Effect of tibial component alignment on knee kinematics and ligament tension in medial unicompartmental knee arthroplasty.

OBJECTIVES: Unicompartmental knee arthroplasty (UKA) is one surgical option for treating symptomatic medial osteoarthritis. Clinical studies have shown the functional benefits of UKA; however, the optimal alignment of the tibial component is still debated. The purpose of this study was to evaluate the effects of tibial coronal and sagittal plane alignment in UKA on knee kinematics and cruciate ligament tension, using a musculoskeletal computer simulation. METHODS: The tibial component was first aligned perpendicular to the mechanical axis of the tibia, with a 7° posterior slope (basic model). Subsequently, coronal and sagittal plane alignments were changed in a simulation programme. Kinematics and cruciate ligament tensions were simulated during weight-bearing deep knee bend and gait motions. Translation was defined as the distance between the most medial and the most lateral femoral positions throughout the cycle. RESULTS: The femur was positioned more medially relative to the tibia, with increasing varus alignment of the tibial component. Medial/lateral (ML) translation was smallest in the 2° varus model. A greater posterior slope posteriorized the medial condyle and increased anterior cruciate ligament (ACL) tension. ML translation was increased in the > 7° posterior slope model and the 0° model. CONCLUSION: The current study suggests that the preferred tibial component alignment is between neutral and 2° varus in the coronal plane, and between 3° and 7° posterior slope in the sagittal plane. Varus > 4° or valgus alignment and excessive posterior slope caused excessive ML translation, which could be related to feelings of instability and could potentially have negative effects on clinical outcomes and implant durability.Cite this article: K. Sekiguchi, S. Nakamura, S. Kuriyama, K. Nishitani, H. Ito, Y. Tanaka, M. Watanabe, S. Matsuda. Bone Joint Res 2019;8:126-135. DOI: 10.1302/2046-3758.83.BJR-2018-0208.R2.

Fruit and Vegetable Consumption and Frailty: A Systematic Review.

OBJECTIVE: To identify currently available evidence on fruit and vegetable consumption in association with frailty by conducting a systematic review of the literature and to summarise and critically evaluate it. DESIGN: Systematic review. SETTING: Four electronic databases (Embase, MEDLINE, CINAHL and PsycINFO) were systematically searched in August 2017 for observational cohort studies providing cross-sectional or prospective associations between fruit and vegetable consumption and frailty risks. Additional studies were searched by manually reviewing the reference lists of the included studies and related review papers and conducting forward citation tracking of the included studies. The methodological quality of prospective studies was assessed using the Newcastle-Ottawa scale. PARTICIPANTS: Community-dwelling general populations. RESULTS: A total of 6251 studies were identified, of which five prospective studies with follow-up periods of 2-10.5 years and two cross-sectional studies were included. Among the five prospective studies, three had adequate methodological quality. Because of different measurements and statistical methodologies, a meta-analysis was not possible. The two studies of good quality showed that fruit and vegetable consumption was mostly associated with lower risk of incident frailty. The other study as a sub-analysis retrospectively examined baseline fruit and vegetable consumption of those who developed frailty and those who did not at follow-up and showed no significant associations. CONCLUSIONS: Although good quality studies on this topic are scarce, there is some suggestion that higher fruit and vegetable consumption may be associated with lower frailty risk. More high quality research is needed.

Yokukansan inhibits morphine tolerance and physical dependence in mice: the role of α2A-adrenoceptor.

Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18ß-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade.

Geissoschizine methyl ether, an alkaloid in Uncaria hook, is a potent serotonin 1A receptor agonist and candidate for amelioration of aggressiveness and sociality by yokukansan.

Yokukansan (YKS), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situation for treating psychiatric disorders such as aggressiveness in patients with dementia. We previously demonstrated that YKS and Uncaria hook (UH), which is a constituent herb of YKS, had a partial agonistic effect to 5-HT(1A) receptors in vitro. However, it has still been unclear whether this in vitro effect is reflected in in vivo, and what the active ingredients are. The purpose of the present study is to find the active ingredient in YKS and to demonstrate the effect in in vivo. In the present study, we first studied the effect of YKS and UH on aggressiveness and sociality in socially isolated mice. YKS and UH ameliorated the isolation-induced increased aggressiveness and decreased sociality, and these ameliorative effects were counteracted by coadministration of 5-HT(1A) receptor antagonist WAY-100635, or disappeared by eliminating UH from YKS. These results suggest that the effect of YKS is mainly attributed to UH, and the active ingredient is contained in UH. To find the candidate ingredients, we examined competitive binding assay and [(35)S] guanosine 5'-O-(3-thiotriphosphate) (GTPγS) binding assay of seven major alkaloids in UH using Chinese hamster ovary cells expressing 5-HT(1A) receptors artificially. Only geissoschizine methyl ether (GM) among seven alkaloids potently bound to 5-HT(1A) receptors and acted as a partial agonist. This in vitro result on GM was further demonstrated in the socially isolated mice. As did YKS and UH, GM ameliorated the isolation-induced increased aggressiveness and decreased sociality, and the effect was counteracted by coadministration of WAY-100635. These lines of results suggest that GM in UH is potent 5-HT(1A) receptor agonist and a candidate for pharmacological effect of YKS on aggressiveness and sociality in socially isolated mice.

Accelerated growth without prepubertal obesity in nutritionally programmed microswine offspring.

Poor fetal growth and associated prepubertal growth acceleration are linked to increased risk of cardiometabolic dysfunction in later life, but whether obesity is integral to 'catch-up' growth and its ensuing risks are unknown. In microswine offspring exposed to perinatal maternal protein restriction (MPR), we measured body and organ sizes (during MPR); linear growth and weight gain (birth to 5 months of age); feed intake and utilization efficiency (5-14 weeks); and body composition at 6 and 11 weeks of age (by dual-energy X-ray absorptiometry, DEXA). During MPR, low protein offspring (LPO) showed asymmetric growth restriction with reduced body weight (Wt):length (Lth) at birth and elevated heart Wt:liver Wt ratio by 2 weeks of age. In LPO, after slow early postnatal growth (0-5 weeks), subsequent linear growth on ad libitum normal feed was absolutely accelerated (cm/week; P < 0.001) over 6-11 weeks but normal thereafter, whereas absolute weight gain (kg/week) was similar to controls but accelerated relative to lower LPO nadir weights. Concurrently, rates of fat and lean tissue accrual in LPO over 6-11 weeks were similar to normal protein offspring in absolute terms (g/5 weeks) but increased relative to lower mass at 6 weeks, yielding normal lean:Lth but reduced fat:Lth ratios at 11 weeks. LPO had higher relative feed intake (g/kg/meal) in both sexes and higher feed efficiency in females over 5-11 weeks of age. Findings suggest that postnatal linear growth acceleration preserved thinness in juvenile LPO. Given separately reported abnormalities of vascular (Bagby et al., 2011) and adipocyte function in juvenile LPO, (DuPriest et al., 2011) findings demonstrate that perinatal MPR programs catch-up growth and cardiovascular abnormalities independently of obesity.

Altered adipocyte structure and function in nutritionally programmed microswine offspring.

Adipose tissue (AT) dysfunction links obesity of any cause with cardiometabolic disease, but whether early-life nutritional deficiency can program adipocyte dysfunction independently of obesity is untested. In 3-5-month-old juvenile microswine offspring exposed to isocaloric perinatal maternal protein restriction (MPR) and exhibiting accelerated prepubertal fat accrual without obesity, we assessed markers of acquired obesity: adiponectin and tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA) levels and adipocyte size in intra-abdominal (ABD-AT) and subcutaneous (SC-AT) adipose tissues. Plasma cortisol, leptin and insulin levels were measured in fetal, neonatal and juvenile offspring. In juvenile low-protein offspring (LPO), adipocyte size in ABD-AT was reduced 22% (P = 0.011 v. controls), whereas adipocyte size in SC-AT was increased in female LPO (P = 0.05) and normal in male LPO; yet, adiponectin mRNA in LPO was low in both sexes and in both depots (P < 0.001). Plasma leptin (P = 0.004) and cortisol (P < 0.05) were reduced only in neonatal LPO during MPR. In juveniles, correlations between % body fat and adiponectin mRNA, TNF-α mRNA or plasma leptin were significant in normal-protein offspring (NPO) but absent in LPO. Plasma glucose in juvenile LPO was increased in males but decreased in females (interaction, P = 0.023); plasma insulin levels and insulin sensitivity were unaffected. Findings support nutritional programming of adipocyte size and gene expression and subtly altered glucose homeostasis. Reduced adiponectin mRNA and adipokine dysregulation in juvenile LPO following accelerated growth occurred independently of obesity, adipocyte hypertrophy or inflammatory markers; thus, perinatal MPR and/or growth acceleration can alter adipocyte structure and disturb adipokine homeostasis in metabolically adverse patterns predictive of enhanced disease risk.

Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid ß proteins in amyloid precursor protein transgenic mice.

The deposition of amyloid ß protein (Aß) is a consistent pathological hallmark of Alzheimer's disease (AD) brains. Therefore, inhibition of Aß aggregation in the brain is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. An in vitro study demonstrated that yokukansan (YKS), a traditional Japanese medicine, inhibited Aß aggregation in a concentration-dependent manner. An in vivo study demonstrated that YKS and Uncaria hook (UH), a constituent of YKS, prevented the accumulation of cerebral Aß. YKS also improved the memory disturbance and abnormal social interaction such as increased aggressive behavior and decreased social behavior in amyloid precursor protein transgenic mice. These results suggest that YKS is likely to be a potent and novel therapeutic agent to prevent and/or treat AD, and that this may be attributed to UH.

Pharmacokinetics and pharmacodynamics of vildagliptin in Japanese patients with type 2 diabetes.

OBJECTIVE: To assess the pharmacokinetics, pharmacodynamics and safety of vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), in Japanese patients with Type 2 diabetes. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, 62 Japanese patients with Type 2 diabetes received vildagliptin 10 mg, 25 mg or 50 mg twice daily for 7 days. Blood samples were collected for the determination of plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin and glucagon. RESULTS: Exposure to vildagliptin (area under the plasma concentration-time curve from 0 to 12 h (AUC0-12h) and the maximum plasma concentration (Cmax)) increased in an approximately dose-proportional manner, and no accumulation was observed following multiple doses of vildagliptin (accumulation factor 1.00 - 1.02). DPP-4 activity was completely inhibited for varying durations by all doses of vildagliptin; the duration of complete DPP-4 inhibition was dose-dependent. DPP-4 inhibition after vildagliptin 50 mg twice daily remained > 80% throughout the 24-h period. Vildagliptin treatment led to a dose-dependent increase in plasma active GLP-1 levels; the overall increases (area under the effect-time course from 0 to 8 h, AUE0-8h) after 7 days' treatment were 1.5-, 1.7-, and 1.8-fold with vildagliptin 10 mg, 25 mg and 50 mg twice daily, respectively (all p < 0.0001 vs. placebo). Postprandial plasma glucose during the 4-h period after breakfast was significantly reduced with the 10, 25 and 50 mg vildagliptin doses by 50.3, 92.2 and 69.5 mg·h/dl, respectively. Insulin levels remained unchanged in the context of reduced glucose levels at all doses studied. CONCLUSIONS: Vildagliptin demonstrated similar pharmacokinetic and pharmacodynamic effects in Japanese patients to those observed previously in non-Japanese patients with Type 2 diabetes.

Gamow-Teller strength distributions in 48Sc by the 48Ca(p,n) and 48Ti(n,p) reactions and two-neutrino double-beta decay nuclear matrix elements.

The double-differential cross sections for the 48Ca(p,n) and 48Ti(n,p) reactions were measured at 300 MeV. A multipole decomposition technique was applied to the spectra to extract the Gamow-Teller (GT) components. The integrated GT strengths up to an excitation energy of 30 MeV in 48Sc are 15.3+/-2.2 and 2.8+/-0.3 in the (p,n) and (n,p) spectra, respectively. In the (n,p) spectra additional GT strengths were found above 8 MeV where shell models within the fp shell-model space predict almost no GT strengths, suggesting that the present shell-model description of the nuclear matrix element of the two-neutrino double-beta decay is incomplete.

Blood vessels of human islets of Langerhans are surrounded by a double basement membrane.

AIMS/HYPOTHESIS: Based on mouse study findings, pancreatic islet cells are supposed to lack basement membrane (BM) and interact directly with vascular endothelial BM. Until now, the BM composition of human islets has remained elusive. METHODS: Immunohistochemistry with specific monoclonal and polyclonal antibodies as well as electron microscopy were used to study BM organisation and composition in human adult islets. Isolated islet cells and function-blocking monoclonal antibodies and recombinant soluble Lutheran peptide were further used to study islet cell adhesion to laminin (Lm)-511. Short-term cultures of islets were used to study Lutheran and integrin distribution. RESULTS: Immunohistochemistry revealed a unique organisation for human Lm-511/521 as a peri-islet BM, which co-invaginated into islets with vessels, forming an outer endocrine BM of the intra-islet vascular channels, and was distinct from the vascular BM that additionally contained Lm-411/421. These findings were verified by electron microscopy. Lutheran glycoprotein, a receptor for the Lm alpha5 chain, was found prominently on endocrine cells, as identified by immunohistochemistry and RT-PCR, whereas alpha(3) and beta(1) integrins were more diffusely distributed. High Lutheran content was also found on endocrine cell membranes in short-term culture of human islets. The adhesion of dispersed beta cells to Lm-511 was inhibited equally effectively by antibodies to integrin and alpha(3) and beta(1) subunits, and by soluble Lutheran peptide. CONCLUSIONS/INTERPRETATION: The present results disclose a hitherto unrecognised BM organisation and adhesion mechanisms in human pancreatic islets as distinct from mouse islets.

Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations.

Application of foreign clinical data across geographic regions can accelerate drug development. Drug disposition can be variable, and identification of factors influencing responsible pharmacokinetic/pharmacogenomic approaches could facilitate the universal application of foreign data and reduce the total amount of phase III clinical trials evaluating risks in different populations. Our objective was to establish and compare genotype (major cytochrome P450 (CYP) enzymes)/phenotype associations for Japanese (native and first- and third-generation Japanese living abroad), Caucasian, Chinese, and Korean populations using a standard drug panel. The mean metabolic ratios (MRs) for the four ethnic groups were similar except for a lower activity of CYP2D6 in Caucasians and CYP2C19 in Asians. Genotype, not ethnicity, impacted the MR for CYP2C9, CYP2C19, and CYP2D6; neither affected CYP1A2, CYP2E1, and CYP3A4/5 activities. We conclude that equivalent plasma drug concentrations and metabolic profiles can be expected for native Japanese, first- and third-generation Japanese, Koreans, and Chinese for compounds handled through these six CYP enzymes.

Functional magnetic resonance imaging is more reliable than somatosensory evoked potential or mapping for the detection of the primary motor cortex in proximity to a tumor.

The accurate localization of the primary motor cortex (M1) is critical for the preservation of motor function during resection of brain tumors in and around the M1. The goal of the present study was to determine which technique provided the most accurate localization of M1. The accuracy of preoperative functional magnetic resonance imaging (fMRI), intraoperative somatosensory evoked potential (SEP) and cortical mapping for the localization of M1 was determined in 17 patients with brain tumors in and around the M1. Because localization of the M1 is typically symmetrical in the cerebral hemispheres, the M1 on the affected side was localized by determination of the M1 location on the unaffected side using fMRI with patient hand clenching. The location of M1 was successfully determined by SEP in 5 of 11 cases. In the remainder of cases, the sulcus at which phase reversal occurred during SEP was shifted 1 or 2 gyri rostral to the central sulcus. The location of M1 was successfully determined by brain mapping in 9 of 15 cases. In the remainder of cases, stimulation failed to elicit a motor response. Finally, the location of M1 was successfully determined by fMRI in 16 of 17 cases. These data indicate that fMRI was more reliable than SEP or brain mapping for the detection of M1 in proximity to a tumor.

Spin correlations of strongly interacting massive fermion pairs as a test of Bell's inequality.

We report the results of the first-time test of the local hidden variable theories (Bell-Clauser-Horne-Shimony-Holt) involving strongly interacting pairs of massive spin 1/2 hadrons from the decay of short-lived (tau<10;-21sec) 2He spin-singlet state, populated in the nuclear reaction 2H+;1H-->;2He+n. The novel features of this experiment are (a) the use of an 'event-ready' [corrected] detector of nearly 100% efficiency to prepare an unbiased sample and (b) a focal-plane polarimeter of full 2pi sr acceptance with a random "post selection" of the reference axes. The spin-correlation function is deduced to be S[exp](pi/4)=2.83+/-0.24stat+/-0.07sys. This result is in agreement with nonlocal quantum mechanical prediction and it violates the Bell-CHSH inequality of |S|

An optical spectrum of the afterglow of a gamma-ray burst at a redshift of z = 6.295.

The prompt gamma-ray emission from gamma-ray bursts (GRBs) should be detectable out to distances of z > 10 (ref. 1), and should therefore provide an excellent probe of the evolution of cosmic star formation, reionization of the intergalactic medium, and the metal enrichment history of the Universe. Hitherto, the highest measured redshift for a GRB has been z = 4.50 (ref. 5). Here we report the optical spectrum of the afterglow of GRB 050904 obtained 3.4 days after the burst; the spectrum shows a clear continuum at the long-wavelength end of the spectrum with a sharp cut-off at around 9,000 A due to Lyman alpha absorption at z approximately 6.3 (with a damping wing). A system of absorption lines of heavy elements at z = 6.295 +/- 0.002 was also detected, yielding the precise measurement of the redshift. The Si ii fine-structure lines suggest a dense, metal-enriched environment around the progenitor of the GRB.

Resolving the discrepancy of 135 MeV pd elastic scattering cross sections and relativistic effects.

Three precise measurements for elastic pd scattering at 135 MeV/A have been performed with the three different experimental setups. The cross sections are described well by the theoretical predictions based on modern nucleon-nucleon forces combined with three-nucleon forces. Relativistic Faddeev calculations show that relativistic effects are restricted to backward angles. This result supports the two measurements recently reported by RIKEN and contradicts the KVI data.

Longevity-associated mitochondrial DNA 5178 A/C polymorphism and blood pressure in the Japanese population.

It has been reported that the mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism, also called NADH dehydrogenase subunit 2-237 methionine/leucine (ND2-237 Met/Leu) polymorphism, may be associated with longevity in Japanese individuals, and that the mt5178A genotype may have an antiatherogenic influence. To determine whether mt5178 A/C polymorphism influences blood pressure, we genotyped 412 healthy Japanese individuals and performed a cross-sectional study investigating the relationship between genotype and blood pressure. In women with mt5178A, the mean diastolic blood pressure was higher than in those with mt5178C by 3.2 mmHg (P=0.040). In men, no statistically significant difference in systolic or diastolic blood pressure was observed between mt5178 A/C genotypes. However, a significant correlation between mt5178 A/C genotypes and the effects of habitual drinking on blood pressure was found. After adjustment for several factors, in men carrying mt5178C, both systolic and diastolic blood pressure were significantly higher in daily drinkers than in occasional (P=0.002 and 0.002, respectively) as well as nondrinkers (P<0.001 and 0.001, respectively), whereas in men carrying mt5178A, no significant differences in blood pressure were detected, irrespective of alcohol consumption. These results suggest that mt5178 A/C (=ND2-237 Met/Leu) polymorphism may influence both diastolic blood pressure in Japanese women and the blood-pressure-increasing effect of drinking in Japanese men.

Congestive heart failure induced by the combination of atrial fibrillation and tricuspid regurgitation.

Atrial fibrillation (AF) and tricuspid regurgitation (TR) may induce congestive heart failure (CHD). Using electrocardiography and echocardiography, we examined the clinical characteristics and haemodynamic findings in 100 patients with AF + TR + CHF, AF + TR, AF or TR. The fractional shortening in all groups with AF was significantly decreased compared with the TR group. The ejection fraction in patients with AF + TR + CHF was significantly lower than in the TR group. Twenty-four of the 72 patients with AF and TR (with or without CHF) were treated, and 13 were monitored for heart rate and severity of TR. Eight months after start of treatment the heart rate and typical symptoms and signs of heart failure had improved significantly in nine patients, but the severity of TR did not change. TR worsened in the remaining four patients but they did not develop CHF. Our results suggest that increased heart rate due to the combination of AF and TR could be responsible for CHF.