Detection of the thyroxine-binding globulin (TBG) gene in six unrelated families with complete TBG deficiency

T4-binding globulin (TBG) is a glycoprotein of hepatic origin which transports thyroid hormone in serum. Inherited TBG defects in man are X-chromosome linked and are expressed in hemizygotes as complete deficiency, partial deficiency, or excess. Since TBG is not necessary for thyroid hormone action, affected subjects are healthy. Using DNA probes for human TBG, we searched for restriction fragment length polymorphisms in six affected males belonging to 6 unrelated families with inherited complete TBG deficiency and an equal number of normal males. TBG could not be detected in the serum of any of the TBG-deficient males by a specific and sensitive RIA capable of detecting as little as 5 micrograms TBG/L or 0.031% of the average normal serum TBG concentration. DNA isolated from white blood cells was digested with 11 restriction endonucleases, and the digests were submitted to DNA blot analysis using two cloned TBG-DNA probes which together covered the entire protein coding and the 5'-flanking sequences of the TBG gene. A total of 26 different bands were detected on DNA blots, identifying 18 restriction sites located within the 4.2-kilobase TBG gene, which includes intronic, exonic, and 5'-flanking sequences. This analysis, which sampled 2.3% of the total TBG genome, failed to reveal differences in fragment size among the 6 TBG-deficient and 6 normal males examined. One restriction endonuclease (NcoI) identified normal sequences at the putative promoter region of the gene, and four other endonucleases (TaqI, SstII, MspI, and HpaII) recognized the cytosine-guanine dinucleotide phosphate sequences representing potential mutation hot spots. Although C was methylated at these sites, no C to T (thymidine) transitions were found. These data suggest that large deletions, insertions, or rearrangements of the TBG gene, or mutations at sites of methylated cytosine-guanine dinucleotide phosphate dimers are not common mechanisms for inherited complete TBG deficiency in man.     

Fulminant pneumonia due to Aeromonas hydrophila in a man with chronic renal failure and liver cirrhosis

A 40-year-old man on hemodialysis was admitted due to dyspnea and chest pain and was diagnosed with pneumonia and pericarditis. Ampicillin was administered, but thereafter severe septic shock developed. The fulminant type of pneumonia progressed rapidly, and he died only 48 hours after the onset of symptoms. The autopsy and sputa culture revealed pneumonia due to Aeromonas hydrophila. The source of this infection remained unkown. Interestingly, there were two types of A. hydrophila found during such a short period. The physician should suspect this disease by questioning the patient's history. Early treatment with adequate antibiotics is the only means of saving such a patient's life.     

Long-term body weight variability is associated with elevated C-reactive protein independent of current body mass index among Japanese men

OBJECTIVE: To elucidate the effect of long-term weight variability on C-reactive protein (CRP) levels. DESIGN: Cross-sectional study of the circulating CRP. SUBJECTS: A total of 637 Japanese men aged 40-49 y in1997. MEASUREMENTS: Serum CRP levels, body mass index in 1997 (current BMI), the slope of weight on age (weight-slope) representing an individual's weight trend of direction and magnitude, and the root mean square error around the slope of weight on age (weight-RMSE) representing the weight fluctuation magnitude, as calculated by a simple linear regression model in which each value of the subject's five actual weights (aged 20, 25, 30 y, five years ago, and current) was a dependent variable and the subject's ages independent variables. RESULTS: After adjustment for age and confounders, including smoking and health status, the odds ratios of elevated CRP (> or =0.06 mg/dl) were 1.83 (95% CI: 1.25-2.69), 2.63 (1.69-4.11), and 10.31 (2.17-48.98) for upper normal-weight (BMI: 22-<25 kg/m(2)), overweight (25-<30), and obese (> or =30) persons, respectively, compared with lower normal-weight persons (18.5-<22). Adjusting for age, confounders, and current BMI, weight-slope was positively associated with CRP level especially among subjects with BMI> or =25 kg/m(2) (trend P<0.01), and weight-RMSE was positively associated with CRP level particularly among subjects with BMI <25 kg/m(2) (trend P<0.05). CONCLUSION: Our results suggest a state of low-grade systemic inflammation not only in overweight and obese persons, but also in normal-weight persons with large weight fluctuation, possibly explaining in part the positive association between weight fluctuation and CVD.     

Risk of neutropenic fever and early infectious complications after autologous peripheral blood stem cell transplantation for malignant diseases

Autologous peripheral blood stem cell transplantation (auto-PBSCT) has facilitated high-dose chemotherapy for the treatment of various types of malignancy, but the factors affecting the treatment outcome have not been well defined. We evaluated patients who underwent auto-PBSCT (46 patients with hematological malignancies and 39 with solid tumors) to elucidate the risks of background factors, including age, in association with infectious complications. In contrast to former reports, faster engraftment did not influence the incidence of documented infection or neutropenic fever, whereas high age (age > or = 50 years old) and delayed platelet recovery (> or = 18 days) were demonstrated to be positively involved. The odds ratio (OR) for documented infection in elderly patients was 4.94 (95% confidence interval, 1.22-15.8). Another risk factor of infection was the HD-ICE regimen (ifosfamide, carboplatin, etoposide) given to patients with solid tumors (OR, 8.00; 95% confidence interval, 1.61-39.7). In conclusion, we found that elderly patients and patients on the HD-ICE regimen have a higher risk of infectious complications even after auto-PBSCT. Although the clinical indications for auto-PBSCT can be extended to elderly patients, thorough precautions should be taken against infectious complications during the pre-engraftment phase.     

Correlation between morphology of colonies formed by human thyroid tumor cells in collagen gel culture and invasive ability.

Two different types of colonies from human thyroid papillary carcinomas were observed in collagen gel culture. One was a branching type, with many three-dimensional outgrowths. The other was a spherical type, with no outgrowths. As viewed by electron microscopy, the tumor cells of spherical-type colonies had more microvilli on their surfaces than did cells in the branching-type colonies. Histochemically, the tumor cells of spherical-type colonies had stronger positive reactions than did tumor cells of branching-type colonies. This suggests that tumor cells of spherical-type colonies have a higher potential for dissemination and invasion than do tumor cells of branching-type colonies. In fact, cases with higher percentages of spherical-type colonies could show extracapsular invasion histopathologically. Our results indicate that collagen gel culture is a useful method for studying the heterogeneity of tumor cells as well as their invasive ability in vitro.     

Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder

Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt-induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor-dependent gene expression, such as Na(+)/H(+) exchanger-1 and serum- and glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals.     

Ocular Manifestation of Acute Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation

A 26-year-old woman with acute myeloid leukemia underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical brother. Eighteen days after transplantation, the patient developed grade II acute graft-versus-host disease (GVHD) and was treated with corticosteroids. On day 38, the patient complained of eye pain and lacrimation. A slitlamp examination revealed corneal ulcers and pseudomembranous formation in both eyes. Histologic and immunohistochemical examinations of the pseudomembrane disclosed an infiltrate dominated by T cells. A cytogenetic study of the pseudomembrane by fluorescence in situ hybridization identified a Y chromosome in the infiltrated mononuclear cells. Surveillance cultures from conjunctival swabs were negative. Thus, we diagnosed these ocular manifestations as an ocular involvement of acute GVHD.     

Occurrence of Mycobacterium tuberculosis and strains of the Mycobacterium avium-M. intracellulare complex together in the sputum of patients with pulmonary tuberculosis

Out of 97 strains of M. tuberculosis isolated from the sputum of the same number of patients, 11 were shown to consist of a mixed population of M. tuberculosis and a strain of the M. avium-M. intracellulare (MAI) complex. The most effective method for isolating strains of the MAI complex was to incubate the culture first at 42 degrees C for 3 weeks and then at 45 degrees C for 3 weeks. By this method, the growth of M. tuberculosis was suppressed, while the contaminant mycobacteria formed colonies.