Structural abnormalities in patients with insular/peri-insular epilepsy: spectrum, frequency, and pharmacoresistance.

SUMMARY: Between 2002 and 2010, a total of 48 patients were seen at our epilepsy clinic with insular/peri-insular cortex epilepsy. Review of their MR imaging scans revealed a neoplastic lesion in 27% of patients, a malformation of cortical development in 21%, a vascular malformation in 19%, and atrophy/gliosis from an acquired insult in 17%. MR imaging results were normal in 4 patients. Other miscellaneous findings included a case of Rasmussen encephalitis, a nonspecific insular millimetric T2 signal abnormality, a neuroepithelial cyst, and hippocampal sclerosis without MR imaging evidence of dual insular pathologic features (despite depth electrode-proven insular seizures). Refractoriness to antiepileptic drug treatment was present in 56% of patients: 100% for patients with malformations of cortical development (1.0; 95% CI, 0.72-1.0), 50.0% (0.5; 95% CI, 0.21-0.78) in the presence of atrophy/gliosis from acquired insults, 39% (0.39; 95% CI, 0.14-0.68) for neoplastic lesions, and 22.2% (0.22; 95% CI, 0.06-0.55) for vascular malformations.

Insular ischemic stroke: clinical presentation and outcome.

BACKGROUND: The insula is a small but complex structure located in the depth of the sylvian fissure, covered by the frontal, parietal and temporal operculum. Ischemic strokes limited to the insula are rare and have not been well studied. Our objective is to better define the clinical presentation and outcome of insular ischemic strokes (IIS). METHODS: We reviewed the institutional prospective, consecutive stroke database from two centers to identify patients with IIS seen between 2008 and 2010. We also searched the Medline database using the keywords insula(r), infarction and stroke to identify previously published IIS cases confirmed by MRI. Minimal extension to an adjacent operculum or subinsular area was accepted. Clinicoradiological correlation was performed by distinguishing IIS involving the anterior (AIC) or posterior insular cortex (PIC). We collected clinical, demographic and radiological data. The outcome was determined using the modified Rankin Scale (mRS). RESULTS: We identified 7 patients from our institutions and 16 previously published cases of IIS. Infarcts were limited to the AIC (n = 4) or the PIC (n = 12) or affected both (n = 7). The five most frequent symptoms were somatosensory deficits (n = 10), aphasia (n = 10), dysarthria (n = 10), a vestibular-like syndrome (n = 8) and motor deficits (n = 6). A significant correlation was found between involvement of the PIC and somatosensory manifestations (p = 0.04). No other statistically significant associations were found. IIS presentation resembled a partial anterior circulation infarct (n = 9), a lacunar infarct (n = 2) or a posterior circulation infarct (n = 2). However, most cases presented findings that did not fit with these classical patterns (n = 10). At the 6 month follow up, mRS was 0 in 8/23 (35%) patients, 1-2 in 7/23 (30%) and unknown in 8/23 (35%). CONCLUSIONS: IIS presentation is variable. Due to the confluence of functions in a restricted region, it results in multimodal deficits. It should be suspected when vestibular-like or motor but especially somatosensory, speech or language disturbances are combined in the same patient. The outcome of IIS is often favorable. Larger prospective studies are needed to better define the clinical presentation and outcome of IIS.

Relationships between factor VIII:Ag and factor VIII in recombinant and plasma-derived factor VIII concentrates.

A variety of plasma-derived (pd) and recombinant (r) factor VIII (FVIII) concentrates are used to prevent and treat bleeding in severe hemophilia A patients. A significant side effect of FVIII replacement is the development of FVIII neutralizing antibodies (inhibitors) in up to 30% of patients receiving FVIII concentrates. The FVIII protein content (FVIII:Ag) per unit of FVIII:C in FVIII concentrates, and how effectively the FVIII:Ag in FVIII concentrates binds to von Willebrand factor (VWF) may provide information relevant for the survival of FVIII:C in vivo and for estimating the risk for inhibitor development. The FVIII:Ag content of nine r-FVIII and nine pd-FVIII concentrates were quantified in this study using two enzyme-linked immunosorbent assay (ELISA) platforms. The two ELISA platforms were based on the use of a monoclonal anti-(FVIII light chain)-IgG and polyclonal anti-FVIII antibodies as capture antibodies and both ELISAs were equally able to detect > or =0.005 IU of FVIII:Ag. Measured in international units, the r-FVIII concentrates contained significantly higher FVIII:Ag per unit of FVIII:C than the pd-FVIII concentrates. The VWF-binding profiles of the r-FVIII and pd-FVIII concentrates were also determined by gel filtration chromatography. Unlike the plasma-derived products, the r-FVIII concentrates invariably contained a fraction of FVIII:Ag molecules (approximately 20%) which was unable to associate with VWF. Given that VWF regulates both factor VIII proteolysis and survival of FVIII:Ag in vivo, the fraction of FVIII:Ag unable to bind to VWF may have a reduced survival and be more susceptible to proteolytic degradation in vivo. The extent to which the fractions of FVIII:Ag in concentrates able and unable to bind to VWF contribute to inhibitor development in severe FVIII-deficient patients is unknown.

Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand.

Engagement of CD40 on resting B cells in the presence of IL-4 triggers B cell proliferation, differentiation and homotypic adhesion. This study was designed to investigate the role of LFA-1/ICAM-1 interactions in homotypic adhesion and proliferation of CD40-activated human B lymphocytes. Freshly isolated B cells were cultured in vitro in the presence of IL-4 and of L cells expressing CD40L, the CD40 ligand. The addition to the culture medium of LFA-1 and ICAM-1 antibodies inhibited homotypic B lymphocyte adhesion. However, these antibodies failed to affect B lymphocyte proliferation and antibody production. These results indicate that aggregation and proliferation are independent events although both induced by CD40 activation.

Evidence for restricted diversity of antigen-specific human antibodies in immunized hu-PBL-SCID mice.

Previous studies have revealed that specific human humoral immune responses could be produced in immunized SCID mice after engraftment of human lymphocytes (hu-PBL-SCID). On the other hand, the engrafted repertoire of B cell clones is known to be skewed in hu-PBL-SCID with the corresponding production of only a limited set of major human antibodies. In this work, we have analyzed the diversity of tetanus toxoid-specific human antibodies produced in immunized hu-PBL-SCID mice in comparison with the total serum antibody population using zone electrophoresis followed by blotting. The results showed that the diversity of tetanus toxoid-specific antibody population was more restricted than that of the total human antibody population, with some animal sera containing a single band of tetanus toxoid-specific antibody molecule, in clear contrast to the polyclonal response of the PBL donor. Absorption experiments showed tetanus toxoid-specific antibodies could account for a significant proportion (up to 10%) of the total human antibodies present in hu-PBL-SCID mouse sera. The inability to expand a high number of different antigen-specific B cell clones in immunized hu-PBL-SCID mice represents an important intrinsic limitation of this animal model which may be caused by defects in T cell help.

Use of hu-IgG-SCID mice to evaluate the in vivo stability of human monoclonal IgG antibodies.

Human and in vitro modified mAbs such as humanized rodent mAbs and immunotoxins are now considered for a variety of applications in humans. The adequate in vivo stability of these Ig preparations is not easily predicted from in vitro studies and may be essential for many therapeutic applications. In this study, we report the development and characterization of an in vivo model for testing this parameter using SCID mice containing a physiological concentration of human IgG (hu-IgG-SCID). The model was tested with several IgG1 and IgG3 human mAbs reacting with the human Rh(D) red cell antigen. It is known that human IgG have a shorter half-life in SCID mice than in humans. However, our results showed that the half-life of IgG3 mAbs (1.5 +/- 0.5 days) was much shorter than the one of IgG1 mAbs (5.8 +/- 1.4 days), indicating that the relative stability of IgG1 and IgG3 human mAbs in hu-IgG-SCID mice is similar to the one previously reported in humans (21 days vs. 7 days respectively). The IgG catabolism rate in humans is known to be inversely proportional to serum IgG concentrations. Accordingly, the dilution of the mAbs in a large excess (200-fold) of human IgG was found to be an important parameter of the hu-IgG-SCID mouse model since much longer (3-4-fold) mAb half-lives were obtained in the presence of a lower dose or in the absence of co-injected human IgG. This study show the usefulness of this animal model for the evaluation of human antibody stability in an in vivo environment.

Efficient preparation of human monoclonal antibody-secreting heterohybridomas using peripheral B lymphocytes cultured in the CD40 system.

The use of peripheral B lymphocytes in the successful preparation of human monoclonal antibodies by hybridoma technology is highly dependent on lymphocyte activation procedures. We studied the ability of peripheral human B lymphocytes cultured in vitro and activated through their CD40 antigen (CD40 system) (Banchereau et al., 1991) to form antibody-secreting heterohybridomas after fusion with murine X63Ag8.653 myeloma cells. The frequency of antibody-secreting heterohybridomas formation was greatly increased (15 times) by culture of B cells in the CD40 system. The CD40 system offers many advantages over other procedures of B lymphocyte activation representing a significant technological advance in the preparation of human monoclonal antibodies by standard hybridoma technology.

Effect of xylitol consumption on the plaque-saliva distribution of mutans streptococci and the occurrence and long-term survival of xylitol-resistant strains.

Since the exposure of mutans streptococci to xylitol is known to select for xylitol-resistant (XR) natural mutants, the occurrence and long-term survival of such xylitol-resistant strains was evaluated in a cross-sectional sampling of participants of the Ylivieska xylitol study four years after the original two-year experimental period. Paraffin-stimulated whole saliva was first collected, and then plaque was collected and pooled. The salivary and dental plaque mutans streptococci were enumerated after growth on TSY20B agar. The proportion of XR strains was determined by autoradiography with 14C-xylitol. A strong and significant correlation (r = 0.645 and p = 0.005) between the number of mutans streptococci in saliva and in dental plaque was observed in non-consumers of xylitol. Such a correlation totally disappeared (r = 0.098 and p = 0.612) in xylitol-exposed consumers (habitual and former xylitol-consumers). The proportion of the salivary XR mutants (35%) in non-consumers (n = 16) was significantly lower than in the xylitol-exposed consumers (79%) (n = 27), (p = 0.0001) or in former consumers (75%) (n = 13), (p = 0.0008) or in the habitual consumers (83%) (n = 14), (p = 0.004). The proportion of XR mutants in dental plaque was, on the average, much lower than in the corresponding saliva. The proportion of XR in the plaque of xylitol non-consumers was half of that of the xylitol-exposed group, but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)