Evaluation of modelling study shows limits of COVID-19 importing risk simulations in sub-Saharan Africa.

Mathematical modelling studies predicting the spread of the coronavirus disease 2019 (COVID-19) have been used worldwide, but precisions are limited. Thus, continuous evaluation of the modelling studies is crucial. We investigated situations of virus importation in sub-Saharan Africa (SSA) to assess effectiveness of a modelling study by Haider N et al. titled 'Passengers' destinations from China: low risk of novel coronavirus (2019-nCoV) transmission into Africa and South America'. We obtained epidemiological data of 2417 COVID-19 cases reported by 40 countries in SSA within 30 days of the first case confirmed in Nigeria on 27 February. Out of 442 cases which had travel history available, only one (0.2%) had a travel history to China. These findings underline the result of the model. However, the fact that there were numbers of imported cases from other regions shows the limits of the model. The limits could be attributed to the characteristics of the COVID-19 which is infectious even when the patients do not express any symptoms. Therefore, there is a profound need for all modelling researchers to take asymptomatic cases into account when they establish modelling studies.

Structure of the human LC-PTP (HePTP) gene: similarity in genomic organization within protein-tyrosine phosphatase genes.

Recently, various cDNA sequences coding protein-tyrosine phosphatases (PTPs) have been reported and their extensive similarities in the catalytic domains clarified, but knowledge of the structures and organizations of their genes is still limited. In this study, a detailed structure and organization of the human intracellular LC-PTP (also called HePTP) gene is reported. The 13 to 18.5 kb genomic clones encoding human LC-PTP have been isolated. The LC-PTP gene is organized into 11 exons, including the 5'-noncoding first exon and the 3'-noncoding exon. Splicing sites for exons 4 to 10, which encode the conserved catalytic PTP domain, arise almost at the same position as for the CD45 gene. This elucidation of the LC-PTP gene structure provides insight into the domain evolution of intracellular LC-PTP and transmembrane CD45, which may be generated by gene duplications of an ancestral gene.

Identification and analysis of the promoter region of the human NeuroD-related factor (NDRF)1.

We isolated and characterized the human NeuroD-related factor (NDRF)/NeuroD2/KW8 gene. The NDRF gene consisted of two exons and one intron. NDRF had one transcriptional starting point, and in its 5'-flanking region, no TATA box was detected, but 16 E boxes (CANNTG) were present. RNA blotting analysis revealed that HIT-T15 and D283 cells expressed a 3.3 kb band of the NDRF transcript. Promoter analysis by luciferase assay demonstrated that luciferase activity changed between -120 and -195, and between -451 and -564, both regions wherein a single E box existed. Radiation hybrid mapping showed that NDRF linked the marker SHGC-36242 with a LOD score of 8.53 and was located on 17q12-22.

Effects of glutathione depletion on the synthesis of proteoglycan and collagen in cultured chondrocytes.

We studied the effect of the depletion of glutathione on the synthesis of proteoglycan and collagen in cultured chick chondrocytes. When the cultured chondrocytes were incubated with 1 mM buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamyl-cysteine synthetase, the intracellular glutathione level markedly dropped within 12 h with no loss of cell viability. Incorporation of 35SO2-4 into proteoglycan was lowered in the presence of BSO. When the 35S-labeled proteoglycans were separated into two fractions by glycerol density gradient centrifugation, the inhibitory effect of BSO on the synthesis of proteoglycan was greater in the fast-sedimenting proteoglycan fraction, which consisted mainly of cartilage specific large proteoglycan (PG-H), than in the slowly sedimenting proteoglycan fraction. The inhibition by BSO of the synthesis of core protein-free glycosaminoglycan chains primed by p-nitrophenyl-beta-D-xyloside was smaller than the inhibition of the synthesis of proteoglycan. Analysis of glycosaminoglycans labeled with [3H]glucosamine indicated that the treatment of chondrocytes with BSO resulted in a small increase in the proportion of synthesis of hyaluronic acid to the synthesis of total glycosaminoglycan. The incorporation of [3H]proline into collagen was also inhibited by BSO. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the 3H-labeled collagen showed that, in the presence of BSO, processing of Type II collagen appeared to slow down and the proportion of Type X collagen synthesis was reduced.

Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3 with sequence similarity to the src-homology region 2.

Protein-tyrosine phosphorylation and dephosphorylation are directly associated with cellular growth, signal transduction, and neoplastic transformation. Here we report the isolation of a complementary DNA (cDNA) clone encoding a novel protein-tyrosine phosphatase (PTP) from a human T cell PEER cDNA library. The predicted open reading frame encodes a approximately 68-kDa protein composed of 593 amino acids which contains two src-homology region 2's (SH2 domains) at the N terminus; this PTP is designated as SH-PTP3. Northern blot analysis revealed that SH-PTP3 mRNA was expressed throughout many tissues and the transcriptional size was consistent at about 6.0 kb. As with other SH2 domains in src-family kinases, the SH2 domains of SH-PTP3 may play a crucial role in interactions with tyrosine phosphorylated signaling proteins, including itself and protein tyrosine kinases (PTKs), to regulate targets' enzyme activity.

Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants.

The expression of human brain-derived neurotrophic factor (BDNF) was investigated in 16 primary human neuroblastomas with favorable biologies, 15 with unfavorable biologies, and in human neuroblastoma cell lines. We demonstrated higher expressions of human BDNF mRNA in neuroblastomas with unfavorable biologies and with N-myc amplification than in those with favorable biologies. For the first time we revealed the composition of splice variants of human BDNF mRNA and analyzed their expression in neuroblastomas by reverse transcription polymerase chain reaction (RT-PCR). Interestingly, human BDNF mRNA consisted of at least six isoforms, four isoforms resembling those of rat BDNF mRNA, a human-specific isoform and a new isoform. The expression of four isoforms were more prominent in tumors with unfavorable biologies than in those with favorable biologies (P<0.05). As previously we had reported, over 80% of the primary tumors expressed either the full-length form of BDNF receptor, TRKB, or a truncated form of TRKB lacking the tyrosine kinase domain. The full-length TRKB was predominantly detected in tumors with unfavorable biologies, and the truncated one in those with favorable biologies. These results suggest that an autocrine and/or paracrine mechanism involving BDNF may stimulate signal transduction via TRKB receptors rich in neuroblastomas with unfavorable biologies, resulting in an aberrant survival of tumor cells.

Superiority of enviomycin or streptomycin over ethambutol in initial treatment of lung disease caused by Mycobacterium avium complex.

The rate of sputum conversion (continuously negative cultures for six months or more) was compared among four regimens given to 83 patients with moderately advanced, cavitary lung disease caused by Mycobacterium avium complex untreated previously. The regimens of rifampin + isoniazid + enviomycin and rifampin + isoniazid + streptomycin appeared to be superior to the regimen of rifampin + isoniazid + ethambutol. No statistically significant difference was observed between the regimens rifampin + isoniazid + enviomycin and rifampin + isoniazid + streptomycin.

Structure and regulation of the human NeuroD (BETA2/BHF1) gene.

In this study, we isolated and characterized the human NeuroD (BETA2/BHF1) gene. This gene was found to consist of two exons and one intron. The promoter regions were well-conserved compared with the mouse NeuroD gene. Two transcription start points (TSPs) were determined by the oligo-capping method. One TATA box was located at -31 bp from the lower TSP. The results of a transient transfection assay using the human neuroblastoma cell line IMR-32 and hamster insulin tumor cell line HIT-T15 suggested that there are at least three positive regulatory regions in the promoter. In these regions, four E boxes (CANNTG), named the E1 to E4 boxes, and two GC boxes were present. Cotransfection of the NeuroD expression vector into IMR-32 cells enhanced the NeuroD promoter activity by about 4-fold. A deletion and mutation analysis revealed that the E1 and E4 boxes, especially the E1 box, are associated with autoactivation and that E2 and E3 boxes are not associated with autoactivation. As mutation analysis of E3 box showed a decrease in the enhancer activity to the basal level, it showed that the E3 box is important to activate the NeuroD transcription. These results raised the possibility that the NeuroD gene expression is positively regulated through the E box sequence, not only by NeuroD itself but also by another E box binding protein.

Differential regulation of aquaporin expression in astrocytes by protein kinase C.

Aquaporins (AQPs) are a family of water-selective transporting proteins with homology to the major intrinsic protein (MIP) of lens, that increase plasma membrane water permeability in secretory and absorptive cells. In astrocytes of the central nervous system (CNS), using the reverse transcription-polymerase chain reaction (RT-PCR), we previously detected AQP3, 5 and 8 mRNAs in addition to the reported AQP4 and 9. However the mechanisms regulating the expression of these AQPs are not known. In this study, we investigated the effects of a protein kinase C (PKC) activator on the expression of AQP4, 5 and 9 in cultured rat astrocytes. Treatment of the cells with TPA caused decreases in AQP4 and 9 mRNAs and proteins in time- and concentration-dependent manners. The TPA-induced decreases in AQP4 and 9 mRNAs were inhibited by PKC inhibitors. Moreover, prolonged treatment of the cells with TPA eliminated the subsequent decreases in AQP4 and 9 mRNAs caused by TPA. Pretreatment of cells with an inhibitor of protein synthesis, cycloheximide, did not inhibit the decreases in AQP4 and 9 mRNAs induced by TPA. These results suggest that signal transduction via PKC may play important roles in regulating the expression of AQP4 and 9.

Interleukin-1beta induces the expression of lipocortin 1 mRNA in cultured rat cortical astrocytes.

Lipocortin 1 (LC1) has been shown to increase in neuronal damage and act as a neuroprotectant and a neurotrophic factor. IL-1beta acts as a mediator of inflammation and has been reported as a potent inducer of various neurotrophic factors including nerve growth factor and fibroblast growth factor. In this study, we investigated the relationship between LC1 and IL-1beta in cultured rat astrocytes. Time-and dose-dependent experiments of IL-1beta on rat cortical astrocytes in culture revealed that the expression of LC1 mRNA was significantly augmented by IL-1beta at 8 h, 10 ng/ml. In addition, IL-1beta evoked an extracellular secretion of LC1 without its cytotoxic effects. The effect of IL-1beta was completely abolished when we treated cells with inhibitor of mitogen-activated protein kinases (MAPKs) (PD98059) (25 microM), phospholipase A(2) inhibitor mepacrine (30 microM) and protein synthesis inhibitor cycloheximide (CHX) (10 microg/ml). This suggests that induction of LC1 by IL-1beta is through a MAPKs and phospholipaseA(2) pathway and requires protein synthesis. These results indicate that IL-1beta released in the central nervous system (CNS) injury can stimulate the transcription of the LC1 gene. Subsequent synthesis and release of LC1 may provide trophic support to neurons and modulate the action of IL-1beta in brain damage.

Phase II study of carboplatin, cisplatin, and vindesine in advanced non-small-cell lung cancer.

Cisplatin in combination with vindesine has been widely used for the treatment of advanced non-small-cell lung cancer (NSCLC), producing an overall response rate of 32%. We conducted a phase II study to examine whether the addition of carboplatin to the combination of cisplatin and vindesine would improve the antitumor activity of the two platinum agents in advanced NSCLC without increasing their toxicity. Carboplatin (240 mg/m2) and vindesine (3 mg/m2) were given intravenously on day 1 and cisplatin (60 mg/m2) and vindesine (3 mg/m2), on day 8. Of the 40 evaluable patients with advanced NSCLC, 12 showed a partial response, for an overall response rate of 30% (95% confidence interval, 17%-47%). The median duration of response was 12 weeks, and the median survival duration for all patients was 38 weeks. The major toxicity was hematologic: leukopenia (WHO grade > or = 3) was observed in 21 patients (53%) and anemia (WHO grade > or = 3), in 13 patients (33%). However, thrombocytopenia was mild and WHO grade 3 toxicity was observed in only 4 patients (10%). Nonhematologic toxicities consisted mainly of WHO grade > or = 2 nausea and vomiting in 16 patients (40%) and WHO grade > or = 2 alopecia in 11 patients (28%). No significant nephrotoxicity or neurotoxicity was seen. Our findings indicate that the addition of carboplatin to the combination of cisplatin and vindesine does not improve antitumor activity in patients with advanced NSCLC.

Quantitative analysis of CSF flow dynamics using MRI in normal pressure hydrocephalus.

In order to clarify the flow dynamics of cerebrospinal fluid (CSF) in normal pressure hydrocephalus (NPH), a phase-contrast cine magnetic resonance (MR) imaging technique with retrospective cardiac gating was used to measure the quantitative flow velocity of CSF in the aqueduct in patients with NPH after subarachnoid hemorrhage (SAH-NPH group, n = 17), idiopathic NPH (1-NPH group, n = 2), asymptomatic ventricular dilatation or brain atrophy (VD group, n = 7) and healthy volunteers (control group, n = 19). Intracranial pressure (ICP) and pressure volume response (PVR) were also measured during the shunt operation in six of the SAH- NPH group. The maximum CSF flow velocity (Vmax) in the aqueduct was significantly larger in the SAH-NPH group (9.21 +/- 4.12 cm/sec, mean +/- SD) than in the control group (5.27 +/- 1.77, p < 0.001) and the VD group (4.06 +/- 1.81, p < 0.005). Vmax was not different between the control and VD groups. There was a positive correlation between the PVR and the peak CSF flow velocity in the SAH-NPH group. These findings suggest that the changes of CSF flow velocity in the SAH-NPH group might be caused by a moderate decrease of intracranial compliance. The CSF flow study using MRI is useful to differentiate NPH from brain atrophy or asymptomatic ventricular dilatation and also to estimate the intracranial compliance.

Turbo spin-echo magnetic resonance imaging depiction of facial nerve compression by a vertebral artery in a patient with hemifacial spasm--technical note.

Turbo spin-echo magnetic resonance (MR) imaging of a patient with hemifacial spasm clearly demonstrated vascular compression of the facial nerve by the vertebral artery. The high resolution images of this method may be an appropriate alternative to preoperative cerebral angiography. Turbo spin-echo MR imaging is a diagnostic procedure of choice for patients with hemifacial spasm and possibly trigeminal neuralgia.

[Studies on surfactant replacement therapy in pediatric measles pneumonitis].

Measles pneumonitis, as well as encephalitis, is the most important complication associated with mortality in measles. Many medications including steroids and vitamin A have been applied to pediatric measles pneumonitis. However, the efficacy of such medication has not yet been established. This study is aimed at evaluating the effectiveness of surfactant replacement therapy in pediatric measles pneumonitis. Five patients (aged 1-2 years) with measles pneumonitis were transferred to our emergency center. On the transferred day, Surfactant-TA was administered by intratracheal method. After administration of surfactant, PaO2/FIO2 increased from 63.6 +/- 11.0 (mean +/- SE) to 206.2 +/- 54.1 in an hour and to 163.8 +/- 34.8 in 24. At the same time, the CO2 elimination and the dynamic compliance were improved. Because of these effects, the peak inspiratory pressure employed in mechanical ventilation could be reduced. It is concluded that surfactant replacement therapy can prevent the patients with measles pneumonitis from hypoxemia and ventilation-induced lung injury. However, further study is needed to maintain the improved oxygenation. Recently, it is reported that the effect of exogenous surfactant on oxygenation and activity of pulmonary neutrophils is regulated by the amount and/or concentration of administered surfactant. Therefore, it is an urgent issue to find out the optimum amount and concentration of exogenous surfactant used clinically.

[Sjögren's syndrome with presenting as aseptic meningoencephaloradiculopathy in an elderly woman].

A 76-year-old woman was found to have acute aseptic meningoencephalitis with meningial irritation, disturbance of consciousness, elevation of cell counts in cerebrospinal fluid, and swelling of a right temporal-lobe lesion on a CT scan of the head. Muscle weakness in the lower extremities and urinary dysfunction developed and progressed gradually. The protein content of cerebrospinal fluid was high, and the distal latencies of F waves were prolonged, which suggested that the inflammation extended to the nerve roots. Sjögren's syndrome was diagnosed on the basis of atrophy of the labial salivary glands; invasions of lymphocytes and plasma cells to the intercellular space; and elevation of the titers of serum antinuclear antibody, anti-SS-A antibody, and anti-SS-B antibody. The patient had no xerosis. Aseptic meningoencephalitis was the first manifestation of Sjögren's syndrome. In recent years, several cases in which Sjögren's syndrome was associated with aseptic meningitis have been reported. However, we know of no previous report of such a case in a patient of this age. Aseptic meningoencephalitis can be the first manifestation of Sjögren's syndrome.

[Chronic neuropathy, a high level of protein in cerebrospinal fluid, and vitamin B1 and folate deficiency in a patient with normal-pressure hydrocephalus].

A 67-year-old woman presented with a 1-year history of gradual weight loss, reduced mental activity, muscle weakness, and urinary dysfunction. Neurological examination revealed mild lethargy, severe muscular atrophy, and diminished deep tendon reflexes in the extremities. The levels of vitamin B1 and folate in blood were low: 1.9 micrograms/dl (normal range 2.0-7.2) and 0.7 ng/ml (normal range 4.0-12.0). respectively. A lumbar puncture was done. The pressure of the cerebrospinal fluid was within normal limits, the level of protein was very high (467 mg/dl), and only a few lymphocytes were seen. A nerve-conduction study showed low amplitudes of action potentials and slow conduction velocities in both the motor and sensory nerves. Myelin irregularity, "onion bulb formation", and axonal atrophy were seen in a specimen obtained by sural nerve biopsy. A T2-weighted magnetic resonance image of the brain showed ventricular dilatation, high-intensity signals around the lateral ventricles, and a flow-void sign of the cerebral aqueduct. Radioisotope cisternography (111In-DTPA) disclosed ventricular reflux and slow clearance of the tracer from the ventricles. These findings indicated the presence of chronic inflammatory demyelinating polyneuropathy, nutritional polyneuropathy, vitamin B1 deficiency, folate deficiency, and normal pressure hydrocephalus. In this patient, the high level of protein in the cerebrospinal fluid may have caused the hydrocephalus.

[Lipoprotein(a) as a risk factor for cardiovascular disease in elderly patients with diabetes].

Lipoprotein(a) (Lp(a)) is an independent risk factor for cardiovascular diseases in non-diabetic people, but few studies have been done in diabetic patients. To investigate whether Lp(a) is a risk factor for cardiovascular disease in elderly people with diabetes, we examined the association of Lp(a) and serum lipid levels (total cholesterol: TC; triglycerides: TG; and high-density lipoprotein cholesterol: HDL-c) with the incidence of coronary artery disease and cerebrovascular disease. We studied 354 outpatients(131 men and 223 women, 60-97 years of age) with non-insulin-dependent diabetes mellitus. The mean concentration of Lp(a) was 21.1 +/- 19.6 mg/dl and the median was 14.0 mg/dl. The Lp(a) concentration did not correlate significantly with age or with sex, but it did correlate significantly with TC (r = 0.152, p < 0.05) and with the level of apoprotein B (r = 0.168, p < 0.05). The incidence of cerebrovascular disease was significantly higher in patients with high concentrations of Lp(a) (> or = 30 mg/ dl) than in those with low concentrations (< 30 mg/ dl). Multivariate logistic regression analysis revealed that male sex, hypertension, a high level of HbA1c, a low level of HDL, and a high level of Lp(a) were independent risk factors for cerebrovascular disease. The incidence of coronary artery disease tended to the higher in those with high concentrations of Lp(a) (> or = 30 mg/dl). However, multivariate logistic regression analysis revealed no significant correlation between Lp(a) concentration and the incidence of coronary artery disease. We conclude that a high concentration of Lp(a) is an independent risk factor for cerebrovascular disease in elderly patients with diabetes.

[A case of polymyositis with anti-Jo-1 antibody preceded by BOOP].

A 56-year-old man experienced dyspnea since August 1995 and the chest X-ray film showed abnormal shadow. The diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP) was established based on the histological findings of transbronchial lung biopsy. The patient was treated with prednisolone and symptoms improved. Myalgia and muscle weakness developed associated with relapse of BOOP after withdrawal of prednisolone. Patient was admitted to our department on December 1995 for further examination. An increased level of serum CPK, histological findings of muscle biopsy consistent with myositis, and positive anti-Jo-1 antibody were identified. Those findings supported a diagnosis of polymyositis (PM), and BOOP was considered as a pulmonary complication of PM. Myositis and pulmonary lesion improved after second course of steroid therapy and patient was discharged on May 1996. Both chronic pulmonary fibrosis and acute progressive interstital pneumonia are well known as pulmonary lesion associated with PM. The former is frequently recognized in cases of PM with anti-Jo-1 antibody and the latter is often observed in cases without autoantibodies. The association of PM and BOOP, however, has rarely been reported. The findings that BOOP frequently preceded PM and anti-Jo-1 antibody was positive in half of the cases were observed in the literature.

[Report on the 89th Scientific Assembly and Annual Meeting of the Radiological Society of North America--micro-focus x-ray CT imaging of breast specimens with microcalcifications].

LEARNING OBJECTIVES: (1)Understand images of breast specimens with microcalcifications obtained by use of micro-focus CT. (2)Learn the relationship between mammographic features, pathologic characteristics, and micro-focus CT images. (3)Learn the usefulness of three-dimensional images in understanding of detailed structures and patterns of microcalcifications without cutting the specimen. ABSTRACT: Microcalcifications are one of the important sign for early detection of breast cancer by use of mammography, and has resulted in the detection of nonpalpable cancer. However, it is difficult to distinguish between benign and malignant microcalcifications, thus causing high false-positive rate. Micro-focus CT employs a x-ray tube of a focal spot size less than 10 microns, and has high spatial resolution, thus resulting in more accurate visualization of structures of microcalcifications. We investigated the relationship between micro-focus CT images of breast specimens with microcalcifications, mammographic features and pathologic characteristics. Micro-focus CT imaging was comparable to pathologic images in terms of resolution and contrast. Microcalcifications were more clearly detected in micro-focus CT imaging than specimen radiographs. Three-dimensional imaging on microcalcifications provided a tool for studying the shape and distribution of calcifications. Micro-focus CT for breast imaging was very useful for understanding of structures and patterns of microcalcifications without cutting the specimen.