Lamotrigine in the treatment of painful diabetic neuropathy

An open trial was conducted to study the potential efficacy of lamotrigine, a novel antiepileptic agent that blocks voltage-sensitive sodium channels and inhibits the release of glutamate, in relieving the pain associated with diabetic neuropathy. Subsequent to a 1 week washout period from previous analgesics, lamotrigine was administered at a dose of 25 mg/day for 1 week. The dose was doubled on a weekly basis up to 400 mg/day over 6 weeks. The McGill pain questionnaire (MPQ), spontaneous pain and a series of mechanical and thermal stimuli-induced pain were measured with the use of 0–100 visual analogue scale (VAS), on seven office visits. Pain level was also recorded by each patient twice daily, 1 week before, during, and 2 weeks after the treatment period with the use of a 0–10 numerical pain scale (NPS). Quantitative mechanical (Von Frey filaments) and thermal testing (QTT), and routine blood tests were performed at the beginning and at the end of the study. Thirteen patients completed the study. Spontaneous pain measured by VAS and NPS gradually dropped from a baseline of 49 ± 8 and 6.8 ± 0.6, to 20 ± 8.6 ( p < 0.001) and 4.3 ± 0.9 ( p < 0.001), respectively, at the end of the treatment period. Similarly, cold allodynia dropped from 38 ± 9.2 to 16 ± 15.3 ( p = 0.01), and the MPQ score from 13.6 ± 0.8 to 11.0 ± 1.5 ( p < 0.01). In contrast, no significant changes were found in the QTT, mechanical pain thresholds and laboratory results. Two patients were withdrawn from the study because of adverse effects. A long-term follow up showed that most patients were still using lamotrigine 6 months after the end of the study. The results of the study suggest that lamotrigine is potentially effective and safe in treating painful diabetic neuropathy.     

Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients

Ulcerative colitis (UC) and Crohn's disease (CD) are heterogeneous disorders characterized by chronic intestinal inflammation. Genetic predisposition is a major risk factor in both diseases. The CARD15 (NOD2) gene has been implied as a candidate gene in the pathogenesis CD. Our aim was to delineate the frequency of three missense and one frameshift variant of CARD15 in Israeli Jewish CD and UC patients. DNA was extracted from blood samples from 238 unrelated inflammatory bowel disease (IBD) patients, 68 with UC and 170 with CD. The DNA was genotyped for two missense mutations, R675W and G881R, and one frameshift mutation, 980FS981X. Mutations in CARD15 were observed with significantly greater frequency in CD patients (46/170, 27%) than in UC patients (7/68, 10%) (P = 0.005). Homozygous and compound heterozygous carriers were restricted to seven (4%) patients with CD as compared to none of the UC patients (P = 0.01). Similar rates in Ashkenazi and non-Ashkenazi Jewish patients were observed. Age-of-onset of disease was lower in Ashkenazi mutation carriers as compared to non-carriers of Ashkenazi origin (18.7 +/- 8.6 years vs. 25.8 +/- 13.4 years, respectively, P = 0.03). No other phenotypic characteristics could distinguish mutation carriers from non-carriers. We conclude that germline mutations in the CARD15 gene are more frequently found in CD than UC patients and appear to predict an earlier age-of-onset in Ashkenazi Jewish patients. No association could be demonstrated between CARD15 mutations and specific disease course or behavior.     

Inhibition of CD4+ T lymphocyte binding to fibronectin and immune-cell accumulation in inflammatory sites by non-peptidic mimetics of Arg-Gly-Asp.

The Arg-Gly-Asp (RGD) cell adhesion motif has been demonstrated in various studies to play a pivotal role in leucocyte and platelet interactions with plasma and extracellular matrix (ECM) glycoproteins. The recognition of the RGD sequence is mediated by heterodimeric receptors designated integrins of the beta 1 subfamily, expressed on distinct cell types, including T lymphocytes. We have recently shown that flexible non-peptidic mimetics of RGD, in which the two ionic side groups were separated by a linear spacer of 11 atoms, bound specifically to the platelet integrin alpha 11b beta 3, and inhibited T cell-mediated immune responses. The present study was designed to (i) further characterize the structural requirements for RGD interactions with CD4+ T cells, and (ii) examine the mechanisms by which the RGD mimetics interfere with immune cell reactivity in vivo. We now report that freezing the conformational degrees of freedom in the spacer chain, which fixes the relative orientation of the guanidinium and carboxylate side groups in a favourable manner, results in a higher level of inhibition of T cell binding to immobilized fibronectin, an RGD-containing ECM glycoprotein. In vivo, treatment of mice with relatively low doses of the RGD mimetics, but not the RGD peptide, inhibited the elicitation of an adoptively transferred DTH reaction. This inhibition was achieved by direct impairment of the ability of antigen-primed lymph node cells to migrate and accumulate in inflammatory sites. Hence, we suggest that the design and production of non-peptidic mimetics of RGD offers a novel approach to study defined parameters related to the structure-function requirements of small adhesion epitopes. Furthermore, this approach could be used therapeutically to inhibit pathological processes which depend on RGD recognition.     

Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

1. Download high-res image (356KB)
2. Download full-size image

     

Immune cell migration in inflammation: present and future therapeutic targets

The burgeoning field of leukocyte trafficking has created new and exciting opportunities in the clinic. Trafficking signals are being defined that finely control the movement of distinct subsets of immune cells into and out of specific tissues. Because the accumulation of leukocytes in tissues contributes to a wide variety of diseases, these 'molecular codes' have provided new targets for inhibiting tissue-specific inflammation, which have been confirmed in the clinic. However, immune cell migration is also critically important for the delivery of protective immune responses to tissues. Thus, the challenge for the future will be to identify the trafficking molecules that will most specifically inhibit the key subsets of cells that drive disease processes without affecting the migration and function of leukocytes required for protective immunity.     

Histocompatibility Determinants in Israeli Jewish Patients with Multiple Sclerosis

The distribution of 24 HLA antigens of the A and B loci was investigated in 197 Israeli Jewish patients with multiple sclerosis (MS) from various Jewish ethnic origins including central and eastern Europe, countries bordering the Mediterranean, the Middle East and from native-born Israelis. The results were compared with the HLA antigen frequencies in a control sample of 455 unrelated individuals representing the general Jewish population. The frequency of HLA-Bw40 among all MS patients (15%) was significantly greater (P less than 0.001) than among the controls (7%). In contrast to the findings in MS patients from other populations, there was no increased frequency of A3 and B7 and Dw2 was present in only one out of 28 patients. The study showed a similar distribution of HLA-A and -B locus antigens, especially of Bw40, in Jews of diverse ethnic origins represented in the control group.     

Inheritance of idiopathic torsion dystonia among Jews.

Idiopathic torsion dystonia (ITD) has long been considered to be genetically determined, but the pattern of inheritance has been unclear. It has been suggested that inheritance may differ in Jews and non-Jews. In the present study, data gathered in a nationwide survey of ITD in Israel were analysed. Between 1969 and 1980, 47 patients were collected, of whom 40 were of European origin. In these European Jews, the ITD frequency was about 1:23 000 live births, which was five-fold greater than in Jews of Afro-Asian origin. Assuming that all cases fit the same genetic model, an X linked or a simple autosomal recessive model of inheritance did not agree well with our data. An autosomal dominant model with low penetrance could have accounted for our observations and would yield an ITD gene frequency in European Jews of 3 to 4:100 000. In view of the increased ages of their fathers, the isolated cases may have included some new mutations. Multifactorial inheritance was also possible. However, it may be inappropriate to assume that all cases have the same genetic basis, or even that all are inherited.     

Failure of ureteral stents subject to extrinsic ureteral obstruction and stent occlusions

International Urology and Nephrology - To quantify the occurrence of stent failure and the dynamic behavior of urine flow in ureter-stent systems, including the relative flow in the ureter and...     

Testicular sperm retrieval: What should we expect from the fresh and subsequent cryopreserved sperm injection?

We sought to compare ICSI outcomes of cycle using fresh versus thawed TESE spermatozoa obtained during the previous fresh TESE. All consecutive couples undergoing ICSI cycles using fresh TESE spermatozoa, followed by ICSI cycle using cryopreserved sperm remaining from the previous fresh TESE procedure were included. Ovarian stimulation (OS)/laboratory variables and cycle outcome were assessed and compared between those utilising fresh versus thawed TESE spermatozoa. Seventy-five couples were evaluated, with no in-between groups differences in OS nor embryological variables. While implantation and LBR per embryo transfer were nonsignificantly higher in the frozen as compared to the fresh TESE, there was a trend towards higher LBRs per patient in the frozen TESE group. The cumulative miscarriage rate (4% versus 14.7%, p < .022 respectively) was significantly lower and the cumulative LBR (34.7% versus 16%, p < .007 respectively) was significantly higher using frozen TESE spermatozoa. Moreover, significantly higher proportion of frozen TESE sperm samples used pentoxifylline to enhance sperm motility. In conclusion, the results of ICSI cycles using frozen TESE spermatozoa are as good, or even better than using fresh TESE spermatozoa. Further studies are required to explore the factors responsible for the improved ICSI outcome, while using frozen versus fresh TESE sperm samples.