Relationship of Serum Carnitine Level with Falls and Gait Disturbance in the Elderly.

BACKGROUND: Gait disturbance and falls are serious events that can impair activities of daily living (ADL) in the elderly. On the other hand, carnitine plays essential roles in energy production, and carnitine deficiency leads to low activity levels. OBJECTIVES: We examined whether a lower serum carnitine concentration was correlated with falls and gait disturbances in the elderly. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study. One hundred and ninety-eight elderly patients (male, 83; female, 115; 81 ± 6 years old) were enrolled in this study. MEASUREMENTS: Physical performance (hand grip strength, leg strength, walking speed, one-leg standing time, and tandem gait steps) and frailty status (The Edmonton Frail Scale: EFS) were evaluated. The serum total, free, and acylated carnitine levels were measured using an enzyme cycling method. We then investigated the associations between the serum carnitine level, history of falls, and the results of these physical examinations. RESULTS: Of the 198 subjects, 56 (28%) had a history of falls within the past one year. The patients with a history of falls had lower serum total carnitine and free carnitine levels than those without a history of falls. Regarding the physical performance results, the patients with a history of falls had higher EFS scores, a weaker hand grip strength, a slower walking speed, a shorter one-leg standing time, and a smaller number of tandem gait steps than those without a history of falls. A logistic regression analysis showed that the low serum total carnitine concentration was identified as an independent factor associated with a history of falls, a slow walking speed after adjustments for age, sex and modified EFS. CONCLUSIONS: A low serum carnitine level is associated with a history of falls and gait disturbances in elderly people.

Characterization of Transporters in the Hepatic Uptake of TAK-475 M-I, a Squalene Synthase Inhibitor, in Rats and Humans.

TAK-475 (lapaquistat acetate) is a squalene synthase inhibitor and M-I is a pharmacologically active metabolite of TAK-475. Preclinical pharmacokinetic studies have demonstrated that most of the dosed TAK-475 was hydrolyzed to M-I during the absorption process and the concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration to rats. In the present study, the mechanism of the hepatic uptake of M-I was investigated.The uptake studies of (14)C-labeled M-I into rat and human hepatocytes indicated that the uptakes of M-I were concentrative, temperature-dependent and saturable in both species with Km values of 4.7 and 2.8 µmol/L, respectively. M-I uptake was also inhibited by cyclosporin A, an inhibitor for hepatic uptake transporters including organic anion transporting polypeptide (OATP). In the human hepatocytes, M-I uptake was hardly inhibited by estrone 3-sulfate as an inhibitor for OATP1B1, and most of the M-I uptake was Na(+)-independent. Uptake studies using human transporter-expressing cells revealed the saturable uptake of M-I for OATP1B3 with a Km of 2.13 µmol/L. No obvious uptake of M-I was observed in the OATP1B1-expressing cells.These results indicated that M-I was taken up into hepatocytes via transporters in both rats and humans. OATP1B3 would be mainly involved in the hepatic uptake of M-I in humans. These findings suggested that hepatic uptake transporters might contribute to the liver-selective inhibition of cholesterol synthesis by TAK-475. This is the first to clarify a carrier-mediated hepatic uptake mechanism for squalene synthase inhibitors.

Pharmacokinetics of TAK-475, a Squalene Synthase Inhibitor, in Rats and Dogs.

The pharmacokinetics of TAK-475 (lapaquistat acetate), a squalene synthase inhibitor, was investigated in rats and dogs. After oral administration of (14)C-labeled TAK-475 ([(14)C]TAK-475) to rats and dogs at a dose of 10 mg/kg, the bioavailability (BA) was relatively low at 3.5 and 8.2%, respectively. The main component of the radioactivity in the plasma was M-I, which has a comparable pharmacological activity to TAK-475 in vitro. The radioactivity in the portal plasma after intraduodenal administration of [(14)C]TAK-475 to portal vein-cannulated rat was also mainly M-I, suggesting that most of the TAK-475 was hydrolyzed to M-I during the permeable process in the intestine. The concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration of [(14)C]TAK-475 to rats. The main elimination route of the radioactivity was fecal excretion after oral administration of [(14)C]TAK-475 to rats and dogs, and the absorbed radioactivity was mainly excreted via the bile as M-I in rats. M-I excreted into the bile was partially subjected to enterohepatic circulation. These results suggest that although the BA values of TAK-475 are low, M-I can exert compensatory pharmacological effects in the animals. These pharmacokinetic characteristics in animals were also confirmed in the clinical studies. The evaluation of M-I disposition is important for the pharmacokinetics, pharmacodynamics and toxicity of TAK-475 in animals and humans.

Heavy holes as a precursor to superconductivity in antiferromagnetic CeIn3.

Numerous phenomenological parallels have been drawn between f- and d-electron systems in an attempt to understand their display of unconventional superconductivity. The microscopics of how electrons evolve from participation in large moment antiferromagnetism to superconductivity in these systems, however, remains a mystery. Knowing the origin of Cooper paired electrons in momentum space is a crucial prerequisite for understanding the pairing mechanism. Of special interest are pressure-induced superconductors CeIn(3) and CeRhIn(5) in which disparate magnetic and superconducting orders apparently coexist-arising from within the same f-electron degrees of freedom. Here, we present ambient pressure quantum oscillation measurements on CeIn(3) that crucially identify the electronic structure-potentially similar to high-temperature superconductors. Heavy hole pockets of f-character are revealed in CeIn(3), undergoing an unexpected effective mass divergence well before the antiferromagnetic critical field. We thus uncover the softening of a branch of quasiparticle excitations located away from the traditional spin fluctuation-dominated antiferromagnetic quantum critical point. The observed Fermi surface of dispersive f-electrons in CeIn(3) could potentially explain the emergence of Cooper pairs from within a strong moment antiferromagnet.

Precision measurement of neutrino oscillation parameters with KamLAND.

The KamLAND experiment has determined a precise value for the neutrino oscillation parameter Deltam21(2) and stringent constraints on theta12. The exposure to nuclear reactor antineutrinos is increased almost fourfold over previous results to 2.44 x 10(32) proton yr due to longer livetime and an enlarged fiducial volume. An undistorted reactor nu[over]e energy spectrum is now rejected at >5sigma. Analysis of the reactor spectrum above the inverse beta decay energy threshold, and including geoneutrinos, gives a best fit at Deltam21(2)=7.58(-0.13)(+0.14)(stat) -0.15+0.15(syst) x 10(-5) eV2 and tan2theta12=0.56(-0.07)+0.10(stat) -0.06+0.10(syst). Local Deltachi2 minima at higher and lower Deltam21(2) are disfavored at >4sigma. Combining with solar neutrino data, we obtain Deltam21(2)=7.59(-0.21)+0.21 x 10(-5) eV2 and tan2theta12=0.47(-0.05)+0.06.

Fermi surface of CeIn3 above the Néel critical field.

We report measurements of the de Haas-van Alphen effect in CeIn(3) in magnetic fields extending to approximately 90 T, well above the Néel critical field of mu(0)H(c) approximately 61 T. The unreconstructed Fermi surface a sheet is observed in the high magnetic field polarized paramagnetic limit, but with its effective mass and Fermi surface volume strongly reduced in size compared to that observed in the low magnetic field paramagnetic regime under pressure. The spheroidal topology of this sheet provides an ideal realization of the transformation from a "large Fermi surface" accommodating f electrons to a "small Fermi surface" when the f-electron moments become polarized.

Rewarming following accidental hypothermia in patients with acute subdural hematoma: case report.

A 57-year-old man was admitted to the Emergency and Critical Care Department with accidental hypothermia (31.5 degrees C) after resuscitation from cardiopulmonary arrest (CPA). Brain CT revealed an acute subdural hematoma. Active core rewarming to 33 degrees C was performed using an intravenous infusion of warm crystalloid. The patient underwent craniotomy soon after admission, with bladder temperature maintained at 33 to 34 degrees C throughout the surgery. Therapeutic hypothermia (34 degrees C) was continued for 2 days, followed by gradual rewarming. After rehabilitation, the patient was able to continue daily life with assistance. Traumatic brain injury (TBI) following CPA is associated with extremely unfavorable outcomes. Very few patients with acute subdural hematomas presenting with accidental hypothermia and CPA have been reported to recover. No suitable strategies have been clearly established for the rewarming performed following accidental hypothermia in patients with TBI. Our experience with this patient suggests that therapeutic hypothermia might improve the outcome in some patients with severe brain injury. It also appears that the method used for rewarming might play an important role in the therapy for TBI with accidental hypothermia.

Importance of cerebral perfusion pressure management using cerebrospinal drainage in severe traumatic brain injury.

OBJECTIVE: To evaluate hemodynamics in patients with severe traumatic brain injury (TBI) after cerebral perfusion pressure (CPP) management using cerebrospinal fluid (CSF) drainage. METHODS: Twenty-six patients with TBI (Glasgow Coma Score = 8 or less) were investigated. Mean arterial blood pressure, CPP, cardiac index (CI), systemic vascular resistance index (SVRI), and central venous pressure were measured. The patients were divided into 2 groups after craniotomy: the intraparenchymal ICP (IP-ICP) monitoring group (n = 14) and ventricular ICP (V-ICP) monitoring group (n = 12). Patient hemodynamics were investigated on the second hospital day to identify differences. Measurements indicated a target CPP above 70 mmHg and a central venous pressure of 8 10 mmHg in both groups. Mannitol administration (IP-ICP group) or CSF drainage (V-ICP group) was performed whenever the CPP remained below 70 mmHg. RESULTS: High SVRI and low CI (p < 0.05) were observed in the IP-ICP group. The V-ICP group exhibited a reduction in the total fluid infusion volume of crystalloid (p < 0.01) and a reduction in the frequency of hypotensive episodes after the mannitol infusion. CONCLUSIONS: CPP management using CSF drainage decreases the total infusion volume of crystalloid and may reduce the risk of aggravated brain edema after excess fluid resuscitation.

Clinical characteristics of postoperative contralateral intracranial hematoma after traumatic brain injury.

OBJECTIVES: To investigate the clinical characteristics of contralateral intracranial hematoma (ICH) after traumatic brain injury. METHODS: The subjects included 149 patients with traumatic ICH treated by hematoma evacuation. The patients were retrospectively divided into a bilateral ICH (B-ICH) group and unilateral ICH (U-ICH) group after craniotomy using brain CT scans for comparison of the following parameters: complicated expanded brain bulk from the cranial window, hypotension during craniotomy, and outcome. RESULTS: Post-craniotomy brain CT scans revealed U-ICH in 106 patients and B-ICH in 43 patients. Average Glasgow Coma Scale on arrival did not differ between the groups, but a higher proportion of patients in the B-ICH group deteriorated after admission (p = 0.02). The B-ICH patients also exhibited a significantly higher rate of expanded brain bulk from the cranial window (p < 0.05). No significant difference was observed between the groups with hypotension during craniotomy. The B-ICH group exhibited a lower rate of favorable outcome (p < 0.05) and higher mortality (p < 0.05). CONCLUSION: The B-ICH patients had a worse outcome than the U-ICH patients. Contralateral ICH was difficult to forecast based on pre- and intraoperative clinical conditions. Subdural hematoma or contusional ICH was frequently observed as a contralateral ICH.

Changes in coagulative and fibrinolytic activities in patients with intracranial hemorrhage.

OBJECTIVE: To investigate whether any changes occur in the coagulative/fibrinolytic cascade in patients with subarachnoid hemorrhage (SAH) or hypertensive intracerebral hemorrhage (HICH). DESIGN AND METHODS: Subjects included 143 patients with intracranial hemorrhage (SAH, n = 50; HICH, n = 82; ROSC-SAH [return of spontaneous circulation after cardiopulmonary arrest due to SAH], n = 11). Coagulative and fibrinolytic factors were measured in blood samples taken on admission. RESULTS: The prothrombin fragment 1+2 level was significantly higher (p < 0.005) in SAH patients than in HICH patients. The fibrinolytic factors (plasmin alpha 2-plasmin inhibitor complex, D-dimer, or fibrinogen degradation products) in SAH and ROSC-SAH were both significantly higher than those in HICH, but the significance of difference was stronger in the case of ROSC-SAH (p < 0.05). DISCUSSION: Both coagulative and fibrinolytic activities were altered after the onset of SAH. These results demonstrate that the coagulative/fibrinolytic cascade might be activated via different mechanisms in different types of stroke. It remains unclear, however, whether a significant alteration of the fibrinolytic cascade in patients with ROSC-SAH might be a nonspecific phenomenon attributable to the reperfusion after collapse.

Brain oxygen metabolism may relate to the temperature gradient between the jugular vein and pulmonary artery after cardiopulmonary resuscitation.

OBJECTIVE: A gradient between the jugular vein temperature and core body temperature has been reported in animal and clinical studies; however, the pathophysiological meaning of this phenomenon remains unclear. This study was conducted to identify the temperature gradient between the jugular vein and pulmonary artery in comatose patients after cardiopulmonary resuscitation. MATERIALS AND METHODS: The temperatures of the jugular vein and pulmonary artery were measured in 19 patients at 6 and 24 hours after cardiopulmonary resuscitation. Jugular venous blood saturation (SjO2; %) was also measured concomitantly. The patients were divided into 2 groups: high SjO2 (SjO2 > 75%: H-group; n = 10) and normal SjO2 (SjO2 < or = 75%: N-group; n = 9). The temperature gradient was calculated by subtracting the temperature of the pulmonary artery from that of the jugular vein (jugular - pulmonary = dT degrees C). Statistical significance was defined as p < 0.05. RESULTS: dT was significantly lower in the H-group than in the N-group at 6 hours (0.120 +/- 0.011: mean +/- SD vs. 0.389 +/- 0.036: p = 0.0012) and 24 hours (0.090 +/- 0.005 vs. 0.256 +/- 0.030: p = 0.0136) after cardiopulmonary resuscitation. CONCLUSION: The temperature gradient between the jugular vein and pulmonary artery was significantly lower in patients with high SjO2 after cardiopulmonary resuscitation. This temperature gradient may be reflected in brain oxygen metabolism.

Acceleration of chemokine production from endothelial cells in response to lipopolysaccharide in hyperglycemic condition.

UNLABELLED: Chronic hyperglycemia is an established risk factor for endothelial damage. It remains unclear, however, whether brief hyperglycemic episodes after acute stress alter the function of vascular endothelial cells in response to endotoxin. We hypothesize that brief hyperglycemic episodes enhance the production of interleukin-8 (IL-8) after lipopolysaccharide (LPS) stimulation. METHODS: Human umbilical vein endothelial cells (HUVECs; 1 x 10(5) cells/mL, cells from subcultures 2-5, n = 6) were cultivated in various concentrations of glucose (200, 300, 400, and 500 mg/dL) with or without LPS stimulation (1 microg/mL) for 24 hours. After culture, IL-8 levels in the supernatant were measured using ELISA. RESULTS: HUVECs cultured at glucose concentrations of 300 and 400 mg/dL produced more (p < 0.01) IL-8 than control cells (200 mg/dL). HUVECs cultured at glucose concentrations of 300 and 400 mg/dL also produced more (p < 0.01) IL-8 than those cultured in the absence of LPS. CONCLUSIONS: Hyperglycemic conditions enhance IL-8 production by vascular endothelial cells, and this response is augmented by LPS. Infections may foster neutrophil accumulation at injury sites. These results suggest that it is important to manage even short-term increases in blood glucose after acute stress.

Evolution of spin and field dependences of the effective mass with pressure in CeIn(3).

We have studied the field and spin dependences of the effective masses in CeIn3 as a function of pressure via the de Haas-van Alphen (dHvA) effect. The effective mass increases with the field at pressures up to about 10 kbar and then decreases with the field. The spin direction of the dominant dHvA oscillation is likely to be reversed across the same pressure. The dHvA frequency changes significantly at the pressure P(c) for the antiferromagnetic quantum critical point and two neighboring pressures P2 and P4 below and above P(c). The spin and field dependences rapidly diminish across P(c) and finally disappear above P4. These observations are discussed in conjunction with relevant observations and theories.

Dependence of the effective masses in YbAl3 on magnetic field and disorder.

The susceptibility and specific heat--and hence the effective mass--of the intermediate valence compound YbAl3 show anomalous enhancement below the Fermi liquid temperature T(coh) approximately 40 K. We show that these anomalies are suppressed by alloying in Yb1-xLuxAl3 indicating high sensitivity to lattice coherence. The de Haas-van Alphen effective masses for key branches of the Fermi surface are reduced by magnetic fields B>40 T. We argue that this reduction does not arise from 4f polarization but reflects renormalization of the quasiparticle states by the field.

Two energy scales and slow crossover in YbAl3.

Experimental results for the susceptibility, magnetization, specific heat, 4f occupation number, Hall effect, and magnetoresistance for single crystals of the intermediate valence (IV) compound YbAl3 show that, in addition to the Kondo temperature scale T(K) approximately 670 K, there is a low temperature scale T(coh) approximately 30-40 K for the onset of Fermi liquid coherence. Furthermore, the crossover from the low temperature Fermi liquid regime to the high temperature local moment regime is slower than predicted by the Anderson impurity model. We suggest that these effects are generic for IV compounds and we discuss them in terms of the theory of the Anderson lattice.

Inhibition by docosahexaenoic acid of receptor-mediated Ca(2+) influx in rat vascular smooth muscle cells stimulated with 5-hydroxytryptamine.

The effect of docosahexaenoic acid treatment on intracellular Ca(2+) dynamics in rat vascular smooth muscle cells stimulated with 5-hydroxytryptamine (5-HT) has been investigated in order to elucidate one of the mechanisms for its beneficial effect on cardiovascular disorders. The treatment of cells with 30 microM docosahexaenoic acid for 2 days inhibited an increase in intracellular Ca(2+) concentration induced by 5-HT (10 microM) and a depolarizing concentration of KCl (80 mM). Docosahexaenoic acid treatment significantly inhibited divalent cation influx stimulated by 5-HT and KCl, as measured by Mn(2+) quenching method, whereas had no effect on 5-HT-induced Ca(2+) release from the internal stores. Docosahexaenoic acid treatment also significantly inhibited 5-HT receptor-mediated Ca(2+) influx through Ni(2+)-insensitive channels that were distinct from store-operated channels. These results suggest that the specific inhibition of intracellular Ca(2+) dynamics in vascular smooth muscle cells may contribute to the beneficial properties of docosahexaenoic acid on cardiovascular disorders.