Association of Pharmacist-led Deprescribing Intervention with the Functional Recovery in Convalescent Setting.

So far, no studies investigated the association between pharmacist intervention and rehabilitation outcomes. The aim of study was to establish whether the pharmacist-led deprescribing intervention affects rehabilitation outcomes. This retrospective, observational, single-center, cohort study included consecutive geriatric patients (n = 448) with pharmacist-led intervention between 2017 and 2019. Participants were divided based on pharmacist-led deprescribing and non deprescribing interventions during hospitalization. Demographic data, laboratory data, the Functional Independence Measure were (FIM) analyzed between the groups. Multiple linear regression analysis was performed to analyze the relationship between pharmacist-led deprescribing and FIM total gain. The primary outcome was FIM total gain. The rate of pharmacist intervention during the study period was 92.4%. A multiple linear regression analysis of FMI-T gain, adjusting for confounding factors, revealed that the pharmacist-led deprescribing intervention was independently correlated with FMI-T gain. Particularly, the use of dyslipidemia drugs, antipsychotic drugs, hypnotics, and nonsteroidal anti-inflammatory drugs significantly decreased during hospitalization. The pharmacist-led deprescribing intervention was independently and significantly associated with FIM-T gain. The pharmacist-led deprescribing intervention improved functional recovery in a rehabilitation setting.

Cytogenetic dosimetry by micronucleus assay using peripheral blood cells is modified by thyroid hormones.

Cytokinesis-block micronucleus (CBMN) assay is a convenient and easy method of radiation biodosimetry that uses peripheral blood (PB) cells. However, for micronuclei (MN) frequency induced by ionising radiation, a dose-response relationship in abnormal condition, such as in cancer patients, has not been assessed. To clarify the difference between the dose-response curve generated by the CBMN assay in conditions when thyroid hormone levels were normal and during thyroid hormone withdrawal (THW) prior to (131)I treatment, 12 thyroid cancer patients who underwent thyroidectomy were studied. The collected PB mononuclear cells were exposed to 0.5-3.0 Gy X-ray irradiation. Under normal conditions, dose dependency and independency of MN frequency were observed in 92 % and 8 %, respectively. In contrast, during THW, the number of patients who showed dose independency significantly increased to 42 % in comparison with control. Furthermore, a higher concentration of serum thyroglobulin in dose-independent patients was observed. These results suggest that MN frequency in cytogenetic dosimetry is affected by thyroid hormones.

A pilot study to assess the efficacy of photodynamic therapy for Japanese patients with actinic keratosis in relation to lesion size and histological severity.

BACKGROUND/PURPOSE: Topical 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) is effective for actinic keratosis (AK); few studies have examined Oriental patients. The aim of this study is to assess the efficacy of PDT for the treatment of Japanese AK patients classified by lesion size and histological severity. METHODS: Thirty patients with solitary AK lesions were divided into two groups according to diameter: a small lesion group (SL), diameter < or =10 mm and a larger lesion group (LL), diameter >10 mm, and histological severity: Group I (mild and moderate) and Group II (severe). After application of 20% ALA for 4 h, exposure to an excimer-dye laser at 630 nm was performed at a dose of 50 J/cm(2) three times at an interval of 7 days. Therapeutic effects were assessed and followed for 12 months. RESULTS: In all 10 SL patients, atypical cells disappeared after PDT and did not recur for 12 months. However, for the 20 LL patients, recurrence was seen in 2 of the 14 Group I patients, while 4 of 6 Group II patients showed residual tumor cells after the first PDT session. CONCLUSION: The present study demonstrated that ALA-PDT might be useful for treatment of Japanese AK. The therapeutic outcome might depend on the lesion size and the histopathological severity.

Granulomatous colitis associated with botryomycosis of Propionibacterium acnes.

Propionibacterium acnes, an anaerobic, non-spore-forming, gram-positive bacillus, is a common inhabitant of the skin, and its virulence is considered to be low in humans. This report describes an unusual case of granulomatous colitis associated with P acnes infection in a 46-year-old woman. The affected cecum exhibited a tumor histologically characterized by massive transmural infiltrates of small lymphocytes and noncaseating epithelioid granulomas with multinucleated giant cells. Botryomycotic granules were also found in the muscular layer and paracolic connective tissues and consisted of gram-positive bacilli with filamentous growth. Polymerase chain reaction confirmed the presence of P acnes 16S ribosomal DNA in the surgical specimen of the colon. The patient developed a postoperative P acnes-induced peritonitis, which subsided with treatment with antibiotics and surgical drainage. The present case indicates that P acnes is one of the possible pathogens for granulomatous colitis.

A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF.

Arsenic trioxide (As2O3) effectively induces clinical remission via apoptosis in relapsed acute promyelocytic leukemia (APL). However, because this new anti-leukemic drug is also considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. We here investigated, both in vitro and in vivo, the effects of a combination of As2O3 and GM-CSF as a novel therapeutic approach for the treatment of APL. Treatment of both retinoic acid (RA)-sensitive and -resistant APL cell lines (NB4 and UF-1 cells, respectively), as well as primary APL cells with a combination of As2O3 and GM-CSF for 4 days resulted in inducing differentiation, but not apoptosis, to mature granulocytes. In addition, a combination of both agents induced degradation of the PML/RARalpha protein. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells, and a specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of As2O3-treated UF-1 cells. In in vivo analysis, As2O3 induced differentiation of APL cells in a RA-resistant APL model of human GM-CSF-producing transgenic SCID mice that had a high level of human GM-CSF in their sera. In contrast, As2O3 alone diminished tumors in UF-1 cells transplanted into NOD/SCID mice via induction of apoptosis. In conclusion, a combination of As2O3 and GM-CSF appears to be a novel differentiation-inducing therapy in patients with APL, including relapsed or RA-resistant cases.

Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells.

Activin A, one member of the transforming growth factor (TGF)-beta superfamily, is known to be a commitment factor for cell death and differentiation. In the present study, we demonstrate that human chronic myeloid leukemia (CML) cell lines, KU812 and K562 cells, either induced apoptosis or differentiation, respectively, by treatment with activin A. During these cell fate decisive events caused by activin A, rapid and transient up-regulation of Mcl-1 was observed in both cell lines. In activin A-induced apoptosis of KU812 cells, continuous up-regulation of Bax was observed. After the decrease in Mcl-1 expression had occurred, activation of caspase-9 and caspase-3 and cleavage of DFF45 were shown to take place in KU812 cells, resulting in the fragmentation of the genomic DNA of the cells. In contrast, the down-regulation of Mcl-1 without up-regulation of Bax caused accumulation of hemoglobin (Hb) contents in activin A-treated K562 cells. Interestingly, erythropoietin (EPO) prevented activin A-induced apoptosis with continuous expression of Mcl-1 and caused KU812 cells to undergo erythroid differentiation. To address the role of Mcl-1 in activin A-treated CML cells, KU812 and K562 cells were stably transfected with cDNA encoding Mcl-1 (designated as KU812/mcl and K562/mcl cells). As in combined effect of activin A and EPO on the parental KU812 cells, activin A induced differentiation, but not apoptosis, of KU812/mcl cells without modulating Bax levels. Activin A-treated K562/mcl cells, as well as parental cells, were only differentiated to erythroid cells. These results suggest that Mcl-1 is an early inducible gene activated by the activin A signaling pathway for both cellular differentiation and apoptosis, and continuous expression of Mcl-1 may be contributed to differentiation signals to the erythroid lineage in CML cells.

[An automated electronic anesthesia record and automated urine output measurement].

We can now collect many parameters (NIBP, HR, ABP, SpO2, EtCO2, CCO, etc) from an anesthesia monitor in an automated electronic anesthesia record system. The function of automated urine output measurement has been added to an automated electronic anesthesia record system. A digital weight meter connected with a personal computer by RS-232 C is used to measure the weight of urine. We convert the weight to the volume hypothesizing that the density of urine is 1 g.ml-1. Physiologic parameters are recorded every 10 seconds from an anesthesia monitor and we can set the period of automated urine output measurement we like. We must enter the initial and final urine output but the intraoperative urine output is collected automatically to an automated electronic anesthesia record and visualized in urine bar graph. The total volume of urine is calculated. Computerized urine output measurement can record data more frequently, for example, every 10 minute. At the end of the operation, intraoperative data are sent to a host computer and the anesthesia record is printed. Combining the automated urine output measurement with an automated electronic anesthesia record system is useful in anesthesia practice of a long operation.

Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-beta superfamily, are a group of related proteins that are capable of inducing the formation of cartilage and bone but are now regarded as multifunctional cytokines. We show in this report a novel function of BMPs in hematopoietic cells: BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPMI 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 cells), but also in primary samples from patients with multiple myeloma. The mechanism of BMP-2-induced apoptosis was investigated with the use of U266 cells, which are dependent on the interleukin-6 autocrine loop. We showed that BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells. BMP-2 up-regulated the expression of cyclin-dependent kinase inhibitors (p21(CIP1/WAF1) and p27(KIP1)) and caused hypophosphorylation of retinoblastoma (Rb) protein. In studies of apoptosis-associated proteins, BMP-2 was seen to down-regulate the expression of Bcl-x(L); however, BMP-2 had no effects on the expression of Bcl-2, Bax, or Bad. Therefore, BMP-2 induces apoptosis in various human myeloma cells by means of the down-regulation of Bcl-x(L) and by cell-cycle arrest through the up-regulation of p21(CIP1/WAF1) and p27(KIP1) and by the hypophosphorylation of Rb. Further analysis showed that the signal transducer and activator of transcription 3 (STAT3) was inactivated immediately after BMP-2 treatment. We conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients.

[Activities of antimicrobial agents against 5,180 clinical isolates obtained from 26 medical institutions during 1998 in Japan. Levofloxacin--Surveillance Group].

The surveillance study was conducted to determine the antimicrobial activity of fluoroquinolones (ofloxacin, levofloxacin, ciprofloxacin, tosufloxacin) and other 20 antimicrobial agents against 5,180 clinical isolates obtained from 26 medical institutions during 1998 in Japan. The resistance to fluoroquinolones was remarkable in Enterococci, methicillin-resistant staphylococci and Pseudomonas aeruginosa from UTI. However, many of the common pathogens such as Streptococcus pneumoniae including penicillin-resistant isolates, methicillin-susceptible Stahylococcus aureus, Moraxella catarrhalis, the family of Enterobacteriaceae, Haemophilus influenzae including ampicillin-resistant isolates have been kept to be susceptible to fluoroquinolones. About 90% of P. aeruginosa isolates from RTI were susceptible to fluoroquinolones. In conclusion, the results from this surveillance study suggest that fluoroquinolones are useful in the treatment of various bacterial infections including respiratory infections.

[Anesthetic management of a patient with hepatocellular carcinoma with tumor thrombus extending into the right atrium].

A 58 year-old male was scheduled for surgery of his hepatic cancer. Tumor invaded to the right atrium through the inferior vena cava. The operative method of removing the tumor in the right atrium was scheduled under extracorporeal circulation after the left lobe hepatectomy. Since there was a tumor in the right atrium, central venous pressure monitoring could not be reliable. Transesophageal echocardiography (TEE) was employed in order to detect the part of the tumor flowing into the pulmonary artery or occluding the tricuspid valve. Due to massive blood loss during hepatectomy, the capacity in the right atrium decreased and the tumor was often about to engage the tricuspid valve. After the rapid fluid therapy, the right atrium capacity increased preventing the engagement of the tumor. TEE was useful not only to observe the movement of the tumor in the right atrium but also to monitor the circulating blood volume.

Two-dimensional analysis of production of IL-6 and TNF-alpha can predict the efficacy of IFN-alpha therapy.

BACKGROUND/AIMS: Many patients with chronic hepatitis C are now treated with interferon-alpha (IFN-alpha). The increase in the number of patients treated with IFN-alpha, however, has resulted in increased reports of adverse drug reactions (ADR). This prompted us to investigate for a useful parameter for predicting the effects of IFN-alpha treatment before initiating the therapy for the benefit of patients. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) obtained from patients with chronic hepatitis C and healthy volunteers were incubated at 37 degrees C for 24 hours at various concentrations of IFN-alpha (1, 10(2), and 10(4) IU/ml). The tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) formed in the culture medium were determined. Also, the binding of 125I-labeled IFN-alpha to PBMCs and 2', 5'-oligoadenylate synthetase (2-5AS) activities were measured. RESULTS: The addition of IFN-alpha to PBMCs at concentrations of 1-10(4) IU/ml showed dose-dependent changes in the binding of 125I-labeled IFN-alpha to PBMCs and 2-5AS activities. There was a strong correlation between the production of IL-6 and that of TNF-alpha (r>0.9). The production of IL-6 by the PBMCs of the high responders is significantly higher than that of the low-responders at the same value of TNF-alpha. A statistically significant difference was demonstrated by analysis of covariance. CONCLUSIONS: The findings of this study suggest that two-dimensional analysis of the in vitro production of TNF-alpha and IL-6 by PBMCs induced by IFN-alpha is useful for predicting the outcome of the IFN-alpha treatment in patients.

Targeted disruption of a melanin biosynthesis gene affects conidial development and UV tolerance in the Japanese pear pathotype of Alternaria alternata.

Structural analysis of the BRM2 gene involved in melanin biosynthesis of the Japanese pear pathotype of Alternaria alternata suggested that this gene encodes 1,3,8-trihydroxynaphthalene reductase. Targeted disruption of the BRM2 gene did not affect pathogenicity, vegetative growth, or the number of conidia produced. Targeted disruption, however, did reduce conidial size and septal number, suggesting that melanin is associated with conidial development. The conidia of brm2 mutant transformants were more sensitive to UV light than those of the wild type, demonstrating that melanin confers UV tolerance.

The melanin biosynthesis genes of Alternaria alternata can restore pathogenicity of the melanin-deficient mutants of Magnaporthe grisea.

The phytopathogenic fungi Magnaporthe grisea and Alternaria alternata produce melanin via the polyketide biosynthesis, and both fungi form melanized colonies. However, the site of melanin deposition and the role of melanin in pathogenicity differ between these two fungi. M. grisea accumulates melanin in appressoria, and their melanization is essential for host penetration. On the other hand, A. alternata produces colorless appressoria, and melanin is not relevant to host penetration. We examined whether the melanin biosynthesis genes of A. alternata could complement the melanin-deficient mutations of M. grisea. Melanin-deficient, nonpathogenic mutants of M. grisea, albino (Alb-), rosy (Rsy-), and buff (Buf-), were successfully transformed with a cosmid clone pMRB1 that carries melanin biosynthesis genes ALM, BRM1, and BRM2 of A. alternata. This transformation restored the melanin synthesis of the Alb- and Buf- mutants, but not that of the Rsy- mutant. The melanin-restored transformants regained mycelial melanization, appressorium melanization, and pathogenicity to rice. Further, transformation of Alb- and Buf- mutants with subcloned ALM and BRM2 genes, respectively, also produced melanin-restored transformants. These results indicate that the Alternaria genes ALM and BRM2 can restore pathogenicity to the mutants Alb- and Buf-, respectively, due to their function during appressorium development in M. grisea.

The Alternaria alternata Melanin Biosynthesis Gene Restores Appressorial Melanization and Penetration of Cellulose Membranes in the Melanin-Deficient Albino Mutant of Colletotrichum lagenarium

Colletotrichum lagenarium and Alternaria alternata produce a dark pigment, melanin. The C. lagenarium PKS1 and A. alternata ALM genes are involved in polyketide synthesis in the melanin biosynthesis pathway. PKS1 encodes a type I polyketide synthase. For functional comparison of the ALM gene with the PKS1 gene, we examined whether the A. alternata ALM gene could restore melanin synthesis in C. lagenarium albino mutant (Pks1(-)). The ALM gene transformed the albino mutant (Pks1(-)) to melanin-producing phenotypes, designated CAL transformants. The pigment intensity of both melanized colonies and appressoria of CAL transformants was weaker than that of the wild type. Ultrastructural studies of the cell walls of appressoria demonstrated that CAL transformants formed an outer melanized layer, as did the wild type. On the other hand, the thin inner and middle layers were less electron-dense than those of the wild type. CAL transformants were able to penetrate cellulose membranes as effectively as the wild type. By contrast, the penetration frequency of CAL transformants on cucumber cotyledons was remarkably reduced compared to that of the wild type. During conidial germination, the PKS1 transcript accumulated de novo in both the wild-type and CAL transformants after the start of conidial incubation. On the other hand, ALM transcript accumulated in conidia of CAL transformants before the start of conidial incubation.

The Alternaria alternata melanin biosynthesis gene restores appressorial melanization and penetration of cellulose membranes in the melanin-deficient albino mutant of Colletotrichum lagenarium.

Colletotrichum lagenarium and Alternaria alternata produce a dark pigment, melanin. The C. lagenarium PKS1 and A. alternata ALM genes are involved in polyketide synthesis in the melanin biosynthesis pathway. PKS1 encodes a type 1 polyketide synthase. For functional comparison of the ALM gene with the PKS1 gene, we examined whether the A. alternata ALM gene could restore melanin synthesis in C. lagenarium albino mutant (Pks1-). The ALM gene transformed the albino mutant (Pks1-) to melanin-producing phenotypes, designated CAL transformants. The pigment intensity of both melanized colonies and appressoria of CAL transformants was weaker than that of the wild type. Ultrastructural studies of the cell walls of appressoria demonstrated that CAL transformants formed an outer melanized layer, as did the wild type. On the other hand, the thin inner and middle layers were less electron-dense than those of the wild type. CAL transformants were able to penetrate cellulose membranes as effectively as the wild type. By contrast, the penetration frequency of CAL transformants on cucumber cotyledons was remarkably reduced compared to that of the wild type. During conidial germination, the PKS1 transcript accumulated de novo in both the wild-type and CAL transformants after the start of conidial incubation. On the other hand, ALM transcript accumulated in conidia of CAL transformants before the start of conidial incubation.