Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aß) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aß is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aß-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. METHODS: We used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aß or LPS and INFγ. RESULTS: We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aß does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aß formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain. CONCLUSIONS: These results suggest that synthetic Aß treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains.

Laparoscopic versus open ventral hernia repair in the elderly: a propensity score-matched analysis.

BACKGROUND: Ventral hernia repair is common in the expanding aging population, but remains challenging due to their frequent comorbidities. The purpose of this study is to compare the surgical outcomes of open vs. laparoscopic ventral hernia repair in elderly patients. METHODS: Patients ≥ 65 years of age that underwent elective open or laparoscopic ventral hernia repair were identified from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. To reduce potential selection bias, propensity scores were created for the likelihood of undergoing laparoscopic surgery based on patients' demographics and comorbidities. Patients were matched based on the logit of the propensity scores. Thirty-day surgical outcomes were compared after matching using Chi-square test for categorical variables and the Wilcoxon Rank-Sum test for continuous variables. RESULTS: 35,079 (71.1%) and 14,270 (28.9%) patients underwent open and laparoscopic ventral hernia repairs, respectively. Laparoscopic surgery was associated with a lower overall morbidity (5.9% vs. 9.1%; p < 0.001) compared to open repair. The incidence of surgical site infections (1.1% vs. 3.5%; p < 0.001), post-operative infections (2.7% vs. 3.6%; p < 0.001), and reoperation (1.7% vs. 2.1%; p = 0.009) were all lower after laparoscopic repair. All other major surgical outcomes were either better with laparoscopy or comparable between both treatment groups except for operative time. CONCLUSION: Although open surgery remains the most prevalent in the elderly population, the results of this study suggest that laparoscopic surgery is safe and associated with a lower risk of overall morbidity, surgical site infections, and reoperation.

Vascular control by infrarenal aortic cross-clamping in placenta accreta spectrum disorders: description of technique.

We describe a novel surgical technique in 31 women with histopathologically confirmed placenta accreta spectrum (PAS) disorders managed by a multidisciplinary team using a prophylactic infrarenal abdominal aortic cross-clamping technique during caesarean hysterectomy. We conclude that this new surgical procedure is a relatively safe technique to potentially control operative blood loss. Our work may stimulate others to develop protocols assessing this innovative technique to improve the surgical outcome of PAS disorders.

Routine chest CT for staging of gastric cancer.

BACKGROUND: International guidelines on clinical staging of gastric cancer recommend the use of chest CT for the detection of pulmonary metastases. This study assessed the clinical value of routine chest CT in the staging of gastric cancer. METHODS: This retrospective study included patients identified from the gastric cancer registry of Chang Gung Memorial Hospital, Linkou, Taiwan. All patients who underwent clinical staging between 2008 and 2014 were included. The pattern, site and number of metastases at initial presentation and after surgery with curative intent were evaluated. Pulmonary metastases were defined as multiple small round pulmonary nodules with a random distribution or of variable size. RESULTS: Some 1669 patients were included, of whom 478 (28·6 per cent) had metastatic disease at clinical presentation. The majority of metastases were to the peritoneum (75·7 per cent of patients) or liver (30·5 per cent), and only 27 patients (5·6 per cent) had pulmonary metastases at presentation, none of which were isolated to the lung. Of these 27 patients, 11 had primary lesions located at the cardia/fundus. In 19 patients the lung metastases were also detected on the staging chest X-ray. After surgery there were 196 cancer recurrences. Some 15 patients (7·6 per cent) had lung metastasis and this was not the only site of metastases in any patient. The prevalence of lung metastasis at presentation of the disease and after surgery was 1·6 and 1·5 per cent respectively. CONCLUSION: This study does not support the routine use of chest CT for staging of gastric cancer as isolated pulmonary metastasis in the absence of other metastatic sites could not be detected.

Survival without peripheral neuropathy after massive acute arsenic poisoning: Treated by 2,3-dimercaptopropane-1-sulphonate.

WHAT IS KNOWN AND OBJECTIVE: Massive acute arsenic poisoning is rare yet potentially life-threatening. 2,3-dimercaptopropane-1-sulphonate (DMPS) appears to have the appropriate chelating property. However, clinical experience on the use of DMPS in massive arsenic poisoning is limited. CASE DESCRIPTION: A 37-year-old woman attempted suicide by ingesting 37.5 g of arsenic trioxide. DMPS was promptly initiated based on history and clinical symptoms. The patient recovered completely, with no complications or side effects of the therapy. WHAT IS NEW AND CONCLUSION: TDMPS is useful for the treatment of massive acute arsenic poisoning.

Neoadjuvant therapy versus upfront surgical strategies in resectable pancreatic cancer: A Markov decision analysis.

BACKGROUND: Neoadjuvant therapy is gaining acceptance as a valid treatment option for borderline resectable pancreatic cancer; however, its value for clearly resectable pancreatic cancer remains controversial. The aim of this study was to use a Markov decision analysis model, in the absence of adequately powered randomized trials, to compare the life expectancy (LE) and quality-adjusted life expectancy (QALE) of neoadjuvant therapy to conventional upfront surgical strategies in resectable pancreatic cancer patients. METHODS: A Markov decision model was created to compare two strategies: attempted pancreatic resection followed by adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy followed by restaging with, if appropriate, attempted pancreatic resection. Data obtained through a comprehensive systematic search in PUBMED of the literature from 2000 to 2015 were used to estimate the probabilities used in the model. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Of the 786 potentially eligible studies identified, 22 studies met the inclusion criteria and were used to extract the probabilities used in the model. Base case analyses of the model showed a higher LE (32.2 vs. 26.7 months) and QALE (25.5 vs. 20.8 quality-adjusted life months) for patients in the neoadjuvant therapy arm compared to upfront surgery. Probabilistic sensitivity analyses for LE and QALE revealed that neoadjuvant therapy is favorable in 59% and 60% of the cases respectively. CONCLUSION(S): Although conceptual, these data suggest that neoadjuvant therapy offers substantial benefit in LE and QALE for resectable pancreatic cancer patients. These findings highlight the value of further prospective randomized trials comparing neoadjuvant therapy to conventional upfront surgical strategies.

CT-guided percutaneous core-needle biopsy of pancreatic masses: comparison of the standard mesenteric/retroperitoneal versus the trans-organ approaches.

AIM: To compare the safety and efficacy of percutaneous computed tomography (CT)-guided core-needle biopsy (CNB) of pancreatic masses traversing the gastrointestinal tract or solid viscera versus trans-mesenteric and retroperitoneal approaches. MATERIALS AND METHODS: CT-guided CNB of pancreatic lesions performed between May 2004 and December 2014 were retrospectively analysed at a single centre. Biopsies were performed using 18- or 20-G needles with a coaxial system. CT images, histopathology reports, medical records, and procedural details for all patients were reviewed to evaluate the biopsy route, complications, and diagnostic accuracy. According to the routes, biopsies were divided into trans-mesenteric, retroperitoneal and trans-organ approaches for comparison. RESULTS: A total of 85 patients, who had undergone 89 CNBs for pancreatic masses were reviewed. The overall sensitivity, specificity, and accuracy of CNB for detecting malignancy via various routes were 88.8%, 100%, and 89.9%, respectively, with a complication rate of 20.2%. Trans-organ biopsies of pancreatic masses (n=22) were performed safely via a direct pathway traversing the stomach (n=14), colon (n=3), small bowel (n=2), liver (n=2), and spleen (n=1). The sensitivity, specificity, and accuracy were 90.5%, 100%, and 90.9%, respectively. In the trans-organ biopsy group, three biopsies (13.6%) resulted in minor haematomas, but no major complications occurred. There were no statistically significant differences in the diagnostic efficacy or complication rate among the different biopsy routes. CONCLUSION: Percutaneous CT-guided CNB using a trans-organ approach is a feasible technique for diagnosing pancreatic malignancy; however, as this series was small, more data is required.

Microstructure analysis of complex CuO/ZnO@carbon adsorbers: what are the limits of powder diffraction methods?

Activate carbon impregnated with a mixture of copper oxide and zinc oxide performs well as active adsorber for NO2 removal in automotive cabin air filters. The oxide-loaded activated carbon exhibits superior long-term stability in comparison to pure activated carbon as has been shown in previous studies. The carbon material was loaded only with 2.5 wt% of each metal oxide. Characterization of the oxide nanoparticles within the pores of the activated carbon is difficult because of the rather low concentration of the oxides. Therefore, a systematic study was performed to evaluate the limits of line profile analysis of X-ray powder diffraction patterns. The method allows evaluation of crystalline domain size distributions, crystal defect concentrations and twinning probabilities of nanoscopic materials. Here, the analysis is hampered by the presence of several phases including more or less amorphous carbon. By using physical mixtures of defined copper oxide and zinc oxide particles with activated carbon, potential errors and limits could be identified. The contribution of the activated carbon to the scattering curve was modeled with a convolution of an exponential decay curve, a Chebyshev polynomial, and two Lorentzian peaks. With this approach, domain size distributions can be calculated that are shifted only by about 0.5-1.0 nm for very low loadings (≤4 wt%). Oxide loadings of 4 wt% and 5 wt% allow very reliable analyses from diffraction patterns measured in Bragg-Brentano and Debye-Scherrer geometry, respectively. For the real adsorber material, mean domain sizes have been calculated to be 2.8 nm and 2.4 nm before and after the NO2 removal tests.

A BODIPY-luminol chemiluminescent resonance energy-transfer (CRET) cassette for imaging of cellular superoxide.

Spectroscopic and in cellulo studies are here reported on the very first BODIPY-luminol chemiluminescent resonance energy-transfer (CRET) cassette where the luminol CL agent is covalently linked to the BODIPY energy-transfer acceptor in a molecular dyad. The efficiency of intramolecular CRET investigated for the BODIPY-luminol dyad was found to be 64% resulting in a dual emissive response. Successful in cellulo biochemiluminescence via CRET was achieved in PMA activated splenocytes.

Trans-organ versus trans-mesenteric computed tomography-guided percutaneous fine-needle aspiration biopsy of pancreatic masses: feasibility and safety.

AIM: To evaluate the safety and efficacy of computed tomography (CT)-guided percutaneous fine-needle aspiration biopsy (FNAB) of pancreatic masses that traverses the gastrointestinal tract or solid viscera. MATERIALS AND METHODS: From January 2002 to December 2012, 144 patients underwent 165 CT-guided biopsies of pancreatic masses. Biopsies were performed using a 21 or 22 G needle. Cytology reports, medical records, and procedure details for all patients were retrospectively reviewed to evaluate the biopsy route, complications, and diagnostic accuracy. RESULTS: Trans-organ biopsies of pancreatic masses were safely performed via a direct pathway traversing the stomach (n = 45), colon (n = 14), jejunum (n = 4), or liver (n = 5). There were five self-limiting mesenteric haematomas along the biopsy route on immediate post-procedure CT and all patients remained asymptomatic. All haematomas occurred after a trans-mesenteric approach rather than passage through abdominal organs. Three patients had acute pancreatitis. There was no significant difference in complications and diagnostic yields between the groups. The sensitivity, specificity, positive predictive value, and negative predictive value of final FNAB cytology for malignancy were 98.3%, 100%, 100% and 71.4%, respectively. The overall accuracy was 98.4%. CONCLUSION: Percutaneous FNAB using the trans-organ approach is a safe and effective technique to diagnose pancreatic malignancy.

Acute respiratory distress syndrome in a pregnant woman with systemic lupus erythematosus: a case report.

When the disease activity of systemic lupus erythematosus (SLE) is controlled appropriately, a pregnant woman who has lupus is able to carry safely to term and deliver a healthy infant. While the physiology of a healthy pregnancy itself influences ventilatory function, acute pulmonary distress may decrease oxygenation and influence both mother and fetus. Though respiratory failure in pregnancy is relatively rare, it remains one of the leading conditions requiring intensive care unit admission in pregnancy and carries a high risk of maternal and fetal morbidity and mortality, not to mention the complexity caused by lupus flare. We report a case of SLE complicated with lupus pneumonitis and followed by acute respiratory distress during pregnancy. Though there is a high risk of maternal and fetal morbidity and mortality, maternal respiratory function improved after cesarean section and treatment of the underlying causes. The newborn had an extremely low birth weight but was well at discharge.

Sleep disruption in tetraplegia: a randomised, double-blind, placebo-controlled crossover trial of 3 mg melatonin.

STUDY DESIGN: Randomised, double-blind, placebo-controlled crossover trial of melatonin supplementation to people with complete tetraplegia. OBJECTIVES: To investigate the effect that 3 mg melatonin supplementation has on objective and subjective sleep, quality of life and mood of people living with complete tetraplegia. SETTING: Austin Hospital Sleep Laboratory and participants' homes, Melbourne, Victoria, Australia. METHODS: Two week run-in followed by 3 week nightly administration of 3 mg melatonin or placebo, 2-week washout and further 3 week administration of the opposite treatment. Four testing sessions were conducted; the last nights of the run-in, treatment and washout periods. Testing sessions involved recording full polysomnography, completing a questionnaire battery and collecting urine and blood samples. The questionnaires assessed mood, sleep symptoms and health-related quality of life, and the urine and plasma samples assayed 6-sulphatoxymelatonin (aMT6s) and melatonin levels, respectively. A sleep diary was completed throughout the study. RESULTS: Eight participants (mean (s.d.): age 49.5 years (16), postinjury 16.9 years (7.1)) were recruited in which seven concluded the protocol. Endogenous-circulating melatonin was significantly higher (P < or = 0.01) following melatonin (urine: 152.94 µg h(-1) (74.51), plasma: 43,554.57 pM (33,527.11)) than placebo (urine: 0.86 µg h(-1) (0.40), plasma: 152.06 pM (190.55)). Subjective sleep improved significantly following melatonin specifically for duration of sleep per night and psychological wellbeing. Objective sleep showed a significant increase in light sleep with melatonin, with all other sleep parameters being unchanged. CONCLUSION: These results suggest that increasing melatonin in people with complete tetraplegia is beneficial, especially for subjective sleep. Investigation of the pharmacokinetics of melatonin metabolism in this population is warranted. SPONSORSHIP: This project is proudly supported by the Transport Accident Commission.

Overexpression of Aurora-C interferes with the spindle checkpoint by promoting the degradation of Aurora-B.

The chromosomal passenger complex (CPC) plays a pivotal role in controlling accurate chromosome segregation and cytokinesis during cell division. Aurora-B, one of the chromosomal passenger proteins, is important for the mitotic spindle assembly checkpoint (SAC). Previous reports noted that Aurora-C is predominantly expressed in male germ cells and has the same subcellular localization as Aurora-B. Increasing evidence indicates that Aurora-C is overexpressed in many somatic cancers, although its function is uncertain. Our previous study showed that the aberrant expression of Aurora-C increases the tumorigenicity of cancer cells. Here, we demonstrate that overexpressed Aurora-C displaces the centromeric localization of CPCs, including INCENP, survivin, and Aurora-B. When cells were treated with nocodazole to turn on SAC, both the Aurora-B protein stability and kinase activity were affected by overexpressed Aurora-C. As a result, the activation of spindle checkpoint protein, BubR1, and phosphorylation of histone H3 and MCAK were also eliminated in Aurora-C-overexpressing cells. Thus, our results suggest that aberrantly expressed Aurora-C in somatic cancer cells may impair SAC by displacing the centromeric localization of CPCs.

A young male adolescent with feminine appearance: diagnosis of 46, XX syndrome neglected for 4 years with gynaecomastia presentation.

Gynaecomastia is common in infancy and adolescent boys, but other inciting causes should be kept in mind and necessitate further evaluation should be conducted to determine any underlying conditions. A 22-year-old unmarried male adolescent visited our endocrinology clinic for feminine appearance despite operations for bilateral gynaecomastia 4 years ago. Physical examination showed inverted triangular distribution of pubic hair, sparse beard, small-sized testes, flaccid short penis and surgical scar of the chest wall. Serum hormones study revealed primary hypergonadotropic hypogonadism, and cytogenetic study disclosed female complement (46, XX). The authors recommend that sexual chromosome abnormality should be considered in patients with hypogonadism to avert androgen deficiency-related complications early and that long-term team care should be provided to improve the patient's health-related quality of life.

Sindbis viral vectors target hematopoietic malignant cells.

Sindbis viral vectors target and inhibit the growth of various solid tumors in mouse models. However, their efficacy against blood cancer has not been well established. Here, we show that Sindbis vectors infect and efficiently trigger apoptosis in mouse BW5147 malignant hematopoietic T-cells, but only at low levels in human lymphoma and leukemia cells (Jurkat, Karpas, CEM, DHL and JB). The Mr 37/67 kD laminin receptor (LAMR) has been suggested to be the receptor for Sindbis virus. However, JB cells, which are infected by Sindbis at low efficiency, express high levels of LAMR, revealing that additional factors are involved in Sindbis tropism. To test the infectivity and therapeutic efficacy of Sindbis vectors against malignant hematopoietic cells in vivo, we injected BW5147 cells intraperitoneally into (C3HXAKR) F1 hybrid mice. We found that Sindbis vectors targeted the tumors and significantly prolonged survival of tumor-bearing mice. We also tested the Sindbis vectors in a transgenic CD4-Rgr model, which spontaneously develop thymic lymphomas. However, infectivity in this model was less efficient. Taken together, these results demonstrate that Sindbis vectors have the potential to target and kill hematopoietic malignancies in mice, but further research is needed to evaluate the mechanism underlining the susceptibility of human lymphoid malignancies to Sindbis therapy.

Management of precancerous lesions prior to conception and during pregnancy: a narrative review of the literature.

Special considerations aiming at preserving reproductive function have to be implemented when treating young patients with precancerous lesions of the lower genital tract. These high-grade lesions may progress into invasive cancer if left untreated. Currently, there are limited data on the impact of vulvar and vaginal precancerous lesions on fertility and its management during pregnancy. However, management and outcomes for cervical lesions have been extensively reported. The main approach for vulvar and vaginal lesions are maintaining anatomical function and cosmetics; whereas, treatment options for cervical precancerous lesions range from observation, cryotherapy or the more aggressive conisation. Gestational age is the most important factor in determining expectant management or surgical intervention. This narrative review draws attention to the relevant aspects of precancerous lesions of the lower genital tract, the potential effects and management prior to conception and during pregnancy.