Indocyanine green lymphography in the congenital chylothorax and chylous ascites.

BACKGROUND: The prognosis of congenital chylothorax and ascites ranges from spontaneous resolution to death, but no established examination exists to predict the prognosis. We aimed to develop a clinically useful method to evaluate lymphatic abnormalities using indocyanine green (ICG) lymphography in infants with congenital chylothorax and ascites. METHODS: We retrospectively evaluated infants with congenital chylothorax and chylous ascites who underwent ICG lymphography in our hospital between 2012 and 2022. The ICG lymphography findings was evaluated. We defined the dermal backflow in the trunk as the lymphatic flow from the end of the limb back through the lymphatic vessels on the surface of the trunk. The association between the dermal backflow in the trunk and clinical outcomes, as follows, are investigated: the duration of the drainage period, the duration of endotracheal intubation, and the length of hospital stay. RESULTS: Twenty infants had a dermal backflow in the trunk, and ten did not. Clinical outcomes in infants with and without dermal backflow in the trunk were as follows (median): the duration of the drainage period (20 vs. 0 days, p = 0.001), the duration of endotracheal intubation (12 vs. 2 days, p = 0.04), and the length of hospital stay (62 vs. 41 days, p = 0.04), respectively. In multivariate linear regression analysis adjusted for gestational age, the duration of the drainage period was correlated with the dermal backflow in the trunk [exp(B) = 2.62; p = 0.003]. CONCLUSIONS: The dermal backflow in the trunk in ICG lymphography was useful in predicting the clinical course of congenital chylothorax and ascites.

Predictive value of serum interleukin-6 for neonatal encephalopathy outcomes.

BACKGROUND: Serum interleukin-6 (IL-6) may predict adverse outcomes of neonatal encephalopathy (NE); however, limited data regarding the predictive utility of IL-6 during neurodevelopmental follow-up are available. We aimed to determine the utility of IL-6 for predicting adverse outcomes at 18 to 22 months of age. METHODS: Eighty-seven patients with NE who received therapeutic hypothermia were enrolled in this study. Serial serum IL-6 levels during the first 3 postnatal days were collected. Patients were classified into three groups: 1) death, 2) survival with moderate to severe neurodevelopmental disability (NDD) at 18-22 months of age, and 3) survival without NDD (favorable outcome). The predictive ability of IL-6 was determined by the area under the receiver-operating characteristic curve (AUC). RESULTS: Serial IL-6 data of 80 patients with NE were available and showed peak levels on postnatal day 1; these levels gradually decreased toward day 3. By 18-22 months of age, 13 and 17 patients died and experienced moderate to severe NDD without death, respectively. Fifty patients experienced favorable outcomes. Higher IL-6 levels on day 1 predicted the composite adverse outcome (including death and survival with NDD; n = 30; AUC, 0.648). Higher IL-6 levels on day 1 predicted death (n = 13; AUC, 0.799), whereas higher IL-6 levels on day 1 predicted survival with NDD (n = 17; AUC, 0.536). CONCLUSIONS: The AUC of IL-6 that predicted survival with NDD was lower than the AUC of IL-6 that predicted death; therefore, IL-6 may have insufficient utility for predicting NDD without death.

Frequency of HER2 expression of circulating tumour cells in patients with metastatic or recurrent gastrointestinal cancer.

BACKGROUND: The clinical significance of circulating tumour cell (CTC) detection in gastrointestinal (GI) cancer remains controversial and the molecular biological characteristics of CTCs are poorly understood. METHODS: A total of 87 patients with metastatic or recurrent GI cancer were prospectively enrolled. Circulating tumour cells and their HER2 status were assessed using the CellSearch System. RESULTS: Among the 62 CTC-positive cases, we found 22 discordant cases (35.5%). Among the HER2-negative primary tumours, 17 of 54 developed HER2-positive CTCs. Five of eight had HER2-negative CTCs among the HER2-positive primary tumours. CONCLUSION: The findings in the current study suggest that it is critical to evaluate the HER2 status of not only the primary tumour but also the CTCs because the metastasising tumour cells are the primary target of systemic therapy.

Reopening of ductus arteriosus in idiopathic premature constriction or closure of ductus arteriosus: A case series.

BACKGROUND: There is no consensus on managing pregnancy when the fetus is diagnosed with idiopathic premature constriction or closure of the ductus arteriosus (PCDA). Knowing whether the ductus reopens is valuable information for managing idiopathic PCDA. We conducted a case-series study to investigate the natural perinatal course of idiopathic PCDA and examined factors associated with ductal reopening. METHODS: We retrospectively collected information about the perinatal course and echocardiographic findings at our institution, which, on principle, does not determine delivery timing based on fetal echocardiographic results. We also examined perinatal factors related to the reopening of the ductus arteriosus. RESULTS: Thirteen cases of idiopathic PCDA were included in the analysis. The ductus reopened in 38% of cases. Among cases diagnosed in < 37 weeks of gestation, 71% reopened, which was confirmed seven days after diagnosis (interquartile range 4-7). Diagnosis earlier in gestation was associated with ductal reopening (p = 0.006). Two cases (15%) developed persistent pulmonary hypertension. No fetal hydrops or death occurred. CONCLUSIONS: The ductus is likely to reopen when prenatally diagnosed before 37 weeks gestation. There were no complications due to our pregnancy management policy. In idiopathic PCDA, especially if the prenatal diagnosis is made before 37 weeks of gestational age, continuing the pregnancy with careful monitoring of the fetus's well-being is recommended.

Difference between "Physical Fitness Age" Based on Physical Function and Chronological Age Is Associated with Obesity, Hyperglycemia, Depressive Symptoms, and Low Serum Albumin.

OBJECTIVES: This study aimed to (1) develop the physical fitness age, which is the biological age based on physical function, (2) evaluate the validity of the physical fitness age for the assessment of sarcopenia, and (3) examine the factors associated with the difference between physical fitness age and chronological age. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Community-dwelling older adults and outpatients. MEASUREMENTS: A formula for calculating the physical fitness age was created based on the usual walking speed, handgrip strength, one-leg standing time, and chronological age of 4,076 older adults from the pooled data of community-dwelling and outpatients using the principal component analysis. For the validation of the physical fitness age, we also used pooled data from community-dwelling older adults (n = 1929) and outpatients (n = 473). Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus. The association of D-age (the difference between physical and chronological ages) with cardiovascular risk factors, renal function, and cardiac function was examined. RESULTS: The receiver operating characteristic analysis, with sarcopenia as the outcome, showed that the area under the curve (AUC) of physical fitness age was greater than that of chronological age (AUC 0.87 and 0.77, respectively, p < 0.001). Binomial logistic regression analysis revealed that the D-age was significantly associated with sarcopenia after adjustment for covariates (odds ratio 1.22, 95% confidence interval 1.19-1.26; p <0.001). In multivariate linear regression analysis with D-age as the dependent variable, D-age was independently associated with a history of diabetes mellitus (or hemoglobin A1c as a continuous variable), obesity, depression, and low serum albumin level. D-age was also correlated with estimated glomerular filtration rate derived from serum cystatin C, brain natriuretic peptide, and ankle-brachial index, reflecting some organ function and arteriosclerosis. CONCLUSIONS: Compared to chronological age, physical fitness age calculated from handgrip strength, one-leg standing time, and usual walking speed was a better scale for sarcopenia. D-age, which could be a simple indicator of physical function, was associated with modifiable factors, such as poor glycemic control, obesity, depressive symptoms, and malnutrition.

Association of B cell antigen receptor with protein tyrosine kinase Lyn.

Antigen is thought to cross-link membrane-bound immunoglobulins (Igs) of B cells, causing proliferation and differentiation or the inhibition of growth. Protein tyrosine kinases are probably involved in signal transduction for cell proliferation and differentiation. The Src-like protein tyrosine kinase Lyn is expressed preferentially in B cells. The Lyn protein and its kinase activity could be coimmunoprecipitated with IgM from detergent lysates. Cross-linking of membrane-bound IgM induced a rapid increase in tyrosine phosphorylation of at least ten distinct proteins of B cells. Thus, Lyn is physically associated with membrane-bound IgM, and is suggested to participate in antigen-mediated signal transduction.

The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity.

Antibodies were raised against a synthetic peptide corresponding to 14 amino acid residues at the COOH-terminus of a protein deduced from the human c-erbB-2 nucleotide sequence. These antibodies immunoprecipitated a 185-kilodalton glycoprotein from MKN-7 adenocarcinoma cells. Incubation of the immunoprecipitates with (gamma-32P)ATP resulted in the phosphorylation of this protein on tyrosine residues. These results indicate that the human c-erbB-2 gene product is the 185-kilodalton glycoprotein that is associated with tyrosine kinase activity. Although the c-erbB-2 protein was predicted to encode a protein very similar to epidermal growth factor (EGF) receptor, EGF did not stimulate this kinase activity either in vivo or in vitro.

Location of the c-yes gene on the human chromosome and its expression in various tissues.

Analysis of DNA from human embryo fibroblasts showed that ten Eco RI fragments were hybridizable with the Yamaguchi sarcoma virus oncogene (v-yes). Four of the Eco RI fragments were assigned to chromosome 18 and one to chromosome 6. There was evidence for multiple copies of yes-related genes in the human genome; however, only a single RNA species, 4.8 kilobases in length, was related to yes in various cells.

Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells.

The sequence of the human epidermal growth factor (EGF) receptor shows great homology with the avian erythroblastosis virus v-erb B oncogene, raising the possibility that the receptor gene is identical to the c-erb B protooncogene. Human A431 epidermoid carcinoma cells, which have an unusually high number of EGF receptors, were examined to determine whether elevated EGF receptor levels correlate with gene amplification. Southern blots of genomic DNA's from A431 and other human cell lines were probed with either a v-erb B gene fragment or a human EGF receptor complementary DNA clone (pE7), previously isolated from an A431 complementary DNA library. When either probe was used to analyze Eco RI- or Hind III-generated DNA fragments, EGF receptor DNA sequences were amplified about 30-fold in A431. Differences in the banding pattern of A431 DNA fragments relative to normal fibroblast DNA indicate the occurrence of a rearrangement in the region of the receptor gene. Furthermore, A431 cells contain a characteristic, prominent 2.9-kilobase RNA. These results are consistent with the hypothesis that, in A431 cells, gene amplification, possibly associated with a translocation event, may result in the overproduction of EGF receptor protein or the appearance of the transformed phenotype (or both).

Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin.

Wnt/Wingless directs many cell fates during development. Wnt/Wingless signaling increases the amount of beta-catenin/Armadillo, which in turn activates gene transcription. Here the Drosophila protein D-Axin was shown to interact with Armadillo and D-APC. Mutation of d-axin resulted in the accumulation of cytoplasmic Armadillo and one of the Wingless target gene products, Distal-less. Ectopic expression of d-axin inhibited Wingless signaling. Hence, D-Axin negatively regulates Wingless signaling by down-regulating the level of Armadillo. These results establish the importance of the Axin family of proteins in Wnt/Wingless signaling in Drosophila.

Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein.

The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors, and its product binds to the adherens junction protein beta-catenin. Overexpression of APC blocks cell cycle progression. The APC-beta-catenin complex was shown to bind to DLG, the human homolog of the Drosophila discs large tumor suppressor protein. This interaction required the carboxyl-terminal region of APC and the DLG homology repeat region of DLG. APC colocalized with DLG at the lateral cytoplasm in rat colon epithelial cells and at the synapse in cultured hippocampal neurons. These results suggest that the APC-DLG complex may participate in regulation of both cell cycle progression and neuronal function.

Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene.

Familial adenomatous polyposis coli (FAP) is a disease characterized by the development of multiple colorectal adenomas, and affected individuals carry germline mutations in the APC gene. With the use of a conditional gene targeting system, a mouse model of FAP was created that circumvents the embryonic lethality of Apc deficiency and directs Apc inactivation specifically to the colorectal epithelium. loxP sites were inserted into the introns around Apc exon 14, and the resultant mutant allele (Apc580S) was introduced into the mouse germline. Mice homozygous for Apc580S were normal; however, upon infection of the colorectal region with an adenovirus encoding the Cre recombinase, the mice developed adenomas within 4 weeks. The adenomas showed deletion of Apc exon 14, indicating that the loss of Apc function was caused by Cre-loxP-mediated recombination.

Cognitive function and number of teeth in a community-dwelling elderly population without dementia.

Although the number of sound or decayed teeth has been reported to be associated with cognitive function in elderly populations with dementia, little is known about this association in elderly populations without dementia. We evaluated this relationship, with adjustment for confounding factors, in Japanese populations of 60-year-old (n = 270; 120 males and 150 females) and 65-year-old (n = 123; 57 males and 66 females) individuals residing in Fukuoka Prefecture of Japan. Dental examinations were performed in all subjects, along with the Mini-mental state examination (MMSE) for assessing cognitive function. Among the total of 393 subjects, the mean MMSE score was 27.9 +/- 1.9, and 391 subjects scored 24 or higher. The mean numbers of sound and decayed teeth were 12.0 +/- 6.3 and 0.5 +/- 1.2, respectively. Associations were found between the numbers of sound and decayed teeth and MMSE in total subjects and males, but not in females, by multiple regression analysis adjusted for gender, age, level of education, marital status, smoking, alcohol drinking, working status, systolic blood pressure and blood glucose. An association was also found between MMSE and the number of sound teeth in a logistic regression analysis. In conclusion, associations were found between normal-range cognitive function and the numbers of sound and decayed teeth, after adjustment for various confounding factors, in an elderly Japanese population.

Correction: Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Physical fitness and cognitive function in an 85-year-old community-dwelling population.

BACKGROUND: Little is known about the association between physical fitness and cognitive function in very elderly people (over 80 years of age). OBJECTIVES: To evaluate that relationship in 85-year-old community-dwelling individuals. METHODS: Out of 207 participants (90 males, 117 females) who were 85 years old and community-dwelling, 205 completed the Mini-Mental State Examination (MMSE) for evaluating cognitive function. The numbers of subjects who completed physical fitness measurements such as hand-grip strength, isometric leg extensor strength, one-leg standing time, stepping rate, and walking speed were 198, 159, 169, 168, and 151, respectively. RESULTS: There were significant associations in MMSE with hand-grip strength (right or left hand), isometric leg extensor strength, stepping rate, and walking speed by simple regression analysis. MMSE was still significantly associated with hand-grip strength (beta = 0.305, p = 0.005 for right side; beta = 0.309, p = 0.004 for left side), stepping rate (beta = 0.183, p = 0.046), and walking speed (beta = -0.222, p = 0.014) by multiple regression analysis after adjustments for the amount of education, gender, smoking, drinking, complication of stroke, body weight, body height, regular medical care, serum albumin, blood HbA1c, and marital status. By logistic regression analysis, the prevalence of a normal MMSE score (MMSE >or=24) was increased by 9% with each 1-kg increase in hand-grip strength of the left hand (OR 1.087, 95% CI 1.003-1.179, p = 0.042), and was increased by 6% with each step per 10 s in stepping rate (OR 1.060, 95% CI 1.000-1.122, p = 0.048). CONCLUSION: In a very elderly population of 85-year-olds, cognitive function was associated with some physical fitness measurements, independent of confounding factors.

Specific expression of human c-fgr in natural immunity effector cells.

The c-fgr gene product was shown by immune complex protein kinase assay with specific antibodies to be a 58-kilodalton protein (p58c-fgr) with tyrosine-specific autophosphorylating activity. On examination of peripheral blood cells by immunoblotting with anti-c-fgr antibodies, p58c-fgr was found only in the fractions of monocytes, granulocytes, and natural killer cells. On the other hand, histochemical studies of hybridization demonstrated accumulation of c-fgr transcripts on most monocytes and large lymphocytes. In hematopoietic cell lines, p58c-fgr was detected in differentiated granulocytic cells as well as in differentiated monocytic cells of HL-60-cell origin. These data suggest a specific role for p58c-fgr in natural immunity effector cells.

Human c-fgr induces a monocyte-specific enzyme in NIH 3T3 cells.

The mutant c-fgr protein (p58c-fgr/F523) containing Phe-523 instead of Tyr-523 exhibited transforming activity in NIH 3T3 cells like other protein-tyrosine kinases of the src family, but normal p58c-fgr (p58c-fgr/wt) did not. The mutant protein showed tyrosine kinase activity threefold higher than that of the normal protein in vitro. Surprisingly, transfection of the normal c-fgr gene into NIH 3T3 cells resulted in induction of sodium fluoride (NaF)-sensitive alpha-naphthyl butyrate esterase (alpha-NBE), a marker enzyme of cells of monocytic origin, which was not induced in v-src-, v-fgr-, or lyn-transfected NIH 3T3 cells. The NaF-sensitive alpha-NBE induced in c-fgr transfectants was shown by isoelectric focusing to have a pI of 5.2 to 5.4, a range which was the same as those for thioglycolate-induced murine peritoneal macrophages and 1 alpha,25-dihydroxyvitamin D3-treated WEHI-3B cells. Immunoblotting studies with antiphosphotyrosine antibodies revealed that 58-, 62-, 75-, 120-, 200-, and 230-kDa proteins were commonly phosphorylated at tyrosine residues in NIH 3T3 cells transfected with normal and mutated c-fgr, while 95-kDa protein was significantly phosphorylated at tyrosine residues in cells transfected with the mutated c-fgr. These findings suggest that tyrosine phosphorylation of specific cellular substrate proteins is important in induction of NaF-sensitive alpha-NBE and cell transformation by p58c-fgr.

Activation of the cellular src gene by transducing retrovirus.

Newly isolated strains of avian sarcoma virus, S1 and S2, were shown to have the transduced cellular src gene as their viral transforming gene (Yamagishi et al., Virology 137:266-275, 1984). In this work, the S1 and S2 genomes were molecularly cloned, and the junction sequences between the viral genomes and the c-src genes and the complete nucleotide sequences of the v-src genes transduced in these viruses were determined. Data on the junction sequences suggested that 5' recombination had occurred between the 5'-noncoding region of c-src and the 5' region of the gag sequence encoding p19 in both viruses and that 3' recombination had occurred in the last coding exon of c-src with either the middle portion of the env sequence encoding gp85 for S1 or the 3' portion of pol coding for reverse transcriptase for S2. Comparison of the amino acid sequences of the S1 and S2 src products deduced from the nucleotide sequences (pp62S1-src and pp62S2-src with that of c-src protein (pp60c-src) indicated that in pp62S1-src the 8 carboxy-terminal amino acid residues of the total of 533 in pp60c-src are replaced by 43 residues translated from the env sequence at the wrong frame. In pp62S2-src, on the other hand, the 14 carboxy-terminal amino acids of pp60c-src are replaced by the 38 carboxy-terminal residues of reverse transcriptase. The mechanism of c-src transduction and the structural changes necessary for pp60c-src activation are discussed.

Structure, expression, and chromosomal location of the human c-fgr gene.

The nucleotide sequence of seven exons of the human c-fgr gene, a cellular homolog of the oncogene of Gardner-Rasheed feline sarcoma virus, was determined. Twenty-six independent genomic clones were obtained from a human gene library with a DNA clone of Y73 avian sarcoma virus oncogene, v-yes, as a probe under relaxed hybridization conditions. Restriction mapping and partial sequence analyses revealed that two of these clones were derived from the c-fgr gene, distinct from the c-yes gene. Interestingly, the splicing points of the c-fgr gene were identical with those of the c-src gene throughout the seven exons, suggesting that the two proto-oncogenes were generated by gene duplication of an ancestral gene containing intervening sequences. On RNA blot hybridization the major transcript was found to be 2.6 kilobase long. Two additional transcripts of 3.5 and 4.7 kilobases were also detected. Furthermore, karyotype analysis of several human-mouse hybrid cells and Southern blot analyses of DNAs of the hybrids with a human c-fgr locus-specific probe showed that this gene is located on chromosome 1.