Mortality risk factors and fulminant sub-phenotype in anaerobic bacteremia: a 10-year retrospective, multicenter, observational cohort study.

PURPOSE: During the last decade, the incidence of anaerobic bacteremia (AB) has been increasing. Patients with AB may develop complex underlying diseases, which can occasionally be accompanied by fatal or fulminant outcomes. However, the risk factors for AB-related mortality remain unclear. Herein, we sought to elucidate the risk factors for AB-related mortality. METHODS: In this multicenter, retrospective, observational study, we enrolled patients with culture-proven AB from six tertiary hospitals in Japan, between January 2012 and December 2021. Data on patient and infection characteristics, laboratory findings, treatment, and outcome were collected, and their associations with mortality were analyzed. RESULTS: A total of 520 participants were included. The 30-day mortality in the study cohort was 14.0% (73 patients), and malignant tumors were frequently observed comorbidities in 48% of the entire cohort. Multivariable logistic regression analysis showed a Charlson comorbidity score of > 6, serum creatinine level of > 1.17 mg/dL, and hypotension to be independent risk factors for 30-day mortality in AB (odds ratios [ORs] 2.12, 2.25, and 5.12, respectively; p < 0.05), whereas drainage significantly reduced this risk (OR, 0.28; p < 0.0001). Twelve patients (2.3% of the whole cohort and 16.4% of the deceased patients) presented with extremely rapid progression leading to fatal outcome, consistent with "fulminant AB." CONCLUSIONS: This study identified acute circulatory dysfunction and performance of drainage as independent predictive factors for 30-day AB-related mortality and revealed the existence of a fulminant AB sub-phenotype. Our findings could serve as a practical guide to predict the clinical outcomes of AB.

Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene.

BACKGROUND: TRPA1 is a Ca-permeable nonselective cation channel expressed in sensory neurons and acts as a nocisensor. Recent reports show that some monoterpenes, a group of naturally occurring organic compounds, modulate TRP channel activity. Here, we report that limonene, being contained in citrus fruits and mushrooms, shows a unique bimodal action on TRPA1 channel. METHODS: We examine the effects of limonene on sensory neurons from wild-type, TRPV1- and TRPA1-gene-deficient mice and on heterologously expressed channels in vitro. Molecular determinants were identified with using mutated channels. Cellular excitability is monitored with ratiometric Ca imaging. Nociceptive and analgesic actions of limonene are also examined in vivo. RESULTS: In wild-type mouse sensory neurons, limonene increased the intracellular Ca(2+) concentration ([Ca(2+) ]i ), which was inhibited by selective inhibitors of TRPA1 but not TRPV1. Limonene-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. Limonene failed to stimulate sensory neurons from the TRPA1 (-/-) mouse. Heterologously expressed mouse TRPA1 was activated by limonene. Intraplantar injection of limonene elicited acute pain, which was significantly less in TRPA1 (-/-) mice. Systemic administration of limonene reduced nociceptive behaviours evoked by H2 O2 . In both heterologously and endogenously expressed TRPA1, a low concentration of limonene significantly inhibited H2 O2 -induced TRPA1 activation. TRPA1 activation by limonene was abolished in H2 O2 -insensitive cysteine-mutated channels. CONCLUSIONS: Topically applied limonene stimulates TRPA1, resulting in elicitation of acute pain, but its systemic application inhibits nociception induced by oxidative stress. Because limonene is a safe compound, it may be utilized for pain control due to its inhibition of TRPA1 channels. What does this study add: Limonene, a monoterpene in essential oils of various plants, has been known for its antitumor and anti-inflammatory properties. However, molecular basis of their actions has not been identified. This study shows that limonene activates nociceptive TRPA1 and elicits acute pain, when it is topically applied. In addition, systemic application of limonene exerts inhibitory effects on nociception induced by an oxidative stress-induced TRPA1 activation.

Use of a Latent Topic Model for Characteristic Extraction from Health Checkup Questionnaire Data.

OBJECTIVES: When patients complete questionnaires during health checkups, many of their responses are subjective, making topic extraction difficult. Therefore, the purpose of this study was to develop a model capable of extracting appropriate topics from subjective data in questionnaires conducted during health checkups. METHODS: We employed a latent topic model to group the lifestyle habits of the study participants and represented their responses to items on health checkup questionnaires as a probability model. For the probability model, we used latent Dirichlet allocation to extract 30 topics from the questionnaires. According to the model parameters, a total of 4381 study participants were then divided into groups based on these topics. Results from laboratory tests, including blood glucose level, triglycerides, and estimated glomerular filtration rate, were compared between each group, and these results were then compared with those obtained by hierarchical clustering. RESULTS: If a significant (p < 0.05) difference was observed in any of the laboratory measurements between groups, it was considered to indicate a questionnaire response pattern corresponding to the value of the test result. A comparison between the latent topic model and hierarchical clustering grouping revealed that, in the latent topic model method, a small group of participants who reported having subjective signs of urinary disorder were allocated to a single group. CONCLUSIONS: The latent topic model is useful for extracting characteristics from a small number of groups from questionnaires with a large number of items. These results show that, in addition to chief complaints and history of past illness, questionnaire data obtained during medical checkups can serve as useful judgment criteria for assessing the conditions of patients.

Prediction model for glucose metabolism based on lipid metabolism.

OBJECTIVES: We developed a robust, long-term clinical prediction model to predict conditions leading to early diabetes using laboratory values other than blood glucose and insulin levels. Our model protects against missing data and noise that occur during long-term analysis. METHODS: RESULTS of a 75-g oral glucose tolerance test (OGTT) were divided into three groups: diabetes, impaired glucose tolerance (IGT), and normal (n = 114, 235, and 325, respectively). For glucose metabolic and lipid metabolic parameters, near 30-day mean values and 10-year integrated values were compared. The relation between high-density lipoprotein cholesterol (HDL-C) and variations in HbA1c was analyzed in 158 patients. We also constructed a state space model consisting of an observation model (HDL-C and HbA1c) and an internal model (disorders of lipid metabolism and glucose metabolism) and applied this model to 116 cases. RESULTS: The root mean square error between the observed HbA1c and predicted HbA1c was 0.25. CONCLUSIONS: In the observation model, HDL-C levels were useful for prediction of increases in HbA1c. Even with numerous missing values over time, as occurs in clinical practice, clinically valid predictions can be made using this state space model.

Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function.

BACKGROUND: Recently, it has been reported that frequent premature ventricular contractions (PVCs) may be associated with causing heart failure in patients with left ventricular (LV) dysfunction. However, the prognostic significance of frequent PVCs in asymptomatic patients with a normal LV function is unclear. METHODS: Two hundred and thirty-nine consecutive patients presenting with frequent PVCs (>1000 beats/day) originating from the right or left ventricular outflow tract without any detectable heart disease were enrolled in the study. Structural heart disease was ruled out by echocardiography and cardiac magnetic resonance imaging, and Holter-ECG monitoring was repeated two or three times to evaluate the PVC prevalence at the initial evaluation. All patients were followed up for at least 4 years, and further observation was continued if possible. RESULTS: During an observation period of 5.6 (1.7) years, no patients exhibited any serious cardiac events. Although there was no significant change in the mean LV ejection fraction (LVEF) and mean LV diastolic dimension (LVDd), there was a significant negative correlation between the PVC prevalence and DeltaLVEF (p<0.001) and positive correlation between the PVC prevalence and DeltaLVDd (p<0.001). When the development of LV dysfunction was defined as DeltaLVEF>-6%, 13 patients exhibited LV dysfunction. For the prediction of the development of LV dysfunction, PVC prevalence and LVEF at the initial evaluation were independent predicting factors (p<0.01). CONCLUSION: Although the prognosis in patients with frequent PVCs was considered relatively benign, attention should be paid to the progression of the LV dysfunction during a long-term observation, especially in patients with a high PVC prevalence.

Synergistic roles of amelogenin and ameloblastin.

Amelogenin and ameloblastin, the major enamel matrix proteins, are important for enamel mineralization. To identify their synergistic roles in enamel development, we generated Amel X(-/-)/Ambn(-/-) mice. These mice showed additional enamel defects in comparison with Amel X(-/-) or Ambn(-/-) mice. In 7-day-old Amel X(-/-)/Ambn(-/-) mice, not only was the ameloblast layer irregular and detached from the enamel surface, as in Ambn(-/-), but also, the enamel width was significantly reduced in the double-null mice as compared with Amel X(-/-) or Ambn(-/-) mice. Proteomic analysis of the double-null teeth revealed increased levels of RhoGDI (Arhgdia), a Rho-family-specific guanine nucleotide dissociation inhibitor, which is involved in important cellular processes, such as cell attachment. Both Amel X(-/-)/Ambn(-/-) mice and Ambn(-/-) mice displayed positive staining with RhoGDI antibody in the irregularly shaped ameloblasts detached from the matrix. Ameloblastin-regulated expression of RhoGDI suggests that Rho-mediated signaling pathway might play a role in enamel formation.

Proliferation and adhesion of periodontal ligament cells on synthetic biominerals.

OBJECTIVE: Hydroxiapatite (HA) has been suggested as a useful biomaterial to support the regeneration of tissues. In this study, we investigated the adhesion of periodontal ligament (PDL) cells on octacalcium phosphate (OCP) and its hydrolyzed apatitic product (HL), which are known precursors of HA. METHODS: Rat PDL cells were cultured on OCP or HL-coated dishes. Cell proliferation and adhesion and mRNA expression of collagen I, fibronectin integrin subunits were examined. Cell adhesion inhibition assays were carried out by GRGDSPK (Gly-Arg-Gly-Asp-Ser-Pro-Lys). RESULTS: In early culture period, the cell number of PDL cells was lower on OCP and HL than that on control without any coating. However, the cell number on OCP or HL caught up with control later period. mRNA expression level of collagen I and fibronectin on OCP and HL were similar among OCP HL and control, although they differed early in the culture period. Integrin subunits were expressed on both OCP and HL as well as on control. Cell adhesion was inhibited by RGD inhibitor peptide. CONCLUSION: Our findings indicated that rat PDL cells produce collagen I and fibronectin on OCP and HL, and then show increased cell numbers depending on adhesion to the matrices through integrins.

3D digital subtraction angiography of intracranial aneurysms: comparison of flat panel detector with conventional image intensifier TV system using a vascular phantom.

BACKGROUND AND PURPOSE: Compared with the image intensifier (I.I.)-TV system, the flat panel detector (FPD) system of direct conversion type has several theoretic advantages, such as higher spatial resolution, wide dynamic range, and no image distortion. The purpose of this study was to compare the image quality of 3D digital subtraction angiography (DSA) in the FPD and conventional I.I.-TV systems using a vascular phantom. MATERIALS AND METHODS: An anthropomorphic vascular phantom was designed to simulate the various intracranial aneurysms with aneurysmal bleb. The tubes of this vascular phantom were filled with 2 concentrations of contrast material (300 and 150 mg I/mL), and we obtained 3D DSA using the FPD and I.I.-TV systems. First, 2 blinded radiologists compared the volume-rendering images for 3D DSA on the FPD and I.I.-TV systems, looking for pseudostenosis artifacts. Then, 2 other radiologists independently evaluated both systems for the depiction of the simulated aneurysm and aneurysmal bleb using a 5-point scale. RESULTS: For the degree of the pseudostenosis artifacts at the M1 segment of the middle cerebral artery at 300 mg I/mL, 3D DSA with FPD system showed mild stenoses, whereas severe stenoses were observed at 3D DSA with I.I.-TV system. At both concentrations, the FPD system was significantly superior to I.I.-TV system regarding the depiction of aneurysm and aneurysmal bleb. CONCLUSION: Compared with the I.I.-TV system, the FPD system could create high-resolution 3D DSA combined with a reduction of the pseudostenosis artifacts.

Reduction of radiation dose for cerebral angiography using flat panel detector of direct conversion type: a vascular phantom study.

BACKGROUND AND PURPOSE: Compared with image intensifier television (I.I.-TV) system, an angiography system using the flat panel detector (FPD) of direct conversion type has a high spatial resolution, which may improve image quality, reduce patient exposure, or both. Our purpose was to evaluate the detection of simulated aneurysmal blebs under dose reduction with the FPD system in comparison with the I.I.-TV system. MATERIALS AND METHODS: A vascular phantom was designed to simulate various intracranial aneurysms with and without blebs, and this phantom was filled with 3 different concentrations of contrast material (300, 150, and 100 mg I/mL). 2D digital subtraction angiography (DSA) at low-dose mode of FPD system was compared with 2D DSA at a standard-dose mode of FPD system and a conventional mode of I.I.-TV system. Data analysis was based on 171 observations (57 aneurysms [20 with bleb and 37 without bleb] x 3 contrast material concentrations) by each of 7 radiologists, and the detection performances of blebs were compared using a receiver operating characteristic (ROC) analysis. RESULTS: The mean dose measurements with a phantom during 2D DSA were 0.36 mGy/frame with low-dose mode of FPD system, 0.72 mGy/frame with standard-dose mode of FPD system and 0.76 mGy/frame with I.I.-TV system. The mean Az at 100 mg I/mL was significantly higher for low-dose mode of FPD than for conventional-dose mode of I.I.-TV mean Az, 0.85 versus 0.56; P < .01), though differences were not significant with 150 and 300 mg I/mL between both systems. CONCLUSION: The FPD system allows a considerable dose reduction during 2D DSA without loss of the image quality.

Amelogenin-mediated regulation of osteoclastogenesis, and periodontal cell proliferation and migration.

We previously reported that amelogenin isoforms M180 and leucine-rich amelogenin peptide (LRAP) are expressed in the periodontal region, and that their absence is associated with increased cementum defects in amelogenin-knockout (KO) mice. The aim of the present study was to characterize the functions of these isoforms in osteoclastogenesis and in the proliferation and migration of cementoblast/periodontal ligament cells. The co-cultures of wild-type (WT) osteoclast progenitor and KO cementoblast/periodontal ligament cells displayed more tartrate-resistant acid phosphatase (TRAP)-positive cells than the co-cultures of WT cells. The addition of LRAP to both co-cultures significantly reduced RANKL expression and the TRAP-positive cells. Proliferation and migration rates of the KO cementoblast/periodontal ligament cells were lower than those of WT cells and increased with the addition of either LRAP or P172 (a porcine homolog of mouse M180). Thus, we demonstrate the regulation of osteoclastogenesis by LRAP, and the proliferation and migration of cementoblast/periodontal ligament cells by LRAP and P172.

A case of POEMS syndrome associated with reactive amyloidosis and Waldenström's macroglobulinaemia.

A72-year-old Japanese man presented with a 5-year history of fatigue, night sweats, oedema of dorsum of foot, muscle weakness, and paresthesia of the lower extremities. On examination, the patient fulfilled the diagnostic criteria for POEMS syndrome, but was unusual in that he also had underling Waldenström's macroglobulinaemia with IgM kappa. The M protein of POEMS syndrome is usually IgG and IgA with lambda light chains. To our knowledge, there are only three cases of POEMS syndrome with IgM kappa including our case. Autopsy findings revealed that small lymphocytes were more prominent than plasma cells in the bone marrow. These plasma cells were stained with IgM kappa. Amyloid deposits identified by Congo red stain were detected predominantly in the vascular walls of the gastrointestinal tract, pancreas and kidney. This amyloid protein was classified as amyloid associated protein. This is the first case of POEMS syndrome associated with reactive amyloidosis and Waldenström's macroglobulinaemiae.

Transcriptional regulation of uncoupling protein-2 gene expression in L6 myotubes.

OBJECTIVE: To increase the understanding of the transcriptional regulation of UCP2 gene expression in skeletal muscle cells, we examined the effect of all-trans-retinoic acid (tRA), a ligand (after the conversion to 9-cis-RA) of the retinoid X receptor (RXR), and linolenic acid, a polyunsaturated fatty acid and peroxisome proliferator-activated receptors (PPARs) ligand, on the expression of UCP2 mRNA in cultured L6 myotubes. RESEARCH METHODS AND PROCEDURES: UCP2 gene expression in L6 myotubes was confirmed by Northern blot analysis. The time- and concentration-dependency of tRA and linolenic acid on UCP2 gene expression was assessed by dot blot quantification. The mRNA levels of PPAR subtypes (alpha, gamma and delta) were determined by RT-PCR. RESULTS: tRA induced UCP2 gene expression in a time- and concentration-dependent manner. Similar to tRA, UCP2 mRNA was markedly increased by 0.5 mM linolenic acid. In L6 myotubes, PPARdelta mRNA was abundant, whereas PPARalpha mRNA was lower and PPARgamma mRNA was minimal. CONCLUSIONS: UCP2 mRNA expression in L6 myotubes is up-regulated by tRA and linolenic acid, possibly through a mechanism involving PPAR and RXRs.

Function of the 3 portions of the inferior glenohumeral ligament: a cadaveric study.

The stabilizing function of the inferior glenohumeral ligament of the anterior band and posterior band has been investigated, but little is known about the function of the axillary pouch. The strain of the 3 portions of the inferior glenohumeral ligament in 17 fresh-frozen cadaveric shoulders was measured with use of linear transducers. The measurements were performed under the following conditions: 0 degrees, 30 degrees, 45 degrees, and 60 degrees of glenohumeral elevation in the coronal, scapular, and sagittal planes and internal to external rotations in 10 degrees increments. The anterior band and axillary pouch showed significant strain increases when the arm was elevated and externally rotated in the coronal and scapular planes but no increase in the sagittal plane. The posterior band showed no strain in the coronal and scapular planes, but a significant strain increase with the arm elevated and internally rotated in the sagittal plane. We conclude that the anterior band and axillary pouch, which showed the greatest strain in abduction and external rotation, are anterior stabilizers, whereas the posterior band, which showed the greatest strain in flexion and internal rotation, is a posterior stabilizer. We recommend that the 6 o'clock position be firmly repaired during the Bankart procedure.

Effect of arm elevation and rotation on the strain in the repaired rotator cuff tendon. A cadaveric study.

In 14 cadaveric shoulders, a rotator cuff tear (2 cm wide and 1.5 cm long) was created and repaired under a 3-kg tensile force with the arm in adduction. Strain on the repaired tendon was measured at 0 degrees, 15 degrees, 30 degrees, and 45 degrees of elevation in the sagittal, scapular, and coronal planes and from 60 degrees of internal rotation to 60 degrees of external rotation. The strain in all of the planes decreased significantly with the arm elevated more than 30 degrees. With 30 degrees of elevation in the scapular and coronal planes, the strain increased in internal rotation and decreased in external rotation. In all of the positions measured, the strain in the sagittal plane was significantly greater than in the other planes. We concluded that more than 30 degrees of elevation in the coronal or scapular plane and rotation ranging from 0 degrees to 60 degrees of external rotation compose the safe range of motion after repair of the rotator cuff.

Effect of superior capsule and coracohumeral ligament release on strain in the repaired rotator cuff tendon. A cadaveric study.

Twelve cadaveric shoulders were used to determine the effects of release of the superior capsule and the coracohumeral ligament on the strain in the repaired rotator cuff tendon. A rotator cuff tear (2 cm wide and 1.5 cm long) was created and repaired under a 3-kg tensile force. The strain in the repaired tendon was measured with use of linear transducers with the arm in 50 different positions. Release of either the superior capsule or the coracohumeral ligament diminished the tension of the repaired rotator cuff by an average of 25% with the arm in adduction. Release of both of these structures further reduced the tension by an average of 44% in adduction and 43% to 60% with the arm in 15 degrees of elevation. The maximum reduction of tension in the repaired rotator cuff occurred when both the superior capsule and coracohumeral ligament were divided and when the arm was positioned in adduction and in 60 degrees of external rotation. Release of the coracohumeral ligament is equally as efficient as releasing the superior capsule in reducing the strain of the repaired rotator cuff. Releasing both structures seems to be desirable when releasing one structure or the other is not sufficient.

[Intermittent administration of 5-FU and isovorin to patients with advanced and recurrent colon cancer].

We attempted a new regimen of intermittent administration of 5-FU and low-dose Isovorin (F.I) to four patients with advanced and recurrent colon cancer. A partial response (PR) was achieved in two of four patients who had evaluable lesions for this treatment. We observed few side effects among these patients. Only one patient among four showed grade 1 neuropathy after two administrations of this chemotherapy. However, after a two-week pause in administration, the neuropathy disappeared and we could continue the therapy. This patient with multiple liver metastases achieved a partial response. Other patients had no side effects such as bone marrow suppression or digestive symptoms. This intermittent F.I treatment might be an effective and promising therapy with few side effects even for patients with poorer conditions.

Superior labral strain during the throwing motion. A cadaveric study.

We studied the strain on the superior labrum of 10 fresh-frozen cadaveric shoulders with the arm in simulated positions of a pitching motion. We used linear transducers to measure the strain in both the anterior and posterior superior labrum with the arm in various planes and rotations simulating the motions of pitching: early cocking, late cocking, acceleration, deceleration, and follow-through. Predetermined loads, according to the percent of maximum voluntary contraction of the biceps muscle during each phase of pitching, were calculated and applied to the long head of the biceps tendon using a spring device. Only during the late cocking phase, when the arm was in maximal external rotation, was the increase in strain statistically significant for the anterior and posterior portions and the strain on the posterior portion significantly greater than that on the anterior portion of the labrum. The increased strain in the posterior portion may be due to the anatomic orientation of the long head of the biceps tendon at the superior labrum. The increased strain in the late cocking phase may contribute to the detachment of the labrum with the eccentric contraction of the biceps muscle that occurs with rapid extension of the elbow.

Effects of biceps loading and arm rotation on the superior labrum in the cadaveric shoulder.

Effects of loading the long head of the biceps brachii (LHB) and arm rotation on the strain of the superior labrum (anterior and posterior) in 10 fresh frozen cadaveric shoulder joints were studied. Loads were applied to the rotator cuff muscles to stabilize the humeral head. The strain of the anterior and posterior portions of the labrum with the biceps loaded with 0.42 kg, 1.36 kg, and 2.31 kg were measured using linear transducers. The humerus was rotated externally (30, 45, 60, and 90 degrees) and internally (30, 45, and 60 degrees) with the arm elevated 60 degrees at glenohumeral joint (simulated 90 degrees elevation of arm to the trunk). The strain increased with an increase in the weight of the load to LHB and with increase in rotation angle both internally and externally. Since the strain in the posterior portion was larger than that of the anterior portion it seems likely that the labrum, especially the posterior portion, is subject to large strain during biceps loading and arm rotation.

Cloning of the gene coding for Staphylococcus hyicus exfoliative toxin B and its expression in Escherichia coli.

The Staphylococcus hyicus exfoliative toxin B (SHETB) gene was cloned into pUC118 and expressed in Escherichia coli. The nucleotide sequence of the SHETB gene consists of a coding region of 804 bp specifying a polypeptide of 268 amino acid residues, which included a putative 20-residue signal sequence.

Stereoselective permeation of new fluorinated quinolone derivatives across LLC-PK1 cell monolayers.

We examined the stereoselective membrane permeation of new fluorinated quinolone derivatives (NQs) across LLC-PK1 cell monolayers, using levofloxacin (LVFX) and its R-(+) isomer. LVFX permeation was 1.6-fold greater in the basal-to-apical direction than that in the apical-to-basal direction, suggesting that LVFX permeated LLC-PK1 cell monolayers in a secretory-oriented manner. In contrast to LVFX, the permeation of the R-(+) isomer was almost identical in both directions. LVFX permeation in the basal-to-apical direction was significantly reduced in the presence of guanidine, enoxacin, and L-arginine, whereas tetraethylammonium, D-arginine, D- and L-lysine had no effect on the basal-to-apical permeation of LVFX. Basal-to-apical permeation of the R-(+) isomer was not affected by these compounds. Cellular accumulation of LVFX was inversely increased when guanidine suppressed the appearance of LVFX in the apical medium in a concentration-dependent manner. These results imply that the inhibitory effect of guanidine on the basal-to-apical permeation of LVFX involves the permeation process across the apical membrane. Guanidine trans-stimulated the efflux of LVFX from LLC-PK1 cells but did not affect cimetidine efflux. These results suggest that some NQs, like LVFX and its R-(+) isomer, are stereoselectively secreted across LLC-PK1 cell monolayers and that an organic cation transport system, which favors guanidine as a typical substrate, may be involved in the secretory-oriented permeation of some NQs.