W+ W- production at hadron colliders in next to next to leading order QCD.

Charged gauge boson pair production at the Large Hadron Collider allows detailed probes of the fundamental structure of electroweak interactions. We present precise theoretical predictions for on-shell W+ W- production that include, for the first time, QCD effects up to next to next to leading order in perturbation theory. As compared to next to leading order, the inclusive W+ W- cross section is enhanced by 9% at 7 TeV and 12% at 14 TeV. The residual perturbative uncertainty is at the 3% level. The severe contamination of the W+ W- cross section due to top-quark resonances is discussed in detail. Comparing different definitions of top-free W+ W- production in the four and five flavor number schemes, we demonstrate that top-quark resonances can be separated from the inclusive W+ W- cross section without a significant loss of theoretical precision.

Stroke care in young patients.

The aims of this study were (i) to evaluate the clinical features of a consecutive series of young patients with ischemic stroke and (ii) to assess the changes in the clinical management of these patients over the study period. All consecutive cases of young adults aged 16 to 44 years, with ischemic stroke, that were admitted between 2000 and 2005 in 10 Italian hospitals were included. We retrospectively identified 324 patients. One or more vascular risk factors were present in 71.5% of the patients. With respect to the diagnostic process, an increase in the frequency of cerebral noninvasive angiographic studies and a decrease in the use of digital subtraction angiography were observed (P < 0.001 and P = 0.03, resp.). Undetermined causes decreased over 5-year period of study (P < 0.001). The diagnosis of cardioembolism increased. Thrombolysis was performed for 7.7% of the patients. PFO closure (8%) was the most frequently employed surgical procedure. In conclusion, the clinical care that is given to young patients with ischemic stroke changed over the study period. In particular, we detected an evolution in the diagnostic process and a reduction in the number of undetermined cases.

Evaluation of plasma antioxidant levels during different phases of illness in adult patients with bipolar disorder.

The aim of the present study is to evaluate role of plasma antioxidants (albumin, bilirubin and uric acid) in patients suffering from type I Bipolar Disorder (BD-I) during different phases of illness: acute mania, euthymia and bipolar depression. Medical records of consecutive 110 BD-I patients (38 patients with acute mania, 35 in euthymic state, full remission, and 37 in depressive phase) were reviewed to evaluate plasma antioxidant levels. Laboratory data of 40 healthy controls were also obtained. The scores of Young Mania Rating Scale (YMRS), Bech-Rafaelsen Manic Rating Scale (BRMRS) and Hamilton Rating Scale for Depression (HAM-D) were evaluated. Serum uric acid levels were higher in acute mania than other patient subgroups and healthy controls. Serum uric acid levels directly correlated with BRMRS and YMRS scores. No differences were found between clinical groups during different phases and healthy controls concerning albumin and bilirubin. In conclusion, the results of the present study support the notion that serum uric acid levels may be higher in patients with BP-I (especially during manic phases) which may suggest a dysregulation of the purinergic system. However, limitations should be considered and further studies are needed.

Progressive liver injury in chronic hepatitis C infection is related to altered cellular immune response and to different citokine profile.

Natural immune responses, both cellular and humoral, are not capable of terminating HCV infection in most patients. The aim of this study was to evaluate: a) the importance of the immune system in the pathogenesis of chronic HCV infection; b) analysis of successful immunoresponses in persons infected with C virus; c) immuno mechanisms in the progression of hepatic damage; d) different cytokine profiles from patients with persistent and self-limited hepatitis C virus infection; e) development of new antiviral strategies when virus is resistant to interferon treatment. The inadequate T helper1 (Th1) immunity as well as the weak HCV-specific T-cell response at the site of inflammation is associated with failure to clear the virus and a chronic course of disease. The production of interleukin 12 (IL-12) is critical for induction of Th1 immunity, directed towards elimination of intracellular pathogenes and viruses. The core protein of HCV seems to have a suppressive action on IL-12 production at the transcriptional level. The specific Th1 cell defect is correlated with insufficient Th and CTL responses, and lower production of type 1 cytokine (IL-2, IFN-gamma, lymphokine-activated killer cells). Taken together, these results are probably responsible for non-eradication of HCV infection. Particularly the effects of interferon-gamma may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGF-beta, and an effect on HCV induced carcinogenesis. These data suggest an HCV-related cellular immune defect in patients with hepatitis C that can be restored in most patients by IL-12. New approaches using a combination of nucleoside analogs or other strategies, such as immune intervention (DNA vaccine, stimulation of the Th1 response) or gene therapy (antisense oligonucleotides dominant negative mutants) should therefore be evaluated in animal models to optimize the current antiviral protocols.

Clinical, morphological and immunological evaluation of six patients with dysferlin deficiency.

Limb girdle muscular dystrophy (LGMD) type 2B and distal Miyoshi myopathy (MM) are caused by mutations in a recently discovered mammalian gene coding for a skeletal muscle protein called dysferlin. The protein is normally expressed at the skeletal muscle level and absent or reduced in affected patients. We selected a clinically heterogeneous population of Italian myopathic patients with clinical evidence of myopathy and/or hyperCKemia, EMG myopathic pattern, and no alterations of the dystrophin-sarcoglycan complex. Calpain, merosin, emerin and caveolin were also tested and found normal in all patients. Dysferlin immunohistochemical and Western blot analyses allowed us to identify six patients with dysferlin deficiency: one with distal myopathy, four with limb girdle myopathy and one with hyperCKemia. No apoptosis was found in any of the six muscle specimens, although expression of the pro-apoptotic Fas antigen was mildly increased in two cases. Inflammatory reactions were present in two of the six cases, but we found no evidence of immune-mediated processes.

High prevalence of hepatitis C virus infection in a southern Italian rural region. Clinical aspects and evidence of inapparent parenteral exposure.

AIM: Infection by hepatitis C virus (HCV) generally determines an asymptomatic acute hepatitis which becomes chronic in about 90% of cases. In order to contribute data on the prevalence and the transmission of HCV infection and its associated conditions, anti-HCV seropositivity records in a large sample of a population living in a rural area in Southern Italy were collected and examined. METHODS: Data were obtained from the registers of local general practitioners operating in 4 neighbouring countries which make up the region analysed. Information on established or potential risk factors for HCV transmission was obtained by means of a questionnaire. RESULTS: More than half of the entire population of the examined region (19,800 subjects, 60%) had a record for an anti-HCV blood testing. Out of these 19,800 subjects, 2,213 were found to be seropositive, with a resulting overall anti-HCV prevalence higher than that reported for the whole country (11.1% vs 3%). Genotype 1b was the most commonly detected (86%). Anti-HCV prevalence was significantly higher in the 50-59 and 60-69 year age groups than in other age groups. The results of multiple regression analysis showed that blood transfusion, use of glass syringes, surgical interventions, promiscuous use of tooth-brush, promiscuous use of sharp-edged instruments and lowest number of years of schooling were all independent predictors of anti-HCV positive. No association was found with family history of liver disease and alcohol consumption. A total 46.6% of the subjects had chronic hepatitis, 24.4% had cirrhosis, 1.8% had hepatocellular carcinoma and cirrhosis and 27.2% were "asymptomatic" (with normal serum ALT levels and no histological features of chronic hepatitis despite HCV viremia). CONCLUSION: The most striking result of the study was that the high levels of HCV endemicity was not frequently associated with apparent evidence of parenteral exposure, suggesting that HCV spread in the community can even occur mostly through inapparent parenteral routes.

Primary sclerosing cholangitis.

To discuss exhaustively: clinical, serological and pathologic aspects of primary sclerosing cholangitis (PSC); recent advantages in the knowledge of the disease's pathogenesis, therapeutic approaches that still appear today less preferable than liver transplantation. We have reviewed the most important researches on PSC of recent years. PSC is characterized by chronic inflammation of the main bile ducts, except for the gallbladder. HLA-B8 and HLA-DR3 haplotypes have been associated with PSC. It is probable that PSC is an organ-specific disease. Some studies have shown the presence of antibodies against the cytoplasm of neutrophils (ANCA) in the serum of more than 50% of patients, and the presence of anticatalase antibodies in 60% of patients. ANCAs induce leukocyte metabolic activation, that forms H2O2 and the anion superoxide O-2, which in turn impair components of both cell and cellular matrix. Catalase is mainly found in the liver; it is active in the "antioxidative defense system" against toxic O2 metabolites. Anticatalase antibodies are directed against an essential region of catalases, by inhibiting their enzymatic functions. In these conditions, a state of oxidative stress is determined by imbalanced ratio of oxidative to antioxidative factors, due to effective production of radical species as well as to simultaneous failure of antiradical defenses. Radical stress results in irreversible impairment of tissues. In PSC, primary lesions seem to be secondary to the production of radicals by ANCAs, deposited immunocomplex, complementary proteins and bacterial toxins. The subsequent lysis of bile epithelial cells seems to release catalases, that are thought to act as "nonself" once recognized by the immunocompetent system. Since the neoantigen catalase seems to be highly expressed in PSC patients, it may easily associate itself with MHC molecules for presentation to the immune system. Thus, in turn, B lymphocytes would be forced to produce anticatalase antibodies. Since anticatalase antibodies inhibit catalases, it can be hypothesized that they play a role in the pathogenesis of PSC. From a therapeutic viewpoint, the only effective cure is transplantation.

[Alcoholic hepatopathy]. / Epatopatia alcolica.

OBJECTIVES: To extensively discuss clinical features, laboratory data and pathology findings associated with alcoholic hepatitis as well as the new insights into pathogenesis and the appropriate therapy. DESIGN: Review of current literature. RESULTS: Acetaldehyde gives rise to neoantigens by complexing with various proteins, which, in turn, favors the appearance of autoantibodies. Antibodies against the hepatic lipoprotein and a number of hepatocyte surface glycoproteins have been detected in alcoholic hepatitis. Experimental studies have shown that acetaldehyde and malonyldialdehyde form highly immunogenic aggregates (MAA adducts). Antibody titers are usually higher in patients with more advanced disease, which argues for a major etiologic role. HLA antigens such as B8, DR3, DR4, which are usually associated with autoimmune diseases, are more frequently observed in alcoholic hepatitis patients. CONCLUSIONS: Despite the above, it is still questionable whether alcoholic hepatitis pathogenesis is autoimmune in origin. Why do only 15-20% of subjects who have long been abused alcohol develop hepatitis? What are the predisposing factors? What events trigger the immunologic reactivity? If MAA adducts play a role, why are not all the alcohol abusers affected by hepatitis? Transplantation outcome in well selected patients with alcoholic hepatitis is as good as--or even better than--the one reported for patients with different types of hepatitis.

Retrospective study of a large population of patients affected with mitochondrial disorders: clinical, morphological and molecular genetic evaluation.

Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80% of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defects. Abnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow "protected" against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling.

Primary beta-sarcoglycanopathy manifesting as recurrent exercise-induced myoglobinuria.

We report an unusual presentation of a primary beta-sarcoglycanopathy (LGMD type 2E). A 12- year-old boy came to our attention after six episodes of exercise-induced myoglobinuria. Electromyogram showed mild myopathic features of the proximal lower limb muscles. Electrocardiogram was normal. Neurological examination revealed normal muscle strength and reduced deep tendon reflexes. A muscle biopsy showed rare regenerating fibers; the immunohistochemistry was normal for dystrophin, while all the sarcoglycans were diffusely decreased. Western blot analysis showed a relevant decrease of all sarcoglycan proteins and a mild dystrophin reduction. beta-Sarcoglycan gene analysis demonstrated a compound heterozygous status for these mutations: a novel A-T base pair substitution at nucleotide 85 in exon 2, changing the codon Arg to a stop codon; a C-T base pair substitution at nucleotide 272 in exon 3 changing a Arg to a Cys residue. We consider that exercise-induced myoglobinuria may be the presenting sign of primary beta-sarcoglycanopathy.

Severe polyneuropathy in a patient with Churg-Strauss syndrome.

We describe the clinicopathologic features of a 56-year-old woman affected with Churg-Strauss syndrome with major peripheral nerve involvement. The patient presented with a 1-month history of mainly distal upper-limb symmetrical paresthesias and hypostenia (bilateral "wrist drop"), palpable purpura and eosinophilia. Multiple pulmonary infiltrates and asthma had been present since the age of 52. Skin biopsy demonstrated an eosinophilic necrotizing vasculitis. During the hospitalization she was submitted to cardiac, bronchopulmonary, renal, and gastrointestinal evaluation and EMG. Peripheral nerve and skeletal muscle biopsies were performed. Sural nerve biopsy showed a marked degree of demyelination. A perivascular cellular infiltrate within the epineurium was immunoreactive for T lymphocytes and macrophages. Strong HLA-DR immunostaining was present in the endoneurium. IgM, IgE and fibrinogen deposition was found in some epi- and endoneurial vessels. Muscle biopsy showed neurogenic changes and 1 thrombosed vessel surrounded by mononuclear cells. Membrane attack complex (MAC) deposition was present in a few capillaries and major histocompatibility complex products I (MHCP I) was expressed at the subsarcolemmal level in a few isolated perivascular muscle fibers. After immunosuppressive therapy, the patient showed progressive improvement of both clinical symptoms and neurophysiological parameters.

Sarcoglycan deficiency in a large Italian population of myopathic patients.

Autosomal recessive limb-girdle muscular dystrophies are a heterogeneous group of genetic diseases with a wide spectrum of clinical severity and age of onset; mutations in the gene encoding the dystrophin-associated sarcoglycan proteins (alpha, beta, gamma and delta) have recently been shown to cause some cases of these myopathies (primary sarcoglycanopathies, types 2D, 2E, 2C and 2F, respectively). In this study we have examined a large population of Italian myopathic patients to determine the frequency of (alpha-, beta- and gamma-sarcoglycan deficiency and to correlate molecular defects with clinical phenotypes; to exclude the presence of primary dystrophinopathies both genetic and immunological analysis of dystrophin was performed. We report 12 patients (10 male and 2 female) with deficiency of either one or more sarcoglycan proteins. They were aged 8-56 years with onset between 4 and 30 years of age; they all presented with either mild, moderate or severe limb-girdle involvement associated with elevated blood creatine kinase levels and myopathic pattern at EMG; one was also affected with a mild dilation cardiomyopathy. All patients, except one, showed pathological muscle histological changes. Absence of all three proteins always correlates with severe forms, whereas mild protein deficiencies or isolated partial alpha-sarcoglycan deficiency correlate with either severe, moderate or mild forms.

[Hepatitis C and systemic diseases]. / Epatite C e malattie sistemiche.

In 1989 HCV was demonstrated to be the leading cause of non-A, non-B hepatitis. Not only HCV is able to determine chronic hepatitis in most patients, often leading to hepatocellular carcinoma, but it has also been shown to be strictly associated with a number of immunologically-mediated diseases. This review focuses on the reported associations between HCV and other diseases and the role that HCV might play in their pathogenesis.

Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication.

Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without delta 9 tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals.

Brain glucose metabolism in violent psychiatric patients: a preliminary study.

Positron emission tomography with 18F-deoxyglucose was used to evaluate regional brain glucose metabolism in eight normal subjects and eight psychiatric patients with a history of repetitive violent behavior. Seven of the patients showed widespread areas of low brain metabolism. Although the location of the abnormal regions varied among patients, they showed significantly lower relative metabolic values in medial temporal and prefrontal cortices than did normal comparison subjects. These regions have been implicated as substrates for aggression and impulsivity, and their dysfunction may have contributed to the patients' violent behavior.

The admissibility of scientific evidence in psychiatric malpractice: junk science and the Daubert case.

The defence in malpractice cases has traditionally relied upon a commonly accepted body of knowledge. According to the American 'Frye rule', this knowledge could either have been accepted generally or by a 'respectable minority' of physicians. The US Supreme Court, however, has recently ruled in the Daubert case that conclusions not subject to peer review are acceptable in malpractice cases. The authors analyse the implications of the Daubert decision using the case-study method. Two alternative-scenarios of a hypothetical case are analysed. The potential effect of Daubert places the US psychiatrist-defendant in an untenable position. Either use or non-use of non-peer-reviewed studies in clinical practice could produce a finding of negligence. Furthermore, the responsibility to assess scientific acceptability in US courts has shifted from expert witnesses to judges who are usually without scientific training.

Current and future applications of SPECT in clinical psychiatry.

Over the past 10 years several studies have been conducted in psychiatric and neurologic patients with single photon emission computed tomography (SPECT) to determine if patterns of brain dysfunction exist that characterize the different mental diseases. Although there has not been any finding that can be referred to as specific for a particular disease, SPECT studies have been able to demonstrate evidence of brain dysfunction in patients who, when tested with other means, showed no evidence of brain abnormalities. In this manuscript, the current and future applications of SPECT in the clinical practice of psychiatry are analyzed.

Advancing the epidemiology of injury and methods of quality control: ACEs as an outcomes-based system for quality improvement.

Accelerated-compensation events (ACEs) are classes of avoidable medical injuries. Originally, these classes were used in tort reform to speed payment for avoidable injuries. However, ACEs also have potential as tools to monitor and improve the quality of health care. ACEs are developed by physicians, based on medical decision making. Rather than simply identify an adverse outcome, they link that outcome to clinical processes. Therefore, ACEs can help identify the critical elements of care that would result in desirable outcomes. Also, ACEs are discerning: they identify only events of which the vast majority are preventable. In one project, ACEs have been developed for obstetrics/gynecology, general surgery, and orthopedic surgery, using a three-phase process of sifting data and honing definitions. Future plans include improving these ACEs, statistically evaluating them, and testing them for utility in quality monitoring and improvement.

Creating outcomes-based systems for quality and malpractice reform: methodology of accelerated compensation events (ACEs).

Today's unduly erratic and expensive payment system for medical malpractice undercuts its own goal of compensating victims. Its lack of scientific legitimacy hampers its other main goal of deterring injury. Reform is needed, but most "tort reform" fails to make fundamental changes and does not promote quality of care. Alternative systems using "Accelerated Compensation Events" (ACEs) offer a better way to replace or improve judicial resolution of liability claims as well as independent, quality-oriented reform. ACEs do not cover all injuries, just classes of adverse outcomes that are normally avoidable, given good care. This article explains the scientific methodology of ACE development and the benefits of ACE-based reforms.