Frequency, causes and phenomenology of late seizure recurrence in patients with juvenile myoclonic epilepsy after a long period of remission.

PURPOSE: To determine frequency, causes, and phenomenology of late seizure recurrence (SR) in patients with juvenile myoclonic epilepsy (JME) after remission of at least 1 year. METHODS: Among 2722 epileptic patients from tertiary referral center, we retrospectively identified 105 patients (62 females; mean age 22.3+/-7.2 years) with an established diagnosis of JME. All patients were treated with valproates (83.3%), or lamotrigine, topiramate, phenobarbital, add-on clobazam, or combinations (16.2%). RESULTS: The median period of follow-up was 4.2+/-3.2 (range: 1-17) years. SR occurred in 74 patients (70.5%) after median period of 2.4+/-3.2 years. Twenty-two patients (29.7%) experienced myoclonic seizures (MS), 13 (17.7%) generalized tonic-clonic seizures (GTCS), 37 (50%) a combination of MS and GTCS, and two (2.6%) a combination of MS, GTCS and absence seizures. SR was associated most frequently with sleep deprivation and AED withdrawal, and rarely with alcohol intake, drug abuse, photostimulation, or menstruation. No provoking factors for SR were identified in 31.1% and 45% of cases with MS and GTCS, respectively. The majority of patients (59/74) had a single SR. A second SR occurred less frequently in patients in whom valproate dosage was increased after the first SR (p=0.0048). CONCLUSION: Late SR (mainly MS and GTCS) is detected frequently after prolonged follow-up in patients with JME despite the use of best-known therapy, usually due to AED withdrawal or erratic life style. Instead of futile efforts to persuade the patient to conform to restrictive life style, it is probably more efficient to use initial higher doses of AEDs.     

Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations

Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax(-/-)p53(-/-) mice succumb predominantly to immature alphabeta T-cell lymphomas with translocations, deletions, and genomic amplifications that do not involve T-cell receptor (TCR). In addition, H2ax(-/-)p53(-/-) mice also develop at lower frequencies B and T lymphomas with antigen receptor locus translocations. V(D)J recombination is initiated through the programmed induction of DNA double-strand breaks (DSBs) by the RAG1/RAG2 endonuclease. Because promiscuous RAG1/RAG2 cutting outside of antigen receptor loci can promote genomic instability, H2ax(-/-)p53(-/-) T-lineage lymphomas might arise, at least in part, through erroneous V(D)J recombination. Here, we show that H2ax(-/-)p53(-/-)Rag2(-/-) mice exhibit a similar genetic predisposition as do H2ax(-/-)p53(-/-) mice to thymic lymphoma with translocations, deletions, and amplifications. We also found that H2ax(-/-)p53(-/-)Rag2(-/-) mice often develop thymic lymphomas with loss or deletion of the p53(+) locus. Our data show that aberrant V(D)J recombination is not required for rapid onset of H2ax/p53-deficient thymic lymphomas with genomic instability and that H2ax deficiency predisposes p53(-/-)Rag2(-/-) thymocytes to transformation associated with p53 inactivation. Thus, H2AX is essential for suppressing the transformation of developing thymocytes arising from the aberrant repair of spontaneous DSBs.     

Comparison of nateglinide and gliclazide in combination with metformin,for treatment of patients with Type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone

Aims To compare the effects of nateglinide plus metformin with gliclazide plus metformin on glycaemic control in patients with Type 2 diabetes. Methods Double‐blind, double‐dummy, parallel group, randomized, multicentre study over 24 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to additionally receive nateglinide (n = 133) or gliclazide (n = 129). Changes from baseline in HbA_1c, fasting plasma glucose (FPG) and mealtime glucose and insulin excursions were examined. Results HbA_1c was significantly (P < 0.001) decreased from baseline in both treatment groups (mean changes: nateglinide ?0.41%, gliclazide ?0.57%), but with no significant difference between treatments. Proportions of patients achieving a reduction of HbA_1c ≥ 0.5% or an end point HbA_1c < 7% were also similar (nateglinide 58.1%, gliclazide 60.2%). Changes from baseline in FPG were similarly significant in both treatment groups (nateglinide ?0.63, gliclazide ?0.82 mmol/l). Reduction from baseline in maximum postprandial glucose excursion were significant in the nateglinide group only (nateglinide ?0.71, gliclazide ?0.10 mmol/l; P = 0.037 for difference). Postprandial insulin levels were significantly higher with nateglinide compared with gliclazide. The overall rate of hypoglycaemia events was similar in the nateglinide group compared with the gliclazide group. Conclusions No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA_1c. However, the nateglinide combination demonstrated better postprandial glucose control.     

Prognostic value of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase N/CD13 in breast cancer patients

The aim of this study was to analyse the expression of matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase APN/CD13 in breast carcinoma samples, and their possible prognostic value in breast cancer patients. The expression of MMP-2, MMP-9 and APN/CD13 in tumor cells was analysed in 138 breast carcinomas by immunohistochemical staining of tumor cells using the semiquantitative method for the detection of cytoplasmic and membrane reaction in tumor cells as well as stromal cells positivity. MMP-2 was positive in tumor cells of 52.9% patients and in stromal cells of 74.6% patients, while MMP-9 positive tumor and stromal cells were found in 84.8 and 63.8% patients, respectively. Tumor cell APN/CD13 expression was found in 36.2% patients. Stromal cell MMP-2 expression correlated significantly with tumor size and neoangiogenesis. A positive correlation was also observed between tumor cell MMP-9 expression and hormone receptor status. Stromal cell coexpression of MMP-2/MMP-9 correlated significantly with tumor size. APN/CD13 expression in tumor cells significantly correlated with tumor type and neoangiogenesis. Overall survival was significantly shorter in patients with MMP-2, MMP-2/MMP-9 positive tumor cells, and tended to be shorter in patients with APN/CD13 positive tumor cells. Coexpression of MMP-2/MMP-9 in tumor cells was an independent risk factor for patient survival (OD = 13.9). Our results suggest that MMP-2, MMP-9, APN/CD13 expression and MMP-2/MMP-9 coexpression in combination with other standard prognostic factors can serve as a poor prognostic factor in the evaluation of breast cancer prognosis.     

Late diagnosis of primary hyperoxaluria after failed kidney transplantation

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.     

Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1-year trial results

AIM: To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy. METHODS: Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study. RESULTS: There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain. CONCLUSIONS: No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.     

Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings

We report different immunological phenotypes in three siblings from consanguineous family with recombinase-activating gene 1 ( RAG1 ) gene mutations. Null mutations of RAG genes result in severe combined immunodeficiency (SCID) with absent T and B cells. Hypomorphic mutations with retained activity of RAG genes may lead to a 'leaky' SCID with some features of Omenn syndrome (OS) or typical OS. In our three patients, homozygous, hypomorphic RAG1 gene mutation (g.368–369delAA) was detected. Two patients presented with T−B−SCID phenotype while the youngest patient developed T+B+NK+SCID phenotype with expansion of autologous T-cell receptor (TCR) γδ-positive T cells, increased immunoglobulin levels and retained ability for antibody production. Similar to originally reported patients with this newly recognized immune phenotype, our patient developed disseminated cytomegalovirus (CMV) infection and autoimmune cytopenia.
Conclusion: In infants with disseminated cytomegalovirus infection and autoimmune cytopenia, even if basic immunologic investigation appears normal, RAG1 immunodeficiency should be considered.