Evidence of memory impairment in asymptomatic individuals with hippocampal atrophy

Our objective was to investigate if MRI-determined hippocampal atrophy (HA) is associated with memory deficits independent of seizure frequency. We studied three groups of individuals: (1) 10 asymptomatic first-degree relatives of patients with familial mesial temporal lobe epilepsy (FMTLE), all of them with HA; (2) 14 patients with benign FMTLE, 9 with HA, and 5 with normal hippocampal volumes; and (3) 16 patients with refractory FMTLE, all but one with HA. HA was associated with lower scores on general memory (P=0.015), verbal memory (P=0.020), and delayed recall (P=0.028), even in those with no or few seizures in life. General linear model analyses showed that the interaction between seizure outcome and HA was associated with worse verbal memory (P=0.029), visual memory (P=0.022), and delayed recall (P=0.039) as compared with each of these factors independently. Our findings suggest that seizures and HA are independently associated with memory impairment.     

Role of peroxisome proliferator-activated receptor gamma and its ligands in the control of immune responses

To ensure that efficient immune responses against dangerous antigens are raised while tolerance to self molecules is preserved, the immune system tightly regulates activation and survival of its cellular compartments through mechanisms only partially characterized. In this context, recent evidence indicates a role in immunity of the nuclear receptor PPAR-gamma, which is upregulated in activated lymphocytes and in dendritic cells. Preliminary in vitro studies indicate that PPAR-gamma activation profoundly alters the immune properties of these cells, usually leading to the inhibition of immune responses. Naturally occurring PPAR-gamma ligands include the cyclopentenone prostaglandins of the J series, which are present in bone marrow, thymus, and secondary lymphatic tissues. The levels of these metabolites are increased in inflamed tissues, where they exert strong anti-inflammatory effects leading to resolution of inflammation and wound healing. Cyclopentenone prostaglandins activate both PPAR-gamma-dependent and PPAR-gamma-independent pathways, possess intrinsic proapoptotic potential and are direct inhibitors of NF-kappaB signaling. The relevance of these effects in vivo still awaits proper evaluation in humans. Some of the newly described regulatory pathways might eventually be exploited in the treatment of immune diseases by means of PPAR-gamma ligands, such as thiazolidinediones or prostaglandins.     

Normalized regional brain atrophy measurements in multiple sclerosis

There is still a controversy regarding the best regional brain atrophy measurements in multiple sclerosis (MS) studies. The aim of this study was to establish whether, in a cross-sectional study, the normalized measurements of regional brain atrophy correlate better with the MRI-defined regional brain lesions than the absolute measurements of regional brain atrophy. We assessed 45 patients with clinically definite relapsing–remitting (RR) MS (median disease duration 12 years), and measured T1-lesion load (LL) and T2-LL of frontal lobes and pons, using a reproducible semi-automated technique. The regional brain parenchymal volume (RBPV) of frontal lobes and pons was obtained by use of a computerized interactive program, which incorporates semi-automated and automated segmentation processes. A normalized measurement, the regional brain parenchymal fraction (RBPF), was calculated as the ratio of RBPV to the total volume of the parenchyma and the cerebrospinal fluid (CSF) in the frontal lobes and in the region of the pons. The total regional brain volume fraction (TRBVF) was obtained after we had corrected for the total volume of the parenchyma and the CSF in the frontal lobes and in the region of the pons for the total intracranial volume. The mean coefficient of variation (CV) for RBPF of the pons was 1% for intra-observer reproducibility and 1.4% for inter-observer reproducibility. Generally, the normalized measurements of regional brain atrophy correlated with regional brain volumes and disability better than did the absolute measurements. RBPF and TRBVF correlated with T2-LL of the pons (r=–0.37, P=0.011, and r= –0.40, P=0.0005 respectively) and with T1-LL of the pons (r=–0.27, P=0.046, and r=–0.31, P=0.04, respectively), whereas RBPV did not (r=–0.18, P = NS). T1-LL of the frontal lobes was related to RBPF (r=–0.32, P=0.033) and TRBVF (r=–0.29, P=0.05), but not to RBPV (R=–0.27, P= NS). There was only a trend of correlation between T2-LL of the frontal lobes and RBPF (r=–0.27, P=0.06) and TRBVF (r=–0.28, P=0.057), and no correlation with RBPV (r=–0.23, P= NS). The magnitude of correlation between the expanded disability status scale (EDSS) and pontine and frontal lobe RBPF and TRBVF was more than twice as high as the correlation between EDSS and RBPV of the same regions. These data suggest that normalized regional brain atrophy measurements are preferable to absolute regional measurements in cross-sectional studies.     

Intestinal and systemic endotoxaemia after laparotomic or laparoscopic cholecystectomy

Since laparoscopic cholecystectomy (LC) is widely recognised as being a "mild" or minimally invasive kind surgery, the aim of this prospective non-randomised study was to investigate the effect of intestinal manipulation on intestinal permeability and endotoxaemia in patients undergoing elective cholecystectomy, comparing the laparoscopic and laparotomic approaches. The intestine is susceptible to operations at remote locations, and the barrier function is altered during intestinal manipulation, leading to bacterial or endotoxin translocation into the systemic circulation. Fifty-three patients undergoing elective cholecystectomy were divided into two groups on the basis of laparotomic (n = 27) or laparoscopic (n = 26) approach. Intestinal permeability was measured preoperatively, and on day 1 and day 3 after surgery using the lactulose/mannitol absorption test. Serial venous samples were taken at 0, 30, 60, 90, 120 and 180 minutes, and at 12, 24 and 48 hours after surgery, for endotoxin measurement using the chromogenic limulus amoebocyte lysate assay. Intestinal permeability was significantly increased on day 1 [0.106 +/- 0.0005 (mean +/- S.E.M.)] in the laparotomic group compared to the preoperative level (0.019 +/- 0.005, p < 0.05) and to the laparoscopic group on day 1 (0.019 +/- 0.005, p < 0.05) which showed no change in comparison with the preoperative level. A significantly higher concentration of systemic endotoxin was detected intraoperatively in the laparotomic group of patients in comparison with the laparoscopic group (p < 0.05). There was significant positive correlation between systemic endotoxaemia and intestinal permeability (rs = 0.958; p = 0.001). An increase in intestinal permeability and degree of systemic endotoxaemia are observed during laparotomic cholecystectomy. This suggets that intestinal manipulation may impair the mucosal barrier function of the gut and contribute to the systemic inflammatory response seen in open cholecystectomy.     

Girls growing through adolescence have a higher risk of poor health

Introduction:

Self rated health, in adult population, is strongly associated with mortality and life expectancy. In younger people this association is less evident, but it may anticipate a similar risk in adult life. Our research, based on the HBSC (Health Behaviour in School-Aged Children) International collaboration, contributes to deepen the knowledge in this field by monitoring adolescents’ health through a multi-national survey involving 29 European countries, plus North America (Canada and USA) and Israel.

Methods:

Following an established methodology, the HBSC survey has elaborated a questionnaire on health and health behaviour, filled in by a representative national sample of 11-, 13- and 15-year-old boys and girls. The sample is constituted of more than 160,000 subjects interviewed during the 2001/2002 survey. Reported symptoms and self-rated health have been analysed by sex and age and through the different countries.

Results:

Girls resulted to have a poorer perception of their health, with respect to males, at all ages and in all countries (Overall OR = 1.70, 95% CI: 1.66–1.76). Age increases this risk both for males and females, with an average increase of 32% (95% CI: 29–34%) per year in the age-range 11–15. The situation is similar for reported symptoms, with an overall OR of 1.81 (95% CI: 1.77–1.85) for females of reporting three or more symptoms at least once a week; also this risk increases of 26% (95% CI: 24–27%) per year during the pre-adolescence phase. In both cases it could be shown a significant interaction effect between age and gender: OR = 1.19 (CI: 1.15–1.23) for perceived health and OR = 1.26 (CI: 1.23–1.29) for reported symptoms in females with respect to males.

Conclusions:

Even if adolescence is described as the healthiest period of life, a consistent minority of young people perceive and report a poor health and a high number of symptoms. Females are constantly in a worse position than males and older age groups are worse than younger ones.     

Enhanced nasal absorption of hydrophilic markers after dosing with AT1002, a tight junction modulator

AT1002 is a six-mer synthetic peptide, H-FCIGRL-OH, that retains the delta G and Zot biological activity of reversibly opening tight junctions and increases the paracellular transport of drugs. The objective of this study was to evaluate the possible use of AT1002 in enhancing the nasal availability of macromolecules using large paracellular markers as model agents. Male Sprague–Dawley rats cannulated in the jugular vein were randomly assigned to receive radiolabelled paracellular markers, [¹⁴C]PEG4000 or [¹⁴C]inulin, with/without AT1002, for each intranasal study. The plasma concentration of PEG4000 with AT1002 (10 mg/kg) was significantly higher than that from PEG4000 control over 360 min following intranasal administration. The AUC_0–360 min and C_max from the PEG4000/AT1002 (10 mg/kg) treatment were statistically (p < 0.05) increased to 235% and 357%, of control, respectively. When inulin was administered with AT1002 (10 mg/kg), the plasma concentration was significantly higher (p < 0.05) than control over 360 min, and increases (p < 0.05) of 292% and 315% for AUC_0–360 min and C_max over control were observed, respectively. AT1002 significantly increased the nasal absorption of molecular weight markers, PEG4000 and inulin. This study suggests that AT1002 may be used to enhance the systemic availability of macromolecules when administered concurrently.     

Tamoxifen retinopathy: does it really exist?

· Background: Tamoxifen retinopathy is known to be an adverse effect of high-dose tamoxifen treatment. Evidence of ocular toxicity at lower doses is less convincing: the aim of this study was to assess the prevalence of the above-mentioned retinopathy in a population treated with low-dose tamoxifen. · Methods: One hundred and twenty-nine women treated with low-dose tamoxifen (20 mg/day) were examined. Visual acuity measurement, slit-lamp biomicroscopy and fundus examination were performed. Patients were reexamined after 6–12 months. · Results: Refractile retinal opacities, similar to those previously described as tamoxifen retinopathy, were observed in four patients (prevalence 3.1%; mean duration of therapy 806 days). None of them revealed corneal opacities, papillary and/or macular edema, or visual impairment. The ophthalmoscopic aspect did not change after a mean follow-up of 215 days, although one of these patients had interrupted tamoxifen intake. Statistical analysis (Student’s t-test) did not reveal any difference between patients with and those without refractile retinal opacities as far as age, treatment duration and ERG values were concerned. An early hyperfluorescence, reminescent of cuticular drusen, was demonstrated by fluorescein angiography in all four cases. · Conclusions: The present study would seem to confirm that low-dose tamoxifen may induce retinal toxicity in a low proportion of patients, but we cannot be certain that the refractile retinal opacities observed are really caused by tamoxifen, as differentiation from age-related macular degeneration with cuticular drusen appears nearly impossible. Received: 10 November 1997 Revised version received: 5 January 1998 Accepted: 14 January 1998     

Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience.

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%.