Rowing prevents muscle wasting in older men

We evaluated the effects of rowing on the morphology and function of the leg extensor muscle in old people. The area and the power of the leg extensor muscle were measured in 15 oarsmen – age [mean (SD)] 65 (3) years; height 171 (4) cm, body mass 68 (6) kg – and in 15 sedentary men – age 66 (4) years, height 170 (4) cm, body mass 67 (7) kg – who were matched on the basis of their body size. The leg extensor muscle area of the oarsmen was larger than that of the sedentary men [77.8 (5.4) vs 68.4 (5.1) cm², P<0.05]. Also the bilateral leg extension power of the oarsmen was larger than that of the sedentary men [1,624 (217) vs 1,296 (232) W, P<0.05]. Thus, the leg extension power per the leg extensor muscle area was not significantly different between two groups [20.9 (2.0) vs 19.9 (2.1) W·cm^–2) and leg extension power was correlated to the leg extensor muscle area (59–89 cm², r=0.74, P<0.001). Also the 2,000-m rowing ergometer time of the oarsmen [495 (14) s; range 479–520 s] was related to leg extensor muscle area (68–89 cm², r=0.63, P<0.01). The results suggest that rowing prevents age-related muscle wasting and weakness. Electronic Publication     

Distribution of eye- and arm-movement-related neuronal activity in the SEF and in the SMA and Pre-SMA of monkeys

We analyzed neuronal activity in the supplementary eye field (SEF), supplementary motor area (SMA), and presupplementary motor area (pre-SMA) during the performance of three motor tasks: capturing a visual target with a saccade, reaching one arm to a target while gazing at a visual fixation point, or capturing a target with a saccade and arm-reach together. Our data demonstrated that each area was involved in controlling the arm and eye movements in a different manner. Saccade-related neurons were found mainly in the SEF. In contrast, arm-movement-related neurons were found primarily in the SMA and pre-SMA. In addition, we found that the activity of both arm-movement- and saccade-related neurons differed depending on the presence or absence of an accompanying saccade or arm movement. Such context dependency was found in all three areas. We also discovered that activity preceding eye or arm movement alone, and eye and arm movement combined, appeared more often in the pre-SMA and SEF, suggesting their involvement in effector-independent aspects of motor behavior. Subsequent analysis revealed that the laterality of arm representation differed in the three areas: it was predominantly contralateral in the SMA but largely bilateral in the pre-SMA and SEF.     

906 variations among 27 genes encoding cytochrome P450 (CYP) enzymes and aldehyde dehydrogenases (ALDHs) in the Japanese population

 We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms (SNPs) in genes encoding 13 cytochrome P450 (CYP) enzymes and 14 aldehyde dehydrogenases (ALDHs) by directly sequencing their entire genomic regions except for repetitive elements. This approach identified 810 SNPs and 96 insertion/deletion polymorphisms among the 27 genes. Of the 810 SNPs, 229 were identified among the CYP genes and 581 in the ALDH genes; of the total, 48 SNPs were located in 5′ flanking regions, 619 in introns, 91 in exons, and 52 in 3′ flanking regions. These variants should contribute to studies designed to investigate possible correlations between genotypes and phenotypes of disease susceptibility or responsiveness to drug therapy. Received: April 23, 2002 / Accepted: April 25, 2002     

Influence of PD‐L1 cross‐linking on cell death in PD‐L1‐expressing cell lines and bovine lymphocytes

Programmed death‐ligand 1 (PD‐L1) blockade is accepted as a novel strategy for the reactivation of exhausted T cells that express programmed death‐1 (PD‐1). However, the mechanism of PD‐L1‐mediated inhibitory signalling after PD‐L1 cross‐linking by anti‐PD‐L1 monoclonal antibody (mAb) or PD‐1–immunogloblin fusion protein (PD‐1‐Ig) is still unknown, although it may induce cell death of PD‐L1⁺ cells required for regular immune reactions. In this study, PD‐1‐Ig or anti‐PD‐L1 mAb treatment was tested in cell lines that expressed PD‐L1 and bovine lymphocytes to investigate whether the treatment induces immune reactivation or PD‐L1‐mediated cell death. PD‐L1 cross‐linking by PD‐1‐Ig or anti‐PD‐L1 mAb primarily increased the number of dead cells in PD‐L1^high cells, but not in PD‐L1^low cells; these cells were prepared from Cos‐7 cells in which bovine PD‐L1 expression was induced by transfection. The PD‐L1‐mediated cell death also occurred in Cos‐7 and HeLa cells transfected with vectors only encoding the extracellular region of PD‐L1. In bovine lymphocytes, the anti‐PD‐L1 mAb treatment up‐regulated interferon‐γ (IFN‐γ) production, whereas PD‐1‐Ig treatment decreased this cytokine production and cell proliferation. The IFN‐γ production in B‐cell‐depleted peripheral blood mononuclear cells was not reduced by PD‐1‐Ig treatment and the percentages of dead cells in PD‐L1⁺ B cells were increased by PD‐1‐Ig treatment, indicating that PD‐1‐Ig‐induced immunosuppression in bovine lymphocytes could be caused by PD‐L1‐mediated B‐cell death. This study provides novel information for the understanding of signalling through PD‐L1.     

Endotoxin contamination in wound dressings made of natural biomaterials

Contamination by endotoxin of nine kinds of wound dressings made of natural biomaterials (calcium alginate, collagen, chitin, and poly-L-leucine) was examined with the use of water extracts. By applying the Limulus amoebocyte lysate (LAL) test, high concentrations of endotoxin were detected in extracts from three kinds of products made of calcium alginate. These extracts evoked fever in rabbits and induced the release of a proinflammatory (pyrogenic) cytokine, interleukin-6 (IL-6), from human monocytic cells (MM6-CA8). The effects disappeared when the extracts were treated with endotoxin-removing gel column chromatography or with an endotoxin antagonist, B464, confirming that the contaminating pyrogen was endotoxin. A noteworthy finding was that one of the endotoxin-containing extracts showed very weak IL-6-inducibility in human monocytic cells in contrast to its high pyrogenicity to rabbits. The discrepancy could be explained based on differences between humans and rabbits in sensitivity to the endotoxin, because the extract showed higher proinflammatory-cytokine (TNF-alpha)-inducibility in rabbit whole-blood cells (WBCs) than human WBCs. The results suggest that the LAL test is a useful method of detecting endotoxin contamination in wound dressings and the MM6-CA8 assay is a good supplement to the LAL test for evaluating pyrogenicity in humans accurately.     

Carotid-cardiac baroreflex function does not influence blood pressure regulation during head-up tilt in humans

The influence of the carotid-cardiac baroreflex on blood pressure regulation was evaluated during supine rest and 40 degrees head-up tilt (HUT) in 9 healthy young subjects with and without full cardiac vagal blockade. The carotid baroreflex responsiveness, or maximal gain (G(MAX)), was assessed from the beat-to-beat changes in heart rate (HR) and mean arterial pressure (MAP) by the variable neck pressure and suction technique ranging in pressure from +40 to -80 Torr, with and without glycopyrrolate (12.0 +/- 1.0 microg/kg body weight; mean +/- SE). In the supine position, glycopyrrolate increased the HR to 91 +/- 3 bpm, from 54 +/- 3; MAP to 89 +/- 2 mmHg, from 76 +/- 2; and cardiac output to 6.8 +/- 0.3 l.min(-1), from 4.9 +/- 0.3 (P < 0.05). The G(MAX) of the carotid baroreflex control of HR was reduced to -0.06 +/- 0.01 bpm.mmHg(-1), from -0.30 +/- 0.02 (P < 0.05) with no significant effect on the G(MAX) of the carotid baroreflex control of MAP. During HUT the carotid baroreflex control of MAP was unchanged, though the G(MAX) of the carotid baroreflex control of HR was increased (P < 0.05). During HUT, central blood volume, assessed by electrical thoracic admittance, and total vascular conductance were decreased with and without glycopyrrolate. Furthermore, glycopyrrolate reduced G(MAX) of the carotid baroreflex control of HR during HUT (P < 0.05) with no significant effect on G(MAX) of the carotid baroreflex control of MAP. These data suggest that during supine rest and HUT-induced decreases in central blood volume, the carotid baroreflex control of HR is mediated primarily via parasympathetic activity. Furthermore, the maintenance of arterial blood pressure during postural stress is primarily mediated by arterial and cardiopulmonary reflex regulation of sympathetic activity and its effects on the systemic vasculature.     

Alteration of autophagosomal proteins (LC3, GABARAP and GATE-16) in Lewy body disease

Macroautophagy is a dynamic process whereby cytoplasmic molecules are sequestered within autophagosomes. Based on amino acid similarity, there exist two groups of mammalian autophagy-related gene (Atg) 8 homologues [microtubule-associated protein 1 light chain 3 (LC3) and γ-aminobutyric-acid type A receptor associated proteins (GABARAPs)], which play essential role in autophagosomal formation. Despite recent progress in studies on LC3, the other Atg8 homologues remain to be poorly understood, especially in pathological condition. In this study, we determined whether Atg8 homologues are affected in Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Our findings indicated that biochemical and pathological properties of LC3 were altered and that the level of LC3 was increased in an insoluble fraction from the brain of patients with DLB, whereas the level of GABARAPs was decreased in DLB. Furthermore, immunohistochemical staining revealed that both LC3 and GABARAPs were localized in Lewy bodies in PD and DLB. These findings suggest that autophagic function is impaired through alteration of Atg8 homologues in Lewy body disease.     

Induction chemoradiotherapy and surgical resection for selected stage IIIB non–small-cell lung cancer

Background

Combination chemotherapy using an oral combination of uracil and tegafur (UFT) plus cisplatin and concurrent thoracic radiotherapy is reported to have a high response rate and less toxicity for locally advanced non-small-cell lung cancer (NSCLC) patients. We performed a phase II trial using this chemoradiotherapy as an induction treatment.

Methods

Patients with marginally resectable stage IIIB NSCLC, an age younger than 70 years, a performance status of 0 or 1, and good organ function were eligible. The UFT (400 mg/m²) was administered orally on days 1 through 14 and 22 through 35 and cisplatin (80 mg/m²) was injected intravenously on days 8 and 29. Radiotherapy with a total dose of 40 Gy was delivered in 20 fractions from day 1. A surgical resection was performed from 3 to 6 weeks after completing the induction treatment.

Results

Twenty-seven patients, 18 male and 9 female with a median age of 56 years and ranging from 36 to 69 years, were entered into the phase II trial. Clinical T4 and N3 cancers were observed in 22 and 7 patients, respectively. Twenty-five (93%) achieved a partial response. The most frequently observed adverse event was grade 3 leukopenia in 26%. Of 25 patients who underwent a thoracotomy, 22 had a tumor resection. In all 22 patients a complex resection including a resection of the superior vena cava, carina, and vertebrae was required. Operative morbidity and mortality rates were 36% and 4% respectively. The calculated 1-year and 3-year survival rates of all 27 patients were 73% and 56% respectively.

Conclusions

Chemotherapy using UFT plus cisplatin and concurrent radiotherapy as induction treatment and a surgical resection for patients with marginally resectable stage IIIB NSCLC is feasible and promising. However it is difficult to conduct multi-institutional trials even for selected stage IIIB disease as a complex resection in almost all patients is necessary.