A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17).

BACKGROUND: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification. PATIENTS AND METHODS: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test. RESULTS: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2. CONCLUSIONS: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.

Impact of COVID-19 on CT-diagnosed acute appendicitis and diverticulitis: was there collateral damage?

AIM: To evaluate the change in diagnosis rates, disease severity at presentation, and treatment of acute appendicitis and diverticulitis during the COVID-19 shutdown. MATERIALS AND METHODS: Following institutional review board approval, 6,002 CT examinations performed at five hospitals for suspected acute appendicitis and/or diverticulitis over the 12 weeks preceding and following the shutdown were reviewed retrospectively. Semi-automated language analysis (SALA) of the report classified 3,676 CT examinations as negative. Images of the remaining 2,326 CT examinations were reviewed manually and classified as positive or negative. Positive cases were graded as non-perforated; perforated, contained; and perforated, free. RESULTS: CT examinations performed for suspected appendicitis and/or diverticulitis decreased from 3,558 to 2,200 following the shutdown. The rates of positive diagnoses before and after shutdown were 4% (144) and 4% (100) for appendicitis and 8% (284) and 7% (159) for diverticulitis (p>0.2 for both). For positive CT examinations, the rates of perforation, hospitalisation, surgery, and catheter drainage changed by -2%, -3%, -2%, and -3% for appendicitis (n=244, p>0.3 for all) and +6% (p=0.2) +9% (p=0.06), +4% (p=0.01) and +1% (p=0.6) for diverticulitis (n=443). CONCLUSION: CT examinations performed for suspected appendicitis or diverticulitis declined after the shutdown, likely reflecting patients leaving urban centres and altered triage of non-COVID-19 patients. The diagnosis rates, disease severity at presentation, and treatment approach otherwise remained mostly unchanged.

Image-guided biopsy in the age of personalised medicine: strategies for success and safety.

Oncology has progressed into an era of personalised medicine, whereby the therapeutic regimen is tailored to the molecular profile of the patient's cancer. Determining personalised therapeutic options is achieved by using tumour genomics and proteomics to identify the specific molecular targets against which candidate drugs can interact. Several dozen targeted drugs, many for multiple cancer types are already widely in clinical use. Molecular profiling of tumours is contingent on high-quality biopsy specimens and the most common method of tissue sampling is image-guided biopsy. Thus, for radiologists performing these biopsies, the paradigm has now shifted away from obtaining specimens simply for histopathological diagnosis to acquiring larger amounts of viable tumour cells for DNA, RNA, or protein analysis. These developments have highlighted the central role now played by radiologists in the delivery of personalised cancer care. This review describes the principles of molecular profiling assays and biopsy techniques for optimising yield, and describes a scoring system to assist in patient selection for percutaneous biopsy.

A multicentre comparative study between laparoscopic and open surgery for intussusception in adults.

AIM: Intussusception in adults is rare and requires surgery in most cases. While abdominal laparoscopic surgery (LS) is becoming more popular, there are few reports on the outcomes of adult intussusception treated with LS. This study compared the feasibility of LS vs open surgery (OS) for adult intussusception. METHOD: We reviewed retrospectively the medical records of adult patients with intussusception from three tertiary hospitals between 2000 and 2016. The patients were divided into LS and OS groups, and their surgical outcomes were compared. RESULTS: Surgery was indicated in 71 patients with intussusception (41 LS and 30 OS). The median age of the patients was 49.0 and 51.5 years in the LS and OS groups, respectively (P = 0.930). Overall, nine (12.7%) patients had a negative laparotomy or laparoscopy with spontaneous reduction of the intussusception. Conversion to OS from LS was necessary in one patient (2.4%). The operative time and intra-operative and postoperative complication rates were not significantly different. However, there were more serious complications such as bowel perforation and major vessel injury in the LS group. The patients in the LS group had a shorter time to first food intake and hospital stay vs patients in the OS group (4.0 vs 6.0 days, P < 0.001, and 7.0 vs 10.5 days, P < 0.001, respectively). CONCLUSION: LS may be feasible for adult intussusception; there may be more severe intra-operative complications than in OS.

The red leg dilemma: a scoping review of the challenges of diagnosing lower-limb cellulitis.

BACKGROUND: Presentations of suspected lower-limb cellulitis are commonly misdiagnoses, resulting in avoidable antibiotic prescribing or hospital admissions. Understanding the challenges posed in diagnosing cellulitis may help enhance future care. OBJECTIVES: To examine and map out the challenges and facilitators identified by patients and health professionals in diagnosing lower-limb cellulitis. METHODS: A scoping systematic review was performed in MEDLINE and Embase in October 2017. Thematic analysis was used to identify key themes. Quantitative data were summarized by narrative synthesis. RESULTS: Three themes were explored: (i) clinical case reports of misdiagnosis, (ii) service development and (iii) diagnostic aids. Forty-seven different pathologies were misdiagnosed, including seven malignancies. Two different services have been piloted to reduce the misdiagnosis rates of lower-limb cellulitis and save costs. Four studies have looked at biochemical markers, imaging and a scoring tool to aid diagnosis. CONCLUSIONS: This review highlights the range of alternative pathologies that can be misdiagnosed as cellulitis, and emerging services and diagnostic aids developed to minimize misdiagnosis. Future work should focus on gaining a greater qualitative understanding of the diagnostic challenges from the perspective of patients and clinicians.

Effect of dietary Spirulina (Arthrospira) platensis on the growth performance, antioxidant enzyme activity, nutrient digestibility, cecal microflora, excreta noxious gas emission, and breast meat quality of broiler chickens.

This study examined the effects of dietary Spirulina (Arthrospira) platensis supplementation on growth performance, antioxidant enzyme activity, nutrient digestibility, cecal microflora, excreta noxious gas emission, organ weight and breast meat quality in broiler chickens. In total, 800 Ross 308 male broiler chickens (1-d-old) were randomly divided into 5 dietary treatments with 10 replicate cages (16 birds/replicate) per treatment for 5 wk. The dietary treatments were a control basal diet without Spirulina or with 0.25, 0.5, 0.75, or 1.0% Spirulina. Body weight gain, feed conversion, and/or European production efficiency index improved linearly with supplementation of Spirulina during d 8 to 21, 22 to 35, and overall d 1 to 35 (P < 0.05). Dietary Spirulina supplementation caused a significant increase in the serum enzyme activity of superoxide dismutase and glutathione peroxidase (linear, P < 0.05). Apparent total tract digestibility of dry matter and nitrogen showed a linear increase in Spirulina supplementation (P < 0.05). Cecal Lactobacillus count linearly increased and excreta ammonia gas emission linearly decreased, as dietary Spirulina supplementation increased (P < 0.05). There were no significant effects on relative organ weight and breast meat quality of broilers fed with Spirulina diets; however, 7 d drip loss linearly decreased in treatment groups fed with Spirulina (P < 0.05). These results indicate that adding Spirulina to the diet of broilers can improve antioxidant enzyme activity, dry matter and nitrogen digestibility, cecal Lactobacillus population, excreta ammonia gas emission, and 7 d drip loss of breast meat. In addition, dietary inclusion of 1.0% Spirulina powder might provide a good alternative to improve broiler chicken production.

Effects of Enterococcus faecium SLB 120 on growth performance, blood parameters, relative organ weight, breast muscle meat quality, excreta microbiota shedding, and noxious gas emission in broilers.

This 5-week study was conducted to determine the effects of Enterococcus faecium (SLB 120) on growth performance, blood parameters, relative organ weight, breast muscle meat quality, excreta microbiota shedding, and noxious gas emission in broilers. A total of 816 one-day-old male broilers were allocated to 4 groups with 12 replications (17 broilers/pen) according to body weight (43.2 ± 0.32 g). Dietary treatment groups were: (1) CON, basal diet, (2) T1, CON + 0.05% E. faecium, (3) T2, CON + 0.10% E. faecium, (4) T3, CON + 0.20% E. faecium. From day 1 to 21, dietary E. faecium supplementation showed linear increase (P < 0.05) in gain:feed ratio. From day 21 to 35 and the overall period, dietary E. faecium supplementation showed a linear increase (P < 0.05) in body weight gain and gain:feed ratio. On day 35, dietary E. faecium supplementation showed a linear increase (P < 0.05) in the apparent total tract digestibility of dry matter and nitrogen, and the relative weight of bursa of Fabricius; no differences were observed in white blood cells, red blood cells or lymphocyte counts. Dietary E. faecium supplementation showed a linear decrease (P < 0.05) in excreta E.coli counts on day 7 and 35, while excreta Lactobacillus counts were linearly increased (P < 0.05) on day 35. On day 35, dietary E. faecium supplementation linearly decreased (P < 0.05) excreta NH3, H2S, and total mercaptans emission, but only H2S emission was linearly decreased (P < 0.05) on day 7. In conclusion, the supplementation of E. faecium improved growth performance, the digestibility of dry matter and nitrogen, the relative weight of bursa of Fabricius, and shifted excreta microbiota by increasing Lactobacillus and decreasing E.coli counts, as well as decreased excreta NH3, H2S, and total mercaptans gas emission.

A randomized, multi-center, open-label, phase III study of once-per-cycle DA-3031, a pegylated G-CSF, in comparison with daily filgrastim in patients receiving TAC chemotherapy for breast cancer.

PURPOSE: This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy for breast cancer in terms of the duration of severe neutropenia (DSN). METHODS: Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 µg/m2/day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle. RESULTS: The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = -0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm3 and 161.75/mm3 for the filgrastim and DA-3031 groups, respectively; P = 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively; P = 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug. CONCLUSIONS: DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.

Effects of multistrain probiotics on growth performance, nutrient digestibility, blood profiles, faecal microbial shedding, faecal score and noxious gas emission in weaning pigs.

This experiment was conducted to investigate the efficacy of multistrain probiotics in weaning pigs. A total of 125 28-day-old weaning pigs [(Landrace × Yorkshire) × Duroc] with an initial average body weight (BW) of 7.26 ± 0.76 kg were randomly allotted into 5 treatments, 5 replicate pens/treatment with 5 pigs/pen for 42-day experiment. Dietary treatments were as follows: CON, basal diet; PC1, CON + 0.01% multistrain probiotics; PC2, CON + 0.03% multistrain probiotics; PC3, CON + 0.06% multistrain probiotics; PC4, CON + 0.1% multistrain probiotics. On day 14, pigs fed the PC4 diet had higher BW gain than pigs fed the CON diet. On day 42, pigs fed multistrain probiotics supplementation diets had higher BW gain than pigs fed the CON diet. From days 1 to 14, pigs fed the PC2, PC3 and PC4 diets had higher (p < 0.05) ADG than pigs fed the CON diet. From day 15 to 42, pigs fed the multistrain probiotics supplementation diets had higher (p < 0.05) average daily gain (ADG) and gain: feed ratio (G:F) than pigs fed the CON diet. In the overall period, pigs fed the multistrain probiotics supplementation diets had higher (p < 0.05) ADG and pigs fed the PC2 and PC4 diets had higher (p < 0.05) G:F than pigs fed the CON diet. On day 42, pigs fed the PC4 diet had higher (p < 0.05) apparent total tract digestibility (ATTD) of dry matter (DM), nitrogen (N) and gross energy (GE), faecal Lactobacillus counts and lower (p < 0.05) E. coli counts and NH3 emission than pigs fed the CON diet. Pigs fed the multistrain probiotics supplementation diets had lower (p < 0.05) H2 S and total mercaptans emissions than pigs fed the CON diet. Conclusions, dietary supplementation with 0.1% probiotics improved growth performance, nutrition digestibility and intestinal microflora balance and decreased faecal noxious gas emissions in weaning pigs.

Airborne formaldehyde causes skin barrier dysfunction in atopic dermatitis.

BACKGROUND: It remains to be elucidated whether exposure to air pollutants aggravates atopic dermatitis (AD). OBJECTIVES: This study aimed to evaluate the effects of exposure to formaldehyde for 1 h and 2 h on skin barrier function in both the control and the AD groups. METHODS: In 41 patients with AD and 34 healthy children, a provocation test was performed in which two different areas of normal-appearing skin on the forearm were stimulated with airborne formaldehyde at 500 µg m(-3) or placebo for 2 h. We measured transepidermal water loss (TEWL) and skin pH, and calculated the percentage change from baseline. RESULTS: Exposure to formaldehyde increased TEWL in the control group [P < 0·001; median of difference 1·4; interquartile range (IQR) 0·9-1·6] and in the AD group (P < 0·001; median of difference 2·5; IQR 2·0-3·6). The percentage change of TEWL after formaldehyde exposure in the AD group was higher than in the control group (P < 0·001), whereas exposure to placebo showed no differences between both groups. The AD group also demonstrated a higher percentage increase in skin pH after exposure to formaldehyde than the control group (P < 0·001). CONCLUSIONS: Short-term exposure to formaldehyde causes skin barrier dysfunction in both healthy children and children with AD, and this effect is more prominent in children with AD.

Effect of phytogenics on growth performance, fecal score, blood profiles, fecal noxious gas emission, digestibility, and intestinal morphology of weanling pigs challenged with Escherichia coli K88.

Phytogenic feed additives have become attractive alternatives for use in animal diets. The objective of the present study was to evaluate the effect of a phytogenic-based feed additive on growth performance, nutrient digestibility, blood profiles, fecal noxious gas emission, and intestinal morphology of weaning pigs after dietary challenge with E. coli K88. A total of 120 crossbred pigs [(Yorkshire×Landrace)×Duroc)] with an initial body weight (BW) of 6.09±0.96 kg (21 d of age) were assigned randomly to 1 of the 4 dietary treatments. Each pen housed 5 pigs, and there were 6 pens/treatment. Treatments included: T1, negative control (without antibiotics); T2, T1+antibiotic; T3, T1+0.05% phytogenics; and T4, T1+0.2% commercial mix of organic acids. Overall, the average daily gain (ADG) with the T3 treatment was higher (P<0.05). At wk 1, the apparent total tract digestibility (ATTD) of dry matter (DM) was increased (P<0.05) with T4 treatment. The ATTD of ash with T3 and T4 treatments was greater (P<0.05). At wk 3, pigs fed with the T4 diet had a significantly higher (P<0.05) ATTD of DM. The ATTD of ash and calcium (Ca) was significantly increased (P<0.05) with the T4 treatment. Pigs fed with the T3 diet had a higher (P<0.05) ATTD of phosphorus (P). At wk 6, the ATTD of ash was significantly increased (P<0.05) with the T1 and T3 treatments. The data indicate that phytogenics positively affect growth performance of weaning pigs, indicating that their use as an alternative in the diets of weaning pigs can significantly improve ADG, under challenge with E.coli K88.

NOD2 Mediates Odontoblast Differentiation and RANKL Expression.

The precise regulation of odontoblast differentiation and osteoclastogenic cytokine expression in human dental pulp cells (HDPCs) is crucial for the pathology of bacteria-related pulpitis. Although the up-regulation of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been reported in inflamed human dental pulps, the role of NOD2 in the differentiation of HDPCs remains unclear. Here, we show the involvement of NOD2 in odontoblast differentiation together with osteoclastogenic cytokine expression in HDPCs. Treatment with muramyl dipeptide (MDP), a known NOD2-agonist, significantly inhibited odontoblast differentiation of HDPCs, as revealed by reduced ALP activity, osteoblast/odontoblast marker expression, and mineralized nodule formation. Importantly, the forced down-regulation of NOD2 by small interfering RNA (siRNA) recovered MDP-down-regulated odontoblast differentiation. MDP-elicited suppression of odontoblast differentiation resulted from the increased expression of MKP-1 protein and the subsequent decline of MAPKs phosphorylation, which is a prerequisite for odontoblast differentiation. Furthermore, we found that MDP treatment elevated the expression of osteoclastogenic cytokines in HDPCs, which was also reversed by NOD2 silencing. Analysis of these data, taken together, suggests that the regulation of NOD2 expression upon MDP challenge might serve as an intrinsic mechanism that underlies the hindered dentin formation and accelerated dentin resorption in bacterial infection-mediated pulpitis.

Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis.

BACKGROUND: Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. PATIENTS AND METHODS: This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. RESULTS: Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1-2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. CONCLUSION: In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

Endoplasmic reticulum stress modulates nicotine-induced extracellular matrix degradation in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Tobacco smoking is considered to be one of the major risk factors for periodontitis. For example, about half the risk of periodontitis can be attributable to smoking in the USA. It is evident that smokers have greater bone loss, greater attachment loss and deeper periodontal pockets than nonsmoking patients. It has recently been reported that endoplasmic reticulum (ER) stress markers are upregulated in periodontitis patients; however, the direct effects of nicotine on ER stress in regard to extracellular matrix (ECM) degradation are unclear. The purpose of this study was to examine the effects of nicotine on cytotoxicity and expression of ER stress markers, selected ECM molecules and MMPs, and to identify the underlying mechanisms in human periodontal ligament cells. We also examined whether ER stress was responsible for the nicotine-induced cytotoxicity and ECM degradation. MATERIAL AND METHODS: Cytotoxicity and cell death were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay and flow cytometric annexin V and propidium iodide staining. The mRNA and protein expressions of MMPs and ER markers were examined by RT-PCR and western blot analysis. RESULTS: Treatment with nicotine reduced cell viability and increased the proportion of annexin V-negative, propidium iodide-positive cells, an indication of cell death. Nicotine induced ER stress, as evidenced by survival molecules, such as phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2α and glucose-regulated protein-78, and apoptotic molecules, such as CAAT/enhancer binding protein homologous protein (CHOP). Nicotine treatment led to the downregulation of ECM molecules, including collagen type I, elastin and fibronectin, and upregulation of MMPs (MMP-1, MMP-2, MMP-8 and MMP-9). Inhibition of ER stress by salubrinal and transfection of CHOP small interfering RNA attenuated the nicotine-induced cell death, ECM degradation and production of MMPs. Salubrinal and CHOP small interfering RNA inhibited the effects of nicotine on the activation of Akt, JNK and nuclear factor-κB. CONCLUSION: These results indicate that nicotine-induced cell death is mediated by the ER stress pathway, involving ECM degradation by MMPs, in human periodontal ligament cells.

The role of pre-operative assessment and ringfencing of services in the control of methicillin resistant Staphlococcus aureus infection in orthopaedic patients.

BACKGROUND: MRSA is a major economic and health issue internationally and as such is of particular importance in the appropriate management of orthopaedic patients. Bone, joint and implant infection can lead to unfavourable outcomes with a long protracted in hospital stay inevitable. The cost for the patient, the hospital and society are substantial. MATERIALS AND METHODS: This study was a review of a prospectively maintained database from our unit over three time points from 2005 to 2007. At each time point a new infection control measure was implemented in an effort to reduce MRSA infections. Total rates of MRSA infection and colonisation in all orthopaedic patients were recorded, before and after separation of trauma and elective services, and after the introduction of a screening pre assessment clinic. RESULTS: 12259 orthopaedic patients were reviewed over the three years. The mean age of MRSA infected patients was 71. A higher proportion of female patients were infected than male patients. The mean length of stay for infected patients was 23.4 days. The rate of infection dropped from 0.49% in 2005 to 0.24%in 2007. After the introduction of these measures there was a substantial reduction in organ space and deep tissue infections. CONCLUSION: The separation of emergency and elective orthopaedic services coupled with effective pre-operative screening has resulted in a significant reduction in MRSA infection despite an ever increasing prevalance.

Mechanical stress-activated immune response genes via Sirtuin 1 expression in human periodontal ligament cells.

Recently, Sirtuin 1 (SIRT1) has been implicated in the molecular control of ageing and immune response. Although the remodelling of periodontal ligament (PDL) in response to mechanical stress (MS) is mediated by several host factors, including cytokines and chemokines, the transmission of mechanical stimuli into specific cellular activity is still not understood fully. This study aimed to investigate the effects of MS, particularly cyclic strain, on immune response genes, as well as SIRT1 and its signal transduction pathways, in human PDL cells. MS up-regulated the expression of SIRT1 and immune response genes encoding cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-1ß], chemokines [IL-8, monocyte cheoattractant protein (CCL)-20], defensins [human ß-defensin (hBD)-2, hBD-3] and Toll-like receptors (TLR-2 and TLR-4) in a force- and time-dependent manner. The SIRT1 inducers resveratrol and isonicotinamide attenuated MS-induced cytokine and chemokine expression, but enhanced the expression of defensins and TLRs. Blockade of SIRT1 activity by the SIRT1 inhibitors sirtinol and nicotinamide and down-regulation of SIRT1 expression by SIRT1 siRNA reduced the stimulatory effects of MS on defensins and TLRs, but increased its effects on cytokines and chemokines. MS induced activation of protein kinase B (Akt), protein kinase C (PKC), nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Treatment with the anti-oxidants N-acetylcysteine and glutathione inhibited MS-induced reactive oxygen species production and expression of cytokines, chemokines, defensins and TLRs. These results suggest that MS activates human PDL cells to express immune/defence genes encoding cytokines, chemokines, defensins and TLRs via a SIRT1 pathway.

SPA0355, a thiourea analogue, inhibits inflammatory responses and joint destruction in fibroblast-like synoviocytes and mice with collagen-induced arthritis.

BACKGROUND AND PURPOSE: NF-κB has been implicated as a therapeutic target for the treatment of rheumatoid arthritis. We previously synthesized a thiourea analogue, SPA0355, which suppressed NF-κB activity. Here we have assessed the anti-inflammatory and anti-arthritic effects of SPA0355. EXPERIMENTAL APPROACH: We evaluated the effects of SPA0355 on human rheumatoid fibroblast-like synoviocytes in vitro and on collagen-induced arthritis (CIA) in mice in vivo. KEY RESULTS: In vitro experiments demonstrated that SPA0355 suppressed chemokine production, matrix metalloproteinase secretion and cell proliferation induced by TNF-α in rheumatoid fibroblast-like synoviocytes. In addition, SPA0355 inhibited osteoclast differentiation induced by macrophage colony-stimulating factor and the receptor activator of NF-κB ligand, in bone marrow macrophages. Mice with CIA that were pretreated with SPA0355 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiological and histopathological findings, and inflammatory cytokine levels, than mice treated with vehicle. Mice treated with SPA0355, after the onset of CIA, also showed significantly decreased disease incidence and joint oedema. The in vitro and in vivo protective effects of SPA0355 were mediated by inhibition of the NF-κB signalling pathway. CONCLUSION AND IMPLICATIONS: Taken together, these results suggested that using SPA0355 to block the NF-κB pathway in rheumatoid joints reduced both the inflammatory responses and tissue destruction. Therefore, SPA0355 may have therapeutic value in preventing or delaying joint destruction in patients with rheumatoid arthritis.

Sigmoid colon fistula following totally extraperitoneal hernioplasty: an improper treatment for mesh infection or iatrogenic injury?

BACKGROUND: There are only a few reports of severe mesh-related complications, and major bowel complications after totally extraperitoneal (TEP) hernioplasty are also rare. CASE REPORT: A 75-year-old male patient, who had undergone TEP hernioplasty for a left inguinal hernia 2 months previously, presented with a left inguinal swelling that was found to be due to sigmoid colon-related mesh complications following TEP hernioplasty. CONCLUSIONS: Infection is an accepted complication of hernia operation; however, it may be more serious following laparoscopic techniques. Successful TEP hernioplasty requires adequate dissection and complete exposure and coverage of all potential sites that cause inguinal hernia. If infection and suppuration are resistant to conservative methods or occur in the early postoperative period, aggressive imaging study and treatment provides definitive treatment and reduces the burden of complications.

Gynecologic imaging: current and emerging applications.

Common diagnostic challenges in gynecology and the role of imaging in their evaluation are reviewed. Etiologies of abnormal uterine bleeding identified on pelvic sonography and sonohysterography are presented. An algorithmic approach for characterizing an incidentally detected adnexal mass and use of magnetic resonance imaging for definitive diagnosis are discussed. Finally, the role of F18-fluorodeoxyglucose positron emission tomography in the management of gynecological malignancies, and pitfalls associated with their use are examined.