Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia.

Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P < 0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P = 0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI) = 1·55-5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P = 0·04, OR 2·78; 95% CI = 1·04-7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.

Pedaling alters the excitability and modulation of vastus medialis H-reflexes after stroke.

OBJECTIVE: Individuals post-stroke display abnormal Group Ia reflex excitability. Pedaling has been shown to reduce Group Ia reflexes and to normalize the relationship between EMG and reflex amplitude in the paretic soleus (SO). The purpose of this study was to determine whether these changes extend to the paretic quadriceps. METHODS: H-reflexes were used to examine Group Ia reflex excitability of the vastus medialis (VM). H-reflexes were elicited in paretic (n=13) and neurologically intact (n=13) individuals at 11 positions in the pedaling cycle and during static knee extension at comparable limb positions and levels of VM EMG. RESULTS: VM H-reflexes were abnormally elevated in the paretic limb of stroke survivors. During static muscle activation, H-reflex amplitude did not change with the level of background VM activity. Pedaling reduced the amplitude of paretic VM H-reflexes and restored the normal relationship between VM EMG and H-reflex amplitude. CONCLUSIONS: Pedaling-induced changes in Group Ia reflex excitability that have been reported for the paretic SO are evident in the paretic VM. Pedaling may have a generalized effect on lower extremity Group Ia reflexes post-stroke. SIGNIFICANCE: Pedaling may be therapeutic for reducing Group Ia reflexes after stroke.

The immigration delay disease: adermatoglyphia-inherited absence of epidermal ridges.

In the digital age, personal identification by fingerprints (epidermal ridges) has become more frequent and is often required for biometric passports. The more fingerprints are analyzed, the more variants in their formation are documented. Individuals completely missing fingerprints as an isolated finding are extremely rare. Only 4 kindreds have been described to date, with additional clinical features in most cases. We describe a female patient with missing epidermal ridges on the fingers, palms, toes, and soles as an isolated feature. Absent fingerprints, or adermatoglyphia, were inherited over 4 generations of her family in an autosomal dominant fashion. We present the clinical features of the index patient, and compare the case with previous reports in the literature. Because of problems in personal identification, this embryologic malformation caused the patient significant difficulties when traveling to other countries, which is why we name it the immigration delay disease.

Disadhesion of epidermal keratinocytes: a histologic clue to palmoplantar keratodermas caused by DSG1 mutations.

BACKGROUND: Recent developments in molecular genetics may lead to re-examination of the histopathology of inherited palmoplantar keratodermas (PPKs) based on more precise groupings of the various entities and syndromes. OBJECTIVE: We sought to characterize the histopathological findings in PPKs associated with mutations in DSG1, which encodes desmoglein 1. METHODS: We studied the histopathology of 3 cases of keratosis palmoplantaris striata type I and one case of diffuse PPK, all associated with autosomal-dominant mutations in DSG1. Our cases for comparison included 4 cases with Mal de Meleda PPK associated with autosomal-recessive SLURP1 mutations, one case with pachyonychia congenita type II PPK associated with an autosomal-dominant KRT17 mutation, and one case with focal PPK associated with an autosomal-dominant KRT16 mutation. RESULTS: The distinguishing histopathological features of the 3 keratosis palmoplantaris striata type I cases and the diffuse PPK case associated with DSG1 mutation were: varying degrees of widening of the intercellular spaces and partial disadhesion of keratinocytes in the mid and upper epidermal spinous cell layers, often extending to the granular cell layer. These findings, which are associated with haploinsufficiency of desmoglein 1, were not observed in any of the other 6 PPK cases. Mild perinuclear eosinophilic condensations and cytoplasmic vacuolizations were observed in the spinous cell layer keratinocytes of the pachyonychia congenita type II PPK and the nonspecified focal PPK cases. LIMITATIONS: There were a limited number of patients and control patients with hereditary PPKs. CONCLUSION: Widening of the intercellular spaces and disadhesion of epidermal keratinocytes may serve as a histologic clue to PPKs caused by DSG1 mutations.

Novel mechanism whereby nuclear factor kappaB mediates DNA damage repair through regulation of O(6)-methylguanine-DNA-methyltransferase.

O(6)-Methylguanine-DNA-methyltransferase (MGMT) and nuclear factor kappaB (NF-kappaB) are two key effectors associated with the development of resistance to alkylating agent-based chemotherapy. This prompted us to hypothesize that NF-kappaB might be involved in MGMT regulation. Consistent with this hypothesis, we have discovered two putative NF-kappaB binding sites within the MGMT promoter region and showed a specific and direct interaction of NF-kappaB at each of these sites. Forced expression of the NF-kappaB subunit p65 in HEK293 cells induced an increase in MGMT expression whereas addition of the NF-kappaB super repressor DeltaNIkappaB completely abrogated the induction. We also found a significant correlation between the extent of NF-kappaB activation and MGMT expression in the glioma cell lines and the human glial tumors tested and showed that it was independent of MGMT promoter methylation. Our results are of potential clinical significance because we show that cell lines with ectopic p65 or high constitutive NF-kappaB activity are less sensitive to nitrosourea treatment and that suppression of MGMT activity with O(6)-benzylguanine completely abolishes the chemoresistance acquired by NF-kappaB. The findings of our study strongly suggest that NF-kappaB plays a major role in MGMT regulation and that MGMT is most probably the major player in NF-kappaB-mediated chemoresistance to alkylating agents.

Longitudinal assessment of genetic and epigenetic markers in oligodendrogliomas.

PURPOSE: Because little is known about the evolution of genetic and epigenetic changes that occur during tumor progression in oligodendrogliomas, we evaluated these changes in paired early and progressive oligodendrogliomas. EXPERIMENTAL DESIGN: 1p36, 19q13, 10q22-26, and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were assessed in 46 paired early and progressive oligodendrogliomas from 23 patients. RESULTS: In early tumors, 60.8% were of low grade compared with only 17% low-grade tumors at recurrence. Of 17 early tumors described as pure oligodendrogliomas, 76.5% remained in this lineage, regardless of their grade, whereas others changed to astrocytic tumors. Oligoastrocytic tumors had a significantly higher tendency to transform to astrocytic tumors. All pure oligodendrogliomas with 1p/19q codeletions remained phenotypically unchanged, unlike mixed tumors with codeletions, of which 83% changed their cell lineage. Of tumors with early 1p deletion, 80% remained oligodendroglial at progression, whereas 75% of tumors with an intact 1p changed to astrocytic phenotype. 10q loss was uncommon in both early and progressive tumors. The proportional gain in methylation at progression was 31% for tumors with early 1p deletion, unlike tumors with an intact 1p, which had an 87.5% gain of methylation at progression. CONCLUSIONS: Pure oligodendrogliomas with 1p/19q deletion tend to retain their cell phenotype and genetic profile unlike tumors with no deletions or mixed histology. MGMT promoter methylation is more pronounced at tumor progression, particularly in tumors with an intact 1p. These observations suggest that MGMT promoter methylation is a late event in progressive oligodendrogliomas, and therefore, their chemosensitivity is not necessarily related to MGMT methylation status.

Progressive low-grade oligodendrogliomas: response to temozolomide and correlation between genetic profile and O6-methylguanine DNA methyltransferase protein expression.

BACKGROUND: Loss of heterozygosity (LOH) on chromosomes 1p and 19q has been associated with chemosensitivity and improved prognosis in patients with oligodendrogliomas. The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) may induce resistance to DNA-alkylating agents. Recent studies demonstrated that temozolomide (TMZ), an oral alkylating agent, has efficacy in the treatment of patients with progressive, low-grade oligodendroglioma (LGO). However, to the authors' knowledge, limited data are available regarding the 1p/19q profile and its correlation with MGMT protein expression and response to treatment with DNA-alkylating drugs. METHODS: Adult patients with magnetic resonance imaging (MRI) findings and/or clinical deterioration compatible with progressive LGO were eligible for the study if they were radiotherapy-naive. TMZ cycles were repeated every 28 days at a dose of 200 mg/m2 daily for 5 consecutive days. Clinical and MRI data were used to evaluate outcomes, and Kaplan-Meier estimates were used to assess the median time to tumor progression (TTP). The 1p/19q status was analyzed from paired tumor-blood DNA samples using polymerase chain reaction-based microsatellite analysis. MGMT protein expression was estimated semiquantitatively by immunohistochemistry using paraffin embedded tumor sections. RESULTS: There were 28 patients who received treatment, and the median time from diagnosis to tumor progression was 33.5 months. The median number of TMZ cycles per patient was 12.5. Marked clinical improvements were recorded in 15 patients (54%), and objective responses were recorded in 17 patients (61%). The median TTP was 31 months, and the progression-free survival rate was 70% at 24 months. Loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively). CONCLUSIONS: TMZ was active in patients with progressive LGO, and their response to treatment was associated with 1p deletion and low MGMT protein expression. The authors suggest the possible use of MGMT immunostaining as a surrogate marker for predicting tumor chemosensitivity.