Correlation between national income, HIV/AIDS and political status and mortalities in African countries.

OBJECTIVES: To investigate associations between mortalities in African countries and problems that emerged in Africa in the 1990s (reduction of national income, HIV/AIDS and political instability) by adjusting for the influences of development, sanitation and education. METHODS: We compiled country-level indicators of mortalities, national net income (the reduction of national income by the debt), infection rate of HIV/AIDS, political instability, demography, education, sanitation and infrastructure, from 1990 to 2000 of all African countries (n=53). To extract major factors from indicators of the latter four categories, we carried out principal component analysis. We used multiple regression analysis to examine the associations between mortality indicators and national net income per capita, infection rate of HIV/AIDS, and political instability by adjusting the influence of other possible mortality determinants. RESULTS: Mean of infant mortality per 1000 live births (IMR); maternal mortality per 100,000 live birth (MMR); adult female mortality per 1000 population (AMRF); adult male mortality per 1000 population (AMRM); and life expectancy at birth (LE) in 2000 were 83, 733, 381, 435, and 51, respectively. Three factors were identified as major influences on development: education, sanitation and infrastructure. National net income per capita showed independent negative associations with MMR and AMRF, and a positive association with LE. Infection rate of HIV/AIDS was independently positively associated with AMRM and AMRF, and negatively associated with LE in 2000. Political instability score was independently positively associated with MMR. CONCLUSIONS: National net income per capita, HIV/AIDS and political status were predictors of mortality indicators in African countries. This study provided evidence for supporting health policies that take economic and political stability into account.

Very strong correlation between dominant negative activities of mutant thyroid hormone receptors and their binding avidity for corepressor SMRT.

The syndrome of resistance to thyroid hormone (RTH) is an inherited disorder involving a mutation of the thyroid hormone receptor (TR) gene. Mutant (m) TR inhibits wild-type (wt) TR functions in a dominant negative manner, and this dominant negative effect (DNE) is a crucial factor in RTH pathogenesis. The molecular mechanism of the DNE is still unclear, although several possibilities (including competition between wt- and mTRs at the T(3) response element (TRE), sequestration of TR-associated protein(s) and titration out of functional TR) have been considered. Here we report that the DNE of mTRs is strongly correlated with their binding avidity for the retinoid X receptor (RXR), and especially for corepressor SMRT (silencing mediator for retinoid and thyroid hormone receptor), but not for the nuclear receptor corepressor, NCoR. The DNE of six natural TRs and four artificially constructed mTRs was assayed using a TR reporter gene containing TRE-DR4 (DR=direct repeat), TRE-pal (pal=palindrome) or TRE-lap (lap=inverted palindrome) in CV1 cells treated with 10 nM T(3). Of the mTRs examined, F451X (with a carboxy-terminal 11-amino-acid truncation) identified in a patient with RTH exhibited the strongest DNE on all TREs. The binding affinities between mTRs and corepressors SMRT or NCoR were quantified using a two-hybrid interference assay system consisting of VP16-TR(LBD) (LBD=ligand binding domain) and Gal4(DBD)-SMRT (DBD=DNA binding domain), or Gal4(DBD)-NCoR respectively, together with the Gal4 reporter gene. In this assay, VP16-TR(LBD) and Gal4(DBD)-SMRT (or Gal4 (DBD)-NCoR) interact with each other and trans-activate the Gal4 reporter gene. When an equal amount of mTR is coexpressed, it reduces the transcriptional activity of the reporter gene, depending on its binding avidity for a corepressor. A very strong correlation was observed between the SMRT-binding activity and the potency of the DNE among six natural mTRs and also among all mTRs, including four artificially constructed ones. The relationship between NCoR and DNE, however, was not significant. When we assayed the binding avidity of mTRs for RXR by using a two-hybrid assay system consisting of Gal4(DBD)-RXR(LBD) and VP16-TR(LBD), a significant correlation between DNE and binding avidity for the RXR was also observed. These results suggest that a corepressor plays an important role in DNE pathogenesis.

Difference in dominant negative activities between mutant thyroid hormone receptors alpha1 and beta1 with an identical truncation in the extreme carboxyl-terminal tau4 domain.

Although different expression patterns of thyroid hormone receptor (TR) alpha1 and beta1 have been reported, no essential distinction has been established in their functions. Unlike the TR beta gene, a mutation in the TR alpha1 gene has never been found in patients with resistance to thyroid hormone (RTH). Previously we found a mutant TR beta with an 11-carboxyl (C)-terminal amino acid truncation (betaF451X) in a girl with severe RTH. BetaF451X is a natural mutant with disruption of the transactivation domain, tau4, and it had very strong dominant negative activities. Based on the fact that the 46 amino acid sequence in the extreme C-terminal region is identical in TR alpha1 and TR beta, except for a C-terminal three amino acid extension of TR alpha1, we constructed a mutant TR alpha1 (alphaF397X) with the identical C-terminal truncation to betaF451X, to study functional differences between TR alpha1 and beta1. Both betaF451X and alphaF397X had negligible T3 binding and transcriptional activities even with 1 microM T3. The dominant negative activities of the mutant TRs were remarkable and T3 response element (TRE)-dependent. Co-expression of betaF451X decreased the CAT activity of either wild-type TR alpha1 or beta1 at 100 nM T3 by approximately 90% on the TRE-pal2 and 70% on DR4. AlphaF397X inhibited the transcriptional activities of both wild-type TR alpha1 and beta1 by approximately 50% on TRE-pal2 and by 60% on DR4. The dominant negative potency of betaF451X was significantly stronger than that of alphaF397X on the TRE-pal2, -DR4 and chicken lysozyme silencer F2, but similar on TRE-myosin heavy chain alpha and malic enzyme. No partiality for the TR subtypes was found in the dominant negative effects of betaF451X and alphaF397X. Co-expression with RXR enhanced the dominant negative effects of alphaF397X, but not of betaF451X. The results indicate that there are different dominant negative properties between alphaF397X and betaF451X, which are TRE-dependent, despite their identical C-terminal truncation. Deletion in the tau4 domain might affect the receptor structures of TR alpha1 and beta1 differently.

High incidence of positive autoantibodies against thyroid peroxidase and thyroglobulin in patients with sarcoidosis.

OBJECTIVE: Although abnormalities of the humoral immune system, such as increased immunoglobulin production, are known in sarcoidosis, the relationship between sarcoidosis and autoimmune disorders in uncertain. We studied the incidence of thyroid autoantibodies and the prevalence of Hashimoto's thyroiditis in patients with sarcoidosis. PATIENTS AND MEASUREMENTS: Sixty-two patients with pulmonary sarcoidosis, diagnosed by a combination of clinical, radiographic and histological findings were studied. As controls, three groups of subjects aged 40 and over without a known history of thyroid disease (60 patients with pulmonary diseases other than sarcoidosis, 88 hospital employees and 82 company workers), were also analysed. Antibodies against thyroid peroxidase (TPO-Ab) and purified thyroglobulin (Tg-Ab) were measured by radioimmunoassay and antibodies against microsomal antigen (MCHA) and thyroglobulin (TGHA), by haemagglutination. RESULTS: Seventeen of 62 patients (27.4%) had either positive TPO-Ab or Tg-Ab or both. All the patients with positive thyroid autoantibodies were of middle or advanced age, and the incidence of positive TPO-Ab/Tg-Ab in patients with sarcoidosis aged 40 and over was 54.5% in males, 32.4% in females and 37.8% overall. The prevalence was significantly higher in males compared to age-matched control males (0-7.7% in the controls), and in female patients was twice that found in controls (11.8-16.3%). Seven patients had Hashimoto's thyroiditis, indicating that the prevalence was 11-3%, and much higher than that previously reported. CONCLUSIONS: The data show a remarkably high incidence of thyroid autoantibodies in patients of middle of advanced age with sarcoidosis, especially in males, and a higher prevalence of Hashimoto's thyroiditis than in previous reports.

Factors affecting induction of neurological disorder in mice by PVC viruses and the sequence of env-LTR region of PVC441.

PVC111, PVC211, PVC321 and PVC441 cause neurological disorders associated with tremor and paralysis in rats. We tested the pathogenicity of these viruses in mice. Although histopathological studies revealed spongiform degeneration in the spinal cords of NFS mice infected with each PVC virus, only PVC441 caused a high incidence of tremor and paralysis. Further studies with PVC441 revealed dose and age dependence for tremor induction. In contrast to NFS mice, BALB/c, DBA/2 and C57BL/6 mice infected with PVC441 virus showed no neurological symptoms, although the virus replicated in each strain to titers within 5-fold of the titer in NFS mice. Despite absence of neurological symptoms, high degree of neuronal degeneration in the lumbar spinal cord was found in PVC441-infected BALB/c mice. Low degree of neuronal degeneration was found in PVC441-infected DBA/2 or C57BL/6 mice. Genetic crosses of these resistant mice with susceptible NFS mice indicated that resistance to PVC441-induced tremor induction was dominant in all strains and suggested that various host genes may control the susceptibility of mice to tremor induction by PVC441 virus. Sequencing of env-LTR region of PVC441 revealed an intermediate character between PVC211 and F-MuLV.

Thymic follicular hyperplasia manifested as an anterior mediastinal mass.

A rare case of thymic follicular hyperplasia manifested as an asymptomatic anterior mediastinal mass in a 44-year-old man is herein reported. The resected thymus showed prominent medullary lymphoid follicles, an increased number of Hassall's corpuscles, and cysts of varying sizes. This paper discusses the histopathological condition of this lesion.

Urinary excretion of pyridinoline and deoxypyridinoline measured by immunoassay in hypothyroidism.

OBJECTIVE: We measured pyridinium cross-links, markers of bone resorption, by an enzyme-linked immunosorbent assay (ELISA) in hypothyroid patients to see whether bone resorption was reduced in hypothyroidism and whether it increased with T4 treatment. DESIGN AND PATIENTS: Eight hypothyroid patients, whose initial TSH levels were 268.1 +/- 87.7 mU/l (mean +/- SE), were treated with T4 (100 micrograms/day). Urinary excretion of pyridinium cross-links was assayed before and after T4 treatment. MEASUREMENTS: Pyrilinks and Pyrilinks-D kits were used. The Pyrilinks assay measures free forms of pyridinoline and deoxypyridinoline together (PYD), while the Pyrilinks-D assay measures deoxypyridinoline (DPD) alone. The Pyrilinks reference ranges for normal subjects are 8-24nmol/mmol creatinine in males and 10-28nmol/mmol creatinine in normal premenopausal females. The DPD reference ranges obtained from normal men and women aged 40-50 years were 3.20 +/- 0.75 (mean +/- SD) nmol/mmol creatinine and 4.55 +/- 1.22 nmol/mmol creatinine, respectively. RESULTS: The sensitivity of the assay was enhanced by simply using less diluted urine samples. Concentrations of both compounds of the urinary pyridinium cross-links were low in untreated hypothyroid patients and increased gradually as thyroid hormone status improved from hypothyroidism to euthyroidism. One month after treatment when the TSH levels in the patients were still as high as 74.4 +/- 44.5 mU/l, urinary PYD excretion has increased to 2.6 times the pretreatment level. When the TSH levels of the patients decreased below 10 mU/l, both PYD and DPD increased significantly to 3.8 and 3.3 times pretreatment values, respectively. CONCLUSIONS: Although hyperthyroidism or excess treatment with thyroid hormone has been known to induce bone resorption, this is the first report that urinary excretion of pyridinium cross-links is reduced in hypothyroidism and is normalized by physiological thyroid hormone replacement.

The change in 123I-uptake between 3- and 24-hours is useful in predicting early response to methimazole in patients with Graves' disease.

Some patients with Graves' disease respond well to anti-thyroid drug treatment but others do not. Factors determining the patient's responsiveness to the medical treatment are unclear, but the intrathyroidal iodine pool is believed one of the important factors. In this study, we found that delta radioactive iodine uptake (RAIU) (RAIU at 24 h-RAIU at 3 h) is useful in predicting early response to treatment with methimazole (MMI). Among 32 patients with Graves' disease, who were given 30 mg MMI as an initial dose, 11 patients responded quickly to MMI-treatment. Within one month, serum free T4 levels decreased to below the normal range in 6 patients (< 10.3 pmol/L) or decreased from beyond the highest level of the assay (> 125 pmol/L) to the normal range in 5 patients. When these rapid responders (group A) were compared with the remaining 21 patients who showed a more gradual response to MMI-treatment (group B), a different pattern of 123I-thyroid uptake was noted. RAIU at 3 h was significantly higher in group A than in group B, while RAIU at 24 h was similar in the two groups. As a result, rapid responders had a significantly lower delta RAIU value than gradual responders (-0.7 +/- 8.4% in group A, 14.2 +/- 8.2 in group B, P < 0.01). No significant difference was found between the two groups in various pre-treatment parameters such as severity and duration of thyrotoxicosis, the titer of TSH receptor antibodies (TRAb), frequency of positive antithyroglobulin antibodies (TGHA), urinary excretion of iodine and thyroid volume. The incidence of positive antithyroid microsomal antibodies (MCHA) was higher in group A than in group B, and thyroid ultrasonography showed a tendency to low echogenicity in group A. delta RAIU was negatively correlated with the reduction in the serum free T4 level during the first two weeks after MMI-treatment was initiated (r = -0.60, P < 0.01). Moreover, delta RAIU correlated positively with the biological half-life of the intrathyroidal iodine, calculated in a different series of 24 patients with Graves' disease who received radioisotope treatment (r = 0.54, P < 0.01). The low delta RAIU value is considered to reflect the rapid turnover of the intrathyroidal iodine, and may be related to the small intrathyroidal iodine pool. delta RAIU is useful in predicting early responsiveness of patients with Graves' disease to MMI-treatment.

Treatment of advanced hormone-refractory prostate carcinoma with a combination of etoposide, pirarubicin and cisplatin.

A total of 20 patients with hormone-refractory prostate carcinoma entered a pilot study of combination chemotherapy based on the EAP (etoposide, Adriamycin and cisplatin) regimen, in which Adriamycin was replaced by pirarubicin, a less cardiotoxic derivative of Adriamycin. The response was assessed by criteria modified from those of the National Prostatic Cancer Project: prostate-specific antigen was employed instead of acid phosphatase. Of 18 evaluable patients, 6 achieved a partial response, 5 had stable disease, and in 7 the disease had progressed during therapy; thus, the overall response rate was 33.3% [95% confidence interval (CI) 11.5-55.1%]. Significant pain alleviation and performance status improvement were obtained in 5 of 12 patients (41.7%; CI 13.8-69.6%) and 3 of 13 patients (23.1%; CI 0.2-46.0%), respectively. Although myelosuppression was moderate to severe, no chemotherapy-related deaths or bacteriologically documented sepsis occurred; nor was there any clinical cardiotoxicity. All the responding patients received maintenance chemotherapy with etoposide thereafter. At present, the median duration of response is 33 weeks (range: 23-91 weeks) and the median survival period for all patients is 42 weeks (range: 27(+)-136 weeks), with 12 deaths. In spite of the small number of patients treated, these results suggest that this chemotherapy regimen is active in advanced hormone-refractory prostate carcinoma.

Corticonigral degeneration with neuronal achromasia presenting with primary progressive aphasia: ultrastructural and immunocytochemical studies.

We describe a clinico-pathological variant of a degenerative disorder involving Broca's, Wernicke's, and supplementary motor areas, which presented as primary progressive aphasia, dysarthria, bucco-facial apraxia, and hearing loss as initial symptoms, followed by organic personality changes. Postmortem examination revealed severe focal atrophy of the cerebral convolutions in the frontal operculum, superior frontal gyrus, and superior and transverse temporal gyri in addition to diffuse atrophy of the frontal and temporal lobes in both hemispheres. Microscopical examination revealed argyrophilic neuronal inclusions (ANIs) in the neuronal perikarya and presynaptic terminal throughout the central nervous system, as well as neuronal loss and swollen chromatolytic neurons in the affected cortices. Neocortical ANIs showed a positive immunoreaction with an anti-tau antibody but only a weak reaction with an anti-ubiquitin antibody immunohistochemically. Ultrastructurally, neocortical ANIs consisted of 15-nm thick smooth-surfaced tubules and tubules with constrictions at 120-150-nm intervals; thus they were different from the typical paired helical filaments of the 80-nm interval constrictions observed in the subiculum. ANIs were also found in the basal ganglia, brain stem nuclei, and cervical cord. Accordingly, ANIs appear distinct from neurofibrillary tangles (NFTs) of progressive supranuclear palsy, NFTs of Alzheimer-type dementia, and Pick bodies. The authors consider that this case fits the histopathological criteria of corticonigral degeneration with neuronal achromasia except for the unusual extension to the temporal lobes.

A case of hyperthyroidism due to pituitary resistance to thyroid hormone.

A fifteen-year-old male was admitted to our hospital because his thyroid function showed a lack of TSH suppression in the face of elevated thyroid hormone. This patient complained of heat intolerance, palpitation and hand tremor. Peripheral indices of thyroid hormone action indicated a hypermetabolic state. Serum TSH did not respond sufficiently to TRH stimulation, suggesting TSH-secreting pituitary adenoma. However, sellar CT scan and MRI images did not demonstrate any pituitary adenoma. Moreover, the serum TSH alpha-subunit concentration was not high and serum TSH was partially suppressed by the administration of T3. Furthermore, the results of single stranded conformation polymorphism (SSCP) suggested the existence of mutation(s) in the exon 7 of T3 receptor beta (TR beta) gene of this patient. These findings support the diagnosis of pituitary resistance to thyroid hormone.

A case of adamantinoid basal cell epithelioma.

A 56-year-old woman visited the clinic of dermatology, Yokohama Sakae Kyosai Hospital in May of 1992 with a 5-year history of a blue-gray lesion on her left cheek which had enlarged asymptomatically. The tumor was excised with Z plasty closure. Histopathologically, a loosely encapsulated tumor was situated in the upper to deep dermis. At the periphery of the tumor, there were typical solid basal cell epithelioma (BCE) nests, but within the majority of lobules, intercellular spaces were widened and cells were connected by stellate appendages. Mucoid material filled the spaces and the cells at the periphery palisaded. Histochemical study revealed that the mucoid substance contained hyaluronic acid. An immunohistochemical study was performed using peroxidase antiperoxidase (PAP) method. The antibodies used were anti-epithelial membrane antigen (EMA), anti-carcinoembryonic antigen (CEA), anti-S-100 protein, anti-neurofilament, anti-vimentin, anti-desmin, anti-BRST-1, and anti-BRST-2. The tumor cells and stroma expressed none of these antigens. The tumor was diagnosed as an adamantinoid BCE.

An immunohistochemical study of mixed tumor of the skin.

An asymptomatic tumor developed on the upper lip of a 63-year-old man. Histologically, the tumor contained glandular and cystic structures forming many branching lumina, and many scattered single cells in an abundant mucoid to chondroid stroma. The tumor was diagnosed as mixed tumor of the skin. Histochemically, the cells composing the tubular structures contained neutral mucopolysaccharides and the stroma, acid mucopolysaccharides. Immunohistochemically, the cells of the glandular and cystic structures showed epithelial and sweat gland differentiation (EMA-, CEA-, BRST-1- and BRST-2-positive), while the cells scattered in the stroma showed a tendency toward myoepithelial differentiation (S-100 protein- and vimentin-positive).

[Multivariate analysis of acute leukemia].

The outcome of chemotherapy in patients of 150 cases of acute leukemia was investigated. Patients were divided into two groups, that is group I: 100 cases of acute leukemia treated between 1980-1984, group II: 50 cases of acute leukemia between 1985-1986. Complete remission was achieved in 66% of group I and in 82% of group II. Using multivariate analysis, the initial levels of FDP and WBC count and age were found to be important factors to induce complete remission. Female sex was suggestive of a longer remission duration and survival by discrimination analysis.

Innervation of the tooth pulp by the mesencephalic trigeminal nucleus in the cat: a retrograde horseradish peroxidase study.

HRP was applied to the tooth pulp of 8 cats. Six were subjected to postoperative administration of the anti-inflammatory drug, prednisolone, whereas the remaining two were not. In all prednisolone-treated cats, labeled neurons were found in both the mesencephalic trigeminal nucleus and trigeminal ganglion, ipsilaterally. On the other hand, no labeled neurons were observed in the mesencephalic nucleus in cats receiving no steroid.

[Changes in chewing rhythm during repetitive series of mastication in normal adults as a function of time elapsed and the four basic taste stimuli].

Surface EMG activities in the masseter muscle were recorded from 8 healthy men with normal permanent dentition during habitual chewing of a small cube of synthetic cellulose sponge which had absorbed distilled water. Three parameters of chewing rhythm, viz., cycle time, duration, and interval, were shown as the respective averages of 40 measurements of the EMG traces of a masticatory series of 42 consecutive chewing strokes. Twenty-five recording sessions, in each of which the above masticatory series were repeated 10 times in a day with a 5 minutes' recess between each series, were performed on a subject during continuous 25 days. The amount of scatter in the distribution of 25 cycle time values was great at the 1st masticatory series, gradually decreased to reach a node relatively free from the dispersion at the 5th series, and then gradually increased from the 6th to 10th series. The same phenomenon was observed in all 8 subjects, although there was a small difference among them in the number of the series where the node was apparent. The average of 5 cycle time values was used to compare in the same subject the effect of chewing the cellulose sponge which had absorbed one of the 4 basic taste solutions with the effect of chewing that which had absorbed distilled water. The average value while chewing the sponge which had absorbed 1 M saccharose was significantly lower in the subjects who obtained a relatively large average value during distilled water sponge-chewing, whereas it was significantly greater in those who obtained a relatively small average value while chewing the sponge which had absorbed distilled water. The other 3 taste stimuli induced a significant increase in the average value in most subjects.

Mechanisms of resistance to cis-diamminedichloroplatinum (II) in a rat ovarian carcinoma cell line.

A cis-diamminedichloroplatinum (II) (cisplatin)-resistant subline (Cis-Ptr) demonstrated 20-fold greater resistance to the cytotoxic effects of cisplatin, compared with the parental cloned rat ovarian carcinoma cell line (ROT 68/C1). The uptake of cisplatin into the Cis-Ptr cells was identical to that into the ROT68/C1 cells in vitro and in vivo. Glutathione activity in a cytoplasmic extract was 1.4-fold and 1.8-fold greater in the Cis-Ptr cells than in the ROT68/C1 cells in vitro and in vivo, respectively. There was no difference between the ROT68/C1 and Cis-PTr cells in 195m cisplatin binding per micrograms DNA. DNA repair of cisplatin DNA damage was increased in the Cis-PTr cells but not in the ROT68/C1 cells. These results suggest that the mechanisms of resistance to cisplatin in rat ovarian carcinoma cells involve increased activity of the DNA repair system and increased cytosolic binding to thiols may also be involved.