Ichthyosis Follicularis, Alopecia, and Photophobia (IFAP) Syndrome Due to Mutation of the Gene MBTPS2 in a Large Australian Kindred

Abstract:   Ichthyosis follicularis, alopecia and photophobia (IFAP) is a rare genodermatosis. Most patients have been men without significant family history. We present the largest kindred of IFAP reported to date in the medical literature clearly demonstrating X-linked inheritance. The gene defect has recently been mapped to Xp22.11-p22.13. Missense mutations of the gene, MBTPS2, which codes for an intramembrane zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response, are associated with the IFAP phenotype in this kindred. We describe the clinical features and discuss the differential diagnosis of IFAP. Our proband has benefited from treatment with acitretin.     

Preterm Labor: CD55 in Maternal Blood Leukocytes

Problem Intrauterine inflammation is a frequent and significant factor associated with the pathogenesis of preterm labor/birth (PTL/PTB). However, it remains unclear whether the intrauterine inflammatory responses activate the maternal peripheral circulation. We explored the association between PTL/PTB and the ‘activation’ of the peripheral circulatory system by determining whether CD55 mRNA expression within peripheral WBCs differed between PTL and control patients not in labor. Method of Study RNA was purified from white blood cells collected from pregnant women with preterm labor (n = 45), and from pregnant (n = 30) control women. CD55 gene expression was evaluated by quantitative PCR. Results The mean CD55 mRNA level within the PTL group (0.77 ± 0.03) was 1.48‐fold higher than that observed (0.52 ± 0.02) within the control group (P < 0.0001); 71% of PTL patients and only 6.7% of control subjects expressed elevated CD55 mRNA. The receiver operating characteristics (with 95% CI) of CD55 as a marker for PTL were as follows: Sensitivity, 69% (53–82%); Specificity, 93% (78–99%); Positive Predictive Value, 94% (80–99%); and Negative Predictive Value, 67% (51–80%). In the patient population that delivered prematurely (before 37 weeks), 81% expressed elevated CD55 mRNA levels with a mean of 0.78 ± 0.03 and 95% CI of 0.71–0.84. The receiver operating characteristics were as follows: Sensitivity, 73% (54–88%); Specificity, 86% (71–95%); Positive Predictive Value, 81.5% (62–94%); and Negative Predictive Value, 80% (64–91%). Conclusion Here we report for the first time that CD55 mRNA expression was elevated in the peripheral WBCs of subjects with preterm labor compared with control gestationally‐matched pregnant woman and that elevated leukocyte CD55 may be a useful predictor of subsequent PTB.     

Neuropsychiatric symptoms in dementia: importance and treatment considerations

Neuropsychiatric symptoms are frequent in people with dementia, result in distress for the people experiencing them and their caregivers, and are a common precipitant of institutional care. The safe and effective treatment of these symptoms is a key clinical priority, but is a long way from being achieved. Psychological interventions are recommended as the first line treatment strategy in most good practice guidelines, and there is emerging evidence of efficacy for agitation and depression. Neuroleptics remain the mainstay of pharmacological treatment, although meta-analyses indicate that they are mainly of benefit for the short-term (up to 12 weeks) treatment of aggression in people with Alzheimer's disease, and there have been increasing concerns about serious adverse effects including mortality. The evidence is limited for other pharmacological approaches for the treatment of agitation, and psychosis in people with Alzheimer's disease is limited, but post-hoc analyses do indicate that memantine may be a promising therapy and aromatherapy may be a useful alternative. Autopsy studies indicate that the adrenergic system may be an important therapeutic target. Clinical experience suggests that antidepressants are effective in people with severe depression in the context of dementia, but the evidence base regarding the broader value of antidepressants is far from clear. There are very few trials specifically focusing upon the treatment of neuropsychiatric symptoms in common non-Alzheimer dementias, which is a major limitation and urgently needs to be addressed to provide an evidence base to enable the safe and effective treatment of these individuals.     

A case series of 20 women with hidradenitis suppurativa treated with spironolactone

Hidradenitis suppurativa (HS) is an uncommon chronic skin condition that can range in severity from a single nodule to extensive disease and can have a profound effect on quality of life. Anti‐androgen medication has been suggested as a possible management strategy in female patients with HS and is mentioned in review articles as a treatment option. Despite this, there is limited literature documenting the use of anti‐androgens in HS. We present our experience with 20 patients with HS treated with oral spironolactone. We advocate spironolactone as a useful, low‐cost first‐line treatment for women with HS, with relatively few side‐effects.     

Evidence of an age-related threshold effect of polychlorinated biphenyls (PCBs) on neuropsychological functioning in a Native American population

Polychlorinated biphenyls (PCBs) have been suspected for some time of having adverse effects on neuropsychological functioning in humans. While there is evidence of slowing of cognitive function in children associated with exposure to PCBs, the evidence of comparable effects on adults is far less well understood. We report here on the neuropsychological evaluation of 277 Native American adults, ranging in age from 18 to 79, who were exposed to PCBs by way of environmental contamination in the St. Lawrence region of upstate New York. PCB body burden was estimated by 101 PCB congeners and neuropsychological functioning was assessed by a battery of 18 tests. Spline regression models were fitted to the latent variables of memory, motor function, and higher-order executive functioning. After adjusting for age, gender, and education the analyses revealed a threshold effect of PCBs at approximately 2 ppb. An age-by-PCB interaction effect was also observed for several variables which suggests that the threshold effect was largely confined to the age range of 40-79 and was not observable in the 18-40-year-old group. Implications of these results are discussed in comparison to previously published similar work with adults and in terms of its potential clinical meaningfulness.     

Neural KCNQ (Kv7) channels

KCNQ genes encode five Kv7 K⁺ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate, which is required for channel opening. Some effects of M-channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A-delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after-depolarization and burst-firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.     

Bacterial degradation of microcystin toxins in drinking water eliminates their toxicity.

Microcystin-LR and -LA were readily biodegraded by a bacterium, Sphingpoyxis sp. LH21, in a treated reservoir water. Detection of the microcystins was conducted using high-performance liquid chromatography (HPLC), protein phosphatase 2A (PP2A) inhibition assay and a cell-based cytotoxicity assay. The HPLC results correlated well with the two assays. The decrease in cytotoxicity, coupled with the associated decrease in microcystin concentrations, indicated that no cytotoxic by-products were being generated, highlighting the applicability of biodegradation as a feasible treatment option for effective microcystin removal.