systematic efforts in clinical, laboratory and analytical fields.     

Virulence of enterohemorrhagic Escherichia coli: role of molecular crosstalk

Many bacterial exotoxins, originally defined by cytopathic effects, may also possess additional biological activities. The capacity of exotoxins to elicit the synthesis and secretion of pro- or anti-inflammatory cytokines may be as important as their direct toxic effects in pathogenesis. One example of such 'molecular crosstalk' occurs between Shiga toxins and the cytokines made in response to these toxins during the development of disease.     

Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis

The thrombin thrombomodulin dependent activation of the plasma protein TAFI (Thrombin Activatable Fibrinolysis Inhibitor) and Subsequent Inhibition of Fibrinolysis by the TAFIa is described. Work to date indicates that TAFIa is a carboxypeptidase B enzyme that suppress fibrinolysis most likely by down regulating the cofactor functions of partially degraded fibrin. The existence of TAFI provides the explanation for the apparent profibrinolytic effect of activated protein C. and implies the existence of an explicit molecular connection between the blood coagulation of fibrinolytic cascades that is expressed through the thrombin thrombomodulin dependent activation of TAFI. Thus, thrombin generation can, in principle, result in the suppression of fibrinolysis.     

Aging and the liver: an update

The issue of whether or not liver function is compromised in the elderly population remains unresolved. Numerous age-related changes in hepatic structure and function have been described, but many of these observations are qualitative, were made under suboptimal experimental conditions, or are simply contradictory. Changes in hepato-cellular structural parameters, e.g., increased hepatocyte size, increase in the number of binucleated cells, altered mitochondria, and endoplasmic reticulum, have been reported. However, quantitative morphological analyses have refuted many of these observations. There are few functional data that correlate with structural changes. Serum and biliary cholesterol appear to rise, predisposing elderly people to increased incidences of coronary disease and gallstones, respectively. The rate of liver regeneration declines in old animals, but the regenerative capacity remains unchanged, perhaps reflecting an age-associated reduction in the response to hepatotrophic factors. This senescent change has important clinical implications with regard to surgical intervention for liver disease, e.g., resection or transplantation. Nevertheless, most outcomes studies suggest that age alone should not be a determining factor in such clinical decisions. Geriatric patients exhibit a decline in the hepatic clearance of certain drugs and a marked increase in the frequency of adverse drug reactions, reflecting an increase in polypharmacy regimens and declines in liver volume and blood flow rather than reduced Phase I metabolism. Although the livers of elderly subjects are characterized by a decline in adaptive responsiveness and reduced reserve capacity, clinical tests suggest that liver function is well-maintained in this age group.     

Increased expression of CD11b/CD18 on phagocytes in ischaemic disease: a bridge between inflammation and coagulation

The aim of this study was to assess the expression of CD11b/CD18 integrin adhesion molecules on the phagocytes of patients with ischaemic diseases, and to evaluate the concentration of soluble adhesion molecules that are released from endothelium (sICAM-1) and from phagocytes (sL-selectin). A total of 370 patients were enrolled: 120 with coronary artery disease (CAD); 50 with peripheral artery occlusive disease (PAOD); and 200 control subjects with no clinical manifestations of ischaemic disease. CD11b/CD18 integrin was detected by flow cytometry, whereas sL-selectin and sICAM-1 concentrations were detected using a sandwich-type immunoassay. CD11b/CD18 integrin expression was found to be higher in the patients with ischaemic disease than in the control subjects (P < 0.001). The PAOD patients had higher values of CD11b/CD18 integrin than the CAD ones (P < 0.01). The concentration of soluble adhesion molecules did not show any significant differences within the three groups (P = NS). The high expression of CD11b/CD18 integrin in ischaemic disease patients may depend on the increased, but probably stable, cytokine network that has been demonstrated to occur in chronic ischaemic diseases: the difference observed between PAOD and CAD patients could be the consequence of higher inflammatory activation probably resulting from the greater extent of the atherosclerotic process in PAOD, or of the more localized ischaemic area in CAD patients. CD11b/CD18 can therefore be considered a marker of chronic phagocyte activation during ischaemic disease. On the other hand, sICAM and sL-selectin concentrations were found to be within the normal range; they have recently been considered as a marker for acute ischaemic events and acute inflammatory process activation. Our results confirm that in uncomplicated atherosclerosis no acute inflammatory process activation should occur.     

Ovarian cancer: an update on genetics and therapy

This article reviews the important aspects of the management of both early and advanced ovarian cancer with a particular emphasis on genetic predisposition and recent and anticipated advances in treatment.     

Comparison of ribotyping and arbitrarily primed PCR for molecular typing of Salmonella enterica and relationships between strains on the basis of these molecular markers

Arbitrarily primed PCR (AP-PCR) using a discriminatory 10-mer primer and an automated EcoRI ribotyping technique (Riboprinter) were compared for their ability to discriminate between 100 serovars of Salmonella, including multiple isolates representing Salm. Enteritidis PT4 and Salm. Typhimurium DT104. Profiles generated by each method were subjected to numerical analysis using GelCompar software, resulting in the construction of phylogenetic trees and calculation of Simpson's numerical index of diversity (DI). Both methods were highly discriminatory for isolates of Salmonella (Ribotype DI = 0.990, AP-PCR DI = 0.997) with EcoRI ribotyping proving more discriminatory than AP-PCR for isolates of Typhimurium DT104. The population structure was found to be clonal by numerical analysis of markers generated by both methods with serovars being polyphyletic in some cases and grouped in a single cluster in others. No absolute correlation was observed in the relationships between strains formed on the basis of ribo- and AP-PCR markers and serological characteristics.     

Vitamin D-retinoid association: molecular basis and clinical applications

BACKGROUND AND PURPOSE: The role of single-photon emission CT (SPECT) in the prognosis of cerebral infarction is controversial, but most studies report that SPECT using a variety of radiopharmaceutical agents gives useful prognostic information. Only one study has questioned whether acute perfusion deficits independently add to a valid clinical prognostic score. This study was limited to middle cerebral artery territory infarcts and was negative. We present data on the prognostic utility of SPECT using 99mTc-hexamethylpropyleneamine oxime (HMPAO) in cerebral infarction, unselected by site. METHODS: Fifty consecutive unselected patients admitted to the hospital with acute cerebral infarction, of whom 10 died and 7 withdrew, had SPECT performed serially at onset and at 1 week and 3 months after stroke onset using 99mTc-HMPAO and the NOVO 810 dedicated high-resolution head tomograph. Clinical severity at presentation and outcome was measured with the Canadian Neurological Scale and the Barthel Index. Infarct volumes were measured from both the SPECT and CT scans. The data for the 43 subjects who completed the study or died were evaluated to determine the most powerful prognostic measures. Predictors were the Canadian Neurological Scale score at onset and 1 week, the Barthel Index at 1 week, the CT infarct volume typically done between 3 and 7 days after stroke onset, and the infarct volumes at the first and second SPECT. Outcome measures were the Canadian Neurological Scale score and Barthel Index score at 3 months, scored as zero for those patients who died. RESULTS: The clinical prognostic indicators correlated with the outcome measures, with coefficients between .617 and .821 (P < .0006 in all cases). The Canadian Neurological Scale score measured at 1 week was the best of these. Infarct volumes measured from SPECT correlated less well (coefficients between -.518 and -.683, P < .0019 in all cases). CT infarct volume was the poorest predictor. Although SPECT infarct volumes predicted outcome, they did so less well than clinical examination. Spontaneous infarct reperfusion did not affect outcome. CONCLUSIONS: Although the measurement of infarct volume on SPECT using 99mTc-HMPAO provides a predictor of stroke outcome, it is not a better predictor than the Canadian Neurological Scale score.     

Hay fever: an update on current treatments

The main objective of neurointensive care is to counteract the development of secondary brain ischemia. The management is focused on preventing, detecting and correcting secondary insults that are likely to produce ischemic brain damage. This requires intensive multimodality monitoring of the brain. There is no reliable technique available for continuous monitoring of cerebral blood flow and therefore intermittent methods have to be used in some cases for objective measurement of cerebral perfusion. PET allows measurements of both cerebral blood flow and metabolism, which is essential for the assessment of the energy metabolic state of the brain tissue. PET may be used to guide therapeutic intervention, to evaluate the effect of treatment, to validate new techniques for monitoring of the brain and to determine the efficacy of potential neuroprotective drugs. The possibilities that PET offers in neurointensive care and research are illustrated. The experiences from the application of PET in the evaluation of pharmacological treatment of increased intracranial pressure in head injured patients and the use of PET in combination with intracerebral microdialys, in an MCA-occlusion-reperfusion primate model and in patients with subarachnoid hemorrhage, to validate intracerebral microdialysis as an instrument for chemical monitoring of the brain during neurointensive care, are reported.     

Primary and secondary peritonitis: an update

Intraabdominal infections are commonly encountered in clinical practice and represent a major cause of morbidity and mortality. The most common etiology is contamination of the peritoneal space by endogenous microflora secondary to loss of integrity of the gastrointestinal tract which results in secondary peritonitis. Primary peritonitis or spontaneous bacterial peritonitis is less common and usually occurs in the presence of ascites without an evident source of infection. Peritonitis associated with chronic ambulatory peritoneal dialysis is not discussed in this review. This review summarizes the significant progress which has been made with regard to primary and secondary peritonitis in the last two decades. The review emphasizes the issues of etiology, pathogenesis, microbiology, diagnosis, medical treatment and prevention.     

Biochemical and molecular basis of Bernard-Soulier syndrome: a review

Bernard-Soulier syndrome (BSS) is a rare hereditary recessive autosomal bleeding disorder characterized by a prolonged bleeding time, giant platelets, thrombocytopenia, normal platelet aggregation in response to ADP and no agglutination in response to ristocetin. This disease is due to absence or abnormality of the platelet membrane glycoprotein GPIb-IX-V, the receptor for von Willebrand factor. All four genes encoding the complex have been cloned and 17 forms of BSS have to date been characterized at the functional, immunological and molecular levels. The mutations can be divided into two main groups. Firstly, mutations located in leucine rich repeats (LRR), responsible for conformational modifications of the molecule, in some cases higher sensitivity to proteases and loss of adhesive function of the receptor, which is expressed at lower than normal levels at the platelet membrane. When mutations affect the LRR of GPIbalpha, the presence of the other chains varies from normal to residual amounts. When mutations affect the LRR of GPIX, expression of the other chains is strongly diminished, suggesting that GPIX plays a major role in the stability of the complex. A second type of mutations leads to synthesis of a truncated molecule lacking the transmembrane domain and absence of its expression at the platelet surface, while the other chains are present in residual amounts. Expression of recombinant proteins in eukaryotic cells has recently confirmed the results derived from studies of natural mutations. Separate expression of each chain can be obtained, although the presence of all subunits is required for full expression.