Identification of simultaneous mutation of fibrinogen alpha chain and protein C genes in a Japanese kindred

Afibrinogenaemia usually induces a bleeding tendency during infancy, whereas protein C deficiency increases susceptibility to thrombosis in children or adolescence. Mutations of these genes have been, therefore, established as independent risk factors for coagulation disorders. We describe the homozygous mutation of the fibrinogen alpha chain gene and additional heterozygous mutation of the protein C gene in a male infant who showed prolonged umbilical bleeding after birth. On examination, the plasma fibrinogen was undetectable, and the activity and antigen level of protein C were reduced. The patient showed no fibrinogen Aalpha chain as well as Bbeta and gamma chains by Western blotting. The sequencing analysis showed the homozygous deletion of 1238 bases from intron 3 at position 2008 to intron 4 at position 3245 in the fibrinogen alpha chain gene. Both parents were heterozygous carriers of this mutation. In this patient, an additional mutation was also detected in the protein C gene: the heterozygous deletion of exon 7 at position 6161-6163 or 6164-6166, resulting the deletion of one amino acid (Lys150 or 151). His mother was also a carrier of this mutation. As the simultaneous mutation of the fibrinogen alpha chain and protein C genes has not been previously reported, the influence of the interaction between these two mutations on the clinical manifestations of this patient should be carefully monitored for a long period.     

Associations between sleep habits and mental health status and suicidality in a longitudinal survey of monozygotic twin adolescents

Several epidemiological studies have indicated that there is a relationship between sleep habits, such as sleep duration, bedtime and bedtime regularity, and mental health status, including depression and anxiety in adolescents. However, it is still to be clarified whether the relationship is direct cause‐and‐effect or mediated by the influence of genetic and other traits, i.e. quasi‐correlation. To examine this issue, we conducted a twin study using a total of 314 data for monozygotic twins from a longitudinal survey of sleep habits and mental health status conducted in a unified junior and senior high school (grades 7–12), located in Tokyo, Japan. Three‐level hierarchical linear model analysis showed that both bedtime and sleep duration had significant associations with the Japanese version of the 12‐item General Health Questionnaire (GHQ‐12) score, suicidal thoughts and the experience of self‐harm behaviours when genetic factors and shared environmental factors, which were completely shared between co‐twins, were controlled for. These associations were statistically significant even after controlling for bedtime regularity, which was also associated significantly with the GHQ‐12 score. These suggest that the associations between sleep habits and mental health status were still statistically significant after controlling for the influence of genetic and shared environmental factors of twins, and that there may be a direct cause‐and‐effect in the relationship in adolescents. Thus, late bedtime and short sleep duration could predict subsequent development of depression and anxiety, including suicidal or self‐injury risk. This suggests that poor mental health status in adolescents might be improved by health education and intervention concerning sleep and lifestyle habits.     

Change of a motor synergy for dampening hand vibration depending on a task difficulty

The present study investigated the relationship between the number of usable degrees of freedom (DOFs) and joint coordination during a human-dampening hand vibration task. Participants stood on a platform generating an anterior–posterior directional oscillation and held a water-filled cup. Their usable DOFs were changed under the following conditions of limb constraint: (1) no constraint; (2) ankle constrained; and (3) ankle–knee constrained. Kinematic whole-body data were recorded using a three-dimensional position measurement system. The jerk of each body part was evaluated as an index of oscillation intensity. To quantify joint coordination, an uncontrolled manifold (UCM) analysis was applied and the variance of joints related to hand jerk divided into two components: a UCM component that did not affect hand jerk and an orthogonal (ORT) component that directly affected hand jerk. The results showed that hand jerk when the task used a cup filled with water was significantly smaller than when a cup containing stones was used, regardless of limb constraint condition. Thus, participants dampened their hand vibration utilizing usable joint DOFs. According to UCM analysis, increasing the oscillation velocity and the decrease in usable DOFs by the limb constraints led to an increase of total variance of the joints and the UCM component, indicating that a synergy-dampening hand vibration was enhanced. These results show that the variance of usable joint DOFs is more fitted to the UCM subspace when the joints are varied by increasing the velocity and limb constraints and suggest that humans adopt enhanced synergies to achieve more difficult tasks.     

Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.Angiogenesis plays a central role in many diseases, including age-related macular degeneration (AMD), a leading cause of blindness. Advanced AMD exists in two forms, “atrophic” and “neovascular,” which are defined by the absence or presence of choroidal neovascularization (CNV), respectively (1). Neovascular AMD is characterized by the formation of abnormal blood vessels that grow from the choroidal vasculature, through breaks in Bruch’s membrane, toward the outer retina (1). These vessels generally are immature in nature and leak fluid below or within the retina (2). Although growth factors are thought to play an important role in the late stage of neovascular AMD progression, they likely do not contribute to the underlying cause of the disease. The current standard of care for individuals with neovascular AMD is based on the targeting of VEGF, which promotes both angiogenesis and vascular permeability (3). However, although VEGF-targeted therapy attenuates angiogenesis and vascular permeability, it does not lead to complete vascular regression or disease resolution (3).The ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. The ω-6 LCPUFA, arachidonic acid (AA), and its cytochrome P450 (CYP)-generated metabolites (epoxyeicosatrienoic acids, EETs) recently have attracted much attention as a result of increasing evidence that they play a role in cancer as well as in cardiovascular disease (4–9). EETs are part of the VEGF-activated signaling cascade leading to angiogenesis (10) and promote tumor growth and metastasis (11). The major dietary ω-3 LCPUFAs are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are highly enriched in the central nervous system including the retina (12). The ω-3 LCPUFAs have antithrombotic, antiangiogenic, and anti-inflammatory properties, and they compete with ω-6 LCPUFAs as substrates for synthesis of downstream metabolites by CYP enzymes, cyclooxygenases (COX), and lipoxygenases (LOX) (6, 13–15). Moreover, dietary enrichment with ω-3 LCPUFAs has been shown to protect against pathological angiogenesis-associated cancer and retinopathy (2, 16–19). Of the three main pathways (COX, LOX, and CYP) involved in eicosanoid biosynthesis, the lipid mediators derived from the CYP branch are the most susceptible to changes in dietary fatty acid composition (20–23). The ω-3 double bond that distinguishes DHA and EPA from their ω-6 counterparts provides a preferred epoxidation site for specific CYP family members (20, 22). In fact, most CYP isoforms can metabolize EPA and DHA with significantly higher catalytic efficiency than AA, making them uniquely susceptible to variations in the availability of these lipids (19–22). CYP epoxygenases target the ω-3 double bond, resulting in an accumulation of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) derived from EPA and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from DHA (20, 22). Very recently, it was recognized that19,20-EDP inhibits angiogenesis, tumor growth, and metastasis (24). Thus, it appears that the CYP–epoxygenase pathway has the capacity to produce proangiogenic metabolites from ω-6 LCPUFAs (10, 11) and antiangiogenic metabolites from ω-3 LCPUFAs (24). This unique feature of the CYP enzymes may provide a previously unidentified mechanistic link between the ω-6/ω-3 ratio of dietary LCPUFAs and pathological angiogenesis; however, their roles in ocular angiogenesis have been largely unexplored to date.We now show that dietary enrichment with ω-3 LCPUFAs suppresses CNV, vascular leakage, and immune cell recruitment to the lesion site in a mouse model of laser-induced CNV. We characterized the CYP-dependent pathway by which dietary ω-3 LCPUFAs promote resolution of choroidal neovessels in this model and identified CYP-generated metabolites 17,18-EEQ and 19,20-EDP as mediators of disease resolution. Furthermore, we show that expression of adhesion molecules at the CNV site was down-regulated in association with inhibition of leukocyte recruitment in mice receiving ω-3 LCPUFAs.     

Prognostic value of aortic valve area index in asymptomatic patients with severe aortic stenosis

Recently, an aortic valve area (AVA) index (AVAI) <0.6 cm(2)/m(2) was proposed as an indicator of severe aortic stenosis. The purpose of the present study was to clarify the prognostic value of the AVAI. We identified 103 consecutive asymptomatic patients (mean age 72 ± 11 years) with severe aortic stenosis, defined by an AVA of <1.0 cm(2), who had not undergone aortic valve replacement on initial evaluation. During follow-up (median 36 ± 27 months), 31 aortic valve replacements and 20 cardiac deaths occurred. Multivariate analysis revealed that an AVAI <0.6 cm(2)/m(2) (hazard ratio 2.6, 95% confidence interval 1.1 to 6.3; p = 0.03) and peak aortic jet velocity (Vp) >4.0 m/s (hazard ratio 2.6, 95% confidence interval 1.2 to 5.8; p = 0.02) were associated with cardiac events but that an AVA <0.75 cm(2) was not. The event-free survival of patients with an AVAI of ≥0.6 cm(2)/m(2) was better than that for those with an AVAI <0.6 cm(2)/m(2) (86% vs 41% at 3 years, p <0.01). Furthermore, patients with an AVAI of ≥0.6 cm(2)/m(2) and Vp of ≤4.0 m/s showed an excellent prognosis, but those without these findings had poorer outcomes. In conclusion, AVAI is a powerful predictor of adverse events in asymptomatic patients with severe aortic stenosis. Furthermore, the combination of AVAI and Vp provides additional prognostic information. Watchful observations are required for timely aortic valve replacement in patients with an AVAI of <0.6 cm(2)/m(2) or a Vp >4.0 m/s.     

Repeated artemisinin-based combination therapies in a malaria hyperendemic area of Mali: efficacy, safety, and public health impact

Artemisinin-based combination therapies (ACTs) are the first-line treatment of uncomplicated malaria. The public health benefit and safety of repeated administration of a given ACT are poorly studied. We conducted a randomized trial comparing artemether-lumefantrine, artesunate plus amodiaquine (AS+AQ) and artesunate plus sulfadoxine-pyrimethamine (AS+SP) in patients 6 months of age and older with uncomplicated malaria in Mali from July 2005 to July 2007. The patient received the same initial treatment of each subsequent uncomplicated malaria episode except for treatment failures where quinine was used. Overall, 780 patients were included. Patients in the AS+AQ and AS+SP arms had significantly less risk of having malaria episodes; risk ratio (RR) = 0.84 (P = 0.002) and RR = 0.80 (P = 0.001), respectively. The treatment efficacy was similar and above 95% in all arms. Although all drugs were highly efficacious and well tolerated, AS+AQ and AS+SP were associated with less episodes of malaria.     

Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study)

We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th-75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th-75th percentiles -0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice.