Is urinary incontinence associated with lichen sclerosus in females? A systematic review and meta-analysis.

Background: Lichen sclerosus (LS) is a scarring chronic inflammatory disease with a predilection for genital skin in both sexes. The aetiology of LS is controversial, but evidence increasingly suggests that the occluded exposure of susceptible epithelium to urine is involved in the pathogenesis of genital LS in males. This theory has not yet been robustly investigated in females. Objectives: This review and meta-analysis examined whether there is an association between urinary incontinence (UI) and genital lichen LS in females. Methods: We performed a comprehensive search of MEDLINE, Embase and CINAHL to identify observational studies assessing the prevalence of UI in females with LS. DerSimonian and Laird random-effects models were used to estimate the overall pooled prevalence and risk ratio compared to controls. Heterogeneity was assessed. Results: In total, eight studies met the inclusion criteria and five studies were included in a meta-analysis. Three studies were graded as moderate quality and five were poor. The pooled prevalence for UI in LS was 0.35 (95% confidence interval [CI] 0.13-0.58, I 2 = 98.4%). The risk ratio of UI in LS was 0.97 (95% CI 0.53-1.75, I 2 = 87.5%). Conclusion: There appears to be no difference between patients with LS and those without LS in terms of UI. Studies are limited by clinical and methodological quality and heterogeneity is high. Well-designed prospective studies are needed.

Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma.

Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell-fragility disorders, and are the genetic basis of many inherited palmoplantar keratodermas (PPKs). Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1. Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. We report four unrelated cases (one with sporadic EI and three with autosomal dominant PPK), due to two novel and two recurrent KRT1 mutations. Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern.

Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment.

Apolipoprotein E (apoE)-deficient mice have memory deficits that are associated with synaptic loss of basal forebrain cholinergic projections and with hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. Furthermore, treatment of apoE-deficient mice with the M1 selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline) [AF150(S)] abolishes their memory deficits and results in recovery of their brain cholinergic markers. In the present study, we used a panel of anti-tau monoclonal antibodies to further map the tau epitopes that are hyperphosphorylated in apoE-deficient mice and examined the effects of prolonged treatment with AF150(S). This revealed that tau of apoE-deficient mice contains a distinct, hyperphosphorylated "hot spot" domain which is localized N-terminally to the microtubule binding domain of tau, and that AF150(S) has an epitope-specific tau dephosphorylating effect whose magnitude is affected by apoE deficiency. Accordingly, epitopes which reside in the hyperphosphorylated "hot spot" are dephosphorylated by AF150(S) in apoE-deficient mice but are almost unaffected in the controls, whereas epitopes which flank this tau domain are dephosphorylated by AF150(S) in both mice groups. In contrast, epitopes located at the N and C terminals of tau are unaffected by AF150(S) in both groups of mice. These findings suggest that apoE deficiency results in hyperphosphorylation of a distinct tau domain whose excess phosphorylation can be reduced by muscarinic treatment.

Biochemical and cognitive studies of apolipoprotein-E-deficient mice.

Apolipoprotein-E-deficient mice provide a useful model system for studying the role of apolipoprotein E (apoE) in brain function. In the present study, we characterized the cholinergic function of these mice and the extent of phosphorylation of their cytoskeletal protein tau. Morris water maze tasks revealed deficits in working memory that were accompanied by a specific decrease in hippocampal and cortical choline acetyltransferase activities. Immunoblot experiments utilizing native and dephosphorylated tau and antibodies directed against specific phosphorylated and unphosphorylated tau epitopes revealed that tau of the apoE-deficient mice is hyperphosphorylated. These results show that apoE-deficient mice have cognitive cholinergic and cytoskeletal derangements and point out the importance of this model for studying the role of apoE in neuronal function.

Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice.

Apolipoprotein E-deficient mice provide a useful system for studying the role of apolipoprotein E (apoE) in the function of distinct neuronal systems. In the present study we focused on the cholinergic system of these mice. This was pursued by measurements of specific biochemical, physiological and cognitive parameters. Morris Water Maze tasks revealed impairments in working memory but not in reference memory of the apoE-deficient mice. Measurements of brain choline acetyltransferase activities revealed them to be markedly lower in the hippocampus and frontal cortex of the apoE-deficient mice than in the corresponding brain areas of the controls, but unaltered in other brain areas. In addition, hypothermia induced by the centrally acting muscarinic agonist, oxotremorine, was reduced in the apoE-deficient mice as compared to controls. These results show that apoE-deficient mice have cholinergic deficits and highlight the importance of this mouse model for studying the interactions between apoE and the cholinergic nervous system.

Phosphorylation of tau in apolipoprotein E-deficient mice.

It has been suggested that the deleterious effects of the allele E4 of apolipoprotein E (apoE) in Alzheimer's disease (AD) are related to its inability to interact with the microtubule associated protein tau and to thereby prevent its hyperphosphorylation. In the present study we investigated the effects of apoE on tau phosphorylation by immunoblot analysis of the levels and extents of phosphorylation of tau of apoE-deficient mice. This revealed that mAb AT8, which is directed against a phosphorylated tau epitope, labels tau of the apoE-deficient mice more intensely than that of control mice and that the opposite occurs with mAb Tau1, which is directed against dephosphorylated tau epitopes. mAb ALZ50 also labeled the tau enriched preparations of the apoE-deficient mice more intensely than those of the controls, whereas the extents of their labeling by the phosphorylation insensitive anti-tau mAb 134 were similar. These results suggest that tau of apoE-deficient mice is hyperphosphorylated.

Disc swelling: a tall tail?

A 30-year-old man presented with monocular visual loss secondary to chronic papilledema, due to an ependymoma involving the spinal cord. No other neurological symptoms were present at the time. Initial neuroradiologic tests as well as laboratory investigations were negative, except for elevated pressure and protein concentration of his cerebrospinal fluid. In spite of intensive investigation, the diagnosis of a spinal cord tumor was delayed for approximately 12 months until he presented with neurologic symptoms attributable to a spinal cord lesion. This is only the fourth case reported of a spinal cord tumor associated with papilledema presenting with visual loss, without any other manifestations of either elevated intracranial pressure, or spinal disease. Possible mechanisms for elevated intracranial pressure in cases of spinal cord tumors are reviewed.