Impact of Fat-Free Adipose Tissue on the Prevalence of Low Muscle Mass Estimated Using Calf Circumference in Middle-Aged and Older Adults.

Previous studies proposed calf circumference cutoff values for predicting dual-energy X-ray absorptiometry (DXA)-derived low muscle mass. However, DXA-derived appendicular lean mass (aLM) includes non-skeletal muscle components such as the appendicular fat-free component of adipose tissue fat cells (aFFAT). The purpose of this study was to compare the calf circumference method of classification before (Model #1) and after (Model #2) eliminating the influence of FFAT in healthy Japanese adults (50 to 79 years; mean age 70 (SD 7) years). Model 1, and Model 2 for classifying low muscle mass had a sensitivity of 78% and 64%, specificity of 76% and 75%, positive predictive value of 31% and 28%, and negative predictive value of 96% and 93%, respectively. Appendicular fat-free component of adipose tissue has the potential to influence the ability of calf circumference to accurately classify individuals with low muscle mass. Consideration should be made when using this as a screening tool for low muscle mass.

Lorlatinib for the treatment of patients with non-small cell lung cancer.

Lorlatinib is a novel third-generation tyrosine kinase inhibitor (TKI) which targets anaplastic lymphoma kinase (ALK) as well as receptor tyrosine kinase c-ros oncogene 1 (ROS1). A critical limitation of conventional ALK/ROS TKIs is their association with acquired resistance mutations (particularly ALK G1202R and ROS1 G2032R) in the ALK or ROS1 gene, although these are not the only resistance mechanisms. Another limitation of this class of drugs is their inadequate efficacy against central nervous system metastasis, likely attributable to the blood-brain barrier (BBB). Therefore, lorlatinib was developed to overcome these limitations by being more potent, selective and permeable to the BBB than previous-generation ALK/ROS1 TKIs and subsequently received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) in April 2017. In September 2018, Japan became the first country where lorlatinib received approval for treating patients with ALK-rearranged non-small cell lung cancer. Eventually, the FDA approved lorlatinib (Lorbrena; Pfizer) in November 2018. Lorlatinib use is expected to increase in importance, owing to its promising efficacy in clinical trials.

DXA-Rectified Appendicular Lean Mass: Development of Ultrasound Prediction Models in Older Adults.

OBJECTIVE: Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean soft tissue mass (aLM) is used to diagnose sarcopenia. However, DXA-derived aLM includes non-skeletal muscle components, such as fat-free component of adipose tissue fat cell. These components, if not accounted for, could falsely inflate the aLM in individuals with a high amount of adipose tissue mass. B-mode ultrasound accurately measures muscle size in older adults. We sought to develop regression-based prediction equations for estimating DXA-rectified appendicular lean tissue mass (i.e. DXA-derived aLM minus appendicular fat-free adipose tissue (aFFAT); abbreviated as aLM minus aFFAT) using B-mode ultrasound. DESIGN: Cross-sectional study. MEASUREMENTS: Three hundred and eighty-nine Japanese older adults (aged 60 to 79 years) volunteered in the study. aLM was measured using a DXA, and muscle thickness (MT) was measured using ultrasound at nine sites. An ordinary least-squares multiple linear regression model was used to predict aLM minus aFFAT from sex, age and varying muscle thicknesses multiplied by height. Based on previous studies, we chose to use 4 MT sites at the upper and lower extremities (4-site MT model) and a single site (1-site MT model) at the upper extremity to develop prediction models. RESULTS: The linear prediction models (4 site MT model; R2 = 0.902, adjusted R2 = 0.899, and 1-site MT model; R2 = 0.868, adjusted R2 = 0.866) were found to be stable and accurate for estimating aLM minus aFFAT. Bootstrapping (n=1000) resulted in optimism values of 0.0062 (4-site MT model) and 0.0036 (1-site MT model). CONCLUSION: The results indicated that ultrasound MT combined with height, age and sex can be used to accurately estimate aLM minus aFFAT in older Japanese adults. Newly developed ultrasound prediction equations to estimate aLM minus aFFAT may be a valuable tool in population-based studies to assess age-related rectified lean tissue mass loss.

Synthesis of betaine-homocysteine S-methyltransferase is continuously enhanced in fatty livers of thyroidectomized chickens.

We examined thyroidectomized chickens in terms of plasma lipid concentration and protein expression within the liver. Although the body weight of thyroidectomized chickens was remarkably low due to growth retardation, the livers were enlarged and fatty compared to those of sham-operated chickens. An increase in phospholipid, triglyceride, and total cholesterol levels within the blood plasma of thyroidectomized chickens was observed, clearly reflecting increased lipid synthesis within the liver. Overexpression of some proteins, for example, 29- and 45-kDa proteins, was observed in thyroidectomized chicken livers by means of electrophoresis. A peptide map was made for the protein that exhibited the greatest degree of overexpression. One of them demonstrated a molecular mass of 45 kDa and an isoelectric point (pI) between 7.5 and 8.0, depending on its form. Partial N-terminal amino acid sequences were determined from three random peptides of this protein. The amino acid sequence of this protein showed a high degree of homology with the betaine-homocysteine S-methyltransferase (BHMT, EC 2.1.1.5) of some mammalian species. We identified this protein as chicken BHMT because, in addition to its sequence homology with mammalian BHMT, there were similarities were also observed between this 45-kDa protein and mammalian BHMT with respect to molecular mass and isoelectric behavior. In the liver, 10 d after thyroidectomy, the synthesis of hepatic BHMT had already been enhanced, and the high expression was maintained at 50 d of age. Generally, BHMT catalyzes the transfer of a methyl group from betaine to L-homocysteine. In addition, it seems that this enzyme is also closely related to lipid metabolism in the liver; in this study expression of BHMT in the liver corresponded to plasma lipid levels. Moreover, hypothyroidism may be directly or indirectly related to overexpression of BHMT. Due to similarities between the BHMT of chickens and mammalian species, the chicken model might provide a useful means by which to study BHMT, its role in lipid metabolism, and methods of targeting the expression of BHMT. Another 29-kDa protein was unidentified in the homology search.

Ionic mechanisms underlying burst firing of layer III sensorimotor cortical neurons of the cat: an in vitro slice study.

We examined the ionic mechanisms underlying burst firing in layer III neurons from cat sensorimotor cortex by intracellular recording in a brain slice. Regular spiking was observed in 77.4% of 137 neurons in response to constant intracellular current pulses of 0.5- to 1-s duration. The rest of the neurons showed burst firing. An initial burst followed by regular-spike firing was seen in 71.0% of 31 bursting neurons. The rest of the bursting neurons (n = 9) exhibited repetitive bursting. In the bursting neurons, spikes comprising the burst were triggered from the afterdepolarization (ADP) of the first spike of the burst. We examined the ionic mechanisms underlying the ADP by applying channel-blocking agents. The ADP was enhanced (rather than blocked) by Ca2+ channel blockade. This enhancement of the ADP by Ca2+ channel blockade was apparent even after blockade of the afterhyperpolarization by apamin or intracellular Ca2+ chelation by EGTA. The firing rate of the regular-spiking cells was increased by apamin, intracellular EGTA or Ca2+ channel blockers. In 17.9% of the neurons examined (n = 56), these agents switched the regular-spiking pattern into a bursting one. Burst firing could not be changed to regular spiking by these agents. Four neurons that responded with a single initial burst in control solution responded with repetitive bursting after application of these agents. We conclude that the main function of Ca2+ influx in layer III neurons is to activate Ca2+-dependent K+ conductance, which prevents or limits burst firing. At a time when spike amplitude was unchanged, the ADP was blocked and the burst firing changed to regular spiking by extracellularly applied tetrodotoxin (TTX) or intracellularly applied N-(2,6-dimethylphenylcarbamoylmethyl) triethyl ammonium bromide (QX314). We concluded that a TTX- and QX314-sensitive Na+ current underlies the ADP and therefore contributes to the burst firing of layer III neurons from the cat cortex.

Activity-dependent slow hyperpolarization in cat sensorimotor cortex in vitro.

The synaptic regulatory mechanism of resting membrane potential of layer III and V pyramidal neurons was analyzed intracellularly in the slice preparation of cat sensorimotor cortex. During the tetanic stimulation of white matter, subthreshold membrane depolarization was induced, and after that, a slowly developing hyperpolarization was induced in the normal solution. When the membrane potential showed a slow change, spike duration and input resistance did not change and evoked single synaptic response did not reveal the enhancement of slow IPSPs. However, afterhyperpolarization following action potential was enhanced. The slow hyperpolarization and the enhancement of afterhyperpolarization were not observed in the cells treated with an NMDA receptor antagonist or a calcium channel blocker Ni(2+) (50-100 microM), or the cells hyperpolarized more than -80 mV before the tetanic stimulation.

Long-term observation on the changes of somatotopy in the facial nucleus after nerve suture in the cat: morphological studies using retrograde labeling.

To examine the time course of plasticity of the cranial nucleus during axonal regeneration, we followed the topographical reorganization of the cat facial nucleus (FN) up to 24 months after facio-facial nerve suture using retrograde labeling methods. The trunk of the temporal-zygomatico-orbital and both superior and inferior buccolabial branches (defined as main branch) of the facial nerve was cut and sutured again under ketamine hydrochloride anesthesia. At 11-722 days after nerve suture, Fast Blue (FB) and 1,1'-dioctadecyl-3, 3, 3', 3'-tetramethylindocarbocyanine perchlorate (Dil) or horseradish peroxidase (HRP) were injected into the distal part of the sutured main branch and the unoperated posterior auricular branch, respectively. Until about 3 months after suture, the topographical pattern in FN was similar to that observed in normal cats. At about 4 months after suture, FB-labeled motoneurons were distributed not only in the lateral part (including intermediate, dorsal and ventrolateral divisions) but also in the medial subdivision of FN. After a survival period of 18-24 months, FB-labeled neurons were found all over the FN, and their number increased significantly. Interestingly, in the longer survival cases, we noticed that the Dil- or HRP-labeled posterior auricular branch motoneurons also showed a tendency to distribute outside the medial region. The present study showed that somatotopic disorganization starts at around 4 months after suture, which seems to be somewhat slower than that in rats, and continues until a much later postoperative period. Furthermore, we suggested a possibility that the regeneration of one branch may affect the somatotopy of the unoperated nerve branch. These phenomena may contribute to aberrant facial nerve functions such as abnormal associated movement and facial spasm observed after nerve injury.

Studies on rabies virus RNA polymerase: 1. cDNA cloning of the catalytic subunit (L protein) of avirulent HEP-flury strain and its expression in animal cells.

To investigate the RNA polymerase of rabies virus, we cloned a cDNA of the catalytic subunit (called L protein because of its large molecular size) of the HEP-Flury strain, an avirulent strain obtained by high frequencies of serial embryonated hen egg passages. Nucleotide sequencing showed that the cDNA encodes a long polypeptide of 2,127 amino acids (Mr. 242,938). A comparison of the deduced amino acid sequence with that of other strains (PV and SAD B19) indicated that the sequence was highly conserved, except for several amino acid substitutions which were accumulated in some limited regions. A fragment of the cDNA was used for expression in Escherichia coli (E. coli) to prepare the L antigen for raising the antibodies in rabbits. Immunoprecipitation studies with the rabbit antiserum showed that the polypeptides produced in the L cDNA-transfected COS-7 cells displayed almost the same electrophoretic mobility as that of authentic L protein. Immunofluorescence studies indicated that both L and P (another subunit of RNA polymerase) proteins displayed colocalized distribution with the nucleocapsid antigen (N) in the cytoplasmic inclusion bodies, where envelope proteins (G and M) were absent. On the other hand, expression of the L protein alone did not cause inclusion body-like granular distribution, suggesting that the inclusion body-like accumulation depends on certain interaction(s) with other viral gene products, probably with the ribonucleoproteins comprising the inclusion bodies.

Effects of exercise training and etidronate treatment on bone mineral density and trabecular bone in ovariectomized rats.

This study was designed to assess the effects of exercise training (Tr) following an etidronate treatment (E) on bone mineral density (BMD) of the femur and trabecular bone of the tibia in ovariectomized (ovx) rats. Female Wistar rats were ovariectomized (ovx) or sham-operated (sham) at 15 weeks of age and divided into five experimental groups: sham; ovx; ovx + E; ovx + Tr; ovx + E + Tr. Etidronate treatment of 5 mg/kg, 5 days/week was administered for 2 weeks and exercised on a treadmill for 30 m/min, 60 min/day, 5 days/week for 10 weeks. BMD of the femur and the trabecular bone area of the proximal tibia were significantly (p < 0.05) higher in E and/or Tr compared to ovx groups. However, the cortical region was not affected significantly by ovariectomy. The area partially filled with the trabecular bone at the constant width was observed only in the E rats. The number of osteoclasts in E group was significantly lower (p < 0.05) than in the ovx and ovx + Tr groups. The ovx + Tr rats had a higher number of osteoblasts (p < 0.05) than the ovx and ovx + E groups. There was a significant interaction between ovx + Tr and ovx + E on BMD in the proximal region of the femur (p < 0.05) and trabecular bone area of the tibia (p < 0.001). These results suggest that the etidronate treatment for 2 weeks beforehand influenced the effects of subsequent exercise training on maintaining the BMD in the proximal femur and the trabecular bone area of the tibia.

Alternate activity in the synergistic muscles during prolonged low-level contractions.

The purpose of this study was to investigate the functional interrelationship between synergistic muscle activities during low-level fatiguing contractions. Six human subjects performed static and dynamic contractions at an ankle joint angle of 110 degrees plantar flexion and within the range of 90-110 degrees (anatomic position = 90 degrees) under constant load (10% maximal voluntary contraction) for 210 min. Surface electromyogram records from lateral gastrocnemius (LG), medial gastrocnemius (MG), and soleus (Sol) muscles showed high and silent activities alternately in the three muscles and a complementary and alternate activity between muscles in the time course. In the second half of all exercise times, the number of changes in activity increased significantly (P < 0.05) in each muscle. The ratios of active to silent periods of electromyogram activity were significantly higher (P < 0.05) in MG (4.5 +/- 2.2) and Sol (4.3 +/- 2.8) than in the LG (0.4 +/- 0.1), but no significant differences were observed between MG and Sol. These results suggest that the relative activation of synergistic motor pools are not constant during a low-level fatiguing task.

[Successful chemotherapy based on in vitro chemosensitivity testing in a case of recurrent thymic carcinoma].

A 71-year-old woman underwent radical resection in May 1994 for a mediastinal mass invading the anterior chest wall. Histopathological examination revealed adenosquamous cell carcinoma. She was treated with postoperative chemotherapy including 5-fluorouracil (5-FU) and 4'-D-tetrahydropyrayl-doxorubicin (THP), based on in vitro chemosensitivity testing (CST), by MTT assay, using a surgical specimen. In December 1994, a recurrent tumor was detected on the left anterior chest wall and the patient received two courses of 5-FU, THP and methotrexate (MTX). The size of the chest-wall tumor decreased 25%. In July 1995, the patient had involvement of the left axillary lymph node and brain metastases in addition to the mass on the chest wall. Therefore, cisplatin, 5-FU and MTX were selected as treatment agents, based on CST using a metastatic axillary lymph node. After two courses of these agents, chest computed tomography showed a 91% reduction in the size of the chest wall tumor. Radiation was administered for the brain metastasis. In March 1997, the patient died of thymic carcinoma.

Effects of an artificially carbonated bath on athletic warm-up.

The effects of an artificially carbonated bath (36 degrees C, CO2 300 ppm, 20 minutes) on the warm-up of swimmers was compared with those of a freshwater bath (36 degrees C, 20 minutes). Carbon dioxide is reported to have a vasodilatory effect on peripheral blood vessels of cutaneous and muscular tissue and to promote blood flow. We observed that the warm-up effects of a carbonated bath before swimming on the hematocrit, white blood cell, total plasma protein, and total cholesterol levels in venous blood were significantly increased more than those of a freshwater bath before swimming in recovery period (p < 0.05). Thus the carbonated bath tended to be more effective for increasing the concentrations of blood components. In the recovery period, the carbonated bath before swimming also resulted in significantly smaller changes in blood lactic acid and heart rate than those of a freshwater bath before swimming (p < 0.05). The decrease in electromyography of the M. rectus femoris during swimming suggested more efficient muscle activity after a carbonated bath. Therefore after a carbonated bath, swimmers should have a higher reserve left in the cardiovascular system, resulting in better performance during swimming and less accumulation of fatigue-related metabolites after swimming.

Electromyogram patterns during plantarflexions at various angular velocities and knee angles in human triceps surae muscles.

To investigate the influence of the various knee angles and ankle angular velocities on synergistic muscle activities, the surface electromyograms (EMG) were recorded from the triceps surae muscles, i.e. lateral gastrocnemius (LG), medial gastrocnemius (MG) and soleus (SOL) muscles. Six healthy young men performed ankle plantarflexions at three ankle angular velocities of 6, 30 and 60 degrees.s-1 and three knee angles of 0, 30 and 60 degrees (0 degree equalling full extension) under constant load (5% and 10% maximal voluntary contraction). At the fully-extended knee angle (0 degree), peak values of integrated EMG (peak iEMG) during ankle plantarflexions were significantly increased (P < 0.05) in MG and in LG, but significantly decreased (P < 0.05) in SOL with increasing angular velocity. On the other hand, although the patterns of variation of the peak iEMG in each muscle at flexed knee angles (30 and 60 degrees) were very similar to the patterns seen at the fully-extended knee angle, there were no significant differences among angular velocities. During ankle plantarflexions at any of the angular velocities (6, 30 and 60 degrees.s-1) the peak iEMG were significantly increased (P < 0.05) in SOL, but were significantly decreased (P < 0.05) in MG following increases in the knee angles. These results would suggest the possibility of selective recruitment of motor units in humans depending on the angular velocity; however, this behaviour would appear to be weakened by fixing at flexed knee angles which cause an inhibitory influence on gastrocnemius muscles and a facilitative influence on SOL.

[Importance of timing for radiation therapy in limited-stage small cell lung cancer].

We defined one group of patients who underwent radiotherapy within 75 days from the beginning of treatment as the early RT group, whereas another group of patients who underwent radiotherapy at least 75 days after the beginning of treatment was defined as the late RT group. The response rate (CR + PR) of the early RT group was 92.1% while that of the late RT group was 72.3%. The response rate for radiation therapy thus was significantly better in the early RT group. The 2 and 5-year actuarial survival rates of the early RT group were 22.1% and 9.2%, while those of the late RT group were 19.1% and 8.5%. Then respective median survival times (MST) were 14 months and 13 months. There was no significant difference in survival rates between the two groups. As much as the quality of life is concerned, early RT group would show here better results.

Interferon-alpha is effective in HTLV-I-associated myelopathy: a multicenter, randomized, double-blind, controlled trial.

A double-blind, multi-center study was performed on patients with HTLV-I-associated myelopathy (HAM) to evaluate the therapeutic effect of treatment with natural interferon-alpha (HLBI). Forty-eight HAM patients were enrolled and treated with either 0.3 MU (n = 15), 1.0 MU (n = 17), or 3.0 MU (n = 16) of HLBI for 28 days. Clinical evaluation included motor dysfunction, urinary disturbances, and changes of neurologic signs. The frequency of therapeutic response judged as excellent to good 4 weeks after starting therapy and 4 weeks after completion of therapy were 7.1% (1 of 14) and 8.3% (1 of 12) in the 0.3-MU group, 23.5% (4 of 17) and 26.7% (4 of 15) for the 1.0-MU group, and 66.7% (10 of 15) and 61.5% (8 of 13) for the 3.0-MU group. The therapeutic benefit in the 3.0-MU group was significantly higher than in the 0.3-MU group. There was no significant difference in the incidence of symptomatic side effects between groups. Abnormal laboratory data were obtained for some patients in the 1.0-MU and 3.0-MU groups; however, the treatment schedule could be continued in most patients. These results suggest that HAM patients may be safely treated with HLBI 3.0 MU every day for 4 weeks with favorable clinical effects.

Cross-cultural generalizability of personality dimensions: relating indigenous and imported dimensions in two cultures.

The cross-cultural generalizability of personality dimensions was investigated by (a) identifying indigenous Philippine dimensions, (b) testing the cross-cultural replicability of the NEO 5-factor model (P. T. Costa & R.R. McCrae, 1992), and (c) relating Philippine and Western dimensions in Philippine and U.S. samples of college students. Filipino self-ratings (N = 536) on indigenous items were factor analyzed, and 6 Philippine dimensions were obtained. Conclusions about the replicability of the 5-factor model in the Philippines (N = 432) depended on whether exploratory, Procrustes, or confirmatory factor methods were used. In regression and joint factor analyses, moderate to strong associations were found between the Philippine dimensions and (a) dimensions from the 5-factor model in both Philippine (N = 387) and U.S. (N = 610) samples, and (b) the Tellegen model (A. Tellegen, 1985; A. Tellegen & N.G. Waller, in press) in a U.S. sample (N = 603).