Impact of inadequate initial antimicrobial therapy on mortality in patients with bacteraemic cholangitis: a retrospective cohort study.

OBJECTIVES: Acute cholangitis is a common cause of bacteraemia resulting in severe sepsis or septic shock. The impact of the appropriate initial antimicrobial therapy on short-term mortality in bacteraemic cholangitis has not been well investigated. METHODS: We conducted a retrospective cohort study of patients with bacteraemic cholangitis at two large tertiary care centres in Tokyo, Japan between 2009 and 2015. We determined the factors associated with 30-day all-cause mortality from the date of drawing the first positive blood culture, using a multivariate logistic regression analysis. RESULTS: We identified 573 patients with bacteraemic cholangitis (median age, 77 years; male, 58.3%). The 30-day all-cause mortality rate was 6.6% (38/573). Inadequate initial antimicrobial therapy occurred in 133 (23.2%) patients. Factors associated with 30-day all-cause mortality included the Charlson co-morbidity index score >3 (adjusted odds ratio (aOR) 4.12; 95% CI 1.18-14.38), jaundice (total bilirubin >2.5 mg/dL) (aOR 3.39; 95% CI 1.46-7.89), septic shock within 48 h of the first positive blood culture (aOR 3.34; 95% CI 1.42-7.89), biliary obstruction due to hepatobiliary malignancy (aOR 8.00; 95% CI 2.92-21.97), and inadequate initial antimicrobial therapy (aOR 2.78; 95% CI 1.27-6.11). CONCLUSIONS: Inadequate initial antimicrobial therapy was an important, modifiable determinant of survival.

Comparison of the computed tomography values of the bone fragment gap after sagittal split ramus osteotomy in mandibular prognathism with and without asymmetry.

The purpose of this study was to compare computed tomography (CT) Hounsfield unit values of bone fragment gaps after sagittal split ramus osteotomy (SSRO) in patients with and without asymmetry, and to evaluate differences between the deviated and non-deviated sides in asymmetric patients. Thirty-two patients who underwent a bilateral SSRO were included in this retrospective study. Patients were divided into symmetric and asymmetric groups by cephalometric analysis. CT values of the bone fragment gap were measured at 1 week and at 1 year after surgery. There were significant differences between CT values obtained at 1 week and at 1 year after surgery for all measurement points. However, there were no significant differences in CT values between symmetric and asymmetric patients at either 1 week or 1 year after surgery. Among asymmetric patients, there were no significant differences between the deviated and non-deviated sides at 1 week or 1 year after surgery. This study showed ossification of the bone fragments and adaptation to change the mandible form in patients with and without asymmetry following SSRO.

Changes in the computed tomography (pixel) value of mandibular ramus bone and fixation screws after sagittal split ramus osteotomy.

The purpose of this retrospective study was to evaluate the changes in computed tomography (CT) values of ramus bone and screws after sagittal split ramus osteotomy (SSRO) setback surgery. The subjects were 64 patients (128 sides) who underwent bilateral SSRO setback surgery. They were divided into six groups according to the fixation plate type used and the use or not of self-setting α-tricalcium phosphate (Biopex): group 1: titanium plate and screws; group 2: titanium plate and screws with Biopex; group 3: poly-l-lactic acid (PLLA) plate and screws; group 4: PLLA plate and screws with Biopex; group 5: uncalcined and unsintered hydroxyapatite particles and poly-l-lactic acid (uHA/PLLA) plate and screws; group 6: PLLA/uHA plate and screws with Biopex. CT values (pixel values) of the lateral cortex, medial cortex, osteotomy site, and screws were measured preoperatively, immediately after surgery, and 1 year postoperatively using horizontal CT images at the mandibular foramen taken parallel to the Frankfort horizontal plane. There were significant differences in the time-course change of pixel values for the lateral cortex (P<0.0001) and the osteotomy site (P<0.0001) among the six groups. This study suggests that the fixation plate type and use of bone alternative material may affect bone quality during the process of bone healing after SSRO.

Changes in occlusal function after orthognathic surgery in mandibular prognathism with and without asymmetry.

This study aimed to evaluate the postoperative changes in masticatory function in patients with jaw deformities with or without asymmetry treated by orthognathic surgery. Thirty female patients who underwent a Le Fort I osteotomy with sagittal split ramus osteotomy (SSRO) were enrolled. The patients were divided into symmetry and asymmetry groups. The bite force, occlusal contact area, and bite force balance were measured before and at 1, 3, and 6 months and 1 year after surgery; these measurements were compared statistically within and between the two groups. In the symmetry group, there was a significant difference in the preoperative bite force and the 1 month postoperative bite force (P=0.0033). In the asymmetry group, the bite force before surgery was significantly different from that at 1 month (P=0.0375) and at 1 year (P=0.0353) after surgery. Significant differences in the bite force were also observed between the following time points: 1 month and 1 year (P=0.0003), 3 months and 1 year (P=0.0034), and 1 month and 6 months (P=0.0486). The occlusal contact area, bite force, and occlusal balance tended to change after Le Fort I osteotomy with SSRO, with a significantly improved bite force in patients with asymmetry before surgery.

Changes in border movement of the mandible in skeletal Class III before and after orthognathic surgery.

The purpose of this study was to examine the changes in border movement of the mandible before and after mandibular ramus osteotomy in patients with prognathism. The subjects were 73 patients with mandibular prognathism who underwent sagittal split ramus osteotomy (SSRO) with and without Le Fort I osteotomy. Border movement of the mandible was recorded with a mandibular movement measure system (K7) preoperatively and at 6 months postoperatively. Of the 73 patients, 21 had measurements taken at 1.5 years postoperative. Data were compared between the pre- and postoperative states, and the differences analyzed statistically. There was no significant difference between SSRO alone and SSRO with Le Fort I osteotomy in the time-course change. The values at 6 months postoperative were significantly lower than the preoperative values for maximum vertical opening (P=0.0066), maximum antero-posterior movement from the centric occlusion (P=0.0425), and centric occlusion to maximum opening (P=0.0300). However, there were no significant differences between the preoperative and 1.5 years postoperative measurements. This study suggests that a postoperative temporary reduction in the border movement of the mandible could recover by 1.5 years postoperative, and the additional procedure of a Le Fort I osteotomy does not affect the recovery of mandibular motion after SSRO.

Characterization of hepatitis C virus (HCV) quasispecies dynamics upon short-term dual therapy with the HCV NS5B nucleoside polymerase inhibitor mericitabine and the NS3/4 protease inhibitor danoprevir.

In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.

Significance of cadmium concentrations in blood and hair as an indicator of dose 15 years after the reduction of environmental exposure to cadmium.

To evaluate the significance of cadmium (Cd) concentrations in blood (B-Cd) and hair (H-Cd) as an indicator of dose, a cross-sectional study was performed on 40 residents in a Cd-polluted area, Nagasaki Prefecture, Japan, in 1996. In the study area, soil replacement of Cd-polluted rice fields ended in 1981. B-Cd and H-Cd were significantly higher in the study population than in the control subjects. B-Cd was positively correlated with urinary Cd (U-Cd) (Spearman r=0.50, P=0.06 for males and r=0.72, P=0.0001 for females), while H-Cd was weakly or moderately correlated with U-Cd. After adjustment for gender using logistic regression analysis, log(B-Cd) and log(U-Cd), but not log(H-Cd), were significantly associated with the prevalence of increased urinary beta2-microglobulin (P for trend <0.05). These findings suggest that B-Cd is a good indicator of cumulative dose many years after the reduction of environmental exposure to Cd. H-Cd may be weakly or moderately correlated with body burden.

A quantitative analysis of purinoceptor expression in human fetal and adult bladders.

PURPOSE: In adults there is evidence that adenosine triphosphate acting at P2X receptors functions as a co-transmitter at vesical smooth muscle. The contractile mechanisms of human fetal bladder have been studied to a limited extent and it remains undetermined whether P2X receptors contribute. We compared the expression of the 7 known P2X receptors in fetal and adult human bladders using a quantitative polymerase chain reaction (PCR) based method. MATERIALS AND METHODS: Real-time quantitative reverse transcriptase-PCR provides a system for the detection and analysis of RNA. Four complete cadaver fetal bladders were obtained at 16 weeks to full-term gestation and divided into a total of 12 segments. Adult bladder samples were obtained from 4 patients requiring bladder biopsy. Total RNA was extracted from each sample and 10 ng. were used for individual PCR reactions. An ABI 7700 machine (PE Applied Biosystems, California) determined expression levels of the 7 P2X genes in total RNA. RESULTS: In adult bladders P2X1 was by far the predominant purinergic receptor at the messenger RNA level. The remaining purinergic receptors were consistently present in the order P2X1 >> P2X4 > P2X7 >> P2X5 > P2X2 >> P2X3 = P2X6 = 0. In fetal bladders the expression of P2X1 transcripts was much lower than in adult bladders, and P2X4 and P2X7 were also present. The rank order of the P2X transcript level was P2X1 = P2X4 > P2X7 >> P2X5 >> P2X2 >> P2X3 = P2X6 = 0. With increasing gestation the P2X receptor transcript level (expression) shifted from the dome to the body of the bladder. CONCLUSIONS: P2X1 is the predominant purinoceptor subtype in adult human bladders, consistent with pharmacological evidence. The fetal expression of all P2X receptor transcripts is much lower than in adults, suggesting that purinergic transmission is of less importance. However, there are also several marked developmental changes in purinoceptor expression in the bladder, in that P2X4 is expressed in developing bladders at relatively high levels. There is also a marked developmental change in the regional distribution of purinoceptors. These changes are likely to reflect the changing role of purinergic transmission in the control of bladder motility during fetal maturation.

A quantitative analysis of purinoceptor expression in the bladders of patients with symptomatic outlet obstruction.

OBJECTIVE: To compare the expression of the seven known P2X receptors in human bladder from male patients with detrusor instability caused by symptomatic bladder outlet obstruction with that from control bladders, using a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. PATIENTS AND METHODS: Real-time quantitative RT-PCR provides a system for detecting and analysing RNA. Bladder biopsies were obtained from nine patients undergoing prostate surgery and control biopsies were obtained from eight age-matched men undergoing routine bladder endoscopy studies, and who were asymptomatic. Total RNA was extracted from each sample and 10 ng of this used for individual PCR reactions. The expression levels of the seven P2X genes in the total RNA were then determined. RESULTS: In the control bladder, P2X1 was by far the predominant purinergic receptor at the RNA level, the remainder consistently present in the order P2X1 >> P2X4 > P2X2 > P2X7 > P2X5 >> P2X3 = P2X6 = 0. Calponin, a smooth muscle-specific protein, was used as a marker for smooth muscle content. In bladder from symptomatic patients, the P2X1/calponin ratio was greater than that in controls (P = 0.016). There appeared to be no difference in P2X2, but P2X4, P2X5, and P2X7 were all greater in the symptomatic bladder than in the controls, although these differences were not significant. CONCLUSION: P2X1 is the predominant purinoceptor subtype in the human male bladder, consistent with pharmacological evidence. The amount of P2X1 receptor per smooth muscle cell is greater in the obstructed than in control bladder, suggesting an increase in purinergic function in the unstable bladder arising from bladder outlet obstruction.

Mechanism of pH-dependent photolysis of aliphatic amino acids and enantiomeric enrichment of racemic leucine by circularly polarized light.

It has been proposed that the origin of biological homochirality may be the result of irradiation of a racemic sample of amino acids by circularly polarized light (CPL). To determine the mechanism of enantiomeric enrichment, the irradiation of aliphatic amino acids by CPL was undertaken. An enantiomerically enriched sample (e.g., L isomer enrichment from r-CPL) was found to result from the preferential excitation/decomposition of one enantiomer over another via a Norrish Type II mechanism (leucine, valine, and isoleucine), with the enantiomeric excess dependent on the degree of protonation of the amino/carboxylic acid moiety.

[Arterial infusion chemotherapy for liver metastases from colorectal cancer--therapeutic effects of different protocols].

The therapeutic effects of different protocols for arterial infusion chemotherapy were compared in patients with multiple liver metastases from colorectal cancer. A total of 49 patients with colorectal multiple liver metastases treated in our hospital since 1988 were the subjects. In order to compare the therapeutic effects on the regression of cancer and the survival rate, the subjects were assigned into Groups A-D, which were treated using different protocols. Group A received ADR, EPI, CDDP or 5-FU alone at first. If this drug was not effective, it was replaced with another of those mentioned here, and so on. Group B received CDDP 50 mg on day 1, 5-FU 500 mg/day from day 2 to day 7 and 5-FU 500 mg/day for 2 weeks thereafter (FP treatment). Group C received CDDP 50 mg at the time of reservoir insertion and 5-FU 1,000 mg for 5 hours thereafter (WHF treatment). Group D received 5-FU 1,000 mg for 24 hours on day 1, day 3, and day 5 of every week with combination of CDDP 5-10 mg/day from day 1 to day 5 and none on day 6 and day 7 (intermittent F + low-dose P treatment) for 3 weeks. The response rate was 33% for Group A (n = 18), 46% for Group B (n = 13), 25% for Group C (n = 8) and 80% for Group D (n = 10), showing significant differences between Group D and other groups. The 1-year survival rate was 50% for Group A, 46% for Group B, 29% for Group C and 89% for Group D. Significant differences in survival rate were found between Group B and D, and Group C and D.

Navigation system for neurosurgery with PC platform.

This paper presents a navigation system for a surgical microscope and an endoscope which can be used for neurosurgery. In this system, a wireframe model of a target tumor and other significant anatomical landmarks are superimposed in real-time onto live video images taken from the microscope and the endoscope. The wireframe model is generated from a CT/MRI slice images. Overlaid images are simultaneously displayed in the same monitor using the picture-in-picture function so that the surgeon can concentrate on the single monitor during the surgery. The system measures the position and orientation of the patient using specially designed non-contact sensing devices mounted on the microscope and the endoscope. Based on this real-time measurement, the system displays other useful information about the navigation as well as the rendered wireframe. The accuracy of registration between the wireframe model and the actual live view is less than 2 mm. We tested this system in actual surgery several times, and verified its performance and effectiveness.

Triple carcinomas of the biliary tract associated with congenital choledochal dilatation and pancreaticobiliary maljunction.

We report a rare case of triple carcinomas of the biliary tract associated with congenital choledochal dilatation (CCD) and pancreaticobiliary maljunction (PBM). The patient was a 58-year-old Japanese man who complained of epigastralgia. Ultrasonography and computed tomography revealed an elevated lesion inside the markedly dilated extrahepatic bile duct, thickening of the gallbladder wall, and small polypoid lesions in the gallbladder. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed CCD and PBM. With a diagnosis of carcinoma of the bile duct and cholesterol polyps in the gallbladder, pylorus-preserving pancreaticoduodenectomy was performed. The resected specimen showed two elevated lesions in the dilated bile duct, cholesterol polyps, and an area of irregular mucosa in the gallbladder. Histopathological examination showed two carcinomas in the bile duct, an adenosquamous cell carcinoma, and a moderately differentiated tubular adenocarcinoma, and a well differentiated tubular adenocarcinoma of the gallbladder. Two years and 6 months after the operation, a solitary metastatic liver tumor was detected. Left hepatic lobectomy was performed. At present, 7 months after the second operation, the patient is doing well with no signs of recurrence. Multiple carcinomas in the biliary tract associated with CCD and PBM, including the details in the present patient, were reviewed.

Minimally invasive lung and pleural biopsies using 2-mm and standard thoracoscopic equipment.

Videoendoscopic surgery is commonly used to obtain a definitive diagnosis in a patient with pleural lesions or pulmonary infiltration of unknown etiology. We have performed minimally invasive pleural and lung biopsies, using 2-mm mini-videoscopic instruments supported by standard thoracoscopy via one 11.5-mm port, in 10 patients. These involved 8 patients with diffuse pulmonary infiltration, and two with diffuse pleural thickening. They underwent thoracoscopic pulmonary wedge resection and pleural biopsy using one 11.5-mm port and two or three 2-mm mini-ports. The mean operating time was 37 minutes. This procedure was successful in establishing a definitive diagnosis in each patient. Complications included subacute acceleration in pulmonary infiltration in one patient. No patient complained of pain or discomfort at the 2 mm-thoraco port sites. Healing of this port site resulted in excellent cosmesis. Mini-videoscopic surgery supported by standard thoracoscopic equipment can be used to perform lung or pleural biopsy less invasively than standard thoracoscopic approach.

Identification of surface residues of the monocyte chemotactic protein 1 that affect signaling through the receptor CCR2.

The CC chemokine, monocyte chemotactic protein, 1 (MCP-1) functions as a major chemoattractant for T-cells and monocytes by interacting with the seven-transmembrane G protein-coupled receptor CCR2. To identify which residues of MCP-1 contribute to signaling though CCR2, we mutated all the surface-exposed residues to alanine and other amino acids and made some selective large changes at the amino terminus. We then characterized the impact of these mutations on three postreceptor pathways involving inhibition of cAMP synthesis, stimulation of cytosolic calcium influx, and chemotaxis. The results highlight several important features of the signaling process and the correlation between binding and signaling: The amino terminus of MCP-1 is essential as truncation of residues 2-8 ([1+9-76]hMCP-1) results in a protein that cannot stimulate chemotaxis. However, the exact peptide sequence may be unimportant as individual alanine mutations or simultaneous replacement of residues 3-6 with alanine had little effect. Y13 is also important and must be a large nonpolar residue for chemotaxis to occur. Interestingly, both Y13 and [1+9-76]hMCP-1 are high-affinity binders and thus affinity of these mutants is not correlated with ability to promote chemotaxis. For the other surface residues there is a strong correlation between binding affinity and agonist potency in all three signaling pathways. Perhaps the most interesting observation is that although Y13A and [1+9-76]hMCP are antagonists of chemotaxis, they are agonists of pathways involving inhibition of cAMP synthesis and, in the case of Y13A, calcium influx. These results demonstrate that these two well-known signaling events are not sufficient to drive chemotaxis. Furthermore, it suggests that specific molecular features of MCP-1 induce different conformations in CCR2 that are coupled to separate postreceptor pathways. Therefore, by judicious design of antagonists, it should be possible to trap CCR2 in conformational states that are unable to stimulate all of the pathways required for chemotaxis.

[Efficacy of intra-arterial chemotherapy on life prolongation in patients with hepatic metastasis from colorectal cancer].

The efficacy of intra-arterial chemotherapy for life prolongation was investigated in patients with hepatic metastasis from colorectal cancer who visited our hospital from Jan. 1989-Mar. 1999, but without any other remote metastasis when the presence of their hepatic metastasis was detected. The subjects were assigned to 4 groups; group A (n = 8) was only treated by hepatectomy, group B (n = 27) by intra-arterial chemotherapy combined with hepatectomy, group C (n = 42) with intra-arterial chemotherapy alone, and group D (n = 23) by systemic chemotherapy through intra-venous or oral administration. The survival rates of these groups were determined, and the recurrence risk after hepatectomy was compared between group A and B. Further, the survival rate of the patients treated by intra-arterial chemotherapy was compared between the cases of PD and not-PD (including CR, PR, and NC). The median survival in cases of H1 and H2 was 405 days for group A, 1,018 days for group B and 245 days for group C, showing that group B had a significantly more favorable prognosis than either group A or group C. There were also significant differences in the median survival of H3 cases between group C (422 days) and group D (113 days). One-year cumulative recurrence risks in the residual livers of group A and group B were 79% and 28%, respectively. Thus, significant differences in the recurrence risk were found in the two groups. Meanwhile, the median survival of PD and non-PD cases was 240 and 588 days, respectively. These results suggested that local control by intra-arterial chemotherapy is useful for life prolongation.

Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells.

The ST2 gene encodes receptor-like molecules that are very similar to the type I interleukin-1 receptor. Two distinct types of the ST2 gene products, ST2 (a soluble secreted form) and ST2L (a transmembrane form) are produced by alternative splicing. Here we demonstrate that the human ST2 gene has two alternative promoters followed by distinct noncoding first exons, which are located more than 8 kb apart and are spliced to the common exon 2 containing the translation initiation site. Within 1001 bp upstream of the transcription initiation site of the cloned distal promoter, there are four GATA-1. The main promoter used for the expression of the ST2 gene in UT-7, a human leukaemic cell line, is distinct from that in TM12, a human fibroblastic cell line. Although UT-7 cells use both distal and proximal promoters, the distal promoter is used dominantly for expression of both ST2 and ST2L mRNA. On the other hand, almost all transcription in TM12 cells starts from the proximal promoter. These results contrast with those of former studies on the rat system, in which ST2 and ST2L mRNA were generated by use of the proximal and distal promoters, respectively. Furthermore, UT-7 cells use multiple transcription initiation sites in both the proximal and distal promoters, whereas the transcription of the ST2 gene in TM12 cells starts at a unique site. Intriguingly, these results suggest that ST2 and ST2L proteins have distinct functions in different cells within different biological systems, such as those of growth control, differentiation and immunological responses.

Surgical management of idiopathic tracheal stenosis.

Most nonmalignant upper tracheal stenoses are caused by prolonged endotracheal intubation or tracheostomy, and idiopathic stenosis is uncommon. A 43-year-old woman complained of increasing shortness of breath during exercise over a year prior to admission. She had no significant past medical history, including endotracheal intubation. Bronchoscopy and tracheal tomography revealed nonmalignant circumferential upper tracheal stenosis 20 mm long. Single-stage surgical resection with cricotracheal anastomosis completely relieved her respiratory symptoms. Idiopathic tracheal stenosis is extremely rare, and the treatment of choice is surgery.

Successful surgical treatment for implanted intraperitoneal metastases of ruptured small hepatocellular carcinoma: report of a case.

We report herein the case of a 53-year-old man with disseminated intraperitoneal metastases caused by the rupture of small hepatocellular carcinoma (HCC). He was admitted to our hospital in shock after suffering a trauma injury to the upper abdomen. Ultrasonography revealed a massive hemoperitoneum. At surgery, 4000 ml of blood was drained from the abdominal cavity and a ruptured tumor, 2 cm in diameter, was found in the right lobe of the liver. The tumor was resected with an adequate surgical margin and subsequent microscopic examination confirmed a diagnosis of moderately differentiated HCC without associated liver cirrhosis. The patient was readmitted 14 months later following the development of right lower quadrant pain. Ultrasonography and computed tomography revealed extrahepatic abdominal tumors, and abdominal angiography demonstrated four intraperitoneal tumors. At surgery, four implanted metastases adhered to the greater omentum were found and resected. No other tumors were detected. Microscopically, all four tumors were confirmed as moderately differentiated hepatocellular carcinoma. Ruptured HCC may lead to implanted intraperitoneal metastasis, but rupture of small HCC is very rare. While hepatic resection is the treatment of choice for ruptured HCC, according to our review of the literature, only a few patients have survived long-term after resection of implanted metastasis.