Prevalence of COL4A1 and COL4A2 mutations in severe fetal multifocal hemorrhagic and/or ischemic cerebral lesions.

OBJECTIVE: To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury. METHODS: This was a single-center retrospective analysis of all cases of fetal cerebral anomalies suggestive of COL4A1 or COL4A2 gene mutation over the period 2009-2018. Inclusion criteria were: (1) severe and/or multifocal hemorrhagic cerebral lesions; (2) multifocal ischemic-hemorrhagic cerebral lesions. These anomalies could be of different ages and associated with schizencephaly or porencephaly. Between fetuses with and those without a mutation, we compared gestational age at the time of diagnosis, parity and fetal gender. RESULTS: Among the 956 cases of cerebral anomaly diagnosed in our center during the 10-year study period, 18 fetuses were identified for inclusion. A pathogenic COL4A1 gene mutation was found in five of these cases, among which four were de-novo mutations. A variant of unknown significance was found in four fetuses: in the COL4A1 gene in one case and in the COL4A2 gene in three cases. No COL4A1 or COL4A2 mutation was found in the remaining nine fetuses. The median (interquartile range) gestational age at diagnosis was significantly lower in cases with a mutation (24 (22-26) weeks) than in cases without a mutation (32 (29.5-34.5) weeks) (P = 0.03). CONCLUSIONS: A phenotype suggestive of cerebral injury was found in 18 of the 956 (1.9%) cases in our population, in 28% of which there was an associated COL4A1 or COL4A2 mutation. COL4A1 and COL4A2 gene mutations should be sought systematically in cases of severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, with or without schizencephaly or porencephaly. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Forty Postmortem Examinations in COVID-19 Patients.

OBJECTIVES: Although diffuse alveolar damage, a subtype of acute lung injury (ALI), is the most common microscopic pattern in coronavirus disease 2019 (COVID-19), other pathologic patterns have been described. The aim of the study was to review autopsies from COVID-19 decedents to evaluate the spectrum of pathology and correlate the results with clinical, laboratory, and radiologic findings. METHODS: A comprehensive and quantitative review from 40 postmortem examinations was performed. The microscopic patterns were categorized as follows: "major" when present in more than 50% of cases and "novel" if rarely or not previously described and unexpected clinically. RESULTS: Three major pulmonary patterns were identified: ALI in 29 (73%) of 40, intravascular fibrin or platelet-rich aggregates (IFPAs) in 36 (90%) of 40, and vascular congestion and hemangiomatosis-like change (VCHL) in 20 (50%) of 40. The absence of ALI (non-ALI) was novel and seen in 11 (27%) of 40. Compared with ALI decedents, those with non-ALI had a shorter hospitalization course (P = .02), chest radiographs with no or minimal consolidation (P = .01), and no pathologically confirmed cause of death (9/11). All non-ALI had VCHL and IFPAs, and clinically most had cardiac arrest. CONCLUSIONS: Two distinct pulmonary phenotypic patterns-ALI and non-ALI-were noted. Non-ALI represents a rarely described phenotype. The cause of death in non-ALI is most likely COVID-19 related but requires additional corroboration.

Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana demonstrates the need for routine surveillance.

OBJECTIVES: The aim of the study was to evaluate for the presence of drug resistance to HIV medications in treatment-naive individuals in Botswana. METHODS: Two different populations were evaluated for evidence of HIV drug resistance at three different geographical locations in Botswana. In the first study population, consisting of pregnant females diagnosed with HIV during pregnancy, participants were enrolled at the time of their HIV diagnosis. The second population included pre-ART enrollees at Infectious Diseases Care Clinics (IDCCs) who had a CD4 T cell count >350 cells/µL. RESULTS: A total of 422 genotypes were determined: 234 for samples from antenatal clinic (ANC) participants and 188 for samples from IDCC participants. Between 2012 and 2014, 6 of 172 (3.5%) genotypes from ANC participants exhibited transmitted drug resistance (TDR), with 3 (1.7%) showing resistance to first-line ART. In a subset of samples from Gaborone, Botswana's capital and largest city, the TDR rate was 3 in 105 (2.9%), but only 1 in 105 (1.0%) showed first-line ART resistance. Between December 2014 and April 2015, the rate of resistance to any ART in Gaborone was 6 in 62 (9.7%), with 5 (8.1%) exhibiting first-line ART resistance. CONCLUSIONS: These data demonstrate that TDR rates for HIV differ geographically and temporally in Botswana, with significant increases in TDR observed at ANCs in Gaborone between 2012 and 2015. These findings stress the importance of continued testing for TDR, particularly as access to HIV treatment increases and guidelines recommend treatment at the time of HIV diagnosis.

Comparative study of survival of patients with hepatocellular carcinoma predicted by different staging systems using multivariate analysis.

AIMS: In a previous pilot study, we reported the usefulness of the modified the Cancer of the Liver Italian Program (CLIP) score for patients with hepatocellular carcinoma (HCC). To determine the best staging system for predicting the survival of HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 210 Japanese HCC patients who underwent hepatic resection. METHODS: We compared the survival as predicted by various staging systems, including tumour node metastasis (TNM) stage of the American Joint Commission on Cancer (AJCC) and the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), CLIP score and our modified CLIP score using protein induced by vitamin K absence or antagonist II (PIVKA-II). RESULTS: Univariate analysis showed that discrimination of disease-free survival in the early and advanced stages by the JIS score and modified CLIP score was clearer than by the Japanese or AJCC TNM or the original CLIP score. Discrimination between stages of overall survival by all staging systems was significant. Multivariate analysis showed that the JIS, CLIP and modified CLIP scores were better staging systems for predicting survival than the Japanese and AJCC TNM. The modified CLIP score showed the lowest Akaike information criteria statistical value for disease-free and overall survival, which means the best discrimination ability for patient survival compared with the JIS score and CLIP score. CONCLUSIONS: A staging system that combines tumour factors, sensitive tumour marker(s) and hepatic function is the best predictor of prognosis of HCC patients.

Clinical outcome and survival of secondary (AA) amyloidosis.

OBJECTIVE: In order to predict the clinical outcome of secondary (AA) amyloidosis patients with rheumatic diseases, we studied the clinical features at presentation of AA amyloidosis. METHODS: We investigated the clinical characteristics and survival of 42 patients with biopsy-proven AA amyloidosis who were followed up in our department from 1983 to 2001. RESULTS: A presenting factor which adversely influenced clinical outcome was a raised serum creatinine concentration at the time AA amyloidosis was diagnosed. Eight of 42 patients survived for 10 years or more after the presentation of AA amyloidosis, while 24 patients had died within 10 years. At the diagnosis of AA amyloidosis, cardiac involvement was detected in 11 of 24 non-survivors, whereas it was not detected in any of the 8 long-term survivors. Estimated survival at 5 years was 31.3% in those who had cardiac involvement, and was 63.3% in those who had no cardiac involvement at the presentation of AA amyloidosis. CONCLUSION: Our results indicate that clinical outcome is related to renal function and cardiac involvement at the time AA amyloidosis is diagnosed. Amyloid-related cardiac involvement is one of the unfavorable predictive factors in AA amyloidosis patients.

Somatostatin analogue attenuates estrogen-induced augmentation of glomerular injury in spontaneous hypercholesterolemic female Imai rats.

BACKGROUND: Aggravating effect of estrogen replacement therapy on glomerular injury associated with an elevation of growth hormone (GH) levels has been reported. Therefore, in the present study, to clarify an association between GH elevation and the aggravating effect of estrogen on glomerular injury, we investigated the effect of somatostatin, an inhibitor of GH secretion, on glomerular injury in estrogen-treated hypercholesterolemic female Imai rats. METHOD: Control female rats were assigned to group 1 (Cont, n = 10). Group 2 (Cont-E, n = 10) received estrogen, and groups 3 (Cont-E-LS, n = 10) and 4 (Cont-E-HS) received estrogen and either a low dose of somatostatin analogue or a high dose of somatostatin analogue. Body weight, urinary protein, serum albumin, total cholesterol, triglycerides, blood urea nitrogen and serum creatinine were investigated every 4 weeks from 10 weeks through 30 weeks of age. At 30 weeks of age, rats were studied morphologically. RESULTS: Estrogen administration resulted in an increase in urinary protein excretion rates and serum total cholesterol levels, and aggravated glomerular injury associated with an increase in GH. In contrast, somatostatin treatment reduced both urinary protein excretion rates and total cholesterol levels and attenuated glomerular injury to levels close to those of controls associated with a reduction of GH levels. CONCLUSION: The results suggest that increased GH levels may contribute to an enhancing effect of estrogen administration on glomerular injury.

Evaluation of a telemedicine system for supporting thyroid disease diagnosis.

A telemedicine system connecting Japan and Belarus via a communication satellite and the international ISDN has been in use since February, 1999. Two relational databases, which are essentially the same, are set respectively at Nagasaki University School of Medicine and Gomel Regional Specialized Dispensary in Belarus for management of patients' data and for research including epidemiologic studies. The thyroid ultrasonographic images, microscopic images of cytological findings and other information on patients are sent from Gomel to Nagasaki once a week with diagnoses and comments by physicians at Gomel Regional Specialized Dispensary for cases whom they found difficult to diagnose. Thyroid specialists at Nagasaki University School of Medicine correct the diagnoses, if necessary, on the basis of information from Gomel and send their comments and instructions to Gomel for improving diagnosis skills of physicians at Gomel. The findings of 330 cases have been sent from Gomel to Nagasaki by September, 2000 since the commencement of the system in February, 1999. Of the 329 cases, thyroid diagnosis was made at Gomel for 261 cases in whom two or more diagnoses were made for 35 cases. As of the end of October, 2000, the Gomel diagnoses have been reviewed for 217 cases and the remaining 112 cases are under review at Gomel. The diagnoses made at Gomel and Nagasaki were in agreement for 110 (50.7%) of 217 cases. Thyroid cancer was diagnosed in 8 cases in whom 6 had been diagnosed at Gomel while the other 2 were diagnosed anew at Nagasaki. The usefulness of the system for improving thyroid diagnosis in Belarus was indicated.

Detection of early gastric cancer by a real-time autofluorescence imaging system.

A light-induced fluorescence endoscopy in the gastrointestinal tract system was used in 52 patients with 54 lesions (33 early gastric cancers, 21 benign lesions) to assess its ability to detect early gastric cancer. Comparing the images with the histological findings, 21 of the 33 carcinomas appeared dark red, ten had a mixed pattern of dark red and white, and two could not be detected. Of the 21 benign lesions, 18 appeared light blue, as do normal mucosa, with this system. In 85% of the cancer lesions (28/33), cancer extension was correctly detected. The sensitivity and specificity were 94 and 86%, respectively. Real-time autofluorescence endoscopy is a useful adjunct to conventional white-light endoscopy for detecting early gastric cancer.

A mutational analysis of the Abetaz/Aalphad major histocompatibility complex class II molecule that restricts autoreactive T cells in (NZBxNZW)F1 mice. The critical influence of alanine at position 69 in the Aalphad chain.

Autoimmune symptoms of (NZBxNZW)F1 (H-2d/z) mice are reported to be critically related to the heterozygosity at the H-2 complex of the murine major histocompatibility complex (MHC). We previously showed that several Abetaz/Aalphad MHC class II molecule-restricted autoreactive T-cell clones from B/WF1 mice were pathogenic upon transfer to preautoimmune B/WF1 mice. In this study, to identify the crucial amino acid residues in Abetaz/Aalphad molecules for T-cell activation, we generated a panel of transfectant cell lines. These transfectant cell lines express the Abetaz/Aalphad MHC molecules with a mutation at each residue alpha11, alpha28, alpha57, alpha69, alpha70, alpha76 of Aalphad chain and beta86 of Abetaz chain. Replacing alpha69 alanine with threonine, valine or serine completely eliminated the ability to stimulate autoreactive T-cell clones without affecting the ability to present foreign antigen keyhole limpet haemocyanin (KLH) or L-plastin peptide to specific T-cell clones. Replacing beta86 valine with aspartic acid resulted in a decrease in the stimulation for antigen-reactive as well as autoreactive T-cell clones. Substitutions at other residues had minimal or no effect on the stimulation of either auto- or antigen-reactive T-cell clones. These results suggest that alanine at residue 69 of the Aalphad chain is critical for the activation of autoreactive Abetaz/Aalphad-restricted T-cell clones. Possible explanations for this are discussed.

Multi-clonal expansion of unique human T-lymphotropic virus type-I-infected T cells with high growth potential in response to interleukin-2 in prodromal phase of adult T cell leukemia.

We established a simple IL-2-dependent colony-forming assay for T cells infected with human T-lymphotropic virus type-I (HTLV-I). IL-2-dependent cell lines were subsequently established by expanding individual colonies in liquid cultures. Lymphocyte-rich fractions were prepared from 31 HTLV-I carriers, 12 patients with smoldering ATL, 11 chronic ATL, 12 crisis ATL and 10 acute ATL. Primary colonies of CD4+ p19+ T cells were formed in all cases of carriers, smoldering and chronic ATL, and in 10 of 12 crisis cases. In contrast, no colony was formed from cells of patients with acute ATL. The rate of establishment of cell lines in HTLV-I carriers was significantly lower than that in patients of prodromal phase ATL. Cell lines established from cells of three prodromal cases were clonally identical to the parent ATL cells, while others had clonally distinct cell lines. Our results indicated the presence of four components of HTLV-I-infected T cells: (1) normal carrier T cells capable of forming colonies but not cell lines; (2) pre-malignant T cells capable of forming colonies as well as cell lines; (3) malignant T cells capable of forming colonies as well as cell lines; (4) fully malignant T cells unresponsive to IL-2. Our results suggest the presence of a multiclonal expansion of unique T cells in the prodromal phase of ATL, which have a high growth potential in response to IL-2. The coexistence of multiclonality with a dominant ATL clone may be closely related to the underlying pathology in HTLV-I leukemogenesis.

[Small cell carcinoma of the kidney. A case report].

We report a case of small cell carcinoma of the kidney in a 61-year-old female. Chief complaints were left lumbago, gross hematuria and high fever. The computed tomography revealed a large invasive tumor in the left renal pelvis with renal pedicle lymph nodes swelling. Systemic chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) showed a considerable effect and left nephrectomy was performed. But she died within 3 months postoperatively. Histologically, the tumor was composed of hyperchromatic small cells with increased N/C ratio. Immunohistochemical studies revealed positive staining for chromogranin A, synaptophysin, NSE, EMA, cytokeratin, and argyrophilic (Grimelius) silver impregnation stain. Electron microscopy revealed neurosecretory granules also. In conclusion, the present case was diagnosed as small cell carcinoma of the kidney with only 12 similar cases reported in the world literature.

Peptide-binding motifs of the mixed haplotype Abetaz/Aalphad major histocompatibility complex class II molecule: a restriction element for auto-reactive T cells in (NZBxNZW)F1 mice.

We previously showed that the mixed haplotype Abetaz/Aalphad major histocompatibility complex (MHC) class II molecules function as restricting element for autoreactive T-cell clones derived from autoimmune prone (NZBxNZW)F1 (B/WF1) mice. Subsequent analysis revealed that some of these Abetaz/Aalphad-restricted autoreactive T-cell clones were pathogenic upon transfer to pre-autoimmune B/WF1 mice. In this paper, we analysed the peptide-binding motif of Abetaz/Aalphad class II molecules. Amino acid-sequencing analysis of peptides eluted from purified Abetaz/Aalphad molecules revealed several sequences, including one that corresponds to murine l-plastin 588-601. Synthetic 18-mer l-plastin 588-605 peptide (SMARKIGARVYALPEDLV, as described by the amino acid single letter code) was demonstrated to bind to Abetaz/Aalphad MHC class II molecules on transfectant B lymphoma cells (TAbetaz). A competitive binding inhibition assay using truncation peptides revealed the core sequence for binding resides in 591Arg to 601Pro. Binding inhibition assay using substitution peptides, each having substitution to the other 19 residues at positions from 590Ala to 601Pro, revealed four major anchor sites 592Lys (p1), 594Gly (p3), 595Ala (p4), 597Val (p6) and one minor anchor site 600Leu (p9). Positively charged residues are not allowed at p3 and negatively charged residues are not allowed at p4 and p6. Relatively large hydrophobic residues (Leu, Ile) are not tolerated at p3 and p4. Met and Trp are not tolerated at p6. Based on these findings, the characteristics of peptides recognized by autoreactive T cells in B/WF1 mice are discussed.

Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

PURPOSE: To determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome. MATERIALS AND METHODS: Peripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined. RESULTS: Among 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase. CONCLUSION: The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.

Morphological subtyping of acute myeloid leukemia with maturation (AML-M2): homogeneous pink-colored cytoplasm of mature neutrophils is most characteristic of AML-M2 with t(8;21).

Morphologic and cytochemical features of 30 acute myeloid leukemia subtype M2 (AML-M2) patients with t(8;21) were compared with those of 50 AML-M2 patients without t(8;21). It was disclosed that irregular nuclear shape, Auer bodies, and at least 90% myeloperoxidase positivity in blast cells, and pseudo-Pelger-Huët anomaly of the nuclei and homogeneous pink-colored cytoplasm of mature neutrophils were observed in 90-100% of the t(8;21)+ patients. The percentages of patients showing these features were significantly (P < 0.01) lower in the t(8;21)- group. Among these morphological features, homogeneous pink-colored cytoplasm of mature neutrophils is most characteristic of t(8;21)+ AML-M2, because it was seen in 90% of the t(8;21)+ patients but in only 2% of the t(8;21)- patients. Conversely, pale-colored cytoplasm without any granules in mature neutrophils or dyserythropoietic features was observed in 84% of the t(8;21)- patients, but in none of the t(8;21)+ patients. These data suggest that it is possible to subtype AML-M2 patients morphologically by the recognition of homogeneous pink-colored or pale-colored cytoplasm of mature neutrophils and dyserythropoietic features. Thus, the morphologic subtyping of AML-M2 can be utilized alone or in combination with chromosomal or molecular subtyping for biological and clinical studies of AML with maturation.

Increased circulating serum amyloid A protein derivatives in rheumatoid arthritis patients with secondary amyloidosis.

Secondary amyloidosis, a serious complication of chronic inflammatory diseases, is caused by the deposition of amyloid fibrils in various organs. The major component of amyloid fibrils is derived from serum amyloid A protein (SAA) by proteolysis. To explore the mechanisms of amyloidogenesis, we measured SAA concentrations in the sera of 38 patients with rheumatoid arthritis (RA) without secondary amyloidosis and in the sera of 18 RA patients with secondary amyloidosis, using the latex agglutination immunoassay. We also determined whether SAA was present as a full-length protein in the sera of RA patients by immunoblotting. Although SAA concentrations were elevated in the sera, there were no significant differences in these concentrations between RA patients without amyloidosis (128.2 +/- 145.4 micrograms/ml) and RA patients with amyloidosis (165.0 +/- 162.9 micrograms/ml). To test for qualitative abnormalities of SAA, the isolated SAA proteins from individual RA patients were analyzed by anti-SAA immunoblot. In addition to full-length SAA protein, 6-kd and 4.5-kd SAA-derived fragments were detected in the sera of RA patients, and the ratio of these fragments to total SAA proteins was significantly higher in RA patients with amyloidosis (37.0% +/- 0.7%) compared with that of RA patients without amyloidosis (15.0% +/- 5.5%). Although a high serum level of SAA is a predisposing condition for amyloid formation in RA patients, our data suggest that the increased circulating proteolytic cleavage of SAA may potentially contribute to the development of AA-amyloid deposition.

Incidence of intracranial meningiomas in Nagasaki atomic-bomb survivors.

Among the Nagasaki atomic-bomb survivors registered at the Scientific Data Center for Atomic-Bomb Disaster, Nagasaki University School of Medicine, 45 cases of surgically treated intracranial meningioma were collected from 6 hospitals with departments of neurosurgery in or near Nagasaki City during the period from 1973 to 1992. All 45 patients were over 40 years of age at the time of diagnosis. Subsequently, the 45 cases were statistically analyzed in relationship to the estimated distance from the hypocenter by age, gender, intracranial location, histology and latent period. The analysis showed a high correlation between incidence of meningiomas and distance from the hypocenter. The incidence among Nagasaki atomic-bomb survivors over 40 years of age, especially in those proximally exposed, appears to be increasing, in inverse proportion to the exposure distance, since 1981, 36 years after the explosion of the atomic bomb.