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Cardiac surgery with cardiopulmonary bypass is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. We hypothesised that the highly selective α2-adrenergic agonist, dexmedetomidine, attenuates the systemic inflammatory response. Forty-two patients were randomly assigned to receive dexmedetomidine or saline after aortic cross-clamping). The mean (SD) levels of the nuclear protein plasma high-mobility group box 1 increased significantly from 5.1 (2.2) ng ml(-1) during (16.6 (7.3) ng ml(-1) ) and after (14.3 (8.2) ng ml(-1) ) cardiopulmonary bypass in the saline group. In the dexmedetomidine group, the levels increased significantly only during cardiopulmonary bypass (4.0 (1.9) ng ml(-1) baseline vs. 10.8 (2.7) ng ml(-1) ) but not after (7.4 (3.8) ng ml(-1) ). Dexmedetomidine infusion also suppressed the rise in mean (SD) interleukin-6 levels after cardiopulmonary bypass (a rise of 124.5 (72.0) pg ml(-1) vs. 65.3 (30.9) pg ml(-1)). These suppressive effects of dexmedetomidine might be due to the inhibition of nuclear factor kappa B activation and suggest that intra-operative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischaemia-reperfusion injury during cardiopulmonary bypass.

Slow-growing sarcomas may give rise to intractable wounds, which may be attributed to commoner causes. A 57-year-old man with diabetes mellitus presented with a 24-year history of a chronic wound that originated on his left great toe. Because of the long history, the nonspecific histological findings and the complication of ulcerative colitis, we misdiagnosed his ulcer as pyoderma gangrenosum. The wound was eventually diagnosed correctly by histological examination of a skin biopsy and the use of immunohistochemistry to detect cytokeratin, epithelial membrane antigen and vimentin. Specimens obtained 16 years earlier showed the same staining pattern. Radiological examinations revealed no metastasis. The patient received a below-knee amputation without further chemotherapy or radiotherapy. When patients have intractable ulcers, appropriate biopsies and immunohistochemical examinations are sometimes necessary to exclude a malignancy even if the history and symptoms do not suggest a diagnosis of sarcoma.

This study aimed at evaluating the effect of a single oral intake of branched-chain amino acids (BCAA) with Arg on skeletal muscle protein metabolism during moderate exercise in young individuals. Eight healthy volunteers (4 males and 4 females, means +/- SEM, 26 +/- 1 yrs, 177.8 +/- 3.7 cm, 72.6 +/- 3.9 kg) were studied in a randomized double-blind placebo-controlled cross-over trial. The subjects performed 3 bouts of 20-min cycling exercise (5min break between each bout) at 126 +/- 13 W corresponding to 50% of the maximal work intensity. A single oral supplement of either a BCAA drink containing 2 g of BCAA and 0.5 g of Arg or an isocaloric placebo drink was given at 10 min of the 1st exercise bout. Both arterial and venous blood samples were simultaneously taken from the radial artery and the femoral vein, respectively. Blood flow in the femoral artery was determined using the ultrasound Doppler technique. The blood sampling and blood flow measurements were performed at rest, every 10 min during each exercise bout. Net balance of BCAA and Phe across the leg muscles were measured by the arteriovenous difference method. The BCAA ingestion resulted in increases in both the plasma BCAA concentration and BCAA uptake into the working leg. The Phe release from the leg during exercise significantly increased as compared to the basal level in the placebo trial (0.97 +/- 0.28 vs. 0.23 +/- 0.22 mu mol/min, p < 0.05). In the BCAA trial, the cumulative Phe release from the leg during the 3rd exercise bout was significantly lower than that in the placebo trial (5.0 +/- 7.4 vs. 35.9 +/- 13.2 mu mol/25 min, p < 0.05). These results suggest that endurance exercise at moderate intensity enhances proteolysis in working muscles, and a single oral intake of 2 g of BCAA with Arg at onset of exercise effectively suppresses exercise-induced skeletal muscle proteolysis.

Background Esophageal candidiasis is one of the local side effects of inhaled corticosteroid treatment, and it is difficult to prevent this condition. Our previous report indicated that the prevalence of esophageal candidiasis among patients treated with inhaled fluticasone propionate dry powder (FP-dp) reached up to 37% in Japanese patients. Although a reduction in the daily dose of inhaled FP-dp can eliminate this infection, it may lead to asthma not being well-controlled in these patients. Objective The aim of this study was to estimate whether switching to an equal daily dose of inhaled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP), the oropharyngeal deposition of which is very low, can eliminate the infection without deterioration of asthma. Methods A total of 10 stable asthmatic patients with esophageal candidiasis, induced by inhaled FP-dp treatment (400 or 800 microg/ day), were enrolled in this study. A second upper GI endoscopy was performed, more than 1 month but less than 3 months after switching to an equal dose of inhaled HFA-BDP with a tube spacer device, Duopacer. The patients' medications were not changed during the study. Results Esophageal candidiasis was eliminated in 9 of the 10 patients. The degree of candidiasis reduced in another patient. The forced expiratory volume in 1 sec (FEV1.0) did not worsen during the study. Conclusion Switching from FP-dp to HFA-BDP with Duopacer is useful in preventing esophageal candidiasis.

Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of unstable CAG repeats within the coding region of the novel gene, ataxin-2, on chromosome 12q24.1. We analyzed CAG repeat size of the SCA2 allele in two deceased patients (father and daughter) to investigate the repeat mosaicism in CNS regions. The CAG repeat size was examined using lymphoblastoid cell lines, frozen brain tissues, and paraffin-embedded tissues. In each patient the major repeat size of the expanded allele varied within the brain or spinal cord (father, 39-42; daughter, 39-47 repeats), and was smaller by three to eight repeats in the cerebellum than in other CNS regions. Our results are in agreement with the findings in other polyglutamine disorders showing somatic mosaicism.

Androgens stimulate many hair follicles, e.g., beard, but may cause regression on the scalp; occipital areas are considered androgen independent. The mesenchyme-derived dermal papilla that regulates the hair follicle is considered the site of androgen action. Because hair size has been clearly related to dermal papilla size, one of the key functions androgens must regulate is the size of the dermal papilla. This implies that androgens stimulate dermal papilla cells to divide or to secrete autocrine mitogenic factors. As physiologic levels of androgens do not stimulate mitogenesis in cultured dermal papilla cells, this study was designed to determine whether dermal papilla cells cultured from human hair follicles with different responses to androgens in vivo, i.e., androgen-dependent beard and androgen-independent nonbalding scalp, produce soluble autocrine mitogenic factors and, if so, whether either cell type altered their secretion in response to testosterone in vitro. Conditioned medium was prepared by incubating individual primary lines of cells for 24 h with, and without, testosterone (10(-10)-10(-5) M). All conditioned media significantly increased [3H] thymidine incorporation by other dermal papilla cells; trypsin treatment significantly reduced the effect. Although both beard and scalp cell conditioned media had a similar stimulatory potential, beard cells incorporated approximately double the [3H]thymidine of scalp cells, in both types of media. Physiologic levels of testosterone increased mitogenic factor production by beard, but not scalp cells; only beard cells responded to these factor(s). Testosterone added after conditioning had no effect, indicating stimulation was not a synergistic effect of testosterone and conditioned medium. Thus, both beard and scalp cells release similar autocrine growth factor(s), but their response to these factor(s) is determined by their in vivo origin. Testosterone in vitro stimulates secretion of an autocrine growth factor(s) by beard, but not scalp cells, to which only beard cells are able to respond, reflecting the responses to androgens in vivo. These factors may be involved in the key increase of dermal papilla size necessary for androgen-induced changes in hair size.

Androgens regulate the growth of many human hair follicles, but only pubic, axillary, and scalp hair growth occur in men with 5 alpha-reductase deficiency. This suggests that 5 alpha-dihydrotestosterone is the active intracellular androgen in androgen-dependent follicles, except in the axilla and pubis. Since the dermal papilla plays a major regulatory role in hair follicles and may be the site of androgen action, we have investigated androgen metabolism in six primary lines of cultured dermal papilla cells from pubic and axillary hair follicles; previous studies have shown that beard cells take up and metabolize testosterone, retaining and secreting 5 alpha-dihydrotestosterone. After 24 h preincubation in serum-free Eagle's medium 199, 100-mm dishes of confluent cells were incubated for 2 h with 5 nM [1,2,6,7-3H]testosterone. Media were collected and the cells washed with phosphate-buffered saline and extracted with chloroform: methanol (2:1). After the addition of unlabeled and 14C-labeled marker steroids, the extracts were analyzed by a two-step thin-layer chromatography system; steroid identity was confirmed by recrystallization to a constant 3H/14C ratio. Beard and pubic dermal papilla cells were also incubated for 24 h, and the medium was analyzed at various times. The results from pubic and axillary primary cell lines were similar. In both cells and media the major steroid identified was testosterone, but significant amounts of androstenedione were present, indicating 17 beta-hydroxysteroid dehydrogenase activity; androstenedione was also identified within the cells, but a small amount of 5 alpha-dihydrotestosterone was only identified in one pubic cell line. Beard dermal papilla cells secreted large amounts of 5 alpha-dihydrotestosterone into the medium over 24 h in contrast to pubic cells, which produced only very small amounts. The pubic and axillary cell results contrasts with the observations of pronounced 5 alpha-dihydrotestosterone in beard cells and confirm that androgen metabolism in cultured dermal papilla cells reflects the parent follicle's ability to respond to androgen in the absence of 5 alpha-reductase type II in vivo. This supports our hypothesis that androgen acts on hair follicles via the dermal papilla and suggests that cultured dermal papilla cells may offer an important model system for studies of androgen action.

Objective Androgens have paradoxically different effects on hair follicles depending on body site, stimulating beard growth while inducing regression in some areas of the scalp. The mesenchyme derived dermal papilla at the base of the hair follicle regulates many aspects of the growth of follicular epithelium, and is probably the site of androgen action. Since 5 alpha-dihydrotestosterone is considered to be the active intracellular androgen in many target tissues and is required for some androgen-mediated hair growth, such androgen-sensitive cells should contain 5 alpha-reductase. This study was designed to investigate whether cultured human dermal papilla cells contain 5 alpha-reductase and whether the metabolic capacity varies with the body site of the follicle in line with the clinical picture. Design Testosterone metabolism in cultured dermal papilla cells from androgen sensitive beard follicles was compared with less androgen dependent non-balding scalp follicles. Primary cell cultures were established from follicles of 11 patients with normal hair growth. The cells were grown to confluence in 10-cm Petri dishes and incubated with 5 nM 3H-testosterone in serum-free medium for 2 hours. The cells and the culture medium were collected separately for individual analysis. Measurements Unlabelled carrier and 14C-marker steroids were added to both the cell and medium extracts before separation by thin-layer chromatography. The individual steroid identities were confirmed by recrystallizing up to five times to a constant 3H/14C ratio. Results Testosterone was taken up by both cell types; significant amounts of 5 alpha-dihydrotestosterone were recovered inside beard cells, but not in scalp cells, whereas androstenedione was identified in both. An unidentified compound was present intracellularly in both cell types, but was not present in the culture medium. 5 alpha-Dihydrotestosterone was present only in the culture medium of beard cells but androstenedione was present in a similar amount in the medium from both cell types. The presence of other steroids could not be confirmed in either the cell extracts or the culture medium. Conclusions The production of 5 alpha-dihydrotestosterone by beard cells concurs with the poor beard growth in men with 5 alpha-reductase deficiency, supporting our hypothesis that androgens mediate their effects on the hair follicle via the mesenchyme-derived dermal papilla.

The aim of this paper was to assess the effects of branched-chain amino acid (BCAA) supplementation on muscle soreness, muscle damage and inflammation during an intensive training program.Twelve long-distance runners (20 + or - 1 year-old) participated in a double-blinded crossover designed study conducted during two intensive training periods (three-day). The subjects were provided either a drink containing BCAA (0.8% BCAA in a 3.5% carbohydrate solution; 2,500 mL/day) or an isocaloric placebo drink during each training period. All subjects completed the same training program (total running distance: males: 86 km, females: 64 km), and ate the same meals during the training period. Whole body muscle soreness and fatigue sensation were measured in the morning before and during the training period by Visual Analogue Scale method. Plasma creatine kinase (CK), lactate dehydrogenase (LDH), and granulocyte elastase (GEL) levels were measured as indicators of muscle damage and inflammation before and after the training period.Muscle soreness and fatigue sensation during the training period in the BCAA trial were lower than those in the placebo trial (-32% and -24%, respectively; P0.05). The plasma CK, LDH, and GEL levels after the training program in the BCAA trial were lower than those in the placebo trial (-21%, -6%, and -15%, respectively; P0.05).These results demonstrate that BCAA supplementation during an intensive training program effectively reduces the muscle soreness and fatigue sensation, and that the perceived changes could be attributed to the attenuation of muscle damage and inflammation.

Dapsone, an antileprosy drug, was administered to rats with amygdala (AM)-kindled seizures or hippocampal (HIPP)-kindled seizures to elucidate its anticonvulsive efficacy. Adult male Wistar rats were subjected to kindling stimulations 2 weeks after electrode-implantation. The subjects were tested once a day for 7 successive days after inducing three generalized (stage 5) seizures to study the effects of dapsone. Dapsone had an inhibitory effect on stage 5 seizures at 12.50 mg/kg in the AM-kindled rats and at 6.25 mg/kg and 9.375 mg/kg in the HIPP-kindled rats. Thus, there was a distinct difference in the effective dose for generalized seizures between the AM-kindled rats and the HIPP-kindled rats. The inhibitory action of dapsone on stage 5 seizures may be due mainly to the elevation of the afterdischarge-triggering threshold at the stimulation site of the AM or HIPP. Such inhibitory action appears prominently at serum concentrations of about 13 micrograms/ml in AM-kindled rats and about 6 micrograms/ml in HIPP-kindled rats. The level of 6 micrograms/ml almost equals the therapeutic serum concentration of dapsone used in the treatment of leprosy.

A clinical study of 24 patients with respiratory tract infection due to S. aureus detected by transtracheal aspiration (TTA) was conducted, and the following results were obtained. 1) The detection frequency of S. aureus was relatively low (4.6%). 2) Pneumonia was the principal clinical manifestation. 3) Approximately one half of the patients had previously received antimicrobials. 4) Multiple organisms were frequently detected, particularly in cases of hospital-acquired infection. H. influenzae was the most frequently simultaneously detected organism. 5) On sputum examination, approximately 20 ml of purulent sputum was found in most cases, and S. aureus was detected in sputum specimens from 20 of the patients. 6) The largest number of cases was found in 1987. Onset was most common from autumn to spring. 7) Undernutrition was the most frequently associated host factor. As indicated by the above findings, the clinical expression of S. aureus infection is variable, and it is important that it be diagnosed accurately.

We studied the correlation between interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in cerebrospinal fluid (CSF) and clinical/laboratory findings in children with aseptic meningitis. In 19/27 patients (70%), the CSF IFN level was high at initial diagnosis, and reduced to a low or undetectable level during the convalescent phase (5-14 days later) of the disease. There were no differences in IL-1 beta and TNF-alpha levels between the acute and convalescent phase of the patients. The serum IFN-gamma levels in the patients, which were simultaneously examined were undetectable in the acute phase. When we compared the clinical/laboratory findings between the 29 patients with detectable CSF IFN-gamma level and the 21 patients with an undetectable CSF IFN-gamma level in the acute phase, the former demonstrated higher body temperature (P less than 0.01), and higher cell number and protein level in the CSF (P less than 0.05) than the latter. On the other hand, there were no significant differences in the duration of meningeal signs, the titre of C-reactive protein, and the peripheral leucocyte count between the two groups. By the Spearman's rank sum test, the CSF IFN-gamma levels correlated more definitively with the severity of febrile episode (maximal body temperature, duration of fever and body temperature at the first lumbar tap), and the cell number and protein level in the CSF. These results suggest that IFN-gamma produced in the inflamed intrathecal space may be associated with the pathogenesis of aseptic meningitis, especially the production of fever.

We investigated the effect of branched-chain amino acids (BCAA) supplementation on tissue damage during distance running.Eight male distance runners (mean +/- standard deviation; age: 20.4+/-1.2 years, body weight: 58.4+/-4.2 kg) participated in a double blinded cross over designed study conducted during training camp. During each intervention period, the subjects were asked to participate in a 25-km run, and the blood BCAA and lactate dehydrogenase (LDH) level, an index of tissue damage, were measured pre- and post-run. Either a drink containing BCAA (0.4% BCAA in a 4% carbohydrate solution) or an iso-calorie placebo drink was provided to the subjects 5 times during the run without any restriction in the volume.The total volume of the drink consumed by the subjects did not differ substantially between the trials: 591+/-188 (2.36 g BCAA) vs 516+/-169 mL in BCAA and placebo trial, respectively. During the run, the blood BCAA concentration was maintained in the BCAA trial. However, the blood BCAA concentration level tended to decrease in the placebo trial (P0.1). The extent of the blood LDH increase in the BCAA trial was significantly less than that of the placebo trail (48% vs 58%, P0.05).Maintaining the blood BCAA level throughout a long distance run contributes to a reduction in the LDH release and, therefore, the effect of BCAA supplementation is suggested to reduce the degree of muscle damage.

Androgenetic alopecia, or male pattern baldness, is a common, progressive disorder where large, terminal scalp hairs are gradually replaced by smaller hairs in precise patterns until only tiny vellus hairs remain. This balding can cause a marked reduction in the quality of life. Although these changes are driven by androgens, most molecular mechanisms are unknown, limiting available treatments. The mesenchyme-derived dermal papilla at the base of the mainly epithelial hair follicle controls the type of hair produced and is probably the site through which androgens act on follicle cells by altering the regulatory paracrine factors produced by dermal papilla cells. During changes in hair size the relationship between the hair and dermal papilla size remains constant, with alterations in both dermal papilla volume and cell number. This suggests that alterations within the dermal papilla itself play a key role in altering hair size in response to androgens. Cultured dermal papilla cells offer a useful model system to investigate this as they promote new hair growth in vivo, retain characteristics in vitro which reflect their parent follicle's response to androgens in vivo and secrete mitogenic factors for dermal papilla cells and keratinocytes.To investigate whether cultured dermal papilla cells from balding follicles secrete altered amounts/types of mitogenic factors for dermal papilla cells than those from larger, normal follicles. We also aimed to determine whether rodent cells would recognize mitogenic signals from human cells in vitro and whether factors produced by balding dermal papilla cells could alter the start of a new mouse hair cycle in vivo.Dermal papilla cells were cultured from normal, balding and almost clinically normal areas of balding scalps and their ability to produce mitogenic factors compared using both human and rat whisker dermal papilla cells as in vitro targets and mouse hair growth in vivo.Normal scalp cells produced soluble factors which stimulated the growth of both human scalp and rat whisker dermal papilla cells in vitro, demonstrating dose-responsive mitogenic capability across species. Although balding cells stimulated some growth, this was much reduced and they also secreted inhibitory factor(s). Balding cell media also delayed new hair growth when injected into mice.Human balding dermal papilla cells secrete inhibitory factors which affect the growth of both human and rodent dermal papilla cells and factors which delay the onset of anagen in mice in vivo. These inhibitory factor(s) probably cause the formation of smaller dermal papillae and smaller hairs in male pattern baldness. Identification of such factor(s) could lead to novel therapeutic approaches.

We report two siblings with spinocerebellar ataxia type 1 (SCA1) who experienced frequent episodes of spontaneous pneumothorax. Radiologic findings indicated underlying degenerative changes in the lungs. This suggests a possible pathophysiologic relationship between SCA1 and familial occurrence of spontaneous pneumothorax.

To evaluate the role of aging and specific cytokine blockade in the etiology of cachexia caused by adjuvant arthritis (AA), a model of cytokine-associated cachexia.AA was induced in Lewis rats using CFA. In Experiment 1, severity of AA and inflammatory cachexia was assessed in young (Y, age 2-6 months, n = 132) and old rats (O, age 18-22 months, n = 40). In Experiment 2, young rats were divided into 5 different intervention groups: Saline-injected (n = 66); CFA-injected (n = 78); CFA-injected and treated with IL-1 receptor antagonist (IL-1Ra, n = 18); CFA-injected and treated with soluble TNF receptor type I (sTNFrI, n = 27); and CFA-injected and treated with both IL-1Ra and sTNFrI (both treatments, n = 8).In Experiment 1, young Lewis rats developed more severe arthritis (mean joint score on day 21 = 5.1 +/- 0.3) compared to the old group (0.6 +/- 0.6, p0.0001). The young group with AA lost 2.1% of baseline total body weight loss compared to 13.8% total body weight gain in controls (p0.0001). In contrast, old rats injected with CFA lost as much weight (-11%) as age-matched saline injected controls (-13%, p0.05, n = 18, age 18-22 months). In Experiment 2, mean joint scores in rats treated with IL-1Ra, sTNFrI or both were higher then untreated rats injected with CFA (p0.0001). Despite this, rats given both IL-1Ra and sTNFrI lost less weight on day 16 (p0.01) and 21 (p0.002) than untreated rats or those rats treated with either IL-1Ra or sTNFrI.Lewis rats aged 2-6 months are more susceptible to developing AA than older rats (age range 18-22 months). Inhibition of both IL-1 and TNF is needed to mitigate AA-associated weight loss, and this effect is dissociated from the effect of such inhibition on joint inflammation.

We performed (1)H-MR spectroscopy ((1)H-MRS) on multiple brain regions to determine the metabolite pattern and diagnostic utility of (1)H-MRS in multiple system atrophy (MSA).Examining single voxels at 3.0 T, we studied metabolic findings of the putamen, pontine base, and cerebral white matter in 24 MSA patients (predominant cerebellar ataxia (MSA-C), n = 13), parkinsonism (MSA-P), n = 11), in 11 age and duration matched Parkinson's disease patients (PD) and in 18 age matched control subjects.The N-acetylaspartate to creatine ratio (NAA/Cr) in MSA patients showed a significant reduction in the pontine base (p0.0001) and putamen (p = 0.02) compared with controls. NAA/Cr in cerebral white matter also tended to decline in long standing cases. NAA/Cr reduction in the pontine base was prominent in both MSA-P (p0.0001) and MSA-C (p0.0001), and putaminal NAA/Cr reduction was significant in MSA-P (p = 0.009). It was also significant in patients who were in an early phase of their disease, and in those who showed no ataxic symptoms or parkinsonism, or did not show any MRI abnormality of the "hot cross bun" sign or hyperintense putaminal rims. NAA/Cr in MSA-P patients was significantly reduced in the pontine base (p = 0.001) and putamen (p = 0.002) compared with PD patients. The combined (1)H-MRS in the putamen and pontine base served to distinguish patients with MSA-P from PD more clearly.(1)H-MRS showed widespread neuronal and axonal involvement in MSA. The NAA/Cr reduction in the pontine base proved highly informative in the early diagnosis of MSA prior to MRI changes and even before any clinical manifestation of symptoms.

To assess the potential of p21 as a gene therapy treatment for prostate cancer, by introducing p21 into both androgen-dependent (AD) and -independent (AI) human prostate cancer cell lines via a recombinant adenoviral vector, Ad5CMV-p21, carrying human p21 cDNA.The LNCaP, DU145 and PC-3 human prostate cancer cell lines were cultured and infected with Ad5CMV-p21. Cell growth, cell-cycle progression and tumorigenicity were then assessed by thymidine incorporation into cellular DNA, and cell number, flow cytometry, and tumour growth after inoculating the cells into nude mice.Growth was inhibited in Ad5CMV-p21 viral-infected AD and AI prostate cancer cells. The effects were dose-dependent, regardless of the androgen status of the cell lines. Flow cytometric analysis showed that Ad5CMV-p21 arrested cell-cycle progression at G1/S with no appreciable effect on the levels of apoptotic cells. The tumorigenicity of cancer cells infected with Ad5CMV-p21 was greatly reduced in athymic mice.These results suggest that Ad5CMV-p21 may be a new therapeutic agent for human prostate cancer gene therapy.

To clarify the relationship between mitochondrial DNA (mtDNA) sequence variations and phenotypes in patients with A3243G mutation.We studied whole mtDNA sequences in two families with A3243G mutation and characteristic clinical features. Two brothers in Family 1 had shown thiamine deficiency and mitochondrial myopathy without central nervous system involvement. In Family 2, a 16-year-old woman showed the symptoms of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Her mother had had diabetes mellitus and died at the age of 42. The proportion of A3243G mtDNA in blood was 87 and 89% in the patients of Family 1, and 25% in the patient and less than 5% in the mother of Family 2.The mtDNA analysis revealed the following homoplasmic substitutions: T1520C and C12153T found only in Family 1, and A15954G found only in Family 2. These substitutions were not detected in seven other MELAS patients or in 50 controls.These substitutions might be specific to these families and could be one of the factors that modulate their clinical features together with the A3243G mutation.

Lipocortin-1 (also known as annexin-1) is upregulated by corticosteroids and plays a prominent part in many of their anti-inflammatory actions. In our previou investigation, lipocortin-1 gene expression in blood monocytes was higher in sarcoidosis patients tha in healthy subjects or IPF patients. In this study, we examined the amounts of lipocortin-1 gene tran scripts [at baseline and after stimulation by synthetic adrenocorticotrophic hormone (ACTH)] in the blood monocytes of sarcoidosis patients, and then we analyzed the relationships between these amount and several clinical indexes.Serum and blood monocyte samples were prepared from 21 sar coidosis patients before and after ACTH stimulation. The amounts of lipocortin-1 and beta-actin gene tran scripts obtained from monocytes were quantified by RT-PCR. The patients were prospectively followe for at least 2.5 years.1. Serum cortisol was increased in all patients after synthetic ACTH in jection. 2. Lipocortin-1 gene transcripts tended to increase in parallel with increases in serum cortisol but the relationship was not significant. 3. The amounts of lipocortin-1 gene transcripts induced by syn thetic ACTH were related to two indexes of disease activity/extension: the presence of parenchymal lesions (p = 0.018), and the presence of extrathoracic lesions (p = 0.043). 4. After 3 years of follow-up the patients with higher basal amounts of lipocortin-1 gene transcripts in monocytes showed improve ment of sACE activity and FEV1/FVC%.The amounts of lipocortin-1 gene transcripts induced by synthetic ACTH were related to the presence of parenchymal lesions, while their basa amounts correlated with either improvement of sACE activity or stabilization of FEV1/FVC%.

The purpose of this study was to investigate the relationship among expression of procollagen alpha 1 type III mRNA, subacromial adhesion, and limited shoulder elevation in rotator cuff tears. Procollagen alpha 1 type III mRNA was analyzed in the torn supraspinatus tendons and synovial tissue of 42 patients with rotator cuff tears. As a control, four normal supraspinatus tendons of patients who had undergone shoulder surgery other than rotator cuff repair served as controls. Cells stained positively for procollagen alpha 1 type III mRNA were more abundant in the adhesive synovium of the subacromial bursa and in the torn supraspinatus tendons than in controls. Patients with complete-thickness tears who had undergone surgery less than 10 months after trauma were found to have more signal-positive cells than those later than 10 months. We conclude that the adhesive synovium of the subacromial bursa contains abundant cells stained positively for procollagen alpha 1 type III mRNA. We suggest that the production of type III collagen by these cells could contribute to the limitation of shoulder motion in patients with rotator cuff tears, and recommend release and excision of the excess adhesive synovium during rotator cuff surgery.

The results of conservative and operative treatment of massive rotator cuff tears were compared. All 9 men and 5 women who were treated conservatively (group I) had a Hamada Gpoup 4 arthrographic tear. The mean follow-up period was 4 years. The operative group (group II) was composed of 23 men and 3 women who had cuff tears of more than 5.0 cm in longest dimension. The mean age range at surgery was 62 years. Following anterior acromioplasty (n = 26), additional procedures included tenorrhaphy (n = 12), fascial grafting (n = 8), laterl transfer of the long head of the biceps brachii tendon (n = 2), muscle transfer of the teres minor (n = 3), muscle transfer of the supraspinatus (n = 1). The mean follow-up period was 4 years. The results were assessed using the Japanese Orthopaedic Association score. The JOA score was increased from 53.2 to 71.1 in group I, and from 58.8 to 85.9 in group II. More improvement in painrelief, muscle strength, and range of motion was obtained in group II than in group I. There was a significantly better final result in the patients without rupture of the tendon of the long head of the biceps brachii muscle.

We report a case of successful laparoscopic resection of a diverticulum with gastrointestinal bleeding at the third portion of the duodenum. The patient was a 76-year-old man who suffered from persistent tarry stools. An upper gastrointestinal series and endoscopy revealed a large diverticulum with an ulcer and blood clots located at the lateral wall of the distal third portion of the duodenum. Under general anesthesia, a pneumoperitoneum was created by insufflating the abdominal cavity with CO2. There were dense adhesions caused by a previous open cholecystectomy. Four trocars were inserted into the peritoneal cavity for this procedure. After dissecting and identifying the duodenal diverticulum, we performed a diverticulectomy, using an Endo-GIA linear stapler at the base of the retracted diverticulum. There were no intra- or postoperative complications. The operative time was 180 min. Intraoperative bleeding was minimal. Postoperative duodenogram revealed no deformity or stenosis at the resected area. The patient was discharged after an uneventful course, and he has been doing well with no complaints during the follow-up period.

In the present study, the role of the angiotensin II type 2 receptor in the regulation of medullary blood flow in conscious Spontaneous Hypertensive Rats(SHR) was investigated. We tested the hypothesis that AT2 receptor activation may exert the opposite effects of AT1 receptors in terms of renal hemodynamics. Mean arterial pressure(MAP), daily sodium balance, cortical blood flow(CBF), and medullary blood flow(MBF) were measured over a 10-day protocol in several groups of rats in which optical fibers for laser-Doppler flowmetry had been implanted and which received the following drug combinations: the AT1 receptor antagonist CV11976(CV) alone and CV plus AT2 receptor antagonist PD123319 (PD). In the CV alone group, the renal interstitial administration of CV decreased MAP, caused sodium diuresis, and increased MBF significantly. In the CV plus PD group, the renal interstitial administration of PD prevented sustained hypotension, sodium diuresis, and increased medullary blood flow during CV administration. These data indicated that AT2 receptor activation leads to vasodilation in the renal medulla and an antihypertensive effect in SHR. AT2 receptors play an important role in the renal medullary blood flow.

Fifteen patients who were performed a rotator cuff repair were subjected for the determination of a concentration of isepamicin sulfate (ISP), which was infused intravenously, in venous blood and bone marrow blood. The concentrations were measured at 0, 30, 60 minutes after the injection. There was no statistically significance between ISP concentrations in venous and bone marrow blood. This study revealed that the transference of ISP to the bone marrow was excellent.

To study the hypothesis that perforation of the rotator cuff increases the degree of inflammation in the synovium of the glenohumeral joint in rotator cuff diseases.Thirty-five synovial specimens in the glenohumeral joint of patients with rotator cuff diseases were examined. They were obtained during surgery and divided into 2 groups on the basis of the presence or absence of rotator cuff perforation, i.e., perforating and nonperforating tears. The expression levels of inflammatory cytokine mRNA of interleukin 1beta (IL-1beta) and 2 forms (secreted type and intracellular type) of IL-1 receptor antagonist (IL-1ra) were measured by reverse transcriptase polymerase chain reaction (RT-PCR). The protein level of IL-1beta was determined by Western blot analysis. IL-1beta producing cells were also identified by in situ RT-PCR and immunohistochemistry.In perforating tears cytokine mRNA in the glenohumeral synovium was more significantly expressed than in nonperforating tears. Also, higher levels of IL-1beta protein were detected in perforating tears.Perforation of the rotator cuff increases IL-1beta production in the glenohumeral joint, enhancing inflammatory intensity at the site. These findings suggest the possibility that glenohumeral synovitis in rotator cuff diseases may be a factor for the development of glenohumeral arthropathy.

1. The prostate function is regulated by androgens and alpha-adrenergic activity. Clinically, antiandrogens and/or alpha(1)-adrenergic antagonists are commonly used to treat symptomatic prostatic hypertrophy. To elucidate the effects of androgen deprivation on prostate contractility via alpha(1)-adrenoceptor, the characteristics and expression of alpha(1)-adrenoceptors were examined in castrated rats. 2. Isolated prostate strips from intact and castrated rats were subjected to a phenylephrine stimulated contraction. Prazosin (10 nM), [(3)H]-prazosin and phenoxybenzamine (3 - 300 nM) were used for inhibition assay, receptor characterization and partial alkylation of alpha-adrenoceptor, respectively. The mRNA content of three subtypes of alpha-adrenoceptors was determined by reverse transcription combined with polymerase chain reaction (RT - PCR). 3. Contractile response to phenylephrine increased in castrated rats, which could be explained by a relative increase of the stromal component. A lowered contraction potency was also noted in castrated rats. Receptor binding assay indicated minimal changes in the affinity or density of alpha(1)-adrenoceptor. Escalating alkylation of the alpha(1)-adrenoceptor population resulted in a rightward shift in the contraction-response curves before depressing maximal contractile force, and the suppression was detected at lower doses in castrated rats. RT - PCR study confirmed the expression of three types of alpha(1)-adrenoceptor, alpha(1a), alpha(1b) and alpha(1d)-adrenoceptors, in intact rat prostate, and revealed that alpha(1a)-adrenoceptor, but not alpha(1b) or alpha(1d)-adrenoceptors, was down-regulated in castrates. 4. The results show that androgen deprivation suppressed alpha(1)-adrenergic contractility of rat prostate strips, and the suppression was associated with down-regulation of receptor reserve for the alpha(1a)-adreneroceptor population expressed in intact rat prostate.

The authors report two forensic autopsy cases of pilots who died in glider and ultra-light plane crashes in Aso, Kumamoto and review sky sports accidents in Japan (1981-1997). In the glider crash, sharp abdominal pain due to gallstones in a 78-year-old pilot was a possible cause of the accident. In the ultra-light plane crash, unskillful control of the plane by a 38-year-old pilot was the cause of the accident. The incidence of sky sports accidents increased from 12 cases in 1981 to 62 cases in 1997. The mortality rate of the victims of the accidents is very high. Investigation of natural diseases in pilots as a cause of accidents and the mechanisms of fatal injuries will help to assess preventive measures against sky sports accidents.

Left cervical lymphadenopathy developed in a 50-year-old male who had a history of adult-onset Still's disease for the preceding 18 months. Still's disease is characterized by rash, fever, and leukocytosis. Lymphadenopathy has been reported in about 60% of the patients, and most histopathologic studies have shown non-specific reactive hyperplasia. However, in this case, an open biopsy of the cervical node revealed a histology of diffuse large B-cell lymphoma. The B-cell malignant lymphoma that developed may have resulted from a sequential progression of a previous stage of benign lymphoproliferative lesion. Our case suggests that the pathophysiology of adultonset Still's disease involves the stimulation of lymphoid systems to the point of progression towards lymphoma. Malignant lymphoma should be added to the list of life-threatening complications which, although rare, are associated with this disease.

In spite of the known role of cigarette smoking in the development of airflow limitation (AL), fewer than 20% of smokers actually develop chronic obstructive pulmonary disease (COPD).We examined how smoking histories and indices in blood are related to the degree of AL in asymptomatic smokers in order to determine whether they can predict the development of AL.Spirometry and peripheral blood tests were examined in 433 Japanese asymptomatic current smokers at the initial examination. Forced expiratory volume in 1 s (FEV(1)) was measured periodically for 2 or more years (2-13 years) in 66 of the subjects.AL defined as an FEV(1)/vital capacity of less than 0.7, was found in 11.3% (49 of 433) of the smokers. Pack-years of smoking, serum amounts of alpha(1)-proteinase inhibitor, and serum procollagen III peptide activities were correlated with the degree of AL. Fifteen percent (10 of 66) of subjects underwent rapid declines in FEV(1) that were found to be related not with smoking amounts or initial FEV(1), but with low FEV(1) (%pred) adjusted by pack-years and an elevated serum neutrophil elastase/alpha(1)-proteinase inhibitor ratio. These results suggest that smokers with a low FEV(1) out of proportion to pack-years are susceptible smokers at a high risk of developing COPD, and further, that increased proteinase burden relative to antiproteinase activity may contribute to the development of COPD.We conclude that the serum neutrophil elastase/alpha(1)-proteinase inhibitor ratio and FEV(1) (%pred) adjusted by pack-years can be reliable predictors of the development of COPD.

A 20-year-old male presented with traumatic basal subarachnoid hemorrhage after being involved in a fight. Antemortem clinical examinations could not exclude the possibility of rupture of abnormal blood vessels because of the absence of external injuries. Careful postmortem examination of the head and neck regions and histological examination of the intracranial arteries demonstrated traumatic rupture of the left posterior inferior cerebellar artery due to a fist blow to the jaw. This case indicates the need for careful autopsy examination for the differentiation of traumatic and non-traumatic basal subarachnoid hemorrhages.

DNA analysis of the androgen receptor gene in a patient with complete androgen insensitivity syndrome identified a substitutional mutation (tyrosine converted to cysteine at position 571) in the DNA binding domain. In vitro transfection experiments with the patients' androgen receptor gene, indicated normal expression of the androgen receptor in transfected COS-7 cells compared to the wild type gene. There was also no evidence of impaired thermal stability of the 5 alpha-dihydrotestosterone-androgen receptor complex. However, the capacity of the androgen receptor to activate target gene transcription was found to be completely disrupted in a luciferase assay. These results confirmed that only one substitutional mutation in the DNA binding domain was related to the pathogenesis of the complete androgen insensitivity syndrome.

In order to determine whether adrenal and gonadal weak androgens are utilized to form active androgens in human hair, we studied the expression of mRNA for androgen receptor (AR), 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in cultured dermal papilla cells (DPCs) from various body sites. AR mRNA was expressed in beard (Be) and axillary hair (Ax) DPCs from both sexes, but only at a low level in DPCs from occipital scalp hair (OS). Type I 5alpha-reductase mRNA was expressed by all DPCs. Type II 5alpha-reductase mRNA was identified in beard DPCs, but was absent from OS and Ax DPCs. Type II 17beta-HSD mRNA was strongly expressed in outer root sheath cells (ORSCs), while DPCs except for male Ax expressed no type II 17beta-HSD mRNA. In contrast, type III 17beta-HSD mRNA was strongly expressed in Be DPCs and Ax DPCs from both sexes; ORSCs showed a low level of expression. Expression of type III 17beta-HSD mRNA was not regulated by androgen in DPCs. These results suggest that the sensitivity of hairs to androgen is partially controlled by the site-specific expression of AR, 5alpha-reductase and 17beta-HSD in DPCs.

Variable clinical courses have been recognized in patients with idiopathic pulmonary fibrosis (IPF), but the disease is known to have a fundamentally unfavorable outcome. In addition, we have yet to fully understand whether the regional or population differences are negligible or not. Therefore, we analyzed the clinical outcomes in Japanese IPF patients in a hospital-based historical cohort study.A questionnaire was used to collect records for retrospective analysis of the IPF patients. We analyzed data collected from 51 hospitals and clinics in Japan on 234 Japanese IPF patients (males 170, females 64) with IPF who had been followed up after diagnosis.1. Five and ten years after the detection of exertional dyspnea, the overall survival rates were 41.0% and 20.1%, respectively. A higher age at the time of detection (over 59) was related to a decrease in survival rates. 2. The incidence of complications was no higher in the corticosteroid-treated cases than in the untreated cases. The effects of corticosteroid treatment on survival was not confirmed in this type of study.The survival rates of histologically proven Japanese patients with IPF were similar to the rates previously reported in different populations. Age at the detection of exertional dyspnea was critical in terms of the survival rate.

In this study time for initial assessment of monthly intravenous cyclophosphamide (CP) pulse therapy is discussed for a better outcome with less complications. Eleven patients with lupus nephritis (LN) resistant to conventional therapy (serum creatinine levelor = 2.7 mg/dl) were given 500 mg/m2 of CP 7-9 times with an interval of one month. Urinary protein (Up) decreased in all patients after 3 courses of CP pulse therapy and kept similar levels thereafter. In one group of patients (n = 7), Up decreased to2 g/day after 3 courses, while in the other group (n = 4), it did not decrease to4 g/day. Creatinine clearance increased by 0-100% in the former group, while it decreased by 5-20% in the latter group after 6-9 courses. Renal function of the patients with insufficient response after 3 courses tended to show no further improvement or worsened thereafter, although Up decreased during CP pulse therapy. A relatively small dose of CP (500 mg/m2) pulse therapy was useful in most LN patients regardless of the renal histology and it was thought important to assess its effects after 3 courses for a prediction of the clinical course. Modification of the protocol at that time might be necessary in regard to dose or interval of CP administration especially for patients with insufficient outcome.

To investigate the contractile responses mediated through alpha1-adrenoceptors in human urethra and to evaluate the effectiveness of NS-49 [(R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulphonanilide++ + hydrochloride], a novel alpha1-adrenoceptor agonist, against contraction of the human urethra.The contractile responses were assessed in 10 male prostatic urethrae and six female urethrae. Antagonism was evaluated in the urethra using phenylephrine, a nonselective alpha1-adrenoceptor agonist, cumulatively applied20 min after applying 0.1 micromol/L prazosin or 0.1 micromol/L 5-methylurapidil, a selective alpha1A-adrenoceptor antagonist. Agonism was determined in both male and female urethrae to obtain the concentration-response curve for the agonist.Phenylephrine caused both male and female urethrae to contract, and showed high potency and efficacy. Prazosin antagonized these contractions with low affinity (apparent pKB of 8.30 in male urethrae). 5-Methylurapidil, also antagonized the contractions with low affinity (apparent pKB of 7.88 in male urethrae). Noradrenaline and phenylephrine caused both male and female urethrae to contract, with high potency and efficacy. A novel and selective alpha1A-and alpha1L-adrenoceptor agonist, NS-49, induced contractile responses with high potency and moderate efficacy, whereas methoxamine induced contractions with low potency and moderate efficacy. Norephedrine was a very weak contractile agonist.In the human urethra, phenylephrine-induced contractions were mediated through alpha1L-adrenoceptors and not through alpha1A-adrenoceptors. Contractions of the human urethra induced by NS-49 were also mediated mainly through alpha1L-adrenoceptors, with high potency and moderate efficacy. NS-49 may therefore be useful for the treatment of urinary stress incontinence, with minimal side-effects because it has subtype selectivity.

Macroscopic synovitis of the glenohumeral joint is frequently seen during arthroscopy in patients with anterior instability. Interleukin-1beta is known to be expressed in inflamed tissue, to correlate with the magnitude of inflammation, and to affect articular cartilage in the joint. We hypothesized that chronic synovitis may occur in the glenohumeral joint in patients with anterior instability. The purpose of this study was to examine the expression of interleukin-1beta in the synovium of the glenohumeral joint with anterior instability and to discuss its clinicopathologic significance. Specimens of synovial tissue around the greater tuberosity in the subacromial synovium (as controls) and around the rotator interval in the glenohumeral synovium were obtained from 10 patients who had anterior instability without signs of subacromial impingement. Semiquantitative reverse transcriptase-polymerase chain reaction was used to compare the levels of interleukin-1beta mRNA expression in the glenohumeral joint with those in the subacromial bursa. We also employed immunohistochemistry and in situ reverse transcriptase-polymerase chain reaction to detect the cells producing interleukin-1beta protein and mRNA. The levels of interleukin-1beta mRNA expression were significantly higher in the glenohumeral joint than in the subacromial bursa (p0.01). Histology showed nonspecific inflammation in all 10 samples of glenohumeral synovium, whereas no inflammation was seen in seven of 10 samples of subacromial synovium. Immunohistochemistry identified interleukin-1beta protein in the vessels and inflammatory and synovial cells (from lining to sublining layers) in synovium of the glenohumeral joint, whereas immunoreactivity was negative in seven subacromial bursa. The remaining three synovial specimens of subacromial bursa, however, showed positive immunoreactivity that was unremarkable and confined around the vessels. In situ reverse transcriptase-polymerase chain reaction was exclusively performed in the synovial specimens of the glenohumeral joint, which exhibited a positive reaction (in the same kinds of cells as seen with immunohistochemistry) in the lining and sublining layers and to a lesser extent in the stroma. Thus, our data confirmed the increased production of interleukin-1beta in the synovium of the glenohumeral joint in patients with anterior instability, suggesting the presence of chronic inflammation at the site. We conclude that this chronic synovitis may be partly associated with the development of dislocation arthropathy in the long term.

A new myeloid cell line, MTT-95, was established from the bone marrow of a patient with acute myelogenous leukemia (AML, M7). MTT-95 cells differentiate into mature basophilic cells in culture medium with no chemical component or cytokine. Surface phenotypes were as follows: CD11b 79.3%, CD13 92.4%, CD33 99.8%, CD34 87.9%, CD41a 77.6% and HLA-DR 0.3%. MTT-95 cells were strongly positive for glycoprotein IIb/IIIa by immunohistochemical staining and revealed metachromatic granules. MTT-95 cells seem to possess characteristics of both megakaryocytes and basophils. These findings suggest that MTT-95 cells are basophil progenitors. MTT-95 cells might be useful in the study not only of the biological aspects of basophils, but also of the diversities of AML (M7).

Loss of heterozygosity (LOH) on chromosomes 2q, 9p, 18q, and 22q frequently occurs in advanced non-small cell lung carcinoma (NSCLC). The association of p53 mutations with prognosis is still unclear in NSCLC. Therefore, we investigated the prognostic significance of allelic imbalances (AI) on these chromosomes and p53 mutations in 108 cases of stage I NSCLC by PCR amplification of polymorphic dinucleotide repeat-containing sequences and PCR-single strand conformation polymorphism analysis. AI on 2q, 9p, 18q, and 22q was detected in 22, 38, 29, and 15% of cases, respectively, whereas p53 was mutated in 41% of stage I NSCLC. AI on 9p and 22q and p53 mutations were significantly associated with shortened survival of the patients (P = 0.010, 0.024, and 0.022, respectively). Although gender and smoking history showed more significant associations with prognosis than other clinicopathological and molecular parameters, independent prognostic significance for AI on 9p was observed (P = 0.002) in male patients with a positive smoking history. These results indicate that clinical aggressiveness of early-stage NSCLC can be partly defined by the presence of AI on chromosome 9p in cancer cells, and that AI on 9p could be a clinically useful prognostic indicator for early-stage NSCLC patients.

We reviewed 26 patients with 34 shoulders treated by the inferior capsular shift operation for inferior and multidirectional instability. The mean follow-up was 8.3 years. In total, 12 shoulders showed voluntary subluxation. Eight operations used an anterior and posterior approach, 11 were by the posterior route, and 15 shoulders had an anterior approach. In 30 shoulders (85%) the outcome was satisfactory and 20 (59%) scored good or excellent results on the Rowe system. Instability had recurred in nine shoulders (26%) from three months to three years after the operation. Six of the 12 shoulders with voluntary subluxation (50%) had recurrence, as against three of the other 22 (14%), a statistically significant difference. The operation is therefore not indicated for voluntary subluxation. The 19 shoulders which had been assessed in 1987 at a mean of 3.5 years after surgery, were also reviewed in 1995 and found to have no significant changes in instability or Rowe score. This shows that the capsular shift appeared to have maintained its tension over an eight-year period. After the use of a posterior approach, 64% of the shoulders showed a posterolateral defect on radiographs of the humerus.

A 30-year-old man had been treated for malignant rheumatoid arthritis from 1989 with a non-steroidal anti-inflammatory drug, then bucillamine for six months and prednisolone. Mild proteinuria appeared in May 1994, 4 years after bucillamine therapy was conducted. The patient was admitted to our hospital for a renal biopsy in July 1994. The specimen revealed secondary amyloidosis and membranous nephropathy (MGN). These findings suggest that MGN unrelated to bucillamine therapy might have occurred with secondary amyloidosis in rheumatoid arthritis.

We have already reported that decreased renal medullary blood flow and retention of sodium play an important role in the development of hypertension during chronic systemic L-NAME (NG-nitro-L-arginine methyl ester) administration, despite the absence of measurable changes in renal cortical blood flow as determined from fibers implanted for laser-Doppler flowmetry. In the present experiment, to investigate the interaction between nitric oxide and angiotensin II on renal hemodynamics, the effect of chronic intravenous infusion of L-NAME on blood pressure, sodium and water retention, and intrarenal blood flow distribution were studied in a separate group of rats pretreated with captopril and in which optical fiber for laser-Doppler flowmetry had been implanted. Captopril completely prevented sustained hypertension, sodium retention, and decreased medullary blood flow during chronic L-NAME infusion. These date indicated that angiotensin plays an important role in the regulation of renal medullary blood flow and sodium excretion by modulating the effects of nitric oxide in renal medullary blood flow.

The treatment of a 14-membered ring macrolide, clarithromycin (CAM), prolongs the survival time of patients with unresectable nonsmall cell lung cancer, and improves the host factor. As we previously reported, one of the underlying mechanisms is that the treatment of CAM increases the bioactivity of interleukin-12 (IL-12). In the present study, we administered CAM to murine lung cancer treatment models with Lewis lung carcinoma and to 18 patients with unresectable non-small lung cancer whose anticancer treatment had been terminated. The timing of CAM administration was examined and the time course of NK activity was measured. In the murine lung cancer treatment models, administration of CAM 7 days after anticancer chemotherapy more strongly inhibited the tumor growth and more rapidly and significantly increased NK activity, compared to the concomitant use of CAM with an anticancer chemotherapy. In humans, the NK activity which had decreased after anticancer treatment, tended to be increased after one month of treatment with CAM (p = 0.06). One month of treatment with CAM significantly increased the NK activity (p0.05) of the following subjects: patients with stage III in the clinical stages, patients with squamous cell carcinoma, patients who had received radiotherapy alone as pretreatment therapy, and patients whose pretreatment therapy effect was partial response (PR). We conjectured that increasing NK activity was one of the underlying mechanisms of the macrobiotic effect of CAM. CAM was especially effective for patients in the early clinical stages and patients who responded well to pretreatment therapy. Murine lung cancer models showed that non-concomitant use of CAM with anticancer chemotherapy was more effective.

A 66 year-old man was found to have pointed out a 1-cm tumor shadow, on a chest X-ray film when he underwent a gastrectomy because of advanced gastric cancer. Five months after the operation, edema and proteinuria developed, and a chest X-ray film revealed enlargement of the tumor. There was no sign of recurrence of the gastric cancer. Nephrotic syndrome due to IgA-nephropathy and small cell lung cancer was diagnosed. Chemotherapy (carboplatin and etoposide) was effective against both the lung tumor and the nephrotic syndrome. Small cell lung cancer may have been involved in the pathogenesis of the nephrotic syndrome in this patient.