Impact of antimicrobial treatment duration on outcome of Staphylococcus aureus bacteraemia: a cohort study.

OBJECTIVES: To assess the outcome of Staphylococcus aureus bacteraemia (SAB) according to factors associated with necessity for longer treatment in conjunction with the duration of treatment. METHODS: We prospectively collected the data of patients with SAB consecutively during 12 to 39 months from 11 hospitals. If multiple episodes of SAB occurred in one patient, only the first episode was enrolled. Factors associated with necessity for longer treatment were defined as follows: persistent bacteraemia, metastatic infection, prosthesis and endocarditis. If any of the factors were present, then the case was defined as longer antibiotic treatment warranted (LW) group; those without any factors were defined as shorter antibiotic treatment sufficient (SS) group. Poor outcome was defined as a composite of 90-day mortality or 30-day recurrence. Duration of antibiotic administration was classified as <14 or ≥14 days in the SS group and <28 or ≥28 days in the LW group. RESULTS: Among 2098 cases, the outcome was analysed in 1866 cases, of which 591 showed poor outcome. The SS group accounted for 964 cases and the LW group for 852. On multivariate analysis, age over 65 years, pneumonia, higher Sequential Organ Failure Assessment (SOFA) score and chronic liver diseases were risk factors for poor outcome. Administration of antibiotics less than the recommendation was associated with poor outcome, but this significance was observed only in the LW group (adjusted odds ratio = 1.68; 95% confidence interval, 1.00-2.83; p 0.05). CONCLUSIONS: Inappropriately short antibiotic treatment was associated with poor outcome in the LW group. Vigilant evaluation for risk factors to determine the duration of treatment may improve the outcome among patients with SAB.

Association of high-dose postoperative opioids with recurrence risk in esophageal squamous cell carcinoma: reinterpreting ERAS protocols for long-term oncologic surgery outcomes.

Esophageal squamous cell carcinoma (ESCC) is associated with a poor prognosis and high postoperative recurrence rate. Although postoperative opioid use has been associated with cancer recurrence, its relevance in ESCC has not been determined. Therefore, this study investigated whether high-dose postoperative opioid use was associated with recurrence risk in patients with ESCC. For this retrospective analysis, the medical records of patients who were diagnosed with ESCC and who underwent surgery between January 2006 and December 2010 in the National Cancer Center, Korea were evaluated. Total opioid administration over a 10-day period, from during surgery to postoperative day 9, was calculated. A cutoff value was determined using receiver operating characteristic curve analysis, and patients were classified into the high-use and low-use groups. The primary and secondary outcomes of the study were freedom from recurrence and overall survival, respectively. After propensity score matching, the effect of opioid use on freedom from recurrence and overall survival was evaluated using the Kaplan-Meier method. The final analysis set included 258 patients. The cumulative opioid dose cutoff point was 1783.5 mg of oral morphine. High-dose postoperative opioid use was a significant factor affecting recurrence (Hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.583-2.954; P < 0.0001). In contrast, postoperative opioid use was not associated with death (HR, 1.274; 95% CI, 0.922-1.761; P = 0.1422). In patients with ESCC, compared with low-dose opioid use, high-dose intraoperative and postoperative opioid use was significantly associated with an increased risk of recurrence. However, opioid dosage did not affect overall survival.

Benefits of active middle ear implants over hearing aids in patients with sloping high tone hearing loss: comparison with hearing aids.

In this retrospective chart review we compared the subjective and objective benefits of active middle ear implants (AMEIs) with conventional hearing aids (HAs) in patients with sloping high tone hearing loss. Thirty-four patients with sensorineural hearing loss were treated with AMEIs. Of these, six had sloping high tone hearing loss and had worn an HA for more than 6 months. Objective assessments, a pure-tone audiogram, as well as a word recognition test, and the Korean version of the Hearing in Noise Test (K-HINT), and a subjective assessment, the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire, were performed. Tests were conducted under three circumstances: 1) the unaided state before surgery; 2) the HA-aided state before surgery; and 3) the AMEI-aided state 3 months after surgery. The average high-frequency hearing gain (≥ 2 kHz) was significantly better with AMEIs than with HAs. Although the result had no statistical significance, AMEIs showed a superior word recognition score (WRS) compared to HAs. However, the most comfortable hearing level at which the WRS was tested was significantly decreased with an AMEI compared to an HA. In the K-HINT, patients with an AMEI showed greater recognition than those fitted with an HA under both quiet and noisy conditions. The APAHB scores revealed that patients were more satisfied with an AMEI rather than an HA on all subscales. The use of vibroplasty in patients with sloping high tone loss resulted in positive hearing outcomes when compared to conventional HAs. Based on the data from this study, AMEIs provided better objective and subjective results and could, therefore, be a better alternative for the treatment of sloping hearing loss.

Robot-assisted laparoscopic adenomyomectomy of adenomyotic nodule implanted in the uterine endometrium manifesting as endometrial cancer: a case report and literature review.

Thickened uterine endometrium with abnormal uterine bleeding highly suggests endometrial hyperplasia or endometrial carcinoma. A case of 35-year-old nulliparous woman came to our department with endometrial mass manifesting as endometrial cancer. Transrectal ultrasonography and magnetic resonance imaging (MRI) showed an 8x6 cm multicystic, ill-defined mass compacted at the uterine endometrium, the anterior wall of the uterus, and 3x3 cm heterogenous mass at the left adnexa. The edometrial mass showed multiple septations with enhancement and low-signal intensity on T2-weighted images. After endometrial biopsy was done and simple hyperplasia without atypia was observed at the histopathologic finding, the patient underwent robot-assisted laparoscopy and diagnosed as adenomyoma at the frozen pathology. After adenomyomectomy, permanent pathologic analysis revealed the same result and she recovered without any complications and responded well to gonadotropin-releasing hormone (GnRH) agonist therapy.

Prognostic significance of venous invasion and maximum standardized uptake value of 18F-FDG PET/CT in surgically resected T1N0 esophageal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to analyze the risk factors of recurrence in patients with early stage esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively analyzed the medical records of 190 patients with confirmed T1N0M0 ESCC after curative esophagectomy. The following potential prognostic factors for recurrence were investigated: age, sex, pathologic T category, tumor location, differentiation grade, tumor size, venous invasion, angiolymphatic invasion, perineural invasion and the maximum standardized uptake value (SUVmax) of the primary tumor. RESULTS: There were 174 male and 16 female patients with a median age of 66.0 years (range, 42.0-79.0 years). The pathologic status of the surgically resected ESCCs was T1a in 93 patients (48.9%) and T1b in 97 patients (51.1%). The median number of dissected lymph nodes was 35 (range, 10 to 86), and all lymph nodes were negative for tumors. The multivariate analysis showed presence of venous invasion [HR (hazard ratio), 11.433; P < 0.001) and SUVmax ≥ 3.2 (HR, 2.830; P = 0.011) as independent risk factors for recurrence. The 5-year recurrence-free survival (RFS) was 25.0% for patients with venous invasion and 78.9% for those without (P < 0.001). The 5-year RFS was 67.1% for patients with an SUVmax ≥3.2 and 81.5% for those with an SUVmax <3.2 (P = 0.003). CONCLUSIONS: Venous invasion and high SUVmax could be important prognostic factors coupled with the TNM staging system, in patients with early stage ESCC.

Additive effects of Artemisia capillaris extract and scopoletin on the relaxation of penile corpus cavernosum smooth muscle.

The objective was to investigate the cellular effect and action mechanism of Artemisia capillaris extract (ACE) and its component, scopoletin, on penile corpus cavernosum smooth muscle (PCCSM). In vitro study with PCCSM, the precontracted PCCSM with phenylephrine was treated with ACE or scopoletin. Cyclic nucleotides in the perfusate were measured by radioimmunoassay and expression of protein and mRNA of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase in the perfused PCCSM were measured by western blot and real-time PCR, respectively. The interaction of ACE or scopoletin with udenafil was also evaluated. ACE and scopoletin exerted a significant and concentration-dependent relaxation in PCCSM. The perfusion with ACE or scopoletin significantly increased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and the perfusion with ACE or scopoletin increased the expression of eNOS mRNA and protein. Furthermore, ACE or scopoletin enhanced udenafil-inducing relaxation in PCCSM. ACE and scopoletin relaxed the PCCSM mainly by activating nitric oxide-cGMP system and cAMP pathway and they may be additive therapeutic candidates for ED patients who do not completely respond to udenafil.

The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-ß receptor on dendritic cells potentiates tumour antigen-specific CD8(+) T cell immunity.

Dendritic cells (DCs) are promising therapeutic agents in the field of cancer immunotherapy due to their intrinsic immune-priming capacity. The potency of DCs, however, is readily attenuated immediately after their administration in patients as tumours and various immune cells, including DCs, produce various immunosuppressive factors such as interleukin (IL)-10 and transforming growth factor (TGF)-ß that hamper the function of DCs. In this study, we used small interfering RNA (siRNA) to silence the expression of endogenous molecules in DCs, which can sense immunosuppressive factors. Among the siRNAs targeting various immunosuppressive molecules, we observed that DCs transfected with siRNA targeting IL-10 receptor alpha (siIL-10RA) initiated the strongest antigen-specific CD8(+) T cell immune responses. The potency of siIL-10RA was enhanced further by combining it with siRNA targeting TGF-ß receptor (siTGF-ßR), which was the next best option during the screening of this study, or the previously selected immunoadjuvant siRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or Bcl-2-like protein 11 (BIM). In the midst of sorting out the siRNA cocktails, the cocktail of siIL-10RA and siTGF-ßR generated the strongest antigen-specific CD8(+) T cell immunity. Concordantly, the knock-down of both IL-10RA and TGF-ßR in DCs induced the strongest anti-tumour effects in the TC-1 P0 tumour model, a cervical cancer model expressing the human papillomavirus (HPV)-16 E7 antigen, and even in the immune-resistant TC-1 (P3) tumour model that secretes more IL-10 and TGF-ß than the parental tumour cells (TC-1 P0). These results provide the groundwork for future clinical development of the siRNA cocktail-mediated strategy by co-targeting immunosuppressive molecules to enhance the potency of DC-based vaccines.

Graft-bending angle and femoral tunnel length after single-bundle anterior cruciate ligament reconstruction: comparison of the transtibial, anteromedial portal and outside-in techniques.

We used immediate post-operative in vivo three-dimensional computed tomography to compare graft bending angles and femoral tunnel lengths in 155 patients who had undergone single-bundle reconstruction of the anterior cruciate ligament using the transtibial (n = 37), anteromedial portal (n = 72) and outside-in (n = 46) techniques. The bending angles in the sagittal and axial planes were significantly greater but the coronal-bending angle was significantly less in the transtibial group than in the anteromedial portal and outside-in groups (p < 0.001 each). The mean length of the femoral tunnel in all three planes was significantly greater in the transtibial group than the anteromedial portal and outside-in groups (p < 0.001 each), but all mean tunnel lengths in the three groups exceeded 30 mm. The only significant difference was the coronal graft- bending angle in the anteromedial portal and outside-in groups (23.5° vs 29.8°, p = 0.012). Compared with the transtibial technique, the anteromedial portal and outside-in techniques may reduce the graft-bending stress at the opening of the femoral tunnel. Despite the femoral tunnel length being shorter in the anteromedial portal and outside-in techniques than in the transtibial technique, a femoral tunnel length of more than 30 mm in the anteromedial portal and outside-in techniques may be sufficient for the graft to heal.

Phospholipase D1 decreases type I collagen levels in hepatic stellate cells via induction of autophagy.

Hepatic stellate cells (HSCs) are major players in liver fibrogenesis. Accumulating evidence shows that suppression of autophagy plays an important role in the development and progression of liver disease. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA) and choline, was recently shown to modulate autophagy. However, little is known about the effects of PLD1 on the production of type I collagen that characterizes liver fibrosis. Here, we examined whether PLD1 regulates type I collagen levels in HSCs through induction of autophagy. Adenovirus-mediated overexpression of PLD-1 (Ad-PLD1) reduced type I collagen levels in the activated human HSC lines, hTERT and LX2. Overexpression of PLD1 in HSCs led to induction of autophagy as demonstrated by increased LC3-II conversion and formation of LC3 puncta, and decreased p62 abundance. Moreover, inhibiting the induction of autophagy by treating cells with bafilomycin or a small interfering (si)RNA for ATG7 rescued Ad-PLD1-induced suppression of type I collagen accumulation in HSCs. The effects of PLD on type I collagen levels were not related to TGF-ß/Smad signaling. Furthermore, treatment of cells with PA induced autophagy and inhibited type I collagen accumulation. The present study indicates that PLD1 plays a role in regulating type I collagen accumulation through induction of autophagy.

Clinical impact of microscopic extrathyroidal extension in patients with papillary thyroid microcarcinoma treated with hemithyroidectomy.

BACKGROUND: Pathologically confirmed microscopic extrathyroidal extension (ETE) is often identified after hemithyroidectomy in patients with papillary thyroid microcarcinoma (PTMC). Without the presence of microscopic ETE, these patients would be optimal candidates for hemithyroidectomy. AIM: The present study aimed at evaluating the clinical impact of microscopic ETE on the recurrence of PTMC treated with hemithyroidectomy. SUBJECTS AND METHODS: We compared the clinicopathological characteristics and 5-year outcomes for 262 PTMC patients without ETE and 86 with microscopic ETE who were treated with hemithyroidectomy between January 2004 and December 2010. RESULTS: The mean tumour size was larger (0.67 vs. 0.54 cm, p < 0.001) and the proportion of tumours measuring ≥0.5 cm was higher (84.9 vs. 66.8 %, p = 0.001) in patients with microscopic ETE as compared with patients without ETE. Occult multifocal disease was more frequent in patients with microscopic ETE than in those without ETE (14.0 vs. 6.5 %, p = 0.030). However, the recurrence rate was not different between the two groups during the mean 55.8-month follow-up period. In addition, univariate and multivariate analyses revealed no meaningful association between recurrence and microscopic ETE in patients with PTMC treated with hemithyroidectomy. CONCLUSIONS: Although microscopic ETE was associated with large tumour size and multifocal disease, its clinical impact on disease recurrence was not significant in PTMC patients treated with hemithyroidectomy. Therefore, microscopic ETE identified after hemithyroidectomy would not be an absolute indication for completion thyroidectomy in patients with PTMC.

Alpha-amylase is a human salivary protein with affinity to lipopolysaccharide of Aggregatibacter actinomycetemcomitans.

Aggregatibacter actinomycetemcomitans lipopolysaccharide (Aa.LPS) is a major virulence factor associated with aggressive periodontitis. Although the recognition of Aa.LPS is potentially initiated by salivary proteins in the oral cavity, Aa.LPS-binding proteins (Aa.LPS-BPs) in saliva are poorly characterized. The purpose of this study was to capture and identify Aa.LPS-BPs in human saliva using a LTQ-Orbitrap hybrid Fourier transform mass spectrometry. Aa.LPS conjugated onto N-hydroxysuccinimidyl-Sepharose(®) 4 Fast Flow beads (Aa.LPS-beads) activated Toll-like receptor 4 and produced nitric oxide and Interferon gamma-inducible protein-10, implying that the conjugation process did not alter the biological properties of Aa.LPS. Aa.LPS-BPs were subsequently isolated from the nine human saliva samples from healthy individuals with the Aa.LPS-beads followed by identification with the mass spectrometry. Aa.LPS-BPs include α-amylase, serum albumin, cystatin, lysozyme C, submaxillary gland androgen-regulated protein 3B, immunoglobulin subunits, polymeric immunoglobulin receptor, deleted in malignant brain tumors 1, prolactin-inducible protein, lipocalin-1, and basic salivary proline-rich protein 2. Specific binding was validated using a pull-down assay with α-amylase which was captured at the highest frequency. Alpha-amylase demonstrated to interfere with the adherence and biofilm formation of A. actinomycetemcomitans. Even heat-inactivated α-amylase showed the interference to the same extent. Conclusively, we identified unique Aa.LPS-BPs that provide useful information to understand bacterial pathogenesis and host innate immunity in the oral cavity.

Injectable hyaluronic acid-tyramine hydrogels for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease caused by inflammation of the synovial membrane, leading in turn to articular cartilage destruction. In this work, injectable tyramine modified hyaluronic acid (HA-Tyr) hydrogels were developed for the treatment of RA. HA-Tyr conjugate was synthesized by amide bond formation between carboxyl groups of HA and amine groups of tyramine. Then, HA-Tyr hydrogels were prepared by radical crosslinking reaction using H(2)O(2) and horse-radish peroxidase. Intra-articular injection of HA-Tyr hydrogels encapsulating dexamethasone (DMT) as a model drug resulted in successful treatment of RA with reduced interlukine-6, prostaglandin E2 and four types of cytokine levels in collagen-induced arthritis animal models. Histological analysis with hematoxylin and eosin (H&E) staining also confirmed the therapeutic effect of injectable HA-Tyr hydrogels with DMT. Taken together, the injectable HA-Tyr hydrogels were thought suitable to be developed as a therapeutically effective drug carrier for the treatment of RA.

Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells.

The expression of hypoxia-inducible factor-1 (HIF-1) correlates with poor clinical outcomes and confers resistance to the apoptosis of the tumor cells that are exposed to hypoxia. Presently, the mechanism underlying this phenomenon is poorly understood. In this study we provide evidence that transglutaminase 2 (TG2), an enzyme that catalyses protein crosslinking reactions, is a transcriptional target of HIF-1 to enhance the survival of hypoxic cells. We found that hypoxia induces TG2 expression through an HIF-1 dependent pathway and concurrently activates intracellular TG2. The hypoxic cells overexpressing TG2 showed resistance to apoptosis. Conversely, the hypoxic cells treated with either TG2 inhibitor or small interfering RNA (siRNA) became sensitive to apoptosis. Activation of TG2 in response to hypoxic stress inhibited caspase-3 activity by forming crosslinked multimer, resulting in insoluble aggregates. TG2 also activates nuclear factor (NF)-kappaB pathway after hypoxic stress, and thereby induces the expression of cellular inhibitor of apoptosis 2. The anti-apoptotic role of TG2 was further confirmed in vivo using xenografts in athymic mice. Our results indicate that TG2 is an anti-apoptotic mediator of HIF-1 through modulating both apoptosis and survival pathways and may confer a selective growth advantage to tumor cells. These findings suggest that the inhibition of TG2 may offer a novel strategy for anticancer therapy.

VDUP1 potentiates Ras-mediated angiogenesis via ROS production in endothelial cells.

Vitamin D3 up-regulated protein 1 (VDUP1) is a tumor suppressor of which expression is reduced in a variety of cancer cells, and enforced expression inhibits the tumor cell proliferation. It inhibits the activity of thioredoxin, thus contributing cellular ROS generation. Since ROS is a critical factor for angiogenesis, we investigated the role of VDUP1 in angiogenesis and endothelial proliferation. The expression of VDUP1 was upregulated by overexpression of an oncogene, Ras. Enforced expression of VDUP1 increases ROS production and proliferation of Ras-overexpressing endothelial cells. Overexpression of VDUP1 increases the resistance to the anchorage-dependent cell death and tube formation of the Ras-overexpressing endothelial cell. In addition, the removal of ROS by ROS scavenger attenuates the effect of VDUP1 on tube formation. These results suggest that VDUP1 is involved in Ras-mediated angiogenesis via ROS generation in endothelial cells.

Formulations for intermittent release of parathyroid hormone (1-34) and local enhancement of osteoblast activities.

The objective of these studies was to develop simple, implantable devices that intermittently release PTH(1-34) and thus could be used for locally stimulating bone formation. The formulations were based on the association polymer system of cellulose acetate phthalate and Pluronic F-127. Release profiles for intermittent devices showed five discrete peaks, whereas sustained devices exhibited zero-order kinetics. Osteoblastic activity was greater for cells intermittently treated with PTH(1-34) compared to sustained exposure. These controlled release devices delivering PTH(1-34) in an intermittent manner may be useful for affecting osteoblast activities in a localized area.

Cloning, expression, and characterization of a methionyl aminopeptidase from a hyperthermophilic archaeon Thermococcus sp. NA1.

Genomic analysis of a hyperthermophilic archaeon Thermococcus sp. NA1 revealed the presence of an 885-bp open reading frame encoding a protein of 295 amino acids with a calculated molecular mass of 32,981 Da. Analysis of the deduced amino acid sequence showed that amino acid residues important for catalytic activity and the metal binding ligands conserved in all of methionyl aminopeptidases (MetAP) were also conserved and belonged to type IIa MetAP. The protein, designated TNA1_MetAP (Thermococcus sp. NA1 MetAP), was cloned and expressed in Escherichia coli. The recombinant enzyme was a Mn(2+)-, Ni(2+)-, Fe(2+)-, or Co(2+)-dependent metallopeptidase. Optimal MetAP activity against L: -methionine p-nitroanilide (Met-pNA) (K (m) = 0.68 mM) occurred at pH 7.0 and 80 to 90 degrees C. The MetAP was very unstable compared to Pyrococcus furiosus MetAP, which was completely inactivated by heating at 80 degrees C for 5 min. It seemed likely that the cysteine residue (Cys53) played a critical role in regulating the thermostability of TNA1_MetAP.

Specimen block counter-staining for localization of GUS expression in transgenic arabidopsis and tobacco.

A simple counter-staining procedure has been developed for comparative beta-glucuronidase (GUS) expression and anatomical localization in transgenic herbaceous arabidopsis and tobacco. This protocol provides good anatomical visualization for monitoring chimeric gene expression at both the organ and tissue levels. It can be used with different histochemical stains and can be extended to the study of woody species. The specimens are paraffin-embedded, the block is trimmed to reveal internal structure, safranin-O staining solution is briefly applied to the surface of the block, then washed off and, after drying, a drop of immersion oil is placed on the stained surface for subsequent photographic work. This gives tissue counter-staining with good structural preservation without loss of GUS staining product; moreover, sample observation is rapid and efficient compared to existing procedures.

[An investigation on the oral surgery patients and their treatments].

The author has studied on the various diseases occurring in the oral and maxillofacial region for the year of 1987 at the Department of Oral & Maxillofacial Surgery, Seoul National University Hospital. The diseases diagnosed and treated have been analyzed according to each disease such as inflammatory, traumatic, cyst, tumor, neoplastic, deformities and so on, in order to get accurate information on the diseases of the oral & maxillofacial region and the information might be helpful to plan the education programmes for students, and interns and residents. The results obtained are as follows; 1. The sex distinction and the percentage of occurrence rate as follow Male 2090 (49.6%) Female 2127 (50.4%) 2. To study compare with the age, both male and female patients showed the highest ratio at the 20-29 age group, and the percentage of the 20-49 age group is 64.1% and the percentage of geriatric patients over 60 years old is 10.2%. 3. To study compare with the month (the patient came first time), August was most abundant in a year. 4. To study compare with the disease, dental-periodontal disease, impacted tooth and eruption abnormality are the most prevalent (51.2%), and next is odontogenic infection (22.4%), cyst & tumor (7.6%), traumatic injury (7.5%), and anomaly or deformity (3.8%). The number of medically compromised patients with oral surgery problems is 183 (4.3%). 5. Classifying the treatments according to the operator group, 1) For students(senior class), simple extraction showed the highest ratio, next is surgical extraction. 2) For interns, simple extraction showed the highest ratio, next is surgical extraction, pre-prosthetic surgery (alveoloplasty and vestibuloplasty).(ABSTRACT TRUNCATED AT 250 WORDS)