Effects of sex hormones on Alzheimer's disease-associated β-amyloid oligomer formation in vitro

The folding of amyloid β-protein (Aβ) into oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathogenic event in Alzheimer's disease (AD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD. Epidemiological studies have indicated that estrogen therapy reduces the risk of developing AD in women. Here, we examined the effects of estrogen (estrone (E1), estradiol (E2), and estriol (E3)) and related sexual steroids (androstenedione (AND) and testosterone (TES)) on the in vitro oligomer formation of Aβ(1–40) and Aβ(1–42) using a method of photo-induced cross-linking of unmodified proteins (PICUP) and electron microscopic studies. Estrogens (E1, E2, and E3) inhibited low-order Aβ oligomer formation, and among them, E3 had the strongest in vitro activity. Estrogen could be a potential therapeutic agent to prevent or delay AD progression, and further understanding of the fact that these very similar molecules have different anti-oligomeric effects would contribute to the development of new agents.     

Valsartan reduces serum cystatin C and the renal vascular resistance in patients with essential hypertension

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40-80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.     

A case of MCTD overlapped by Takayasu’s arteritis, presenting Raynaud’s phenomenon as the initial manifestation of both diseases

Raynaud's phenomenon is characteristic three-phase color change of digits that occurs when hands are exposed to cold and subsequently rewarmed. Raynaud's phenomenon has many possible causes, but evaluation tends to focus on a few notorious etiologies, such as, connective tissue diseases. Thus, having reached a diagnosis, detailed physical exam to rule out other possible causes is often not performed. The authors present a case of mixed connective tissue disease (MCTD) and Takayasu's arteritis overlap in a woman, who showed Raynaud's phenomenon as an initial manifestation. She was first diagnosed as having MCTD, but her treatment did not improve the persistent Raynaud's phenomenon. Several years later, follow-up chest CT showed underlying Takayasu's arteritis and a subsequent physical examination revealed that typical abnormalities consistent with Takayasu's arteritis were present. The authors advocate thorough history taking and complete physical examinations on a routine basis to help unearth other underlying causes.     

Study of the kid-kINDL questionnaire scores for children with developmental disorders in normal classes and their parents

The KINDL-questionnaire is able to measure degrees of health and adaptability in relation to quality of life (QOL) in children. The questionnaire can be completed by children, adolescents, and their parents (parent-version). We had translated Kid-KINDL questionnaire into Japanese as Questionnaire for Measuring QOL in Japanese Elementary School Children, and reported their reliability and validity. This study investigates Japanese elementary school version of the Kid-KINDL questionnaire scores consisting of 6 dimensions (4 items each;total score, 100) for children with developmental disorders without mental retardation including high-functioned pervasive developmental disorder, attention deficit/hyperactivity disorder and learning disorder, and the parent-version scores for their mothers. Twenty individuals in normal class and their mothers participated after informed consents were obtained. Their total QOL scores were significantly lower than those in control group. Four of 6 dimensions consisting of emotional well-being, self-esteem, family, friends and school had significantly lower points. Their mothers' points in total QOL scores and all dimensions except for family dimension were significantly lower than those in control group. In comparison of scores between children with mild developmental disorders and their mothers, children estimated lower in self-esteem and family dimensions instead mother estimated lower in health, emotional well-being and school dimensions. There was no difference in total scores between them. Children with mild developmental disorders and their mothers estimate lower points of QOL scores than those of the normal control group. There are different perceptions in 5 of 6 dimensions between the children and their mothers.     

Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics

Hypoxia-inducible factors (HIFs) are master regulators of angiogenesis and cellular adaptation in hypoxic microenvironments. Accumulating evidence indicates that HIFs also regulate cell survival, glucose metabolism, microenvironmental remodeling, cancer metastasis, and tumor progression, and thus, HIFs are viewed as therapeutic targets in many diseases. Epigenetic changes are involved in the switching ‘on’ and ‘off’ of many genes, and it has been suggested that the DNA hypermethylation of specific gene promoters, histone modifications (acetylation, phosphorylation, and methylation) and small interfering or micro RNAs be regarded epigenetic gene targets for the regulation of disease-associated cellular changes. Furthermore, the hypoxic microenvironment is one of the most important cellular stress stimuli in terms of the regulation of cellular epigenetic status via histone modification. Therefore, drug development and therapeutic approaches to ischemic diseases or cancer for targeting HIFs by modulation of epigenetic status become an attractive area. Here, the authors provide a review of the literature regarding the targeting of HIF, a key modulator of hypoxic-cell response under various disease conditions, by modulating histone or DNA using endogenous small RNAs or exogenous chemicals.     

Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons

High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca²⁺ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca²⁺ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.