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.

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.

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.

Prostaglandin E2 prevents bone loss and adds extra bone to immobilized distal femoral metaphysis in female rats.

The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloading)-induced cancellous bone loss. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to right hindlimb immobilization by bandaging and simultaneously treated subcutaneously daily with 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on the cancellous bone using double-fluorescent labeled, 20 micron thick, undecalcified distal femoral metaphysis sections. We found that PGE2 administration not only prevented diuse-induced bone loss, but also added extra bone to disuse cancellous bone in a dose-response manner. PGE2 prevented the disuse-induced osteopenia by stimulating more bone formation than resorption and shortening the period of bone remodeling. It activated woven bone formation, stimulated lamellar bone formation, and increased the eroded bone surface above that caused by disuse alone. While underloading increased the remodeling period (sigma), PGE2 treatment of underloaded bone shortened the time for osteoclastic bone resorption and bone remodeling, and thus reduced the remodeling space. The study shows that PGE2 is a powerful anabolic agent that prevents disuse-induced osteopenia and adds extra bone to these same bones.

Adaptation of non-growing former epiphysis and metaphyseal trabecular bones to aging and immobilization in rat.

No data exit for distal tibia (DT), a bone site with growth plate closure at 3 months of age and with very low trabecular bone turnover rate. The purpose of this study was to characterize the response of DT to aging and immobilization (IM) in 6 to 16.5 month-old female rats. One hundred and forty six 6 month-old Sprague-Dawley rats were divided into aging controls and right hindlimb immobilization (RHLI) groups. The right hindlimb was immobilized against the abdomen with elastic bandages. Rats were sacrificed serially from 6 to 16.5 months old at intervals of 2 to 8 weeks. The histomorphometric study was performed on areas of former epiphyseal and metaphyseal trabecular bone of DT. No changes on bone mass or architecture were found in aging controls throughout the study. There was a decrease in bone mass of the former epiphysis after 3.5 months of IM due to resorption exceeding formation. Then it reverted to the aging control level at 4 months post IM. At the former metaphyseal site, significant bone loss (-19%) was observed as early as two weeks after IM. The peak bone loss (-54%) was reached at 1.5 months after IM and plateaued thereafter. The bone loss was mainly due to the reduction of trabecular thickness although trabecular number decreased significantly after 3.5 months IM. These results suggest that both former epiphysis and metaphyseal trabecular bones in DT can quickly adapt by losing bone to immobilization.

Prostaglandin E2 prevents disuse-induced cortical bone loss.

The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloaded)-induced cortical bone loss as well as add extra bone to underloaded bones. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to simultaneous right hindlimb immobilization by bandaging and daily subcutaneous doses of 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). Disuse-induced cortical bone loss occurred by enlarging the marrow cavity and increasing intracortical porosity. PGE2 treatment of disuse shafts further increased intracortical porosity above that in disuse alone controls. This bone loss was counteracted by enhancement of periosteal and corticoendosteal bone formation. Stimulation of periosteal and corticoendosteal bone formation slightly enlarged the total tissue (cross-sectional) area and inhibited marrow cavity enlargement. These PGE2-induced activities netted the same percentage of cortical bone with a different distribution than the beginning and age-related controls. These findings indicate the PGE2-induced increase in bone formation compensated for the disuse and PGE2-induced bone loss, and thus prevented immobilization-induced bone loss.

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.

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.

Cardiomyopathy, mental retardation, and autophagic vacuolar myopathy. Abnormal MRI findings in the head.

A 21-year-old man with childhood-onset mental retardation, non-obstructive hypertrophic cardiomyopathy, and vacuolar myopathy is presented. A histopathological study of biopsied skeletal muscle showed lysosomal glycogen storage mimicking acid maltase deficiency, but biochemical analysis showed normal acid alpha-glucosidase activity. Glycogenosomes were also recognized in endothelial cells on electronmicroscopic examination of biopsied skeletal muscle. Magnetic resonance imaging (MRI) findings in the head revealed the involvement of the central nervous system. This is a new type of lysosomal glycogen storage disease with multisystemic involvement. The specific biochemical defect in this disorder remains to be elucidated.

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.

Retinal vasculitis in human T-lymphotropic virus type I associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I) has been recently found to be associated with slowly progressive myelopathy. We have seen 12 patients with HTLV-I associated myelopathy (HAM), three of whom showed retinal vasculitis. In addition two patients had ocular symptoms of vitreous opacity. Retinal vasculitis in these patients appears to be phlebitis and sheathing of retinal veins in the periphery of the fundus.

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).

A method for safe pancreaticojejunostomy.

We devised a new technique to increase the safety of pancreaticojejunostomy in patients with an extended operation for pancreatic cancer. This new pancreaticojejunostomy was created by end-to-side anastomosis with four layers about 7 cm distal to the jejunal stump. The cut surface of the pancreas was placed on the seromuscular coat of the ventral aspect of the jejunum to cover the posterior surface of the anastomosis, and the anastomosis between the pancreas and the jejunum was created using fibrin glue. The pancreatic duct was intubated with a silicone tube, and its stenting tube was brought out through a opening in the jejunum. The anterior surface of the pancreaticojejunostomy was covered by the proximal jejunum as a serosal patch. We used this technique in seven patients. No patient developed an anastomotic leak or any other complication. The anastomosis is covered by the jejunum and is not open to the peritoneum. This new technique of pancreaticojejunostomy may reduce the risk of pancreatic leak, especially when an extended operation is performed.

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.

[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.