Relation between breastfeeding and the prevalence of asthma : the Tokorozawa Childhood Asthma and Pollinosis Study.

Many risk factors for asthma have been proposed including age, gender (male), smoking, and family history of asthma. The importance of breastfeeding to childhood asthma is a controversial issue. The present study investigated the relation between breastfeeding and the prevalence of asthma among a childhood population. The subjects were 25,767 students, representing all public elementary and junior high schools in Tokorozawa, Japan (age range, 6--15 years). The study population included 2,315 students with asthma and 21,513 controls. Participants' parents completed the Japanese version of the American Thoracic Society and Division of Lung Diseases, National Heart, Lung, and Blood Institute, questionnaire for children adopted by the Japanese Environmental Agency in 1998. The authors added supplementary questions on the parental history of asthma and feeding patterns from the age of 0--3 months. The risk of breastfeeding for asthma was compared with that of artificial feeding. After adjustment for age, gender, parental smoking status, and parental history of asthma, a significantly higher prevalence of asthma was noted among children who had been breastfed (adjusted odds ratio = 1.198; 95% confidence interval: 1.054, 1.363; p for trend < 0.01). The results indicated that breastfeeding in infancy might be related to the higher prevalence of asthma during preadolescence.

A cross-sectional study on the relationship between leisure or recreational physical activity and coronary risk factors.

Several researchers have investigated the relationship between physical activity and coronary risk factors. Little is known about the strength of the relationship between physical activity and each coronary risk factor. The aim of this study is to determined the strength of the relationship between leisure or recreational physical activity and selected coronary risk factors. The subjects were 781 male Japanese office workers who underwent an annual physical examination in 1999, including interview about the type and frequency of their leisure or recreational physical activities, other lifestyle questionnaire, and biological measurement, calculated a physical activity index (PAI) for each subject. To investigate the strength of the relationship between PAI and each coronary risk factor, we carried out multiple regression analysis. Smoking habit, log triglycerides, self-rating depression scale (SDS) score, alcohol habit and left ventricular hypertrophy were significantly related to the physical activity (partial R2: 0.031, 0.018, 0.016, 0.0092, 0.0075, respectively). Smoking habit was the strongest determinant of the physical activity. Furthermore, we found the inverse relationship between SDS score and physical activity independently.

Important role of EP4, a subtype of prostaglandin (PG) E receptor, in osteoclast-like cell formation from mouse bone marrow cells induced by PGE2.

Of various PGs, PGE1 and PGE2 are shown to be the most potent stimulators of osteoclastogenesis in vitro. PGE receptors have been classified into four subtypes, EP1-EP4. Little is known about PGE receptors functioning in bone cells. In this study, using mouse marrow culture, we investigated which PGE receptors are important in osteoclast-like cell (OCL) formation induced by PGE. 11-deoxy-PGE1 (EP2, EP3 and EP4 agonist) stimulated OCL formation potently. Butaprost (EP2 agonist) stimulated it slightly, while sulprostone (EP1 and EP3 agonist) and ONO-AP-324-01 (EP3 agonist) did not. AH23848B (EP4 antagonist) inhibited PGE2-induced OCL formation in a dose-dependent manner. The expression of EP4 mRNA in mouse bone marrow was confirmed by RT-PCR. The results indicate an important role of EP4 in PGE2-induced OCL formation in marrow cultures and suggest therapeutic potential of EP4 antagonists in some clinical conditions with accelerated bone resorption.

Chinese hamster ovary cells expressing alpha4beta1 integrin stimulate osteoclast formation in vitro.

It is reported that Chinese hamster ovary cells transfected with human alpha4 cDNA (alpha4CHOs) and expressing functional alpha4beta1 integrin developed bone metasasis in nude mice. To clarify the role of alpha4beta1 integrin in bone metastasis, in terms of tumor-mediated bone destruction, we examined whether alpha4CHOs stimulate osteoclast formation in cocultures with mouse bone marrow cells. The number of osteoclast-like cells identified as tartrate-resistant acid phosphatase positive multinucleated cells (TRAP(+) MNCs) formed from bone marrow cells increased with the increasing number of alpha4CHOs cocultured. The effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and prostaglandin E2 (PGE2) on TRAP(+) MNC formation were enhanced in cocultures with alpha4CHOs. TRAP(+) MNCs induced by alpha4CHOs possessed calcitonin receptors and resorbed calcified tissues. In cocultures, alpha4CHOs and bone marrow stromal cells were in contact with each other and bone marrow stromal cells expressed vascular cell adhesion molecule-1 (VCAM-1), which is one of the ligands for alpha4beta1 integrin. TRAP(+) MNC formation was not stimulated in cocultures where direct contact between alpha4CHOs and bone marrow cells was inhibited by membrane filters. Alpha4CHOs do not support TRAP(+) MNC formation in cocultures with spleen cells but do support TRAP(+) mononuclear cell and MNC formation from spleen cells in the presence of osteoblastic cells. Cultured media from alpha4CHOs, bone marrow cells, and cocultures of alpha4CHOs and bone marrow cells did not stimulate TRAP(+) MNC formation or enhance the effects of 1,25(OH)2D3 and PGE2 in bone marrow cultures. The concentrations of PGE2 and interleukin-6 (IL-6) in cultured media were not different between the cultures of bone marrow cells and the cocultures of bone marrow cells and alpha4CHOs. Anti-human alpha4 and anti-mouse VCAM-1 antibodies inhibited TRAP(+) MNC formation induced by alpha4CHOs. These results indicate that alpha4CHOs stimulated TRAP(+) MNC formation through direct cell-to-cell interaction between alpha4beta1 and VCAM-1. It is suggested that in addition to various soluble factors regulating osteoclast formation, cell-to-cell interaction between tumor cells and bone marrow cells is important for inducing osteoclasts at the site of bone metastasis and leading to bone destruction.

Mouse mammary carcinoma cell line (BALB/c-MC) stimulates osteoclast formation from mouse bone marrow cells through cell-to-cell contact.

We recently reported that numerous osteoclasts (OC) were formed in cocultures of some mouse cancer cell lines and bone marrow cells. In this study, we examined mechanisms by which one of the cell lines, BALB/c-MC, induces OC. BALB/c-MC dose dependently stimulated OC formation in cocultures. In cocultures where direct cell-to-cell contact between BALB/c-MC and bone marrow cells was inhibited by membrane filters, OC formation was not stimulated. The stimulation of OC formation in the coculture was completely abolished by adding 10(-7)-10(-6) mol/L indomethacin. The concentration of prostaglandin E2 (PGE2) in the culture media of cocultures with cell-to-cell contact was higher than that of cocultures without cell-to-cell contact or marrow cultures alone, and it reached levels sufficient to induce OC (11.9 +/- 5.3 ng/mL [about 3.4 x 10(-8) mol/L]). When BALB/c-MC or bone marrow cells were fixed with formalin and then cocultured with bone marrow cells or BALB/c-MC, respectively, the concentration of PGE2 in the culture media of cocultures of fixed BALB/c-MC and bone marrow cells increased, whereas that of cocultures of BALB/c-MC and fixed bone marrow cells did not increase. These results indicate that BALB/c-MC stimulate OC formation through direct cell-to-cell contact with bone marrow cells, and PGE2 released from bone marrow cells through direct cell-to-cell contact are involved in OC formation by the cell line.

A third-generation bisphosphonate, YM175, inhibits osteoclast formation in murine cocultures by inhibiting proliferation of precursor cells via supporting cell-dependent mechanisms.

The theory that bisphosphonates inhibit osteoclast formation through their effects on osteoblastic cells remains controversial. To confirm the inhibitory effect of bisphosphonates on osteoclast formation and gain some insights into the underlying mechanisms, we examined the effect of disodium dihydrogen (cycloheptylamino)-methylene-bisphosphonate monohydrate (YM175) on osteoclast-like multinucleated cell (OCL) formation in various mouse coculture systems. When different origins of osteoclast precursors (bone marrow, spleen, or nonspecific esterase-positive cells) were cocultured with the same supporting cells (calvarial osteoblasts), YM175 inhibited OCL formation similarly in all cultures. When the same osteoclast precursors (spleen cells) were cocultured with supporting cells of different origin, the results were variable. YM175 inhibited OCL formation almost completely in cocultures with calvarial osteoblasts or osteoblastic cell line KS4, while it did not, or only slightly, inhibit OCL formation in cocultures with stromal cell lines, ST2 or MC3T3-G2/PA6. Temporal addition of YM175 in cocultures of spleen cells with osteoblastic cells revealed that YM175 was effective when it was present at an early phase of the culture period. Consistent with this observation, YM175 in the presence of osteoblastic cells inhibited proliferation of preosteoclastic cells, but did not inhibit the fusion of mononuclear prefusion osteoclasts. In conclusion, the inhibitory effect of YM175 on OCL formation was confirmed in various murine coculture systems, but the effect was dependent on the types of bone-derived cells supporting osteoclastogenesis. The findings suggest that YM175 inhibits osteoclastogenesis by inhibiting the proliferation of osteoclast precursors through its action on supporting cells of osteoblast lineage rather than acting directly on osteoclast precursors.

The mouse mammary tumor cell line, MMT060562, produces prostaglandin E2 and leukemia inhibitory factor and supports osteoclast formation in vitro via a stromal cell-dependent pathway.

Osteoclastic bone resorption increases at the site of bone metastasis, but little is known about how tumor cells induce osteoclast (OC) recruitment in the bone marrow microenvironment. To clarify this point, we examined the effects of various mouse tumor cells on OC recruitment using cocultures of tumor cells and mouse marrow cells. The mouse mammary tumor cell lines, MMT060562 (MMT), BALB/c-MC, Jyg-MC(A), or other nonmammary tumor cell lines, LLC and B16, were cocultured with mouse marrow cells, and OC recruitment from marrow cells was determined by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells (TRAP(+) MNCs) formed. Of the tumor cells examined, MMT and BALB/c-MC stimulated OC formation, but other tumor cells did not. OC formation with MMT was dependent on the number of MMTs inoculated, and only ten cells per well were sufficient to induce OC development. OCs appeared on day 4, and the number reached a maximum on days 5-8 and decreased thereafter. TRAP(+) MNCs induced by MMT satisfied the major criteria of OCs, such as the presence of calcitonin receptors and the ability to resorb calcified tissues. The majority of OCs were formed adjacent to the stromal cells, which were positive for alkaline phosphatase. When spleen cells were cocultured with MMT, no OCs were formed. In contrast, when osteoblastic cells were added to cocultures of spleen cells and MMT, many OCs were formed. The cultured media (CM) of MMT induced OC formation in mouse marrow cultures. Neither parathyroid hormone-like nor interleukin 1-like activity was present in the CM. MMT constitutively produced prostaglandin E2 (PGE2) and OC formation in cocultures was completely inhibited by indomethacin. Fractionation of the CM of MMT by ultrafiltration indicated that the OC-inducing activities were present not only in the fraction with molecular weight below 3 kDa but also in the fraction with molecular weight above 3 kDa. OC-inducing activity with high molecular weight was eluted around 50 kDa by Bio-Gel P-60 column chromatography. The active fractions also possessed leukemia inhibitory factor (LIF) activity, and OC-inducing activity of the peak fraction was inhibited in the presence of anti-LIF neutralizing antibody. The results of this study indicated that MMTs release PGE2 and LIF, which in turn stimulate OC formation via a stromal cell-dependent pathway. These culture systems will help to clarify the mechanisms by which tumor cells induce OC formation in a bone marrow microenvironment.

Lack of association between the Trp64 Arg mutation in the beta 3-adrenergic receptor gene and obesity in Japanese men: a longitudinal analysis.

The beta 3-adrenergic receptor (beta 3AR) is implicated in the regulation of thermogenesis and lipolysis, and it is suggested that the Trp64 Arg mutation in this receptor may contribute to the development of obesity. To examine whether the Trp64 Arg mutation had any effect on body weight during adult life, the beta 3AR genotype was determined in 186 unselected Japanese men, most of whom had records of body weight measured yearly from 25-53 yr of age. Of them, 26 subjects were diagnosed as having noninsulin-dependent diabetes mellitus (NIDDM) and 41 as having impaired glucose tolerance. There were 6 subjects (3%) with homozygous mutation, 67 (36%) with heterozygous mutation, and 113 (61%) with normal allele. Among the 3 genotypes, there were no significant differences in body mass index (BMI) at any age between 25-53 yr and the prevalence of NIDDM at the age of 53 yr. When longitudinal changes in body weight were compared between subjects with and without mutation, the former were less prone to gain weight than the latter. The frequency of the mutant allele was 1) not different among obese (BMI, > 26.4), intermediate (BMI, 22-26.4), and nonobese (BMI, < 22.0) subjects (0.21, 0.22, and 0.26, respectively; P = 0.77); 2) lower in subjects with NIDDM than in those without it, but the difference was insignificant (0.12 vs. 0.23; P = 0.07); and 3) similar between 186 unselected men and another group of 100 patients with NIDDM that were randomly selected for comparison (0.21 vs. 0.23). These results suggest that the beta 3AR is not a major contributing factor to obesity or NIDDM in Japanese men.

Role of nonenzymatic glycosylation of type I collagen in diabetic osteopenia.

Formation of advanced glycation end products (AGEs) in extracellular matrix (ECM) is implicated in the development of chronic diabetic complications. However, the involvement of AGEs in diabetic bone disease has not been well established. We have examined whether AGEs are increased in the bone collagen of streptozotocin-induced diabetic rats in vivo and whether glycation of type I collagen affects the functions of osteoblastic cells in vitro. During 12 weeks of observation, AGEs in collagen extracted from the tibiae of diabetic rats increased in a time-dependent manner and were significantly higher than controls at every time point. In vitro, the incubation of collagen with glucose-6-phosphate resulted in a time-dependent increase of AGEs. When osteoblastic cells isolated from fetal rat calvaria were cultured on AGE-modified type I collagen, it dose-dependently inhibited phenotypic expressions of osteoblasts. Among osteoblastic parameters, nodule formation was the most sensitive, being inhibited by approximately 70% by the glycation of collagen for only 1 week. Alkaline phosphatase activity and osteocalcin secretion were inhibited by 20-30% and 15-70%, respectively, by the glycation of collagen for 1-5 weeks. These results indicate that AGE-modified collagen affects osteoblastic cell differentiation and function in vitro and suggest that similar changes occurring in vivo may contribute to diabetic osteopenia.

The results of the "essential laboratory tests" applied to new outpatients--re-evaluation of diagnostic efficiencies of the test items.

We have analyzed diagnostic efficiencies of the individual "Essential laboratory test" items when these tests were applied to 520 new outpatients in the division of comprehensive medicine in a teaching hospital. The integration of these test results with history-taking and physical examination resulted in 544 primary clinical diagnoses which corresponded to the patient's illness complained and in 361 additional diagnoses unrelated to their chief complaints but found by chance by the addition of the test results. Clinical usefulness of these test items were variable depending on the disease category, demonstrating a superior diagnostic efficiency in infectious or inflammatory diseases, liver and biliary tract diseases, hematological disorders or metabolic diseases such as hyperlipidemia and diabetes mellitus, but a lesser degree of usefulness in gastro-intestinal or neurogenic diseases. Urine urobilinogen could not establish its clinical usefulness because of extremely low diagnostic sensitivity even in liver diseases. The leukocyte differential count provided confirmatory information for infectious or inflammatory diseases and was helpful for the estimation of the etiologic nature of infectious diseases. This study failed to terminate a controversy for the adoption of sialic acid instead of erythrocyte sedimentation rate (ESR) in the "Essential laboratory test" items, since the former test showed lower sensitivity, even though higher specificity, in infectious or inflammatory status than ESR. Low albumin globulin ratio (A/G) revealed equivalent diagnostic sensitivity and specificity to the elevated levels in alpha 1 and/or alpha 2 globulin fractions in infectious or inflammatory status, being helpful for the evaluation of patient's general condition at a glance. Incidental analysis for diagnostic values of cholinesterase and random blood glucose for the detection of fatty liver and diabetes mellitus, respectively, suggested that these two tests may be included in the "Essential laboratory tests". Simultaneous measurement of serum creatinine and blood urea nitrogen levels was recommended for the ambulatory screening of renal insufficiency, rather than the measurement either alone. The results in this study provide scientific bases on the usefulness of the individual test items and should be taken into account in the next version of the "Essential laboratory tests".

Urinary type IV collagen as a marker for early diabetic nephropathy.

We investigated the urinary secretion of type IV collagen in 115 subjects with non-insulin-dependent diabetes mellitus (NIDDM) without macroproteinuria, 34 normal healthy subjects and 19 subjects with chronic glomerulonephritis (CGN). We examined the relation between the urinary level of type IV collagen and various clinical parameters. The urinary level of type IV collagen was significantly elevated in NIDDM subjects compared with normal subjects (4.88 +/- 3.12 vs. 1.7 +/- 1.25 micrograms/gCr, P < 0.001). The urinary level of type IV collagen was increased even in NIDDM subjects with normoalbuminuria. The ratio of urinary type IV collagen was significantly lower in subjects with chronic glomerulonephritis (CGN) than those in NIDDM subjects (P < 0.001), although there was no significant difference in the urinary level of type IV collagen between NIDDM and CGN subjects. The ratio of urinary type IV collagen to albumin was under 10.0 x 10(-6) in all subjects with CGN. Our results suggest that measurement of the urinary level of type IV collagen is useful for detection of early diabetic nephropathy and for the differential diagnosis of diabetic nephropathy and chronic glomerulonephritis.

Magnetic resonance imaging of multiple brain abscesses of the bilateral basal ganglia.

A 64-year-old woman developed multiple brain abscesses of the basal ganglia associated with Klebsiella pneumoniae septicemia. Magnetic resonance (MR) images showed three different stages of the brain abscesses. The images of early cerebritis of this site mimicked lacunar infarctions or dilated Virchow-Robin spaces. The differentiation of the brain abscess from lacunae and dilated Virchow-Robin spaces is discussed, together with the evolution of the brain abscesses on MR images.

Non-cushingoid Cushing's syndrome due to adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia.

This case report describes a 68-year-old man with Cushing's syndrome due to adrenocorticotropic hormone (ACTH)-independent bilateral adrenocortical macronodular hyperplasia (AIMAH). He was referred to our hospital for evaluation of bilateral enlargement of the adrenal glands found incidentally by computed tomography (CT). He had a ten-year history of hypertension. Although he was normokalemic and did not show Cushingoid features, the diagnosis of ACTH-independent Cushing's syndrome was established by endocrinological examinations. His plasma cortisol showed no diurnal rhythm and was unsuppressible by high-dose (8 mg/day) dexamethasone. Plasma ACTH was undetectable and did not respond to corticotropin-releasing hormone. Excised adrenal glands were markedly enlarged (right 28 g and left 64 g). Macroscopic appearance of the glands showed multiple yellowish nodules typical for AIMAH; microscopic findings were also compatible with AIMAH. The present case indicates that patients with AIMAH sometimes do not show typical Cushingoid features and therefore AIMAH can be found incidentally from ultrasound or CT examination of the abdomen.

[Application of inflammation markers in the "essential laboratory tests" to new outpatients and analysis for the efficacious selection of these items].

We have re-evaluated the usefulness of the inflammation markers in the "essential laboratory tests" advocated by Japan Society of Clinical Pathology and analyzed for efficacious selection of these items by applying these tests to 349 new outpatients visited Comprehensive Medicine, National Defense Medical College. Among the patients with "tentative initial diagnoses" of infectious or inflammation-related diseases (133 cases), the diagnoses were confirmed in 102 patients by positive inflammation marker(s), whereas additional 22 cases with the diagnoses other than inflammation-related diseases were found to be in the inflammatory status by these tests. Elevated C-reactive protein (CRP) levels were not correlated with the leukocyte number, however, neutrophilia (neutro. > 70%) and/or left shift of the neutrophils (stab > 15%) were demonstrated in approximately 50% of the patients with elevated serum CRP levels. Increases of serum sialic acid highly accompanied with increases of CRP, alpha 1 or alpha 2 fraction of serum protein and elevation of erythrocyte sedimentation rate (ESR), indicating that serum sialic acid levels reflected more strictly inflammatory status than ESR. There is a relatively good correlation (r = 0.813) between serum sialic acid values and the total amounts of alpha 1 and alpha 2 protein fraction, while poor correlations were shown between CRP and sialic acid values (r = 0.606), or ESR and sialic acid values (r = 0.671). These results indicate that (1) simultaneous measurements of CRP, leukocyte number and leukocyte differential fraction are useful for the confirmation of early stage of inflammation and evaluation of the nature of infectious diseases; (2) measurement of serum sialic acid levels is more desirable for the evaluation of inflammatory status than ESR; and (3) serum protein profile can be substituted by sialic acid for the evaluation of acute inflammatory status alone.

A case of 17 alpha-hydroxylase deficiency with retained menstruation.

A patient with 17 alpha-hydroxylase deficiency (17OHD) who continued to menstruate is reported. A 24-year-old woman who presented with hypertension, hypokalemia and irregular menses had increased plasma ACTH and mineralocorticoids without any increase in glucocorticoids or sex steroids, and a bilateral adrenal enlargement on abdominal X-ray CT. ACTH stimulation test revealed hyperresponse of the metabolites of the mineralocorticoid pathway and blunted or absent response of those of the glucocorticoid and androgen pathway. Almost all of the abnormalities disappeared after dexamethasone administration. While 17OHD is usually known to accompany hypergonadotropic hypogonadism, the patient continued to menstruate, though irregularly. Although human chorionic gonadotropin administration failed to induce response, basal plasma levels of ovarian steroid (estradiol) and gonadotropins as well as response to LHRH stimulation test were all normal. Thus, the clinical and biochemical features of this case is compatible with the partial deficiency of both adrenals and ovaries, being less severe in the latter. A further analysis especially at molecular level is needed to elucidate the basis for the heterogeneity of this disorder.

Changes of bone metabolic markers in patients with bone metastases: clinical significance in assessing bone response to chemotherapy.

To determine the changes in bone metabolism in response to combined chemotherapy in patients with bone metastases (BM), we examined osteocalcin (BGP), alkaline-phosphatase (ALP), hydroxyproline (HYP), pyridinoline (PYR), and/or deoxypyridinoline (D-PYR) in 25 cancer patients. In patients without BM, serum BGP was normal and not affected by chemotherapy. In patients with BM, however, BGP was often abnormally high or low, and some patients reacted to chemotherapy with a BGP increase at 4 weeks after initiation of therapy. Such an increase was observed in the group of patients who responded favorably to therapy as judged by a decrease in bone pain and tumor-associated biochemical markers. Urine HYP, PYR, and D-PYR were high in patients with BM before therapy; D-PYR decreased transiently at 2 weeks and increased thereafter. We assume that increased bone-resorption markers along with increased bone formation markers after therapy would indicate recovery of coupled bone metabolism, as the deranged bone remodeling is improved by tumor-regression. This study suggests that BGP and D-PYR can be useful early markers to predict favorable bone response to chemotherapy in patients with BM.

Thyroid dysfunction in isolated adrenocorticotropic hormone (ACTH) deficiency: case report and literature review.

A case of isolated ACTH deficiency accompanying transient primary hypothyroidism was reported along with a review of literature on isolated ACTH deficiency in Japan with special reference to its association with thyroid function. Our case, a 56-year-old woman, developed somnolence and hypoglycemia due to isolated ACTH deficiency. She also had the features of hypothyroidism, namely mounding phenomenon, muscle rigidity, increased plasma myogenic enzymes and cold intolerance. Both free T3 and free T4 were decreased, and basal as well as TRH-stimulated TSH levels were abnormally high. Plasma thyroglobulin was increased and no anti-thyroid antibodies were detected. All thyroid related physical and biochemical abnormalities disappeared after hydrocortisone replacement. A review of the literature on 103 cases disclosed that more than half the cases with isolated ACTH deficiency had a high plasma level of TSH, basal and/or TRH-induced, while the antithyroid antibodies were reported to be positive in only 13 cases. In more than 70% of such cases, the abnormality in the pituitary-thyroid axis was transient and was reversed by glucocorticoid replacement. Our case and cases in the literature indicate that the interference of thyroid hormone synthesis and/or secretion by glucocorticoid deficiency per se is the major cause of thyroid dysfunction rather than associated autoimmune thyroid disease.

[Laboratory tests in primary care medicine: pre-clinical, ambulatory screening test system on the basis of the patient's chief complaints in the initial diagnosis making].

We have explored the efficacious laboratory test system to be performed before the first medical contact with a physician on the basis of the patient's chief complaints and their abnormalities of the "essential laboratory tests" advocated by the Japan Society of Clinical Pathology by analyzing 2,625 complaints from 2,175 new patients visited the outpatient unit of Comprehensive Medicine, National Defense Medical College. The patients with complaints such as general fatigue, fever of unknown origin or reno-urinary symptoms showed higher abnormalities of these diagnostic tests than those in 750 patients performed these tests irrespective of the patient's chief complaints. However, complaints originated from neurological, gastro-intestinal, cardiovascular or respiratory diseases were not associated with abnormalities of these laboratory tests in the patients as compared to those in 750 patients mentioned above. These results indicate that (1) clinical usefulness of the "essential laboratory tests" are variable depending on the patients chief complaints and these tests are recommended for the patients with complaints such as general fatigue, fever of unknown origin or reno-urinary symptoms as pre-clinical ambulatory screening tests before history taking and physical examination to enable to make accurate initial diagnosis and subsequent efficacious medical approach and (2) test items should be selected depending on the patient's chief complaints.

Parathyroid hormone-related protein as a cause of hypercalcemia in a B-cell type malignant lymphoma.

Hypercalcemia occurred in a patient with non-Hodgkin's (B-cell type) lymphoma when generalized lymphadenopathy developed. Despite low normal plasma parathyroid hormone (PTH), nephrogenous cAMP (NcAMP) was not suppressed, and serum and urine PTH-related protein (PTH-rP) levels were elevated. The plasma level of 1,25(OH)2D was within normal range. The combined chemotherapies successfully reduced the tumor size, serum Ca, PTH-rP, and lactic dehydrogenase. Serum osteocalcin was suppressed while the patient was hypercalcemic, and increased after chemotherapy. In the extract of the tumor tissue obtained post mortem, bioactivity stimulating the production of cAMP in osteoblasts was demonstrated along with the immunoreactive PTH-rP. This is the first report of a B-cell lymphoma producing PTH-rP and its association with humoral hypercalcemia of malignancy.