The association of hemoglobin drop with in-hospital outcomes in COVID-19 patients.

BACKGROUND: Bleeding events can be critical in hospitalized patients with COVID-19, especially those with aggressive anticoagulation therapy. AIM: We aimed to investigate whether hemoglobin drop was associated with increased risk of acute kidney injury (AKI) and in-hospital mortality among patients with COVID-19. DESIGN: Retrospective cohort study. METHODS: This retrospective study was conducted by review of the medical records of 6683 patients with laboratory-confirmed COVID-19 hospitalized in the Mount Sinai Health system between 1st March 2020 and 30th March 2021. We compared patients with and without hemoglobin drop >3 g/dl during hospitalization within a week after admissions, using inverse probability treatment weighted analysis (IPTW). Outcomes of interest were in-hospital mortality and AKI which was defined as serum creatine change of 0.3 mg/dl increase or 1.5 times baseline. RESULTS: Of the 6683 patients admitted due to COVID-19, 750 (11.2%) patients presented with a marked hemoglobin drop. Patients with hemoglobin drop were more likely to receive therapeutic anticoagulation within 2 days after admissions. Patients with hemoglobin drop had higher crude in-hospital mortality (40.8% vs. 20.0%, P < 0.001) as well as AKI (51.4% vs. 23.9%, P < 0.001) compared to those without. IPTW analysis showed that hemoglobin drop was associated with higher in-hospital mortality compared to those without (odds ratio (OR) [95% confidential interval (CI)]: 2.21 [1.54-2.88], P < 0.001) as well as AKI (OR [95% CI]: 2.79 [2.08-3.73], P < 0.001). CONCLUSIONS: Hemoglobin drop during COVID-19 related hospitalizations was associated with a higher risk of AKI and in-hospital mortality.

Mortality after transcatheter versus surgical aortic valve replacement: an updated meta-analysis of randomised trials.

BACKGROUND: To determine whether transcatheter aortic valve implantation (TAVI) improves early (30-day) and midterm (1-year) mortality compared with surgical aortic valve replacement (SAVR), we performed an updated meta-analysis of all the currently available randomised controlled trials (RCTs). METHODS: To identify all RCTs providing both 30-day and 1­year mortality after TAVI versus SAVR, PubMed and ClinicalTrials.gov were searched up to and including July 2019. A risk difference (RD) and its 95% confidence interval were generated using data of prespecified outcomes in both the TAVI and SAVR groups. Study-specific estimates were pooled using inverse variance-weighted averages of RDs in the random-effects model. RESULTS: We identified seven eligible high-quality RCTs including a total of 7631 as-treated patients. Pooled analyses demonstrated significantly lower 30-day (RD -0.60%; p = 0.046) and 1­year all-cause mortality (RD -1.12%; p = 0.03) after TAVI than after SAVR. No funnel plot asymmetry was detected for 30-day and 1­year mortality. Meta-regression analyses indicated that RDs of 30-day and 1­year mortality between TAVI and SAVR were not modulated by mean Society of Thoracic Surgeons Predicted Risk of Mortality score. Bleeding complications at 30 days and 1 year and stage 2/3 acute kidney injury at 30 days were significantly less frequent after TAVI than after SAVR, whereas major vascular complications and new permanent pacemaker implantation at 30 days and 1 year were significantly more frequent after TAVI than after SAVR. CONCLUSION: The best evidence from the present meta-analysis of all the currently available RCTs suggests that TAVI may reduce 30-day and 1­year all-cause mortality compared with SAVR.

Autotransplantation of a maxillary first premolar to replace an ankylosed maxillary incisor: 7-year follow-up.

AIM: To present the combined endodontic, surgical and orthodontic treatment of an autotransplanted maxillary first premolar for the replacement of an ankylosed maxillary incisor. SUMMARY: This case report describes the autotransplantation of a maxillary premolar after the extraction of an ankylosed incisor in a 13-year-old boy. To allow better adaptation of the donor tooth, the buccal root of the first premolar was removed using a diamond bur and the denuded root site was filled with acid-etched composite resin. The palatal root canal was dressed with calcium hydroxide for 2 months before filling with gutta-percha. Autotransplantation of a remodelled maxillary first premolar was achieved to substitute for the ankylosed maxillary central incisor. Orthodontic treatment was performed to correct an Angle Class II malocclusion. Seven years after root canal treatment, the autotransplanted tooth and supporting tissues appeared healthy both clinically and radiographically and were functioning well. KEY LEARNING POINTS: • Autotransplantation is a viable option for the treatment of a missing tooth or for the replacement of a traumatized tooth when there is a donor tooth available. • Autotransplantation of a premolar for replacement of a missing anterior tooth is sometimes a suitable alternative to conventional prosthetic rehabilitation or implant treatment in young individuals. • Proper combined endodontic and orthodontic treatment of autotransplanted teeth might be possible without periodontal complications.

Equivocal colonic carcinogenicity of Aloe arborescens Miller var. natalensis berger at high-dose level in a Wistar Hannover rat 2-y study.

A 2-y carcinogenicity study of Aloe, Aloe arborescens Miller var. natalensis Berger, a food additive, was conducted for assessment of toxicity and carcinogenic potential in the diet at doses of 4% or 0.8% in groups of male and female Wistar Hannover rats. Both sexes receiving 4% showed diarrhea, with loss of body weight gain. The survival rate in the 4% female group was significantly increased compared with control females after 2 y. Hematological and biochemical examination showed increase of RBC, Hb, and Alb in the 4% males. The cause of these increases could conceivably have been dehydration through diarrhea. AST and Na were significantly decreased in the males receiving 4%, and Cl was significantly decreased in both 4% and 0.8% males. A/G was significantly increased in the 4% females, and Cl was significantly decreased (0.8%) in the female group. Histopathologically, both sexes receiving 4% showed severe sinus dilatation of ileocecal lymph nodes, and yellowish pigmentation of ileocecal lymph nodes and renal tubules. Adenomas or adenocarcinomas in the cecum, colon, and rectum were observed in 4% males but not in the 0.8% and control male groups. Similarly, in females, adenomas in the colon were also observed in the 4% but not 0.8% and control groups. In conclusion, Aloe, used as a food additive, exerted equivocal carcinogenic potential at 4% high-dose level on colon in the 2-y carcinogenicity study in rats. Aloe is not carcinogenic at nontoxic-dose levels and that carcinogenic potential in at 4% high-dose level on colon is probably due to irritation of the intestinal tract by diarrhea.

Antioxidant effects of flavonoids used as food additives (purple corn color, enzymatically modified isoquercitrin, and isoquercitrin) on liver carcinogenesis in a rat medium-term bioassay.

To clarify the effects of purple corn color, enzymatically modified isoquercitrin (EMIQ), and isoquercitrin (IQ), registered as natural food additives in Japan, on liver carcinogenesis in vivo, a medium-term bioassay was employed. A total of 100 male F344 rats were divided into 5 groups; groups 1 to 4 were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg b.w.) on day 1. From weeks 2 to 8, they were administered basal diet purple corn color, EMIQ, or IQ as containing test chemicals at doses of 1.0% (groups 1 and 5), 0.1% (group 2), 0.01% (group 3), or 0% (group 4) (experiments 1, 4, and 5). All rats were subjected to two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. Purple corn color exerted no significant modifying effects on GST-P positive foci, preneoplastic foci, development in the liver. However, serum of rats treated with purple corn color provided evidence of antioxidant power significantly by potential antioxidant (PAO) test in vivo (experiment 2). And microarray analyses showed purple corn color to induce RNA expression such as P450 (cytochrome) oxidoreductase, phosphatidylinositol 3-kinase, and phospholipase A2 (experiment 3). Higher doses of EMIQ or IQ with strong antioxidant power in vivo by PAO test treated groups were correlated with smaller numbers of GST-P positive foci, with Spearman's rank correlation coefficients of P= 0.002 and P= 0.049, respectively (experiments 4 and 5). Therefore, the tested food additives may be effective as antioxidants in vivo and have chemopreventive potential against liver preneoplastic lesion development.

Promotion potential of madder color in a medium-term multi-organ carcinogenesis bioassay model in F344 rats.

A medium-term multi-organ carcinogenesis bioassay in rats was conducted to assess any possible tumor promoting effects of madder color extracted from the root of madder. Male F344 rats were divided into 5 groups of 20 each. All rats of groups 1 to 4 were given DMD treatment, consisted of multicarcinogens, N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), and N-bis (2-hydroxypropyl) nitrosamine (DHPN), for 4 wk, while group 5 served as untreated control without carcinogens. The animals were then administered a basal diet containing madder color at doses of 5.0% (group 1), 2.5% (group 2 with 0.75% additional dextrin), or 0 (groups 3 with 1.5% additional dextrin, 4 without dextrin and 5) for the following 28 wk (total 32 wk). The total amount of dextrin in groups 1 to 3 diets was adjusted to 1.5% by extra dextrin because madder color powder contained dextrin. Key organs were observed histopathologically and glutathione S-transferase placental form (GST-P) positive foci of the liver were quantified. In the liver, 5.0% and 2.5% treated groups showed statistically significant dose-related increases in both number and area of GST-P positive foci, number: 2.81 +/- 0.90 and 1.96 +/- 0.93 (groups 1 and 2), area: 0.99 +/- 2.49 and 0.37 +/- 0.77, as compared with control, number: 0.87 +/- 0.72, area: 0.06 +/- 0.06 (group 3). In the kidneys, incidences (and numbers) of adenoma treated with 5.0% and 2.5%, 47.4% (0.20 +/- 0.24), and 47.4% (0.13 +/- 0.15) (groups 1 and 2) were significantly increased compared to control, 0% (0) (group 3). In conclusion, madder color demonstrated significant tumor promoting effects in the liver and kidneys in the DMD model.

Endodontic and orthodontic treatment of a cross-bite fused maxillary lateral incisor.

AIM: To describe combined endodontic and orthodontic treatment of a maxillary lateral incisor fused with a supernumerary. SUMMARY: A rare case is presented in which combined endodontic and orthodontic treatment was performed on a cross-bite fused tooth. Clinical and radiographic examination showed the maxillary lateral incisor fused with a supernumerary and an impacted canine. The fused tooth required nonsurgical and surgical endodontic treatment for functional and aesthetic reasons. The root canals were dressed with calcium hydroxide for 2 months before they were obturated with thermoplasticized injectable gutta-percha. Then, the distal part of the fused tooth was removed and the mesial part of the tooth was replanted and fixed. Three months after the completion of orthodontic therapy, the impacted canine erupted between the remaining tooth and the first premolar. Recall examination, 3 years after completion of root canal treatment, showed clinical and radiographic evidence of healing. KEY LEARNING POINTS: Fusion has been described as a development anomaly characterized by the union of two adjacent teeth. Proper combined endodontic and orthodontic treatment resulted in maintaining one tooth half and solving the aesthetic and functional problem of a fused tooth.

Chemoprevention of large bowel carcinogenesis; the role of control of cell proliferation and significance of beta-catenin-accumulated crypts as a new biomarker.

Control of cell proliferation is important for cancer prevention since cell proliferation has essential roles in carcinogenesis in the processes of both initiation and promotion. In large bowel carcinogenesis, carcinogens produce hyperproliferation of cells in the target sites and the cell proliferation persists even after the cessation of carcinogen exposure. Chemopreventive agents principally control the increased cell proliferation when given in the initiation as well as post-initiation phases. Aberrant crypt foci (ACF) which appear soon after carcinogen exposure in large bowel carcinogenesis in rodents have been used as a reliable biomarker for screening of potential chemopreventive agents. Recently, our group demonstrated the presence of probable premalignant lesions with frequent beta-catenin gene mutations and accumulation of the corresponding protein in the colonic epithelium of rats given a large bowel carcinogen. Such early-appearing lesions lack the morphological appearance of ACF. Expression of these beta-catenin-accumulated crypts (BCAC) is markedly suppressed by a chemopreventive cyclooxygenase-2 inhibitor, celecoxib. BCAC are suggested to be more reliable biomarkers than ACF for screening effective chemopreventive agents for colorectal cancer and for investigating the mode of action of the agents.

Flk-1 specific kinase inhibitor (SU5416) inhibited the growth of GS-9L glioma in rat brain and prolonged the survival.

BACKGROUND: Accumulating evidences suggest that tumor growth and metastasis depend on angiogenesis. At present, plenty of efforts are made to discover a chemical compound that specifically inhibits tumor angiogenesis either by reducing pro-angiogenic factor or increasing anti-angiogenic factors. OBJECT: SU5416, a novel, synthetic, potential inhibitor of angiogenesis specifically blocks the Flk-1/KDR tyrosine kinase activity. In vivo effect of SU5416 in the treatment of intracranial tumors has not been previously described. METHODS: We transplanted GS-9L cells into the right caudate nucleus of male Fisher 344 rats and administrated SU5416 intraperitoneally (i.p.) to investigate the impact of SU5416 on tumor angiogenesis and growth in vivo. Starting on Day 1 or Day 8, forty-two animals were treated with SU5416 at three different doses (e.g. 12.5, 25.0 and 50.0 mg/kg body weight) via i.p. injection every day until the end-point. As a control, seven animals received no treatment and after implant fourteen animals were treated with vehicle (DMSO) only. RESULTS: SU5416 prolonged the survival in the treated groups without any significant systemic adverse effect. Median survival in the treated group started on Day.1 was statistically longer compared to that in the control groups (p<0.01). Histological analysis of the treated tumors showed an increase in necroses and reduced in vascularity compared to the control tumors. Furthermore, the number of apoptotic cells increased in the treated tumors on a TUNEL stain. CONCLUSION: Small molecular compounds, such as SU5416 may be useful therapeutics that specifically inhibits the enzymatic activity of Flk-1 kinase and downstream events of tumor angiogenesis.

Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats.

1. Cyclic guanosine monophosphate (cyclic GMP)-mediated mechanism plays an important role in vasodilatation and blood pressure regulation. We investigated the effects of high salt intake on the nitric oxide (NO) - cyclic GMP signal transduction pathway regulating relaxation in aortas of spontaneously hypertensive rats (SHR). 2. Four-week-old SHR and normotensive Wistar-Kyoto rats (WKY) received a normal salt diet (0.3% NaCl) or a high salt diet (8% NaCl) for 4 weeks. 3. In aortic rings from SHR, endothelium-dependent relaxations in response to acetylcholine (ACh), adenosine diphosphate (ADP) and calcium ionophore A23187 were significantly impaired by the high salt intake. The endothelium-independent relaxations in response to sodium nitroprusside (SNP) and nitroglycerin were also impaired, but that to 8-bromo-cyclic GMP remained unchanged. On the other hand, high salt diet had no significant effects on the relaxations of aortic rings from WKY. 4. In aortas from SHR, the release of NO stimulated by ACh was significantly enhanced, whereas the production of cyclic GMP induced by either ACh or SNP was decreased by the high salt intake. 5. Western blot analysis showed that the protein level of endothelial NO synthase (eNOS) was slightly increased, whereas that of soluble guanylate cyclase (sGC) was dramatically reduced by the high salt intake. 6. These results indicate that in SHR, excessive dietary salt can result in downregulation of sGC followed by decreased cyclic GMP production, which leads to impairment of vascular relaxation in responses to NO. It is notable that chronic high salt intake impairs the sGC/cyclic GMP pathway but not the eNOS/NO pathway.

Quantitative evaluation of thalami and basal ganglia in infants with periventricular leukomalacia.

Quantitative analyses of cross-sectional areas of the thalami, caudate nuclei, and lentiform nuclei were performed in 29 preterm infants (16 males, 13 females; mean age 29.6 weeks, age range 27 to 24 weeks,) with periventricular leukomalacia (PVL). MRI was carried out in the infants between 9 and 18 months of corrected age and in 16 control infants. Bilateral thalami, caudate nuclei, lentiform nuclei, cerebral hemispheres, and cerebellum were measured by computer. Ratios of the areas of the thalami (Th), caudate nuclei (Ca), lentiform nuclei (Le), and cerebral hemispheres (CH) to that of the cerebellum (Ce) were calculated in each infant. The ratio of Th:Ce was significantly smaller in infants with moderate and severe PVL than in the control group bilaterally. Abnormal intensity areas were not observed in the thalami in any infants with PVL. CH:Ce was also smaller in infants with severe PVL than in the control group. No significant difference was observed between the groups in ratios Le:Ce or Ca:Ce. Results of our study suggest that the volume of the thalami is reduced and that thalamic involvement is present in infants with white matter lesions who have moderate to severe PVL.

Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib.

Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that beta-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of beta-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts / lesion) of beta-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs) / nucleus in beta-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of beta-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that beta-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that beta-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.

Molecular genetic analysis of the calcineurin signaling pathways.

Calcineurin is a Ca2+- and calmodulin-regulated protein phosphatase that is important in Ca2+-mediated signal transduction. Recent application of the powerful techniques of molecular genetics has demonstrated that calcineurin is involved in the regulation of critical biological processes such as T cell activation, muscle hypertrophy, memory development, glucan synthesis, ion homeostasis, and cell cycle control. Notably, specific transcription factors have been shown to play a key role in regulating these functions, and their calcineurin-mediated dephosphorylation and nuclear translocation appear to be a central event in the signal transduction pathways. This review focuses on recent progress in these areas and discusses the evidence for cross-talk between calcineurin and other signaling pathways.

Its8, a fission yeast homolog of Mcd4 and Pig-n, is involved in GPI anchor synthesis and shares an essential function with calcineurin in cytokinesis.

In fission yeast, calcineurin is required for cytokinesis and ion homeostasis; however, most of its physiological roles remain obscure. To identify genes that share an essential function with calcineurin, we screened for mutations that confer sensitivity to the calcineurin inhibitor FK506 and high temperature and isolated the mutant its8-1. its8(+) encodes a homolog of the budding yeast MCD4 and human Pig-n that are involved in glycosylphosphatidylinositol (GPI) anchor synthesis. Consistently, reduced inositol labeling of proteins suggested impaired GPI anchor synthesis in its8-1 mutants. The temperature upshift induced a further decrease in inositol labeling and caused dramatic increases in the frequency of septation in its8-1 mutants. BE49385A, an inhibitor of MCD4 and Pig-n, also increased the septation index of the wild-type cell. Osmotic stabilization suppressed these morphological defects, indicating that cell wall weakness caused by impaired GPI anchor synthesis resulted in abnormal cytokinesis. Furthermore, calcineurin-deleted cells exhibited hypersensitivity to BE49385A, and FK506 exacerbated the cytokinesis defects of the its8-1 mutant. Thus, calcineurin and Its8 may share an essential function in cytokinesis and cell viability through the regulation of cell wall integrity.

Sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis.

Our previous study (Cancer Res., 60: 3323-3327, 2000) showed that frequent beta-catenin gene mutations are present in beta-catenin-accumulated crypts, which occur early in rodent colonic carcinogenesis, with a lack of the appearance of aberrant crypt foci (ACF). To clarify the nature of such lesions, we performed a sequential analysis of the morphological and biological properties of beta-catenin-accumulated crypts. Azoxymethane was administered s.c. to male F344 rats (15 mg/kg body weight) once a week for 3 weeks, and the animals were sacrificed at 5, 10, and 20 weeks after the carcinogen treatment. Both the number of crypts/lesion and the diameter of beta-catenin-accumulated crypts were significantly increased with time courses of 5, 10, and 20 weeks from carcinogen exposure (P < 0.01). Likewise, the histological abnormality in those crypts, assessed by semiquantitative analyses, was also increased with time (P < 0.01). Conversely, ACF did not show any increase in histological abnormality during the time course and maintained a monotonous histology throughout the experiment. The histological abnormality score for beta-catenin-accumulated crypts was significantly higher than for ACF at every time point (P < 0.001). The number of AgNOR/nucleus in beta-catenin-accumulated crypts was significantly higher than in ACF (P < 0.001). Beta-catenin-accumulated crypts were accompanied frequently by Paneth cells and had decreased hexosaminidase activity. Such data, together with the results in our previous report, strongly suggest that beta-catenin-accumulated crypts, which are independent of ACF, are truly premalignant lesions for colon cancer.

Intravascular ultrasound imaging before and after angioplasty for stenosis of arteriovenous fistulae in haemodialysis patients.

BACKGROUND: Complications of haemodialysis vascular access have emerged as a major cause of patient morbidity. Intravascular ultrasound imaging is a new technical modality providing visualization of the vessel lumen and wall structure in a cross-sectional fashion. Percutaneous transluminal angioplasty has long been used in the treatment of stenoses of arteriovenous fistulae. However, there is no detailed quantitative information on the stenotic lesion and the morphological change by angioplasty. METHODS: Intravascular ultrasound studies were performed in 40 haemodialysis patients with 63 stenoses in arteriovenous fistulae who had percutaneous transluminal angioplasty. The patients were qualitatively and quantitatively evaluated for echogenic patterns and morphological changes before and after angioplasty. RESULTS: Morphological plaque features in stenotic lesions were classified as 37 soft (58%), five hard (8%), 20 mixed (32%), and one calcified sites. Plaque fractures after angioplasty were detected in 45/63 (71%) instances. The lumen cross-sectional area was found to be dilated approximately threefold (from 3.8+/-2.4 to 11.1+/-4.5 mm(2)) and the external elastic membrane cross-sectional area was dilated approximately twofold (from 11.1+/-5.3 to 19.8+/-8.1 mm(2)) after angioplasty. CONCLUSION: These results indicate that intravascular ultrasound allows both qualitative and quantitative assessments of arteriovenous fistulae in haemodialysis patients. The results further suggest that the mechanism of expansion of arteriovenous fistulae stenoses by percutaneous transluminal angioplasty involves stretching of the vessel wall as well as plaque fractures.