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.

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.

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.

The fission yeast pmk1+ gene encodes a novel mitogen-activated protein kinase homolog which regulates cell integrity and functions coordinately with the protein kinase C pathway.

We have isolated a gene, pmk1+, a third mitogen-activated protein kinase (MAPK) gene homolog from the fission yeast Schizosaccharomyces pombe. The predicted amino acid sequence shows the most homology (63 to 65% identity) to those of budding yeast Saccharomyces Mpk1 and Candida Mkc1. The Pmk1 protein contains phosphorylated tyrosines, and the level of tyrosine phosphorylation was increased in the dsp1 mutant which lacks an attenuating phosphatase for Pmk1. The level of tyrosine phosphorylation appears constant during hypotonic or heat shock treatment. The cells with pmk1 deleted (delta pmk1) are viable but show various defective phenotypes, including cell wall weakness, abnormal cell shape, a cytokinesis defect, and altered sensitivities to cations, such as hypersensitivity to potassium and resistance to sodium. Consistent with a high degree of conservation of amino acid sequence, multicopy plasmids containing the MPK1 gene rescued the defective phenotypes of the delta pmk1 mutant. The frog MAPK gene also suppressed the pmk1 disruptant. The results of genetic analysis indicated that Pmk1 lies on a novel MAPK pathway which does not overlap functionally with the other two MAPK pathways, the Spk1-dependent mating signal pathway and Sty1/Spc1/Phh1-dependent stress-sensing pathway. In Saccharomyces cerevisiae, Mpk1 is involved in cell wall integrity and functions downstream of the protein kinase C homolog. In contrast, in S. pombe, Pmk1 may not act in a linear manner with respect to fission yeast protein kinase C homologs. Interestingly, however, these two pathways are not independent; instead, they regulate cell integrity in a coordinate manner.

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.

Radiation inactivation target-size analysis of soluble guanylate cyclase.

The soluble form of guanylate cyclase, which is a heterodimer of two subunits with molecular weights of 82,000 and 70,000, was analyzed by radiation inactivation experiments to determine its functional size. Lyophilized crude extract from rat lung or the purified enzyme were irradiated with different doses from 60Co gamma-rays, and the residual activities were measured in the presence or absence of a potent activator, sodium nitroprusside. The target sizes for the basal activity and for the activity in the presence of sodium nitroprusside were calculated from the decay curve was 77 and 192 kDa, respectively, on the crude enzyme, or as 71 and 163 kDa, respectively, on the purified enzyme. The size for the activatable form of the enzyme was more than twice that of the basal activity and close to the size of the holoenzyme, implying that the enzyme activity must reside on one of the subunits and the activation by sodium nitroprusside requires interaction of both subunits.

cDNA cloning of an alternatively spliced isoform of the regulatory subunit of Ca2+/calmodulin-dependent protein phosphatase (calcineurin B alpha 2).

A cDNA encoding the regulatory subunit of Ca2+/calmodulin-dependent protein phosphatase, calcineurin B (CNB), was isolated from a rat testis cDNA library. It differs from the cDNA obtained from a rat brain cDNA library by an addition of 138 base pairs in the coding region. The codon of the clone from a testis library corresponding to the initiation codon of the clone from a brain library is not ATG but AAG, 5'-noncoding regions of these cDNAs are also different. The addition in the coding region results in the gain of 46 amino acids at the N-terminus. These findings suggest that two distinct isoforms of CNB alpha are derived from the same gene through a process involving alternative utilization of two promoters. We designate the brain type isoform as CNB alpha 1 and the longer isoform as CNB alpha 2. Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot analysis suggest that CNB alpha 2 is specifically expressed in the testis, and its expression is developmentally regulated.

Calyculin A and okadiac acid inhibit human platelet aggregation by blocking protein phosphatases types 1 and 2A.

Two potent inhibitors of protein phosphatase type 1 (PP1) and type 2A (PP2A), calyculin A (CAL-A) and okadaic acid (OKA), inhibited human platelet aggregation induced by thrombin, collagen and 9,11-epithio-11,12-methano-thromboxane A2 (STA2). IC50 values of CAL-A and OKA for STA2-induced aggregation were 53 nM and 3.5 microM, respectively. These drugs also inhibited thrombin-induced [14C]serotonin secretion of platelets. CAL-A and OKA elicited phosphorylation of certain proteins with an apparent M(r) (x 10(-3) of 200, 60, 50 and 20 light chain of myosin (MLC). Agonist-induced 47,000 M(r) protein phosphorylation was strongly inhibited by these compounds, whereas phosphorylation of 20,000 M(r) MLC was enhanced. The increase in 50,000 M(r) protein phosphorylation by CAL-A and OKA was observed in the presence of agonists, and the 50,000 M(r) phosphorylation may be involved in the inhibition of platelet activation by these compounds. Subcellular analysis of the phosphatase activity in human platelets showed that MLC phosphatase activity was present mainly (approx. 78%) in the cytosolic fraction. Chromatography of human platelet extract on heparin-Sepharose resolved two peaks of MLC phosphatase activity: PP2A in 0.1 M NaCl eluate and PP1 in 0.5 NaCl eluate. PP2A and PP1 isozymes (PP1 alpha, PP1 gamma and PP1 delta) have also been identified in human platelets, by cross-reactivity with polyclonal antibodies against PP2A and PP1 isozymes, respectively. These results suggest that PP1 and/or PP2A may play an important role in the process of platelet activation by regulating levels of phosphorylation of certain proteins.

Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics.

Serotonin S2 and dopamine D2 receptors in the prefrontal cortex and caudate nucleus of postmortem brains of chronic schizophrenics were studied using 3H-ketanserin and 3H-spiperone, respectively. In the prefrontal cortex of schizophrenics, we found a significant decrease in the maximum number of 3H-ketanserin binding sites (Bmax), with no change in the dissociation constant (Kd). Conversely, both Bmax and Kd of 3H-spiperone binding to the caudate nucleus were significantly increased in the schizophrenic patients. There were no differences in receptor indices between patients who were taking neuroleptics until their death and those who had taken none for 2 months or more prior to death. These findings suggest that alterations in S2 receptors in the prefrontal cortex may reflect the disease process, per se, and that the increase in the number of D2 receptors in the caudate nucleus of schizophrenics is not due solely to neuroleptic medication.

Cloning and characterization of hsc1+, a heat shock cognate gene of the fission yeast Schizosaccharomyces pombe.

A heat shock cognate gene from the fission yeast Schizosaccharomyces pombe (Sp), designated hsc1+, was cloned. The putative translation product of hsc1+ contains 613 aa, with an estimated molecular mass of 67,205 Da, and is more similar to the Saccharomyces cerevisiae (Sc) heat shock cognate protein SSB1 (69% identity) than the Sp heat-inducible ssp1+ gene product (41% identity). The hsc1+ mRNA was abundant during steady-state growth at 23 degrees C and decreased upon heat shock. Immunoblot analysis showed that the hsc1 protein is also abundant and constitutively expressed, however, we could not observe significant change in the protein level upon heat shock. DNA blot analyses indicated that hsc1+ is localized in Sp chromosome II, and suggested that the Sp genome contains a relatively smaller number of HSP70 genes compared with the Sc genome.

Isolation and characterization of CAJ1, a novel yeast homolog of dnaJ.

A novel member of the Escherichia coli dnaJ family, designated CAJ1, was isolated from a yeast expression library using antiserum against a yeast calmodulin-binding fraction. Although CAJ1 contains neither a Gly-rich region nor a Cys-rich repeat, as are found in other DnaJ relatives, it contains a leucine zipper-like motif.

Isolation and characterization of SSE1 and SSE2, new members of the yeast HSP70 multigene family.

Two new members of the Saccharomyces cerevisiae heat-shock protein 70 multigene (HSP70) family were isolated from a yeast expression library using antisera made against a yeast calmodulin-binding fraction. They are designated as SSE1 and SSE2, because their predicted amino acid (aa) sequences are highly homologous to each other (76% identical), and share homology with known members of the yeast HSP70 multigene family, but their homologies (13 to 28% identity) are not high enough to place them in known subfamilies. SSE1 and SSE2 are thought to encode polypeptides of 693 aa with calculated M(r)'s of 77,408 and 77,619, respectively. The SSE1 mRNAs were moderately abundant during steady-state growth at 23 degrees C, and increased a few-fold upon upshift to 37 degrees C. SSE2 mRNAs were present at low level during steady-state growth at 23 degrees C, and greatly increased upon upshift to 37 degrees C. Disruption of SSE1 results in slow-growing cells at any temperature. No phenotypic effects of the mutation in SSE2 were detected, and the growth property of the sse1sse2 double mutant was the same as that of the sse1 single mutant.

Ca2+/calmodulin-activated protein phosphatase (PP2B) of Saccharomyces cerevisiae. PP2B activity is not essential for growth.

Protein phosphatase (PP2B) whose activity is stimulated 12-20-fold by Ca2+/calmodulin (CaM) was partially purified by CaM-Sepharose and heparin-agarose chromatographies from cell extract of the yeast Saccharomyces cerevisiae. PP2B activity was not detectable in a mutant in which two genes (CMP1 and CMP2) encoding homologs of mammalian PP2B catalytic subunit were disrupted. We have previously shown that the double gene disruption has no significant effect on the growth of yeast [1991, Mol. Gen. Genet. 227, 52-59]. The results indicated that CMP1 and CMP2 are the only genes that encode the PP2B catalytic polypeptide in S. cerevisiae, and PP2B activity is not essential for the growth of the yeast under normal conditions.

Expression of the GABAB receptor in Xenopus oocytes and inhibition of the response by activation of protein kinase C.

The functional GABAB receptor was expressed in Xenopus oocytes by injecting mRNA obtained from the cerebellum of the rat. Application of GABA in the presence of bicuculline induced a hyperpolarization under current-clamp conditions and an outward current under voltage-clamp conditions. Baclofen mimicked the effect of GABA in the presence of bicuculline, and the effect of baclofen was antagonized by phaclofen. The GABA-induced outward current was slightly inhibited by treatment with GDP-beta-S and was completely inhibited by treatment with GTP-gamma-S. The activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA), but not 4 alpha-phorbol-12,13-didecanoate, suppressed the GABAB receptor-mediated hyperpolarization, and the effect of TPA was antagonized by sphingosine. Thus, activation of protein kinase C inhibits the expressed GABAB receptor-mediated response.

Down-regulation by retinoic acid of the catalytic subunit of protein phosphatase type 2A during granulocytic differentiation of HL-60 cells.

Activity of protein phosphatase measured in the absence of divalent cations was decreased by 50% during all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation into the granulocytic phenotype. Treatment of HL-60 cells with ATRA led to a dramatic decrease in the amount of protein phosphatase type 2A (PP2A) protein, whereas that of protein phosphatase type 1 (PP1) protein was relatively constant, as detected by immunoblotting with antibodies specific to PP1 and PP2A. The decreased phosphatase activity may be mainly due to a decrease in the expression of the PP2A protein. The mRNA level of PP2A beta was markedly decreased within 5 h after addition of ATRA, but there was only a slight increase in the mRNA level of PP2A alpha. Selective down-regulation of PP2A beta mRNA clearly preceded the cell differentiation induced by ATRA treatment. Thus, PP2A is down-regulated during ATRA-induced differentiation of HL-60 cells into granulocytes.

Augmentation of retinoic acid-induced granulocytic differentiation in HL-60 leukemia cells by serine/threonine protein phosphatase inhibitors.

To evaluate the involvement of protein phosphatases (PP) in differentiation of human myelogenous leukemia HL-60 cells, we made use of potent inhibitors of PP1 and PP2A, calyculin-A (CAL-A) and okadaic acid (OKA). CAL-A and OKA could augment all-trans retinoic acid (ATRA)-induced granulocytic differentiation, whereas the differentiation toward macrophage lineage by 12-o-tetradecanoylphorbol acetate (TPA) was unchanged in the presence of CAL-A. CAL-A augmented the phosphorylation of 18K, 23K and 30K proteins induced by ATRA. The PP1 and PP2A were identified and were present mainly in the cytosol of HL-60 cells. These results suggest that either PP1 or PP2A or both may be involved in regulating granulocytic differentiation of HL-60 cells.

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.

The inhibitory effects of mangiferin, a naturally occurring glucosylxanthone, in bowel carcinogenesis of male F344 rats.

Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-beta-D-glucoside, is one of xanthone derivatives and C-glucosylxanthones, is widely distributed in higher plants and is one of constituents of folk medicines. Recent studies showed that mangiferin has a potential as an anti-oxidant and an anti-viral agent. In this study, we examined the effects of mangiferin in rat colon carcinogenesis induced by chemical carcinogen, azoxymethane (AOM). We performed two experiments: a short-term assay to investigate the effects of mangiferin on the development of preneoplastic lesions by AOM, aberrant crypt foci (ACF), and the following long-term assay for the influence of mangiferin on tumorigenesis induced by AOM. In the short-term assay, 0.1% mangiferin in a diet significantly inhibited the ACF development in rats treated with AOM compared to rats treated with AOM alone (64.6+/-22.0 vs. 108.3+/-43.0). In the long-term assay, the group treated with 0.1% mangiferin in initiation phase of the experimental protocol had significantly lower incidence and multiplicity of intestinal neoplasms induced by AOM (47.3 and 41.8% reductions of the group treated with AOM alone for incidence and multiplicity, respectively). In addition, the cell proliferation in colonic mucosa was reduced in rats treated with mangiferin (65-85% reductions of the group treated with AOM alone). These results suggest that mangiferin has potential as a naturally-occurring chemopreventive agent.