Search

The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelial-derived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

Hirsutism has negative impact on adolescent psychosocial development for both cosmetic and endocrine reasons. This study evaluated the effectiveness of a new intermittent, low-dose finasteride regimen consisting of 2.5 mg of drug given every 3 days (1 day of treatment, 2 days of drug withdrawal) for 6 months in girls with hirsutism by polycystic ovarian syndrome (PCOS) or idiopathic hirsutism (IH).Twenty-eight girls (15-19 y old) with hirsutism were randomly assigned to 2 treatment groups and treated for 6 months. Fourteen patients (7 with IH, 7 with PCOS) received finasteride; fourteen patients (7 with IH, 7 with PCOS) received placebo. Hirsutism score (HS), clinical, and hormonal effects were compared between the 2 groups.In patients treated with finasteride, the HS value at 6 months was 52.9% lower than that observed at baseline in girls with IH, and 52.8% lower in girls with PCOS (P.0001 for both). Similarly, the 3α-17 β-androstenediol glucuronide serum levels were decreased by 34.8% in patients with IH, and by 47.5% in patients with PCOS (P.0001, respectively). Finasteride treatment was well tolerated and did not alter values of BMI, serum levels of sexual hormones, metabolic parameters related to liver and kidney function as well as glycemic and lipidic asset.A low-dose of finasteride, given every 3 days, reduces the HS in young patients affected by PCOS or IH. Compared with conventional continuous finasteride administration, the intermittent low-dose regimen has similar efficacy with the advantage to be safer and less expensive.

New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost-effectiveness analysis of boceprevir (BOC)- and telaprevir (TVR)-based triple therapy according to different patients’ selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1–F4 fibrosis, (ii) only F2–F4 and (iii) only F3–F4. For each strategy, TVR interleukin-28B-guided (IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio (ICER) for F1–F4 strategy relative to F3–F4 was €5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and €7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1–F4 strategy relative to F3–F4 was €1 818 679 (TVR IL28B-guided) and €1 866 437 (BOC RVR-guided) per end-stage liver disease or death (ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization.

This case report describes a preterm newborn infant who was treated with a single dose of rasburicase for an increase in uric acid level. He died on the third day as a result of complications of hemolysis, which appeared to be precipitated by rasburicase. The patient’s death was preceded by progressive respiratory insufficiency, lactic acidosis, and hyperbilirubinemia, culminating in refractory hypoxia and hypotension. A postmortem assay for glucose-6-phosphate dehydrogenase showed deficiency and the glucose-6-phosphate dehydrogenase Mediterranean genotype.

Resveratrol (3,5,4′-trihydroxystilbene) is a natural occurring molecule, synthesized by plants in response to different stresses. Recent literature data seem to converge in indicating Resveratrol as an agent possessing protective effects against oxidative stresses through different mechanisms. Furthermore conflicting data are present in relation to its activity of free radical scavenger. Here we studied the antioxidant activity actually exerted by the agent against reactive oxygen species induced by H 2 O 2 treatments in CHO cells. Our attention has been focused on two major potential mechanisms: scavenging activity and interference with oxidative metabolism, by the analysis of three important targets: intracellular oxidation (Dichlorofluorescein Test), primary DNA damage (Comet Assay) and fixed DNA damage (chromosomal aberrations). Cells were treated with a single H 2 O 2 dose (2×10 −4 M) in order to induce Reactive Oxygen Species and than challenged with Resveratrol to test its ability in modulating damage. Two experimental protocols have been applied: (i) simultaneous treatment and (ii) a 3 h Resveratrol pre-treatment. In our experimental conditions Resveratrol does not appear able, ‘per se’, to induce primary DNA damage whereas a slight increase in endogenous oxidation and chromosomal aberrations at the highest dose have to be noticed. In combined treatments the molecule appears to differently affect primary and fixed DNA damage.

Background and aims: To allocate treatment resources for chronic hepatitis C (CHC) genotype 1 naive patients, we performed a cost-effectiveness analysis of Boceprevir (BOC) and Telaprevir (TVR) based triple therapy according to different patient selection strategies. Methods: A semi-Markov model of CHC natural history and progression toward end stage liver diseases (decompensated cirrhosis, HCC and liver transplantation) was built. Model health states were defined by METAVIR fibrosis stages (F0–F4), and complications of cirrhosis. We considered 3 selection strategies based on fibrosis stage: (1) treat all patients with F1–F4 fibrosis, (2) only F2–F4 and (3) only F3–F4. For each strategy, TVR IL28B-guided and BOC RVRguided therapy was applied. The model assessed the costs and outcomes, including QALYs, Life Years and the number of End Stage Liver Diseases developed or Death (ESLD-D), using lifetime as time horizon and adopting the NHS perspective. An alternative simulation was performed using 5 year as time horizon, as coherent with upcoming main changes in standard of care (all-oral protocols). Results: The F3–F4 selection strategy proved the least expensive and the least effective. Adopting the lifetime horizon, F1–F4 strategy was cost-effective with an ICER of D 5132.13 for QALY, in TVR IL28B-guided, and D 7042.49 for QALY, in BOC RVR-guided therapy. In the 5 year scenario, only F3–F4 strategy showed costeffectiveness, while the F1–F4 strategy was not cost-effective, with an ICER of D 1,818,679 (TVR IL28B guided) and D 1866.437 (BOC RVR-guided) for each ESLD-D avoided. Conclusions: The present simulation study demonstrated that treating all CHC patients regardless of fibrosis stage is cost-effective in a lifetime horizon scenario. In a more realistic 5-year time horizon scenario, to treat patients with advanced fibrosis and cirrhosis was the only strategy to show cost-effectiveness.

Earlier neuroimaging studies of motor function in schizophrenia have demonstrated reduced functional lateralization in the motor network during motor tasks. Here, we used event-related functional magnetic resonance imaging during a visually guided motor task in 18 clinically unaffected siblings of patients with schizophrenia and 24 matched controls to investigate if abnormal functional lateralization is related to genetic risk for this brain disorder. Whereas activity associated with motor task performance was mainly contralateral with only a marginal ipsilateral component in healthy participants, unaffected siblings had strong bilateral activity with significantly greater response in ipsilateral and contralateral premotor areas as well as in contralateral subcortical motor regions relative to controls. Reduced lateralization in siblings was also identified with a measure of laterality quotient. These findings suggest that abnormal functional lateralization of motor circuitry is related to genetic risk of schizophrenia.

A seguito della sentenza Laval della Corte di Giustizia del dicembre 2007, i sindacati svedesi, responsabili di un'azione collettiva tesa ad ostacolare pratiche di social dumping adoperate da un prestatore di servizi straniero, sono stati condannati al risarcimento dei punitive damages. Tale vicenda ha dato avvio ad un processo di revisione della normativa svedese, culminato con l'adozione della legge cd. Laval che ha posto rilevanti limiti all'autonomia collettiva e al conflitto, vietando altresě le azioni collettive nei confronti di imprese estere vincolate da un contratto collettivo stipulato nel proprio Paese d'origine con le organizzazioni sindacali locali.

Background Thiazolidinediones (TZDs) including rosiglitazone (ROSI) are insulin sensitizing agents with beneficial gastrointestinal effects. However, no studies are available on TZDs effect in gastrointestinal motility. We evaluated the effects of ROSI on gastrointestinal inhibitory neurotransmission focusing on the modulatory roles of nitric oxide synthase/nitric oxide (NOS/NO) and heme oxygenase/carbon monoxide (HO/CO) pathways. Methods Spontaneously hypertensive rats (SHR) were used as model of insulin resistance. Duodenal strips were obtained from vehicle-treated SHR, ROSI-treated SHR (5 mg kg−1 by gavage daily per 6 weeks), and Wistar Kyoto (WKY). Inhibitory responses to electrical field stimulation (EFS) were evaluated in the presence of HO inhibitor zinc protoporphyrin IX (ZnPPIX, 10 μmol L−1) or NOS inhibitor NG-nitro-l-arginine (L-NNA, 100 μmol L−1), alone and in combination. Protein levels of HO and NOS isoforms were evaluated by immunohistochemistry and western blot analysis. Key Results Basal responses to EFS were significantly increased in duodenum strips from vehicle-treated SHR vs WKY. This effect was reversed in ROSI-treated SHR. The EFS-mediated relaxation was comparably reduced by ZnPPIX in WKY and SHR, but not in ROSI-treated SHR animals. The L-NNA reduced EFS response to a similar extent in WKY and ROSI -treated SHR, but its effect was significantly higher in vehicle-treated SHR. Expression of HO-1 protein was significantly lower, whereas HO-2 protein levels were unchanged in ROSI-treated SHR with respect to vehicle-treated SHR. Finally, increased levels of nNOS in vehicle-treated SHR were reduced in ROSI-treated SHR. Conclusions & Inferences Chronic ROSI treatment reverses increased SHR duodenal inhibitory response acting on CO and NO components.

The clinical presentation of Bordetella pertussis can overlap with that of respiratory syncytial virus (RSV), and coinfection does occur, but management differs.The prevalence of B. pertussis is2% among Emergency Department (ED) patients with bronchiolitis. Our secondary hypothesis was that the prevalence of Bordetella parapertussis is also2% among these patients.Nasal washings were obtained from children up to 18 months of age (inclusive) who presented to a county hospital ED with a clinical diagnosis of bronchiolitis. These washings were frozen to -70°C before testing for B. pertussis and B. parapertussis using species-specific real-time polymerase chain reaction (PCR) assays. The assays were optimized to target conserved regions within a complement gene and the CarB gene, respectively. A Bordetella spp. genus-specific real-time PCR assay was designed to detect the Bhur gene of B. pertussis, B. parapertussis, and B. bronchiseptica. RSV antigen detection was also performed.There were 227 patients enrolled. After exclusions, 204 remained in the analysis. RSV antigen testing was positive in 109/186 (59%) of the patients in whom it was performed. All samples were tested for B. pertussis. B. parapertussis testing could not be completed on 23 samples. No cases (0/204; 95% confidence interval [CI] 0-1.8%) tested positive for B. pertussis or B. parapertussis (0/181; 95% CI 0-2%).The prevalence of B. pertussis in children presenting to the ED with bronchiolitis was2%.

Punica granatum L. (Punicaceae) whole fruit extracts, have been used in Cuban traditional medicine as an effective drug for the treatment of respiratory diseases. This species showed interesting anti-viral activity, e.g. aqueous or hydroalcoholic extracts of whole fruits have proved highly active against the influenza virus. However, some toxic properties of this extract have also been reported and, to date, very little is known about its genotoxic properties. In the present study, the genotoxicity of a Punica granatum (pomegranate) whole fruit extract was assessed using different in vitro and in vivo assays that detect DNA damage at different expression levels. Results from reversion and gene-conversion test in microorganisms, sister chromatid exchanges, micronuclei and sperm-shape abnormality assays in mice, clearly showed that the hydroalcoholic extract of P. granatum whole fruits is genotoxic when tested both in vitro and in vivo.

Background Vitamin D (Vit D) is important for the regulation of reproductive physiology. In humans, maternal Vit D deficiency has been implicated in several reproductive- and pregnancy-related disorders. Very few data are available regarding the Vit D status in male partners of couples attempting pregnancy. This observational study (IRB Prot. N. 078/13) aimed to evaluate whether low Vit D serum levels in males might decrease the rate of successful conception in couples attempting pregnancy. Methods Male and female partners of infertile couples (n = 102) were classified into 2 GROUPS according to normal (≥30 ng/ml) or low (below 30 ng/ml) serum Vit D levels in male partners. Semen analysis was performed in each male participant based on the WHO reference criteria. The female partners of both groups were subjected to 3 consecutive cycles of gonadotropin-induced mono-ovulation. The main outcome measures included the clinical pregnancy rate, delivery per patient and per cycle, and miscarriage rate between the 2 groups evaluated at the end of the three-month period of the study. Results In male partners of both groups, standard semen analysis did not highlight substantial differences in sperm concentration, sperm progressive motility, or typical form. The pregnancy rates per patient and per cycle and delivery rates per patient and per cycle were all significantly higher (p

Premenstrual syndrome (PMS) might become severe enough to interfere with normal interpersonal relationships. This study was planned to assess whether administration of vitamin D (200,000 IU at first, followed by 25,000 IU every 2 weeks) for a 4-month period might lessen the appearance and the intensity of mood disorders associated with PMS in young girls with severe hypovitaminosis D. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: One hundred fifty-eight young girls (15-21 years old) with PMS-related severe symptoms of the emotional and cognitive domains and low serum 25-hydroxycholecalciferol (25-OH-D) levels (≤10 ng/mL) were randomly assigned to two treatment groups and treated for 4 months with vitamin D (group 1; n = 80) or placebo (group 2; n = 78). Clinical and hormonal effects were compared between the two groups.In patients from group 1, levels of vitamin D reached the normal range (35-60 ng/mL) after the first month and remained stable throughout the whole study. At the end of treatment, anxiety score decreased from 51 to 20 (P .001 vs baseline); irritability score declined from 130 to 70 (P .001 vs baseline). Crying easily and sadness decreased by a score of 41 and 51 to a score of 30 and 31, respectively (P .001). For disturbed relationships, the score decreased from 150 to 70 (P .001). Conversely, no appreciable changes were noted in symptom intensity from patients of group 2. The frequency of adverse events (nausea and constipation) was not different between participants of group 1 and group 2.On the basis of the present findings, vitamin D therapy can be proposed as a safe, effective, and convenient method for improving the quality of life in young women with severe hypovitaminosis D and concomitant mood disorders associated with PMS.

Background Indomethacin-induced enteritis is a model of inflammatory bowel disease. Materials and methods To further characterize this model, rats received two injections of indomethacin (7·5 mg kg−1) 24 h apart and histological damage of intestinal mucosa, oxidative stress, alterations of intestinal motility and mesenteric vascular bed (MVB) reactivity were investigated after 5 days. Results The results show that indomethacin caused several histological and functional changes at the ileal level. In particular, response to carbachol as well as the nonadrenergic-noncholinergic inhibitory response to electrical field stimulation (EFS) was lower in the treated than control rats. Moreover, nitric oxide (NO)-component of the inhibitory response was higher in the treated than control rats. Mesenteric vessels preparations from the treated rats showed increased noradrenaline (NA)-induced perfusion pressure, whereas relaxant responses to acetylcholine, although not significantly reduced in the treated rats, had a higher nitrergic component. This finding suggests that vascular dysfunction may contribute to chronic inflammation. Indomethacin injection also determined acute and severe oxidative stress in ileum mucosa. Conclusions In conclusion, our study contributes to further characterize the rat model of indomethacin-induced enteritis and suggests that it is suitable for drug screening in rats, as this model can be obtained in a very short period and is simple and reproducible.

Summary 1 Prolonged bed rest or exposure to microgravity may cause several alterations in autonomic nervous system response (ANSR). 2 Hindlimb unloading (HU) rats were used as an animal model of simulated microgravity to investigate ANSR changes. The experiments were carried out to investigate the effects of simulated microgravity on the autonomic nervous response of the perfused mesenteric vascular bed (MVB), vas deferens and the colon and duodenum from 2-week HU rats. 3 In MVB preparations of HU rats, the frequency-dependent increases in perfusion pressure with perivascular nerve stimulation (PNS; 8–40 Hz) were inhibited, whereas the noradrenaline (NA) concentration-dependent (1–100 μm) perfusion pressure increases were potentiated. The latter most probably reflected up-regulation of α-adrenergic receptor function. Relaxant responses of NA-precontracted MVB to PNS (4–30 Hz) or isoprenaline were not different between control and HU preparations, while vasodilation induced by the endothelial agonist ACh was reduced. 4 Transmural stimulation (2–40 Hz) induced frequency-dependent twitches of the vas deferens which were reduced in vas deferens of HU rats, while the sensitivity to NA-induced contraction was significantly increased. 5 In the gastroenteric system of HU rat, direct contractile responses to carbachol or tachykinin as well as relaxant or contractile responses to nervous stimulation appeared unchanged both in the proximal colon rings and in duodenal longitudinal strips. 6 In conclusion, HU treatment affects peripheral tissues in which the main contractile mediators are the adrenergic ones such as resistance vessels and vas deferens, probably by reducing the release of neuromediator. This study validates NA signalling impairment as a widespread process in microgravity, which may most dramatically result in the clinical phenotype of orthostatic intolerance.

Background In rodents, interleukins administration induces intestinal changes similar to those found in inflammatory bowel disease. We investigated the effects of in vivo subchronic treatment with IL-1 beta and IL-6 on rat colonic mucosa and circular smooth muscle. Materials and method We evaluated transmucosal electrical parameters (Ussing chambers) and early changes of in vitro direct contractility induced by carbachol and tachykinins. Alterations in excitatory and inhibitory neurotransmission were studied with electrical field stimulation (EFS). Results Treatment with interleukins induces inflammation proved by fever, early signs of colonic histological damage and changes in mucosal ion transport. Concentration response-curve to carbachol was significantly lower in treated rats (P

Background: Hypertension is a recognized risk factor for cardiovascular diseases (eg, myocardial infarction, stroke, arrhythmias, coronary events, heart failure) and for progression of renal disease. In 1995, a new class of antihypertensive drugs—angiotensin II (AII)-receptor blockers (ARBs)—became available for treatment. Objectives: In this retrospective study, we aimed to (1) determine the frequency of prescriptions for ARBs compared with those for all other antihypertensive drugs and (2) examine the indications for, and profile of, the use of ARBs in antihypertensive pharmacotherapy over a 2-year period (July 1997–June 1999). Methods: Medical records of patients who were being treated for the first time at the Division of Hypertension, University of Bari Medical School (Bari, Italy) were included. The investigators analyzed the medical records of patients with grade 1, 2, or 3 essential hypertension, as well as those with a history of essential hypertension whose blood pressure had been normalized by treatment before this first visit and who were already receiving antihypertensive drugs or who were being prescribed antihypertensive drugs for the first time at this visit. Results: The medical records of 880 patients (466 women, 414 men; mean [SD] ages, 55.0 [10.8] and 53.6 [11.3] years, respectively) were included in the study. ARBs accounted for 6% of all antihypertensive prescriptions. No correlation was found between receiving a prescription for an ARB and sex, age group, heart rate, or body mass index. ARB monotherapy was inversely correlated ( P P P Conclusions: The results of this study indicate that although ARBs were prescribed infrequently and cautiously, their prescription rate increased over time, suggesting that this medication is gaining acceptance as treatment for hypertension.

Nowadays, one of the main goals of the building industry and architecture is to exploit the solar source for the air‐conditioning of buildings. Over the last years many activities have started to develop new building and plant technologies oriented to energy saving by improving indoor comfort and reducing pollution emission. The guidelines deriving from various world conferences (Kyoto 1997, Buenos Aires 1998) are known. Industrial countries have committed themselves to try and carry out new strategies to reduce both energy consumption and air‐pollution. These aims have increased research works oriented to find materials, components and systems able to use energy gains from the environment, in particular from the sun. During the study carried out at ITC on the subject, two envelope technologies have been studied and realised. The paper describes such technologies and the methods used for their characterisation. It also reports on the most meaningful results obtained from the experiments carried out.

1 The present study aimed to evaluate the role of kappa-opioid receptors at two peripheral sites, the vas deferens and the proximal colon, in kappa-opioid receptor knockout mice. We investigated the role of the kappa-opioid receptor in the vas deferens twitch response and in the colonic "off-contraction", a rebound contractile response which follows the inhibitory response to low frequencies stimulation (10, 20, 30 Hz) and which has been suggested to "locally" reproduce the contractile component of the peristaltic reflex. 2 Transmural stimulation of the vas deferens at lower frequencies (10 Hz, 10 V, 1 ms pulse trains lasting 0.5 s) evoked a contractile response that was significantly higher in the preparations from knockout mice because of lack of kappa-opioid receptors than in wild type mice. A selective kappa-opioid receptor agonist, U-50,488H, induced a dose-dependent inhibition of the electrically stimulated contraction in vas deferens. The percentages of reduction of the twitch response were significantly lower in knockout mice than in wild type mice after treatment with U-50,488H. The reduction of twitch response caused by U-50,488H was not reversed by administration of nor-binaltorphimine (nor-BNI) (5 x 10-6 m), a selective kappa-opioid receptor antagonist, in preparations from both knockout mice and wild type mice. U-50,488H has no effect on postsynaptic adrenergic receptors, as its administration did not affect the direct contractile response to noradrenaline. 3 Transmural stimulation (5 Hz, 20 V, 2 ms pulse trains lasting 30 s) induced inhibition of spontaneous activity of colonic strips during the period of stimulation, followed by an "off-contraction" after the cessation of stimulation. The statistical evaluation of the "off-contraction" responses between the two strains showed no significant difference. The off-contraction, measured in specimens from knockout mice, was inhibited concentration-dependently by U-50,488H (P < 0.01) and significantly less than from wild type mice. 4 The effect of U-50,488H was not reversed by administration of nor-BNI (5 x 10-6 m), either in preparations from knockout mice or from wild type mice. 5 Our data may suggest that kappa-opioid receptors are involved in some peripheral responses to the nerve stimulation, as indicated by the effect of U-50,488H, a selective kappa-opioid receptor agonist. However, the involvement of kappa-opioid receptor was also present, although less apparent, in kappa -opioid receptor knockout mice, suggesting either that this drug acts not only on kappa-opioid receptors but also on other receptor sites, such as kappa-like receptors. An alternative interpretation can be related to a sodium channel blocking action of U-50,488H, which could explain the inhibitory effects of twitch response still present but less evident in knockout strain and the lack of effect of the antagonist nor-BNI.

The aim of the paper was to perform a chronological assessment of the phenomenon of delayed rupture of the spleen, to assess the phenomenological order about the sub-capsular hematoma transformation to determine the causal relationship with trauma as hypothetical cause of death. 80 cases of blunt trauma with splenic capsular hematoma and subsequent rupture of the spleen were evaluated: 38 had an acute rupture of the spleen, 42 presented a break in days or weeks after the traumatic injury. Time between the traumatic event and delayed rupture of the spleen is within a range of time from one day to more than one month. Data recorded included age, sex, type of trauma, injury severity score, grade of splenic injury, associated intra-abdominal injuries, pathologic specimen evaluation. Immunohistochemical investigation of perisplenic hematoma or laceration was performed utilizing polyclonal antibodies anti-fibrinogen, CD61 and CD68, and showed structural chronological differences of sub-capsular hematoma. Expression of modification and organization of erythrocytes, fibrinogen, platelets and macrophages provides an informative picture of the progression of reparative phenomena associated with sub-capsular hematoma and subsequent delayed splenic rupture. Sub-capsular splenic hematoma dating, which we divided into 4 phases, is representing a task in both clinical practice and forensic pathology.

BackgroundDespite depressive disorders being very common there has been little research to guide primary care physicians on the choice of treatment for patients with mild to moderate depression.AimsTo evaluate the efficacy of interpersonal counselling compared with selective serotonin reuptake inhibitors (SSRIs), in primary care attenders with major depression and to identify moderators of treatment outcome.MethodA randomised controlled trial in nine centres (DEPICS, Australian New Zealand Clinical Trials Registry number: ACTRN12608000479303). The primary outcome was remission of the depressive episode (defined as a Hamilton Rating Scale for Depression score 7 at 2 months). Daily functioning was assessed using the Work and Social Adjustment Scale. Logistic regression models were used to identify moderators of treatment outcome.ResultsThe percentage of patients who achieved remission at 2 months was significantly higher in the interpersonal counselling group compared with the SSRI group (58.7% v. 45.1%, P = 0.021). Five moderators of treatment outcome were found: depression severity, functional impairment, anxiety comorbidity, previous depressive episodes and smoking habit.ConclusionsWe identified some patient characteristics predicting a differential outcome with pharmacological and psychological interventions. Should our results be confirmed in future studies, these characteristics will help clinicians to define criteria for first-line treatment of depression targeted to patients' characteristics.

Background Tachykinins (TKs) have been shown to be involved in the excitatory enteric motor pathway. This study aimed to examine the direct and nerve-mediated effect of specific NK 1 , NK 2 and NK 3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC). Materials and methods Cumulative concentrations of Sar 9 Met(O 2 ) 11 substance P (selective NK 1 receptor agonist), [Ala 5 ,b-Ala 8 ]-neurokinin A (4-10) (selective NK 2 receptor agonist) and [MePhe 7 ]-neurokinin B (selective NK 3 receptor agonist) were tested on colonic circular muscle strips to evaluate the direct drug effects. In addition, in the presence of atropine, the role of TKs in the off-contraction that follows the typical inhibitory response evoked by low frequencies of electrical field stimulation (0.5-10 Hz, 20 V, 1 ms pulse trains lasting 1 min) was investigated. Results In control preparations, the rank order of potency was: NK 2 receptor-selective agonist > NK 3 receptor-selective agonist > NK 1 receptor-selective agonist. The off-contraction was found to be reduced by about 30-40% in colonic circular muscle from ICC patients with respect to controls. Incubation with the NK 1 receptor agonist did not modify the off-contraction measurements in either control or ICC preparations. Conversely, both NK 2 and NK 3 receptor agonists significantly (P < 0.01) increased the off-contraction in ICC preparations only. This increased response was fully antagonized by MEN-10627, a NK 2 and NK 3 receptor antagonist depending on the dose. Conclusions We may conclude that ICC is hyporesponsive to TKs and that the contractile reflex to distension is greatly reduced in ICC disease, but can be restored by incubation with NK 2 and NK 3 receptor agonists.

Aims/hypothesis. This study aimed to determine if the incidence of Type I (insulin-dependent) diabetes mellitus increased over time and if the time trend is attributable to linear trend, calendar period or birth cohort effects.¶Methods. This study was based on a cohort of subjects aged 0–29 years from 1984 to 1996, who resided in the province of Turin, Italy. Poisson regression models were used to estimate the effect of sex, age, calendar time and cohorts on incidence rates.¶Results. The mean incidence rate in the age group of 0 to 29 years was 7.78 of 100,000 person-years (95 % confidence interval: 7.26–8.32), with a lower risk in women than in men [rate ratio (RR): 0.76 (0.67–0.88)]. We found a trend of incidence increasing over time (annual increase of risk 2.25 % a year, 95 % CI 0.44–4.10). In Poisson regression analysis we found that the best model was the one with sex, age and a linear term attributable to either calendar period or cohort effects. The linear term corresponds to a RR of 1.12 (1.02–1.22, p = 0.015) for each 5-year age span.¶Conclusion/interpretation. We found that the time trend in this Mediterranean area was similar in magnitude to that reported in northern European countries. The increase was linear in pattern, each birth cohort and each calendar period showing a higher risk than the preceeding one with some evidence of two steep increases in the incidence of Type I diabetes centered on the years 1964 and 1984. We found that the incidence of diabetes increased in the 0 to 14 age group and also in the older age group of 15 to 29 years and that the age-period models were not statistically significantly better than the age-cohort models. [Diabetologia (2001) 44: 22–25]

Background Children of Sardinian heritage are at high risk of type 1 diabetes, whereas no data are available in young adults. Age at onset of type 1 diabetes could be associated with different relative weight of genetic susceptibility and environmental determinants in the pathogenesis of the disease. We test this hypothesis in subjects with Sardinian heritage 0‐29 years of age living in the city of Turin, a highly industrialized area in Northern Italy. Methods In all, 202 cases with onset of type 1 diabetes aged 0‐29 years during 1984‐1991 and 1010 controls randomly selected from residents of the city of Turin, frequency-matched by sex and year of birth to cases, were included in this study. Name and place of birth of parents were ascertained by postal inquiry and linkage with city population and census files. Social class was based on the highest educational level of parents abstracted from 1991 and 1981 census files. Results Differential effects on risk of type 1 diabetes of Sardinian heritage and social class in the age groups 0‐14 and 15‐29 years were found. In children with one and both Sardinian parents the odds ratios (OR) were 2.09 (95% CI : 0.85‐5.15) and 3.20 (95% CI : 0.75‐13.64); in young adults 0.81 (95% CI : 0.18‐3.64) and 1.95 (95% CI : 0.51‐7.40), respectively. In subjects with low social class the OR were 1.16 (95% CI : 0.68‐1.97) in children and 0.66 (95% CI : 0.41‐1.05) in young adults. Conclusions This study shows higher risk of type 1 diabetes in subjects of Sardinian heritage; higher risk in children than in young adults and a protective effect of low social class in young adults. These findings are consistent with the hypothesis of heterogeneity of type 1 diabetes by age at onset, with prevailing genetic effect in childhood and environmental determinants in adulthood.

Background Erythromycin has been shown to have profound prokinetic effects on the gastrointestinal tract of humans and animals, probably through its action on endogenous motilin receptors. The purpose of this study was to determine both the direct and indirect effects (‘off contraction’) of erythromycin and motilin on ex vivo circular muscle strips of the distal colon from patients with or without idiopathic chronic constipation (ICC). Materials and methods Cumulative concentrations of erythromycin (1–20 μM) and motilin (0.05–1 μM) were tested in both control and ICC preparations in order to evaluate the direct drugs effect. A range doses of both erythromycin (0.5–10 μM) and motilin (0.05–0.5 μM) were tested on their ability to affect the off-contraction that follows the typical inhibitory response evoked by low frequencies of Electrical Field Stimulation (EFS) (1–5 Hz, 20 V, 1 msec pulse trains lasting 1 min). Results The direct effect of both erythromycin and motilin was a slight increase (less than 10% of the maximal ACh-induced contraction) in the basal tension, with no dose–response relationship. The off-contraction, evoked by EFS, was not affected by drugs pretreament in control preparations. Conversely, in ICC preparations both drugs significantly increased the off-contraction (about 30%). Conclusions Erythromycin causes mainly an indirect contractile effect in circular muscle strips from ICC patients. This effect may be related to the activation of inhibitory neuronal motilin receptors. This activation might potentiate NANC relaxation, proportionally increasing the circumferential reflex contraction that follows the EFS-induced relaxation.

Background/aims: According to current guidelines on management of Chronic Hepatitis C (CHC), both interferon (IFN)-containing and IFN-free treatment combinations may be offered to patients, depending on viral genotype, previous treatment and contraindications to IFN. The past two decades of treatment have selected a large population of patients ineligible to IFN. Our aim is to characterize the current CHC population in order to best drive resource allocation. Patients and methods: we retrospectively retrieved the characteristics and outcomes of a cohort of 801 consecutive CHC outpatients followed-up at two tertiary Centers in Northern Italy. Baseline characteristics of never treated and treated CHC patients were compared by means of Chi-Square test for categorical and t-test for continuous variables. Results: fifty-three percent (426 out of 801) of patients had previously received treatment. Among them, 103 (24%) had achieved SVR; 323 (76%) had failed, of whom 74 (23%) did not complete and 249 (77%) did not respond to treatment. Adverse events were the main cause of treatment withdrawal (90%). Forty-seven percent (n = 375) of all participants had never received any treatment, mostly because of contraindications (27% overall, hematologic 11%, psychiatric 24%, cardiovascular 15%, autoimmune 7%, others 43%), advanced age (27%), personal choice (15%) or no fibrosis (10%). Never treated patients differed significantly (p < 0.01) from treated ones by age (61 vs 56 years) and gender (male 49 vs 65%). Six-hundred and ninety-eight patients (323 failed plus 375 never treated) are awaiting new antiviral therapy, of which 442 (63%) are candidate to all-oral combinations because of contraindications or past intolerance to IFN, while the remaining 256 (37%) may still receive an IFN-containing regimen. Conclusions: 37% of the CHC patients being followed in our clinics may receive IFN-containing protocols with newer DAAs, while about the two thirds of these patients are obligated candidates for the more costly, IFN-free regimens.

It is well known that asplenic patients can suffer immediate and long-term infective sequelae, most of all from capsulated bacteria, whereas appropriate immunization can reduce the incidence of post-splenectomy sepsis. We discuss the case of a young adult developing an overwhelming post-splenectomy sepsis (OPSS) due to streptococcus pneumoniae seven years after the splenectomy for a traumatic injury. Neither immunoprophylaxis nor antibiotic therapy, whose value is underlined by literature data and international guidelines, was ever administered, either by the hospital physicians or by the general practitioner.

We have studied the effect of interferon (IF) beta-1a on the basal and TNFalpha-induced intercellular adhesion molecule 1 (ICAM 1) expression and fluid phase endocytosis (FPE) of horseradish peroxidase in cultured rat brain microvascular endothelial cells. Neither basal ICAM 1 expression nor basal FPE were significantly affected by 24-72 h exposure to 1000 U/ml IFbeta-1a. ICAM 1 induction and FPE enhancement caused by 100 U/ml TNFalpha for 24 h was not influenced by simultaneous administration of 1000 U/ml IFbeta-1a. Treatment of cultures with IFbeta-1a for 48 h followed by 24-h coincubation with TNFalpha (100 U/ml) and IFbeta-1a (1000 U/ml) resulted in significant downregulation of TNFalpha-induced ICAM 1 expression and FPE. Downregulation of TNFalpha-induced ICAM 1 expression was not observed when combined treatment with TNFalpha (100 U/ml) and IFbeta-1a (1000 U/ml) for 24 h was followed by 48 h exposure to IFbeta-1a. We concluded that the blood-brain barrier endothelium may be a target of IFbeta-1a. Further, these in vitro findings may correlate with the results of recent clinical trials indicating that chronic treatment of relapsing remitting multiple sclerosis with IFbeta-1a prevents both clinical exacerbations and the appearance on Magnetic Resonance Imaging of new lesions enhanced by gadolinium which is taken up by increased transendothelial fluid phase vesicular transport.

beta-Lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5, 6-dione) was previously shown to enhance the lethality of X-rays and radiomimetic agents and its radiosensitizing role in mammalian cells was attributed to a possible interference with topoisomerase I activity. Furthermore, beta-lapachone alone was found to induce chromosomal damage in Chinese hamster ovary (CHO) cells. The aim of the present study was to further elucidate the possible mechanisms by which beta-lapachone exerts its genotoxic action in cultured mammalian cells. Flow cytometry analysis of beta-lapachone-treated CHO cells indicated a selective cytotoxic effect upon S phase of the cell cycle. beta-lapachone produced DNA strand breaks as determined by alkaline elution assay; alkaline elution profiles from treated cells showed a bimodal dose-response pattern, with a threshold dose above which a massive dose-independent DNA degradation was observed. Furthermore, beta-lapachone increased the capacity of crude CHO cellular extracts to unwind supercoiled plasmid DNA, while significantly inhibiting in vitro poly(ADP-ribose) polymerase (PARP). These results suggest that damage induction is probably mediated by the interaction between beta-lapachone and cellular enzymatic function(s), rather than reflecting a direct action on the DNA. We suggest that the inhibition of PARP plays a central role in the complex biological effects induced by beta-lapachone in CHO cells.

Few studies have investigated neurobehavioral and neurochemical consequences of chronic consumption of low doses of ethanol. The present study shows that in rats exposure to 3% ethanol (vv in drinking water) for 2 months decreased both calcium-dependent and - independent protein kinase C (PKC) activities in the cortex and in the hippocampus. This treatment also reduced ultrasonic calls (UCs), an index of emotional and motivational states of the animal. In addition, at cortical level of ethanol-treated rats, we observed a correlation between calcium-dependent activities and UCs. These results suggest that nonaddicting doses of ethanol affect brain PKC activities and that this enzyme may be involved in the ethanol modulation of emotional and motivational behaviors.

To document the incidence of IDDM in the Province of Turin (Italy) in the 8-year period 1984-91 in children (0-14 years) and young adults (15-29 years), in relation to age, sex, monthly-seasonal variability, calendar year and urban/rural area, (all newly diagnosed cases (502) were ascertained through primary and secondary data sources and completeness of ascertainment estimated with the two sample capture-recapture method (99% in childhood and 95% in young adults). The independent effect of age, sex, calendar year, and urban/rural area was estimated with a Poisson regression model. Age-specific incidence rates were 8.42/100,000 (95% CI 7.37-9.62) and 6.72/100,000 (95% CI 5.96-7.58), respectively, in the age groups 0-14 and 15-29 years. Sex differences were evident in young adults, with an almost 1.5-fold increased risk in men (8.37/100,000, 95% CI 7.21-9.71 vs 5.00/100,000, CI 4.09-6.10). Seasonal trend was evident in childhood. Predictors of incidence rates were age, place of residence and interaction between sex and age; no temporal trend was detected. No significant differences were found in the two age-groups with respect to glycaemia, glycosuria, ketonuria, and fasting C-peptide levels. In conclusion, this study shows sex differences in IDDM risk in young adults; 55% of incident cases occurring in young adults; an independent contribution of urban/rural differences to IDDM risk; no temporal trend in 1984-91; a seasonal pattern of incidence in children; no significant differences in clinical presentation between age groups.