Contribution of Eye-Tracking to Study Cognitive Impairments Among Clinical Populations.

In the field of psychology, the merge of decision-theory and neuroscientific methods produces an array of scientifically recognized paradigms. For example, by exploring consumer's eye-movement behavior, researchers aim to deepen the understanding of how patterns of retinal activation are being meaningfully transformed into visual experiences and connected with specific reactions (e.g., purchase). Notably, eye-movements provide knowledge of one's homeostatic balance and gatekeep information that shape decisions. Hence, vision science investigates the quality of observed environments determined under various experimental conditions. Moreover, it answers questions on how human process visual stimuli and use gained information for a successful strategy to achieve certain goals. While capturing cognitive states with the support of the eye-trackers progresses at a relatively fast pace in decision-making research, measuring the visual performance of real-life tasks, which require complex cognitive skills, is tentatively translated into clinical experiments. Nevertheless, the potential of the human eye as a highly valuable source of biomarkers has been underlined. In this article, we aim to draw readers attention to decision-making experimental paradigms supported with eye-tracking technology among clinical populations. Such interdisciplinary approach may become an important component that will (i) help in objectively illustrating patient's models of beliefs and values, (ii) support clinical interventions, and (iii) contribute to health services. It is possible that shortly, eye-movement data from decision-making experiments will grant the scientific community a greater understanding of mechanisms underlining mental states and consumption practices that medical professionals consider as obsessions, disorders or addiction.

Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies.

BACKGROUND: Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice. RESEARCH DESIGN AND METHODS: The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time. RESULTS: Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype. CONCLUSIONS: Agalsidase beta demonstrated acceptable safety and tolerability, with sustained reductions in blood GL-3 levelsin Japanese patients with Fabry disease in real-world clinical practice. CLINICAL TRIAL REGISTRATION: NCT00233870/AGAL03004 (Special Drug Use Investigation of Agalsidase beta).

Chronic renal failure due to amyloid nephropathy caused by chronic infection after total hip replacement.

A 75-year-old woman was admitted to our hospital because of proteinuria, pitting edema on the foot, and renal impairment. She had undergone total hip replacement (THR) for femoral neck fracture at the age of 66. Nine years later, she met with an accident during farming and was treated at an emergency hospital for severe general trauma. On the basis of systemic symptoms, she was diagnosed with nephrotic syndrome. Renal biopsy by Congo-red staining and electron microscopy revealed amyloid deposition on glomeruli, interstitium, and interlobar arteries. The amyloid was immunohistochemically identified as AA amyloidosis. The patient eventually required maintenance hemodialysis because of impaired renal function. AA amyloidosis is an unusual complication of intractable inflammation. Chronic infection with abscess occurred around the artificial hip joint following THR and possibly induced secondary amyloidosis. THR is a common and necessary procedure adopted for femoral neck fracture. Orthopedic surgeons should, however, carefully monitor the occurrence of chronic infection after THR because such an infection could lead to renal dysfunction and/or failure via AA amyloidosis in rare cases.

Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125).

Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex.

Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for approximately 75-80% of cases (LQT1-11). Direct sequencing of SNTA1, the gene encoding alpha1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S-nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.

Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome.

BACKGROUND: Autopsy-negative sudden unexplained death, including sudden infant death syndrome, can be caused by cardiac channelopathies such as Brugada syndrome (BrS). Type 1 BrS, caused by mutations in the SCN5A-encoded sodium channel, accounts for approximately 20% of BrS. Recently, a novel mutation in the glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) disrupted trafficking of SCN5A in a multigenerational family with BrS. We hypothesized that mutations in GPD1-L may be responsible for some cases of sudden unexplained death/sudden infant death syndrome. METHODS AND RESULTS: Using denaturing high-performance liquid chromatography and direct DNA sequencing, we performed comprehensive open-reading frame/splice site mutational analysis of GPD1-L on genomic DNA extracted from necropsy tissue of 83 unrelated cases of sudden unexplained death (26 females, 57 males; average age, 14.6+/-10.7 years; range, 1 month to 48 years). A putative, sudden unexplained death-associated GPD1-L missense mutation, E83K, was discovered in a 3-month-old white boy. Further mutational analysis was then performed on genomic DNA derived from a population-based cohort of 221 anonymous cases of sudden infant death syndrome (84 females, 137 males; average age, 3+/-2 months; range, 3 days to 12 months), revealing 2 additional mutations, I124V and R273C, in a 5-week-old white girl and a 1-month-old white boy, respectively. All mutations occurred in highly conserved residues and were absent in 600 reference alleles. Compared with wild-type GPD1-L, GPD1-L mutations coexpressed with SCN5A in heterologous HEK cells produced a significantly reduced sodium current (P<0.01). Adenovirus-mediated gene transfer of the E83K-GPD1-L mutation into neonatal mouse myocytes markedly attenuated the sodium current (P<0.01). These decreases in current density are consistent with sodium channel loss-of-function diseases like BrS. CONCLUSIONS: The present study is the first to report mutations in GPD1-L as a pathogenic cause for a small subset of sudden infant death syndrome via a secondary loss-of-function mechanism whereby perturbations in GPD1-L precipitate a marked decrease in the peak sodium current and a potentially lethal BrS-like proarrhythmic substrate.

SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.

BACKGROUND: Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming alpha-subunit associated with 1 or more auxiliary beta-subunits. Four different beta-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. METHODS AND RESULTS: We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na(vbeta)-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel alpha-subunit (hNa(V)1.5). Compared with the wild-type, L179F-beta4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-beta4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations. CONCLUSIONS: We provide the seminal report of SCN4B-encoded Na(vbeta)4 as a novel LQT3-susceptibility gene.

Urban-rural difference in stroke mortality from a 19-year cohort study of the Japanese general population: NIPPON DATA80.

In Japan, cohort studies on stroke have been mainly conducted in rural areas, with few studies comparing stroke mortality between urban and rural areas. We aimed to explore urban-rural difference in stroke mortality throughout Japan using a representative sample of the general Japanese population, the NIPPON DATA80. This study included 9309 subjects (4080 men and 5229 women) aged 30 years or older who were residents of 294 areas in 211 municipalities of Japan in 1980 and followed-up until 1999. Population size of the municipality in which the aforementioned areas were located was used to distinguish between urban and rural areas, because municipalities in Japan are classified as village, town or city principally by population size. We applied a multilevel logistic regression model to take into account the hierarchical data structure of individuals (subjects) (level 1) nested within areas (level 2), and then calculated odds ratios and 95% confidence intervals (CIs) of deaths from total stroke. Statistically significant variance between areas was not observed in men but was in women. Age-adjusted odds ratios of the areas in the medium (population > or = 30,000 and <300,000) and small municipalities (<30,000) compared with the areas in the large municipalities (> or = 300,000) were 1.31 and 1.40 in men, and 1.32 and 1.62 in women, respectively. Multivariate-adjusted odds ratios (adjusted for age, body mass index, total cholesterol, diabetes, hypertension, current smoking, and daily alcohol consumption) of the areas in the medium and small municipalities compared with the areas in the large municipalities were 1.29 and 1.36 in men, and 1.34 and 1.68 in women, respectively. In conclusion, stroke mortality tended to be higher in rural areas than in urban areas in Japan, especially among women.

Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.

OBJECTIVES: We sought to explore the relationship between a Tcap gene (TCAP) abnormality and cardiomyopathy. BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc. METHODS: The TCAP was analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays-yeast two-hybrid and glutathion S-transferase pull-down competition-were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q. RESULTS: Two TCAP mutations, T137I and R153H, were found in patients with HCM, and another TCAP mutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1. CONCLUSIONS: These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.

Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation.

OBJECTIVE: The function of the C-terminus region of the human ether-a-go-go related gene (HERG) has not been well characterized except for its involvement in trafficking. To understand further the role of C-terminus region, we performed a functional analysis of a novel frameshift mutation (1122fs/147) identified in a Japanese long QT syndrome 2 (LQT2) patient who had recurrent episodes of syncope. METHODS: Wild type (WT) and mutant HERG plasmids were transfected into human embryonic kidney (HEK-293) cells, and whole-cell current was recorded by the patch-clamp technique. Confocal microscopy was performed to examine the membrane distribution of channel protein using a green fluorescent protein tagged to the N-terminus of HERG. RESULTS: The mutant 1122fs/147 alone could express current, but reduced density by 74% of control. No dominant negative effect was noted with co-expression of WT and 1122fs/147. Activation and deactivation time constants were not changed, while inactivation was accelerated in 1122fs/147 compared to WT, and V(1/2) of steady-state inactivation curve shifted by 11 mV in the negative direction. Current density of 1123stop mutant revealed 49% reduction compared to WT and showed no shift in steady-state inactivation. Confocal microscopy revealed reduced protein expression on the cell surface both in 1122fs/147 and 1123stop mutants compared to WT. CONCLUSION: Frameshift mutation at the C-terminus region with additional 147 amino acids evoked a loss of function of the HERG channel. A negative shift in steady-state inactivation induced by the additional 147 amino acids and trafficking defect contribute to a reduced current amplitude of 1122fs/147.