Clinical Characteristics, Treatment, and Outcomes of Veterans with Cerebrospinal Fluid Culture Positive for Gram-Negative Rod Bacteria: A Retrospective Analysis over 18 Years in 125 Veterans Health Administration Hospitals.

Optimal management for patients with bacterial ventriculitis/meningitis due to Gram-negative rods (GNRs) has yet to be well investigated. We assessed the clinical characteristics, treatment, and outcomes of patients with a positive cerebrospinal fluid (CSF) culture for GNRs. We conducted a retrospective cohort study of all patients with a positive CSF culture within the Veterans Health Administration (VHA) system during 2003-2020. Clinical and microbiological characteristics between the true meningitis and contamination groups were compared. Of the 5919 patients with positive CSF cultures among 125 nationwide VHA acute-care hospitals, 297 (5.0%) were positive for GNRs. Among 262 patients analyzed, 156 (59.5%) were assessed as patients with true meningitis, and 106 (40.5%) were assessed as patients with contaminated CSF cultures. Patients with true meningitis had a significantly higher CSF protein (median 168 vs 57 mg/dL, p < 0.001), CSF white blood cell count (median 525 vs 3/µL, p = 0.008) and percentage of neutrophils in CSF (median 88 vs 4%, p < 0.001). Enterobacterales were more common in the true meningitis group, while unidentified GNR or polymicrobial CSF cultures were more common in the contamination group. The all-cause 90-day mortality was 25.0% (39/156) in patients with true meningitis and 10.4% (11/106) in those with contaminated CSF cultures. None of the 11 patients with contaminated CSF cultures who died were considered due to missed meningitis. More than 40% of patients with a positive CSF culture with GNR did not receive treatment without negative consequences. Careful clinical judgment is required to decide whether to treat such patients.

Verification of acoustic streaming measurement accuracy via particle image velocimetry considering the interrogation window aspect ratio.

This study measured Rayleigh and Schlichting streaming velocities via particle image velocimetry (PIV) in a standing wave field. Emphasis was placed on balancing high measurement accuracy with high spatial resolution in the boundary layer region. We aimed to achieve high resolution and enhanced measurement accuracy, typically a trade-off, by significantly increasing the aspect ratio of the interrogation window in the flow direction during PIV post-processing. The experiment operated under conditions with a duct axis streaming velocity of approximately 8.3×10-3 m/s in the measurement area. Increasing the aspect ratio from 1 to 21 reduced the standard deviation across the entire radial direction, which served as the accuracy index, from 8.05×10-3 m/s to 5.23×10-4 m/s (94% reduction). Additionally, the method's validity was confirmed through synthetic images with particles of known velocity. This verification demonstrated a decrease in the standard deviation comparable to the experimental images (97% reduction), aligning the analyzed velocity's radial distribution with the known streaming velocity distribution.

Diagnostic Accuracy of Hospital Antibiograms in Predicting the Risk of Antimicrobial Resistance in Enterobacteriaceae Isolates: A Nationwide Multicenter Evaluation at the Veterans Health Administration.

BACKGROUND: Many clinical guidelines recommend that clinicians use antibiograms to inform empiric antimicrobial therapy. However, hospital antibiograms are typically generated by crude aggregation of microbiologic data, and little is known about an antibiogram's reliability in predicting antimicrobial resistance (AMR) risk at the patient-level. We aimed to assess the diagnostic accuracy of antibiograms as a tool for selecting empiric therapy for Escherichia coli and Klebsiella spp. for individual patients. METHODS: We retrospectively generated hospital antibiograms for the nationwide Veterans Health Administration (VHA) facilities from 2000 to 2019 using all clinical culture specimens positive for E. coli and Klebsiella spp., then assessed the diagnostic accuracy of an antibiogram to predict resistance for isolates in the following calendar year using logistic regression models and predefined 5-step interpretation thresholds. RESULTS: Among 127 VHA facilities, 1 484 038 isolates from 704 779 patients for E. coli and 671 035 isolates from 340 504 patients for Klebsiella spp. were available for analysis. For E. coli and Klebsiella spp., the discrimination abilities of hospital-level antibiograms in predicting individual patient AMR were mostly poor, with the areas under the receiver operating curve at 0.686 and 0.715 for ceftriaxone, 0.637 and 0.675 for fluoroquinolones, and 0.576 and 0.624 for trimethoprim-sulfamethoxazole, respectively. The sensitivity and specificity of the antibiogram varied widely by antimicrobial groups and interpretation thresholds with substantial trade-offs. CONCLUSIONS: Conventional hospital antibiograms for E. coli and Klebsiella spp. have limited performance in predicting AMR for individual patients, and their utility in guiding empiric therapy may be low.

Effectiveness of Ultraviolet-C Disinfection on Hospital-Onset Gram-Negative Rod Bloodstream Infection: A Nationwide Stepped-Wedge Time-Series Analysis.

BACKGROUND: The effectiveness of enhanced terminal room cleaning with ultraviolet C (UV-C) disinfection in reducing gram-negative rod (GNR) infections has not been well evaluated. We assessed the association of implementation of UV-C disinfection systems with incidence rates of hospital-onset (HO) GNR bloodstream infection (BSI). METHODS: We obtained information regarding UV-C use and the timing of implementation through a survey of all Veterans Health Administration (VHA) hospitals providing inpatient acute care. Episodes of HO-GNR BSI were identified between January 2010 and December 2018. Bed days of care (BDOC) was used as the denominator. Over-dispersed Poisson regression models were fitted with hospital-specific random intercept, UV-C disinfection use for each month, baseline trend, and seasonality as explanatory variables. Hospitals without UV-C use were also included to the analysis as a nonequivalent concurrent control group. RESULTS: Among 128 VHA hospitals, 120 provided complete survey responses with 40 reporting implementations of UV-C systems. We identified 13 383 episodes of HO-GNR BSI and 24 141 378 BDOC. UV-C use was associated with a lower incidence rate of HO-GNR BSI (incidence rate ratio: 0.813; 95% confidence interval: .656-.969; P = .009). There was wide variability in the effect size of UV-C disinfection use among hospitals. CONCLUSIONS: In this large quasi-experimental analysis within the VHA System, enhanced terminal room cleaning with UV-C disinfection was associated with an approximately 19% lower incidence of HO-GNR BSI, with wide variability in effectiveness among hospitals. Further studies are needed to identify the optimal implementation strategy to maximize the effectiveness of UV-C disinfection technology.

Effects of Antibacterial Agents on Cancerous Cell Proliferation.

Myelosuppression, a side effect of anticancer drugs, makes people more susceptible to infectious diseases by compromising the immune system. When a cancer patient develops a contagious disease, treatment with an anticancer drug is suspended or postponed to treat the infectious disease. If there was a drug that suppresses the growth of cancer cells among antibacterial agents, it would be possible to treat both infectious diseases and cancer. Therefore, this study investigated the effect of antibacterial agents on cancer cell development. Vancomycin (VAN) had little effect on cell proliferation against the breast cancer cell, MCF-7, prostate cancer cell, PC-3, and gallbladder cancer cell, NOZ C-1. Alternatively, Teicoplanin (TEIC) and Daptomycin (DAP) promoted the growth of some cancer cells. In contrast, Linezolid (LZD) suppressed the proliferation of MCF-7, PC-3, and NOZ C-1 cells. Therefore, we found a drug that affects the growth of cancer cells among antibacterial agents. Next, when we examined the effects of the combined use of existing anticancer and antibacterial agents, we found VAN did not affect the growth suppression by anticancer agents. However, TEIC and DAP attenuated the growth suppression of anticancer agents. In contrast, LZD additively enhanced the growth suppression by Docetaxel in PC-3 cells. Furthermore, we showed that LZD inhibits cancer cell growth by mechanisms that involve phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. Therefore, LZD might simultaneously treat cancer and infectious diseases.

Experience of 101 patients with coronavirus infectious disease 2019 (COVID-19) at a tertiary care center in Japan.

INTRODUCTION: Clusters of novel coronavirus infectious disease of 2019 (COVID-19) have spread to become a global pandemic imposing a significant burden on healthcare systems. The lack of an effective treatment and the emergence of varied and complicated clinical courses in certain populations have rendered treatment of patients hospitalized for COVID-19 difficult. METHODS: Tokyo Metropolitan Tama Medical Center, a public tertiary acute care center located in Tokyo, the epicenter of COVID-19 in Japan, has been admitting patients with COVID-19 since February 2020. The present, retrospective, case-series study aimed to investigate the clinical course and outcomes of patients with COVID-19 hospitalized at the study institution. RESULTS: In total, 101 patients with COVID-19 were admitted to our hospital to receive inpatient care. Eleven patients (10.9%) received ECMO, and nine patients (8.9%) died during hospitalization after COVID-19 was diagnosed. A history of smoking and obesity were most commonly encountered among patients with a complicated clinical course. Most patients who died requested to be transferred to advanced palliative care in the early course of their hospitalization. CONCLUSIONS: Our experience of caring for these patients demonstrated a relatively lower mortality rate and higher survival rate in those with extracorporeal membrane oxygenation placement than previous reports from other countries and underscored the importance of proactive, advanced care planning in the early course of hospitalization.

Whole phase curvature-based particle positioning and size determination by digital holography.

We demonstrate the positioning and characterization of a transparent particle with a diameter of 60 µm in sparse particle fields. Particles appear elongated in optical setups with small numerical apertures that are used in digital holography; thus, an accurate method to position them is required. We propose a new optimization method using the whole phase curvature of a reconstructed wave along the optical axis to obtain not only the precise axial position but also the radius and refractive index of a particle. Experimental results show that the axial positions of particles can be detected with a standard deviation of 38.6 µm, corresponding to 66% of the average particle diameter. A radius of 29.3±0.4µm and a refractive index of 1.5910±0.0017 agree well with the manufacturer specifications of particles.

1g versus 2 g daily intravenous ceftriaxone in the treatment of community onset pneumonia - a propensity score analysis of data from a Japanese multicenter registry.

BACKGROUND: Community-onset pneumonia (COP) is a combined concept of community acquired pneumonia and the previous classification of healthcare-associated pneumonia. Although ceftriaxone (CRO) is one of the treatment choices for COP, it is unclear whether 1 or 2 g CRO daily has better efficacy. We compared the effectiveness of 1 g with 2 g of CRO for COP treatment. We hypothesized that 1 g CRO would show non-inferiority over 2 g CRO. METHODS: This study was an analysis of prospectively registered data of the patients with COP from four Japanese hospitals (the Adult Pneumonia Study Group-Japan: APSG-J). We included subjects who were initially treated solely with 1 or 2 g of CRO. The propensity score was estimated from the 33 pre-treatment variables, including age, sex, weight, pre-existing comorbidities, prescribed drugs, risk factors for aspiration pneumonia, vital signs, laboratory data, and a finding from chest xrays. The primary endpoint was the cure rate, for which a non-inferiority analysis was performed with a margin of 0.05. In addition, we performed three sensitivity analyses; using data limited to the group in which CRO solely was used until the completion of treatment, using data limited to inpatient cases, and performing a generalized linear mixed-effect logistic regression analysis to assess the primary outcome after adjusting for random hospital effects. RESULTS: Of the 3817 adult subjects with pneumonia who were registered in the APSG-J study, 290 and 216 were initially treated solely with 1 or 2 g of CRO, respectively. Propensity score matching was used to extract 175 subjects in each group. The cure rate was 94.6 and 93.1% in the 1 and 2 g CRO groups, respectively (risk difference 1.5%; 95% confidence interval - 3.1 to 6.0; p = 0.009 for non-inferiority). The results of the sensitivity analyses were consistent with the primary result. CONCLUSIONS: The propensity score-matched analysis of multicenter cohort data from Japan revealed that the cure rate for COP patients treated with 1 g daily CRO was non-inferior to that of patients treated with 2 g daily CRO.

High spatial resolution pixel synthesis structure for full-complex amplitude modulation with twisted nematic LCD.

Various optics applications require a low-cost twisted nematic LCD that can modulate phase and amplitude independently. We propose a high spatial resolution light-synthesis structure that achieves full-complex amplitude modulation with a twisted nematic LCD. The synthesis structure uses two sparse lateral-shift pixel arrays for the x direction and four sparse lateral-shift pixel arrays for the y direction. The structure recreates an image with two superpixels formed from pairs of adjacent pixels in both directions, and as a result, the spatial resolution is only halved in both directions, which yields an appropriate image quality for the synthesis technique. In experiments, we demonstrate the precise control of amplitude and phase using a twisted nematic LCD.

Transcriptional regulation of acetoacetyl-CoA synthetase by Sp1 in neuroblastoma cells.

Acetoacetyl-CoA synthetase (AACS) is the enzyme responsible for cholesterol and fatty acid synthesis in the cytosol. We have previously shown that AACS has an important role in normal neuronal development and that knockdown of SREBP-2, which orchestrates cholesterol synthesis, resulted in the downregulation of AACS mRNA levels. In this study, we investigated the transcriptional mechanism of AACS in Neuro-2a, neuroblastoma cells. Luciferase assay showed that the minimal core promoter of the mouse AACS gene is located in a region with 110 bps upstream from the transcription start site. Mutagenesis studies showed that the Sp1 binding site was crucial for AACS promoter activity. ChIP assay and DNA affinity precipitation assay showed that Sp1 binds to the Sp1 binding site on the promoter region of AACS. Moreover, overexpression of Sp1 increased AACS mRNA levels. Knockdown of AACS resulted in a decrease in histone deacetylase 9, associated with gene silencing. These results suggest that Sp1 regulates gene expression of AACS in Neuro-2a cells and ketone body utilization affects the balance of histone acetylation.

Prospective cohort study for identification of underlying genetic causes in neonatal encephalopathy using whole-exome sequencing.

PurposeNeonatal encephalopathy, which is characterized by a decreased level of consciousness, occurs in 1-7/1,000 live-term births. In more than half of term newborns, there is no identifiable etiological factor. To identify underlying genetic defects, we applied whole-exome sequencing (WES) in term newborns with neonatal encephalopathy as a prospective cohort study.MethodsTerm newborns with neonatal encephalopathy and no history of perinatal asphyxia were included. WES was performed using patient and both parents' DNA.ResultsNineteen patients fulfilling inclusion criteria were enrolled. Five patients were excluded owing to withdrawal of consent, no parental DNA samples, or a genetic diagnosis prior to WES. Fourteen patients underwent WES. We confirmed a genetic diagnosis in five patients (36%): epileptic encephalopathy associated with autosomal dominant de novo variants in SCN2A (p.Met1545Val), KCNQ2 (p.Asp212Tyr), and GNAO1 (p.Gly40Arg); lipoic acid synthetase deficiency due to compound heterozygous variants in LIAS (p.Ala253Pro and p.His236Gln); and encephalopathy associated with an X-linked variant in CUL4B (p.Asn211Ser).ConclusionWES is helpful at arriving genetic diagnoses in neonatal encephalopathy and/or seizures and brain damage. It will increase our understanding and probably enable us to develop targeted neuroprotective treatment strategies.

Stimulation of Peritoneal Mesothelial Cells to Secrete Matrix Metalloproteinase-9 (MMP-9) by TNF-α: A Role in the Invasion of Gastric Carcinoma Cells.

It has recently been recognized that inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), upregulate the secretion of matrix metalloproteinase-9 (MMP-9) from cancer cells and thereby promote peritoneal dissemination. In this study, we found that TNF-α also stimulated peritoneal mesothelial cells to secrete MMP-9 as assessed by zymography. MMP-9 gene expression in mesothelial cells induced by TNF-α was confirmed by quantitative RT-PCR analysis. We then utilized the reconstituted artificial mesothelium, which was composed of a monolayer of mesothelial cells cultured on a Matrigel layer in a Boyden chamber system, to examine the effects of TNF-α on carcinoma cell invasion. The transmigration of MKN1 human gastric carcinoma cells through the reconstituted mesothelium was promoted by TNF-α in a dose-dependent manner. The increased MKN1 cell migration was partially inhibited by the anti-α3 integrin antibody, indicating that the invasion process involves an integrin-dependent mechanism. Finally, we observed that the invasion of MMP-9-knockdown MKN1 cells into Matrigel membranes was potentiated by the exogenous addition of purified proMMP-9. These results suggest that TNF-α-induced MMP-9 secretion from mesothelial cells plays an important role in the metastatic dissemination of gastric cancer.

Retinoylation (covalent modification by retinoic acid) of Rho-GDIß in the human myeloid leukemia cell line HL60 and its functional significance.

Retinoic acid (RA) has a variety of biological effects in mammalian cells and tissues. It is well known that RA induces differentiation of human acute promyelocytic leukemia (APL) HL60 cells, fresh human APL cells, and clinical remission in patients with APL. Retinoylation (acylation of proteins by RA) is a possible pathway for RA action. However, an understanding of the role that retinoylation plays in the actions of RA is lacking. In the current study, several retinoylated proteins were detected in RA-treated HL60 fractions following Mono Q anion exchange chromatography and analysis using two-dimensional polyacrylamide gel electrophoresis. One of the retinoylated proteins was identified as Rho-GDIß (28kDa) by TOF-MS and co-migration with Rho-GDIß (28kDa). Truncated Rho-GDIß (23kDa, N∆19), a product of cleavage by caspase-3, was not retinoylated. RA covalently bound to the Thr2 residue in Rho-GDIß (5kDa), which is the second product resulting from the cleavage of Rho-GDIß (28kDa) by caspase-3. RA treatment increased the level of Rho-GDIß (28kDa) and decreased the level of Rho-GDIß (23kDa). RA did not induce caspase-3 activity or Rho-GDIß mRNA expression. It is likely that retinoylation of Rho-GDIß increases its metabolic stability.

Protein kinase A activation by retinoic acid in the nuclei of HL60 cells.

BACKGROUND: Activation of protein kinase A (PKA) occurs during retinoic acid (RA)-induced granulocytic differentiation of human promyelocytic leukemia HL60 cells. It is known that the RIIα regulatory subunit of PKA, is modified by RA (retinoylated) in the early stages of differentiation. We have investigated the effects of RA on PKA during cell differentiation in order to understand the potential significance of this process in the retinoylation of RIIα subunits. METHODS: Immunoblotting, immunoprecipitation, confocal microscopy, PCR, and PKA activity assays were employed for characterizing the effects of RA on PKA. RESULTS: We found that RA induces intracellular mobility of RIIα and the activation of PKA in HL60 cells. Increases in RIIα levels were observed in RA-treated HL60 cells. RA treatment altered intracellular localization of the PKA subunits, RIIα and Cα, and increased their protein levels in the nuclei as detected by both immunoblotting and immunostaining analyses. Coincident with the increase in nuclear Cα, RA-treated HL60 cells showed increases in both the protein phosphorylation activity of PKA and the levels of phosphorylated proteins in nuclear fractions as compared to control cells. In addition, RIIα protein was stabilized in RA-treated HL60 cells as compared to control cells. CONCLUSIONS: These results suggest that RA stabilizes RIIα protein and activates PKA in the nucleus, with a resultant increase in the phosphorylation of nuclear proteins. GENERAL SIGNIFICANCE: Our evidence suggests that retinoylation of PKA might contribute to its stabilization and activation and that this could potentially participate in RA's ability to induce granulocytic differentiation of HL60 cells.

Anticancer efficacy of p-dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo.

Neuroblastoma is an aggressive and drug-resistant refractory cancer. The human high-risk neuroblastoma cell line, SK-N-AS (non-amplified N-myc) is derived from stromal cells and it is resistant to treatment with retinoic acid (1, RA), which is a chemotherapeutic agent used to induce neuronal cellular differentiation of neuroblastomas. We have developed p-dodecylaminophenol (3, p-DDAP), based on N-(4-hydroxyphenyl)retinamide (2, 4-HPR), a synthetic amide of 1, since 1 and 2 are associated with the side-effect of nyctalopia. In order to evaluate the effects of 3 on high-risk neuroblastomas, we employed SK-N-AS cells as well asa second high-risk human neuroblastoma cell line, IMR-32, which is derived from neuronal cells (amplified N-myc, drug sensitive). Compound 3 suppressed cell growth of SK-N-AS and IMR-32 cells more effectively than 1, 2, p-decylaminophenol (4, p-DAP), N-(4-hydroxyphenyl)dodecananamide (5, 4-HPDD) or N-(4-hydroxyphenyl)decananamide (6, 4-HPD). In SK-N-AS cells, 3 induced G0/G1 arrest and apoptosis to a greater extent than 1 and 2. In IMR-32 cells, 3 induced apoptosis to a similar extent as 1 and 2, potentially by inhibiting N-myc expression. In addition, i.p. administration of 3 suppressed tumor growth in SK-N-AS-implanted mice in vivo. Since 3 showed no effects on blood retinol concentrations, in contrast to reductions following the administration of 2, it exhibited excellent anticancer efficacy against high-risk neuroblastoma SK-N-AS and IMR-32 expressing distinct levels of N-myc. Compound 3 may have potential for clinical use in the treatment of refractory neuroblastoma with reduced side effects.

Effects of Pre- and Post-Administration of Vitamin A on the Growth of Refractory Cancers in Xenograft Mice.

Vitamin A is an essential nutrient that is obtained from the daily diet. The major forms of vitamin A in the body consist of retinol, retinal, retinoic acid (RA), and retinyl esters. Retinal is fundamental for vision and RA is used in clinical therapy of human acute promyelocytic leukemia. The actions of retinol and retinyl palmitate (RP) are not known well. Recently, we found that retinol is a potent anti-proliferative agent against human refractory cancers, including gallbladder cancer, being more effective than RA, while RP was inactive. In the current study, we determined serum retinol concentrations in xenograft mice bearing tumors derived from four refractory cancer cell lines. We also examined the effects of vitamin A on proliferation of human gallbladder cancer cells in vivo. Serum retinol concentrations were significantly lower in xenograft mice with tumors derived from various refractory cancer cell lines as compared with control mice. The growth of tumors was inhibited with increasing serum retinol concentrations obtained post-administration of RP. In addition, pre-administration of RP increased serum retinol concentrations and suppressed tumor growth. These results indicate that administration of RP can maintain retinol concentrations in the body and that this might suppress cancer cell growth and attachment. The regulation of vitamin A concentration in the body, which is critical biomarker of health, could be beneficial for cancer prevention and therapy.

Growth Inhibition of Refractory Human Gallbladder Cancer Cells by Retinol, and Its Mechanism of Action.

Among the constituents of the essential nutrient vitamin A, retinol is a potent suppressor of refractory cancer cell growth linked to tumor progression, showing greater efficacy than retinoic acid (RA). However, the mechanisms of retinol action on human refractory cancer are not known well. In the current study, we examined the actions of retinol on proliferation of human gallbladder cancer NOZ C-1 cells. Retinol and RA inhibited the proliferation of human NOZ C-1 cells in dose-dependent manner, while RA was less potent than retinol. Cell incorporation of RA was approximately two-fold higher than retinol and was not correlated with anti-proliferative activity. Retinol did not affect caspase-3 activity or mRNA expression of Bax and Bcl-2, which are associated with apoptosis. In addition, protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK and p-Akt/Akt were not significantly changed by retinol treatment. In contrast, retinol treatment significantly increased the mRNA expression of endoplasmic reticulum (ER) stress factors (heme oxygenase 1 (HMOX1), CCAAT/enhancer-binding protein homologous protein (CHOP), 78 kDa glucose-regulated protein (GRP78), and DnaJ (Hsp40) homolog, subfamily B, member 9 (DNAJB9)). Furthermore, the number of cells in the G0/G1 phase was increased, while the number of cells in the S phase were decreased by retinol treatment. Retinol increased expression of the autophagy-associated protein, LC3-II. These results indicate that retinol is a potent suppressor of gallbladder cancer cell growth by mechanisms that involve ER stress, which results in autophagy and cell cycle delay. This suggests that retinol might be useful for anticancer prevention and therapy in the clinic.

High-fat diet-induced obesity stimulates ketone body utilization in osteoclasts of the mouse bone.

Previous studies have shown that high-fat diet (HFD)-induced obesity increases the acetoacetyl-CoA synthetase (AACS) gene expression in lipogenic tissue. To investigate the effect of obesity on the AACS gene in other tissues, we examined the alteration of AACS mRNA levels in HFD-fed mice. In situ hybridization revealed that AACS was observed in several regions of the embryo, including the backbone region (especially in the somite), and in the epiphysis of the adult femur. AACS mRNA expression in the adult femur was higher in HFD-fed mice than in normal-diet fed mice, but this increase was not observed in high sucrose diet (HSD)-induced obese mice. In addition, HFD-specific increases were observed in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and interleukin (IL)-6 genes. Moreover, we detected higher AACS mRNA expression in the differentiated osteoclast cells (RAW 264), and found that AACS mRNA expression was significantly up-regulated by IL-6 treatment only in osteoclasts. These results indicate the novel function of the ketone body in bone metabolism. Because the abnormal activation of osteoclasts by IL-6 induces bone resorption, our data suggest that AACS and ketone bodies are important factors in the relationship between obesity and osteoporosis.

Inhibitory Effects of Retinol Are Greater than Retinoic Acid on the Growth and Adhesion of Human Refractory Cancer Cells.

Vitamin A constituents include retinal, which plays a role in vision, and retinoic acid (RA), which has been used in the therapy of human acute promyelocytic leukemia. However, the effects on cancer of retinol (Rol) and its ester, retinyl palmitate (RP) are not known well. In the current study, we examined the effects of these agents on proliferation and adhesion of various cancer cells. Rol exhibited dose-dependent inhibition of the proliferation of human refractory and prostate cancer cells, while RA and RP showed little or no effect. In contrast, RA inhibited the growth of human breast cancer cells to a greater extent than Rol at low concentrations, but not at high concentrations. Rol suppressed adhesion of refractory and prostate cancer cells to a greater extent than RA, while it suppressed adhesion of breast cancer cells as well as RA and of JHP-1 cells less effectively than RA. These results indicate that Rol is a potent suppressor of cancer cell growth and adhesion, which are both linked to metastasis and tumor progression. Rol might be useful for the clinical treatment of cancer.