Modular megaprosthesis reconstruction for oncological and non-oncological resection of the elbow joint.
Reconstruction of large bone defects around the elbow joint is surgically demanding due to sparse soft tissue coverage, complex biomechanics and the close proximity to neurovascular structures. Modular megaprostheses are established reconstruction tools for the elbow, but only small case series have been reported in the literature. Thirty-six patients who underwent reconstruction of the elbow joint with a modular megaprosthesis were reviewed retrospectively. In 31 patients (86.1%), elbow replacement was performed after resection of a bone tumour, whereas five non-oncological patients (13.9%) underwent surgery because of a previous failed elbow reconstruction. Functional outcome, rate of complications and oncological results were considered as primary endpoints. The mean follow-up was 25 months. The average achieved Mayo Elbow Performance Score (MEPS) was 77.08 (range 40-95) and the average Musculoskeletal Tumor Society (MSTS) score was 22.9 (range 8-30). Six complications (16.7%) were observed: two radial palsies, one temporary radial nerve dysfunction, one ulnar palsy, one disassembling of the articular prosthesis component and one deep infection necessitating the only implant removal. The overall 5-year survival rate of the patients was poor (25.1%) because of rapid systemic progression of the oncological disease in patients with metastatic lesion. However, the 5-year survival rate of the implant was very satisfactory (93%). Modular megaprosthesis is a reliable and effective reconstruction tool in large bone defects around the elbow joint. The complication rates are lower than seen in osteoarticular allografts and allograft-prosthesis composites while the functional outcome is equal. In palliative situations with metastatic disease involving the elbow, modular megaprosthesis enables rapid recovery and pain relief and preserves elbow function.


Renal Resistive Index Measurement by Transesophageal Echocardiography: Comparison With Translumbar Ultrasonography and Relation to Acute Kidney Injury.
The aim of this study was to evaluate the relationship between transesophageal ultrasonography-derived renal resistive index values (RRITEE) and a standard translumbar renal ultrasound-derived RRI (RRITLUSG). The effectiveness of each method to predict acute kidney injury (AKI) after cardiac surgery also was compared. A prospective observational study. A teaching university hospital. Sixty patients undergoing cardiac surgery. First, RRI was measured with both methods after anesthesia induction. Second, another measurement was performed with TEE after cardiopulmonary bypass and immediately following the surgery with translumbar ultrasound. To test the correlation between the 2 methods and to plot a Bland-Altman graph, preoperative RRI values measured by both techniques were used. Receiver operating characteristic curves also were plotted to compare the diagnostic values of RRI measured intraoperatively by TEE after cardiopulmonary bypass and by RRITLUSG after surgery. There was a statistically significant correlation between the 2 RRI measurement approaches (r = 0.86, p<0.0001). The Bland-Altman plot indicated good agreement between the methods. The area under the curve (AUC) of RRITEE in predicting AKI was 0.82 (95% confidence interval [CI] = 0.64-0.9, p = 0.001), and the AUC of RRITLUSG after surgery was 0.85 (95% CI = 0.7-0.98, p<0.0001). In predicting AKI, an uncertainty zone for RRITEE values between 0.68 and 0.71 was computed by the gray-zone approach. RRITEE showed clinically acceptable agreement with RRITLUSG. Indeed, RRI measured intraoperatively with TEE was comparable to RRITLUSG in terms of detecting postoperative AKI.


Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer.
FGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. Expression of FGD4 is altered in patients with heterogeneous hereditary motor and sensory neuropathies as a result of demyelination of peripheral nerves. In this study, we examined the expression of FGD4 in prostate cancer specimens using immunohistochemistry and studied the function of FGD4 in maintaining cell phenotype, behavior and drug sensitivity using overexpression and siRNA-based silencing approaches. We used Mann-Whitney test for comparative analysis of FGD4 expression. Our results show that the expression of FGD4 is upregulated in cancerous prostates compared to the luminal cells in benign prostatic hyperplasia, although the basal cells showed high staining intensities. We noted a gradual increase in the staining intensity of FGD4 with increasing aggressiveness of the disease. Inhibition of expression of FGD4 using siRNAs showed reduced proliferation and cell cycle arrest in G2/M phase of androgen dependent LNCaP-104S and androgen refractory PC-3 cells. Inhibition of FGD4 also resulted in reduced cell migration and CDC42 activities in PC-3 cells whereas, ectopic expression of FGD4 induced cell migration, altered expression of mesenchymal and epithelial markers and activation of CDC42/PAK signaling pathway. Reduced expression of FGD4 improved sensitivity of LNCaP-104S cells to the anti-androgen drug Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel. Our data demonstrate a tumor promoting and a cell migratory function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression enhances the response for both androgen-dependent and independent prostate cancer cells towards currently used prostate cancer drugs.


Educational Colonoscopy Video Enhances Bowel Preparation Quality and Comprehension in an Inner City Population.
Quality of bowel preparation and patient knowledge remains a major barrier for completing colorectal cancer screening. Few studies have tested unique ways to impact patient understanding centering on interactive computer programs, pictures, and brochures. Two studies explored instructional videos but focused on patient compliance and anxiety as endpoints. Furthermore, excessive video length and content may limit their impact on a broad patient population. No study so far has studied a video's impact on preparation quality and patient understanding of the colonoscopy procedure. We conducted a single blinded prospective study of inner city patients presenting for a first time screening colonoscopy. During their initial visit patients were randomized to watch an instructional colonoscopy video or a video discussing gastroesophageal reflux disease (GERD). All patients watched a 6 minutes long video with the same spokesperson, completed a demographic questionnaire (Supplemental Digital Content 1, http://links.lww.com/JCG/A352) and were enrolled only if screened within 30 days of their visit. On the day of the colonoscopy, patients completed a 14 question quiz of their knowledge. Blinded endoscopist graded patient preparations based on the Ottawa scale. All authors had access to the study data and reviewed and approved the final manuscript. Among the 104 subjects enrolled in the study, 56 were in the colonoscopy video group, 48 were in GERD video group, and 12 were excluded. Overall, 48% were male and 52% female; 90% of patients had less than a high school education, 76% were African American, and 67% used a 4 L split-dose preparation. There were no differences between either video group with regard to any of the above categories. Comparisons between the 2 groups revealed that the colonoscopy video group had significantly better Ottawa bowel preparation score (4.77 vs. 6.85; P=0.01) than the GERD video group. The colonoscopy video group also had less-inadequate repeat bowel preparations versus the GERD video group (9% vs. 23%; P<0.01). The overall score on the knowledge questionnaire (Supplemental Digital Content 1, http://links.lww.com/JCG/A352) was significantly higher in the colonoscopy video group as compared with the GERD video group (12.77 vs. 11.08; P<0.001. In all patients the overall quiz score positively correlated with preparation quality (odds ratio, 2.31; confidence interval, 1.35-3.94; P<0.001). Our unique population represented an overwhelmingly under-educated (85% had a high school education or less) and minority group (76% African American). They are one of the most at risk of having multiple barriers such as comprehension and reading difficulties resulting in poor preparation examinations and no shows to procedures. Our instructional video proved to be high yield in this population. The patients assigned to watch the colonoscopy video showed a significant increase in "excellent" grade adequate bowel preparation quality by >23% and a significant decrease in "inadequate" bowel preparations by almost 50%. Our study proves that an educational video can improve both comprehension with regard to all aspects of colonoscopy. ClinicalTrials.gov number, NCT02906969.


Factorial optimization of bleach constituents for silver halide holograms.
A factorial design approach to optimizing rehalogenating bleaches for silver halide holograms is presented. An advantage of this technique is that it allows simultaneous improvement in a number of hologram performance characteristics as a function of several input parameters. Interactive effects of combinations of input parameters can also be examined. A specific experiment is described in which diffraction efficiency, average light loss, thickness change, and noise grating efficiency are optimized as a function rehalogenating agent, oxiding agent, and acid concentrations of a rehalogenating bleach. Results for both Agfa 8E75HD and Ilford SP673 films are presented.


Investigation of the variations in the water leaving polarized reflectance from the POLDER satellite data over two biogeochemical contrasted oceanic areas.
The biogeochemical characterization of marine particles suspended in sea water, is of fundamental importance in many areas of ocean science. Previous studies based on theoretical calculations and field measurements have demonstrated the importance of the use of the polarized light field in the retrieval of the suspended marine particles properties. However, because of the weakness of the water leaving polarized signal and of the limited number of appropriate spatial sensors, such measurements have never been exploited from space. Here we show that the marine polarized remote sensing reflectance, as detected from the POLarization and Directionality of the Earth's Reflectances (POLDER) sensor, can be measured from space over bright waters and in absence of aerosols. This feasibility study is carried out over two oceanic areas characterized by different nature of the bulk particulate assemblage: the Barents sea during an intense coccolithophore bloom, and the Rio de la Plata estuary waters dominated by suspended sediments. The retrieved absolute values of the degree of polarization, P, its angular pattern, and its behavior with the scattering level are consistent with theory and field measurements. Radiative transfer simulations confirm the sensitivity of the POLDER-2 P values to the nature of the particulate assemblage. These preliminary results are very promising for the assessment of the bulk particle composition from remote sensing of the polarized signal, at least over highly scattering waters.


Comparison of 30-day outcomes after emergency general surgery procedures: potential for targeted improvement.
Patients who undergo emergency operations represent a high-risk population and have been shown to have a high risk of poor outcomes. Little is known, however, about the variability in the quality of emergency general surgical care across hospitals or within hospitals across different procedures. The objectives of this study were to identify risk factors associated with adverse events, to compare 30-day outcomes after 3 common emergency general surgery procedures within and across hospitals, and thus, to determine whether the quality of emergency surgical care is procedure-dependent or intrinsic to other aspects of the hospital environment. Patients who underwent emergency appendectomy, cholecystectomy, or colorectal resection at 95 hospitals that submitted at least 20 of each procedure were identified in the 2005-2008 American College of Surgeons National Surgical Quality Improvement Project database. Outcomes of interest included 30-day overall morbidity and serious morbidity/mortality. Step-wise logistic regression generated patient-level predicted probabilities of an outcome. Based on the expected probabilities, observed to expected (O/E) ratios for each outcome, after each of the 3 procedures, were calculated for each hospital. Hospitals were divided into terciles based on O/E ratios. The agreement on hospital outcomes performance for overall morbidity and serious morbidity/mortality after appendectomy, cholecystectomy, and colorectal resection was assessed using weighted kappa statistics. Of the 30,788 appendectomies, 1,984 (6.44%) patients had any morbidity, and 1,140 (3.70%) patients had a serious morbidity or died. Of the 5,824 cholecystectomies, 503 (8.64%) patients had any morbidity, and 371 (6.37%) patients had a serious morbidity or died. Of the 8,990 colorectal resections, 4,202 (46.74%) patients had any morbidity, and 3,736 (41.56%) patients had a serious morbidity or died. For overall morbidity, O/E ratios for appendectomy ranged from 0.26 to 2.36; O/E ratios for cholecystectomy ranged from 0 to 3.04; O/E ratios for colorectal resection ranged from 0.45 to 1.51. For serious morbidity/mortality, O/E ratios for appendectomy ranged from 0.23 to 2.54; O/E ratios for cholecystectomy ranged from 0 to 4.28; O/E ratios for colorectal resection ranged from 0.59 to 1.75. Associations of risk-adjusted hospital outcomes based on tercile rank between procedures demonstrated slight but significant agreement for both overall morbidity (weighted kappa between 0.20 and 0.22) and serious morbidity/mortality (weighted kappa between 0.18 and 0.22). Despite this, 7 (7.4%) hospitals for overall morbidity and 9 (9.5%) hospitals for serious morbidity/mortality were rated in the highest (best) tercile for all procedures. Eight (8.4%) hospitals for overall morbidity and 8 (8.4%) hospitals for serious morbidity/mortality were rated in the lowest tercile for all procedures. Emergency general surgery procedures, particularly colorectal resections, were associated with substantial 30-day overall morbidity and serious morbidity/mortality. Most hospitals did not have consistent risk-adjusted outcomes across all 3 procedures, but for a substantive minority of institutions (7-10%), good or bad performance was generalizable across procedures. Individual hospitals should examine their procedure-specific outcomes after emergency general surgery operations to focus quality improvement initiatives appropriately.


Early onset may predict G101W CDKN2A founder mutation carrier status in Ligurian melanoma patients.
Although the presence of multiple cases of melanoma on the same side of a family is the best predictor of germline CDKN2A mutation, other features (i.e. early age at onset) may be useful to identify carriers. We analysed the records of 682 hospital-based Ligurian melanoma patients. Of these, 238 cases (34 familial, 14 non-familial multiple primary and 190 non-familial single primary melanomas) were consecutively enrolled for screening of the CDKN2A and CDK4 genes. Screening of the 34 familial patients revealed that nine were carriers of the CDKN2A G101W founder mutation. Of the 14 non-familial multiple primary melanoma patients, three carried the G101W founder mutation and one the P48T mutation. For the non-familial patients with a single melanoma, 17 of 190 carried germline CDKN2A mutations, with most (16/17) carrying the G101W Ligurian founder mutation and one a novel single base pair substitution, D74Y. The effect of mutation on age at diagnosis was significant (P=0.012) after correcting for melanoma type (familial or non-familial), number of primaries (single or multiple), gender and disease occurrence (incident or prevalent). Early age at onset may be a good predictor of CDKN2A mutation in Liguria, where the G101W founder mutation is prevalent among melanoma patients, independent of family history.


Characterisation and antimicrobial activity of the volatile components of the flowers of Magydaris tomentosa (Desf.) DC. collected in Sicily and Algeria.
The essential oils of the flowers of Magydaris tomentosa (Desf.) DC. (Apiaceae) collected in Sicily (MSi) and Algeria (MAl), respectively, were obtained by hydrodistillation, and their compositions were analysed. The analyses allowed the identification and quantification of 23 components in MSi and 60 compounds in MAl, respectively, showing a very different profile in the composition of the two populations. The main components of MSi were cembrene (28.2%), α-springene (17.5%) and β-springene (14.8%), also present in MAl but in lesser amount (0.4%, 1.8% and 0.9%, respectively), whereas the principal constituents of MAl were (E)-nerolidol (35.4%), α-costol (13.3%) and β-costol (6.8%). Both MSi and MAl exhibited a significant antibacterial activity against Staphylococcus epidermidis (minimum inhibitory concentration = 25 and 12.5 μg/mL, respectively). The chemotaxonomy markers of the species were identified.


Association between frailty, cerebral oxygenation and adverse post-operative outcomes in elderly patients undergoing non-cardiac surgery: An observational pilot study.
Although both frailty and low cerebral oxygen saturation increase the risk of post-operative complications, their relationship is yet to be investigated. The purpose of this observational study was to investigate the association between frailty, intraoperative cerebral oxygen saturation and post-operative complications in elderly patients undergoing non-cardiac surgery. After approval from the Institutional Review Board, 25 elderly patients (>65 years) undergoing non-cardiac major surgery were included in this study. Pre-operatively, all included patients were assessed for frailty and classified into frail and non-frail groups. All patients had routine intraoperative monitors, and a cerebral oximeter applied during anaesthesia. The 'intraoperative' anaesthesiologist and the post-operative study investigator were blinded to cerebral oximeter readings throughout the study. The incidence of significant intraoperative cerebral oxygen desaturation, adverse post-operative outcomes and length of hospital stay were compared. Statistical significance was defined as a value of P < 0.05. We found that the frail group had more intraoperative cerebral desaturation (odds ratio [OR] [95% confidence interval [CI]]: 1.75 [1.11-2.75]) and longer median (interquartile range) length of hospital stay compared to the non-frail group (13.5 days [8.75-27.5] and 8 days [6-11], respectively). Furthermore, in patients with a low-baseline cerebral oxygen saturation (<55%), intraoperative cerebral desaturation (OR [95% CI]: 2.10 [1.00-4.42]), adverse post-operative outcomes (OR [95% CI]: 1.80 [1.00-3.23]) and median (interquartile range) length of hospital stay (15 days [9-31.5] vs. 9 days [6.25-13.75], P = 0.04) were significantly higher compared to subjects with higher baseline (≥55%) cerebral oxygen saturation. Frail patients have more intraoperative cerebral desaturation and longer lengths of hospital stay compared to non-frail patients.


Sexual conflict over the maintenance of sex: effects of sexually antagonistic coevolution for reproductive isolation of parthenogenesis.
Sexual reproduction involves many costs. Therefore, females acquiring a capacity for parthenogenetic (or asexual) reproduction will gain a reproductive advantage over obligately sexual females. In contrast, for males, any trait coercing parthenogens into sexual reproduction (male coercion) increases their fitness and should be under positive selection because parthenogenesis deprives them of their genetic contribution to future generations. Surprisingly, although such sexual conflict is a possible outcome whenever reproductive isolation is incomplete between parthenogens and the sexual ancestors, it has not been given much attention in the studies of the maintenance of sex. Using two mathematical models, I show here that the evolution of male coercion substantially favours the maintenance of sex even though a female barrier against the coercion can evolve. First, the model based on adaptive-dynamics theory demonstrates that the resultant antagonistic coevolution between male coercion and a female barrier fundamentally ends in either the prevalence of sex or the co-occurrence of two reproductive modes. This is because the coevolution between the two traits additionally involves sex-ratio selection, that is, an increase in parthenogenetic reproduction leads to a female-biased population sex ratio, which will enhance reproductive success of more coercive males and directly promotes the evolution of the coercion among males. Therefore, as shown by the individual-based model, the establishment of obligate parthenogenesis in the population requires the simultaneous evolution of strong reproductive isolation between males and parthenogens. These findings should shed light on the interspecific diversity of reproductive modes as well as help to explain the prevalence of sexual reproduction.


Metastasis-induced acute appendicitis in small cell bronchogenic carcinoma.
I have reported a case of acute appendicitis with perforation caused by metastatic small cell bronchogenic carcinoma. There was no evidence of distant spread apart from that to the appendix, and at operation, there was no macroscopic evidence of other metastases in the abdomen.


Pediatric median arcuate ligament syndrome: surgical outcomes and quality of life.
The existence, etiology, diagnosis, and treatment of median arcuate ligament syndrome (MALS) have long been subjects of debate. To our knowledge, there have not been any studies assessing the effectiveness of surgical treatment in improving physical and psychological quality of life in pediatric patients. This is an Institutional Review Board-approved prospective study including all patients undergoing surgical treatment of MALS between 2009 and 2012 at our institution. Demographic information, presenting symptoms, radiological imaging, procedure duration, hospital length of stay, and perioperative complications were gathered for analysis. Patients and their parents were asked to complete the Child Health Questionnaire, a physical and psychological health survey, both within 1 week prior to and at least 3 months following their surgery. Six patients underwent laparoscopic release for MALS. The majority of patients were female (n=5 [83.3%]), with an average age of 15.7±1.5 years. Presenting symptoms lasted on average 16.5±12.7 months prior to treatment. Average pre- and postsurgical ultrasound celiac artery peak velocities with inspiration were 332.0±34.1 cm/second and 224.3±31.2 cm/second, respectively, with a statistically significant decrease of 107.67 cm/second (P=.03). The average follow-up period from time of surgery to time of quality of life survey completion was 13±11.3 months, with a range of 3-29 months. A significant improvement from pre- to postsurgical scores was observed in the physical functioning (P=.03), mental health (P=.03), and self-esteem categories (P=.03) of the child assessment. Similarly, there was a significant postsurgical improvement in all categories pertaining to the parent's quality of life (P=.03). Improvement was also seen in the parents' perception of their child's physical functioning (P=.03), bodily pain/discomfort (P=.03), mental health (P=.03), and general health perceptions (P=.03). No intraoperative or postoperative complications occurred. Our preliminary results demonstrate that laparoscopic median arcuate ligament release for MALS in the pediatric population is safe and effective and improves overall quality of life for the patients and their parents. In carefully selected patients, laparoscopic release for MALS without additional celiac artery reconstruction normalizes blood flow in the celiac artery and improves physical and psychosocial quality of life for the child and his or her parents.


A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation.
Ro5-4864 and PK11195, prototypical synthetic ligands of translocator protein 18 kDa (TSPO), have shown anti-inflammatory effects in several models of inflammatory diseases; however, their biochemical mechanisms remain poorly understood. Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation as a part of the innate immune system, has been implicated in a variety of inflammatory diseases. Here, we demonstrate for the first time that TSPO ligands, especially Ro5-4864, potently suppressed ATP-induced NLRP3 inflammasome activation in THP-1 and BMDM cells. Detailed action mechanism was further investigated in THP-1 cells. Ro5-4864 efficiently attenuated NLRP3 translocation to mitochondria, inflammasome assembly/oligomerization, activation of caspase-1, and subsequent secretion of the mature forms of interleukin-1β and -18. Ro5-4864 also reduced the production of mitochondrial superoxide and preserved the mitochondrial membrane potential in ATP-treated cells, suggesting that Ro5-4864 may act on mitochondria or more upstream targets in NLRP3 inflammasome signaling. We also observed the distinct effects of the TSPO ligands between THP-1 monocytes and macrophages, which suggested different NLRP3 inflammasome signaling depending on cell type. Collectively, our novel findings demonstrate that Ro5-4864 effectively inhibited ATP-induced NLRP3 inflammasome activation through the prevention of mitochondrial perturbation. Our results indicate Ro5-4864 as a promising candidate for the treatment of NLRP3 inflammasome-related diseases.


Simultaneous determination of seven phthalates and four parabens in cosmetic products using HPLC-DAD and GC-MS methods.
Studies on the determination of seven kinds of phthalates, i.e. diethyl phthalate, dipropyl phthalate, dibutyl phthalate, benzyl butyl phthalate, dicyclohexyl phthalate, di-(2-ethylhexyl) phthalate, and dioctyl phthalate, and four parabens, i.e. methylparaben, ethylparaben, propylparaben, and butylparaben, in 15 kinds of cosmetic products, including hair sprays, perfumes, deodorants, cream, lotion, etc., by HPLC with diode array detection and GC-MS in electron impact ionization mode with selected-ion monitoring have been carried out. Methods have been developed for both qualitative and quantitative detection of phthalates and parabens. Extraction, clean-up, and analysis procedures have been optimized. HPLC and GC-MS determinations were performed after sonication-assisted extraction with methanol and clean-up with C18 SPE. These techniques permit detection of phthalates at a level of 10.0-100.0 microg/kg and of parabens at a level of 20.0-200.0 microg/kg. Overall recoveries were 85-108% with RSD values of 4.2-8.8%. Only one of the 15 examined samples was free from phthalates and parabens. The remaining 14 samples were found to contain at least three or more of these phthalates and/or parabens. The predominant phthalates and parabens detected in the studied samples were methylparaben, propylparaben, diethyl phthalate, dibutyl phthalate, dicyclohexyl phthalate, and di-(2-ethylhexyl) phthalate. The residue level is at 1.22-5289 mg/kg.


A model of collaboration: the Academic Practice Council.
If the profession of nursing is to survive in the changing health care delivery system, new models of collaboration between nursing education and nursing practice must be developed. Nursing is both an academic discipline and a practice profession. The historic dissonance between education and practice has never served the profession of nursing; the pressing challenge is to blend one with the other now. In an effort to respond to the demands of the discipline and profession of nursing, an academic institution and a health care delivery system developed a model of interagency collaboration. This article addresses historical perspectives, and evolution, structure, activities, evaluation, and future plans to the Academic Practice Council.


Chemical characterization of unconventional palm oils from Hyophorbe indica and two other endemic Arecaceae species from Reunion Island.
Chemical characteristics of novel seed oils, yet not investigated, from three endemic Arecaceae (palm) species from Reunion Island are described. Fatty acid profiles are performed using two-dimensional gas chromatography-mass spectrometry. Carotenoid contents are determined by high performance liquid chromatography-mass spectrometry. The results of the investigations emphasize the particular composition of the unconventional red seed oil from Hyophorbe indica. Characteristic features of this oil reveal a high degree of unsaturation (50% of polyunsaturated fatty acids, with a high content (17%) of omega-3), which is possibly a unique fatty acid composition in the Arecaceae family. The two other palm oils from Dictyosperma album and Latania lontaroides contain high level of saturated fatty acids very similar to that of the edible palm oil. H. indica oil is also very rich in valuable carotenoids; in particular, lutein, β-carotene and lycopene are detected in a high content (respectively 45, 23 and 35 mg.kg-1 in oil).


Mechanical feedback amplification in Drosophila hearing is independent of synaptic transmission.
Vertebrate inner-ear hair cells use mechanical feedback to amplify sound-induced vibrations. The gain of this 'cochlear amplifier' is centrally controlled via efferent fibres that, making synaptic contacts with the hair cells, modulate the feedback gain. The sensory neurons of the Drosophila ear likewise employ mechanical feedback to assist sound-evoked vibrations, yet whether this neuron-based feedback is also subject to efferent control has remained uncertain. We show here that the function of Drosophila auditory neurons is independent of efferent modulation, and that no synaptic transmission is needed to control the gain of mechanical feedback amplification. Immunohistochemical, mechanical and electrophysiological analyses revealed that the Drosophila auditory organ lacks peripheral synapses and efferent innervations, and that blocking synaptic transmission in a pan-neural manner does not affect the afferent electrical activity of the sensory neurons or the mechanical feedback gain. Hence, unlike the cochlear amplifier of vertebrates, mechanical feedback amplification in Drosophila is not associated with an efferent control system but seems to be a purely local process that is solely controlled peripherally within the ear itself.


Comparison of epigeic moss (Hypnum cupressiforme) and lichen (Cladonia rangiformis) as biomonitor species of atmospheric metal deposition.
In the present work epigeic moss (Hypnum cupressiforme Hedw.) and epigeic lichen (Cladonia rangiformis Hoffm.) samples were collected simultaneously in the Thrace region, Turkey according to a regular sampling grid. Whereas the moss was found at all 68 sampling sites, the lichen could be collected only at 25 of the sites, presumably because lichens are more sensitive than mosses with respect to air pollution and climatic variations. All elements showed higher accumulation in the moss than in the lichen whereas element inter-correlations were generally higher in the lichen. All considered the moss was judged to be a better choice than the lichen for biomonitoring of atmospheric deposition of metals in this case, and it is argued that mosses may be generally more suited than lichens for this purpose.


High-Yielding Flow Synthesis of a Macrocyclic Molecular Hinge.
Many molecular machines are built from modular components with well-defined motile capabilities, such as axles and wheels. Hinges are particularly useful, as they provide the minimum flexibility needed for a simple and pronounced conformational change. Compounds with multiple stable conformers are common, but molecular hinges almost exclusively operate via dihedral rotations rather than truly hinge-like clamping mechanisms. An ideal molecular hinge would better reproduce the behavior of hinged devices, such as gates and tweezers, while remaining soluble, scalable, and synthetically versatile. Herein, we describe two isomeric macrocycles with clamp-like open and closed geometries, which crystallize as separate polymorphs but interconvert freely in solution. An unusual one-pot addition cyclization reaction was used to produce the macrocycles on a multigram scale from inexpensive reagents, without supramolecular templating or high-dilution conditions. Using mechanistic information from NMR kinetic studies and at-line mass spectrometry, we developed a semicontinuous flow synthesis with maximum conversions of 85-93% and over 80% selectivity for a single isomer. The macrocycles feature voids that are sterically protected from guests, including reactive species such as fluoride ions, and could therefore serve as chemically inert hinges for adaptive supramolecular receptors and flexible porous materials.


Walking training at the heart rate of pain threshold improves cardiovascular function and autonomic regulation in intermittent claudication: A randomized controlled trial.
This study investigated the effects of walking training (WT) on cardiovascular function and autonomic regulation in patents with intermittent claudication (IC). Randomized controlled trial. Forty-two male patients with IC (≥50years) were randomly allocated into two groups: control (CG, n=20, 30min of stretching exercises) and WT (WTG, n=22, 15 bouts of 2min of walking interpolated by 2min of upright rest-walking intensity was set at the heart rate of pain threshold). Both interventions were performed twice/week for 12 weeks. Walking capacity (maximal treadmill test), blood pressure (auscultatory), cardiac output (CO2 rebreathing), heart rate (ECG), stroke volume, systemic vascular resistance, forearm and calf vascular resistance (plethysmography), and low (LF) and high frequency (HF) components of heart rate variability and spontaneous baroreflex sensitivity were measured at baseline and after 12 weeks of the study. WT increased total walking distance (+302±85m, p=0.001) and spontaneous baroreflex sensitivity (+2.13±1.07ms/mmHg, p=0.02). Additionally, at rest, WT decreased systolic and mean blood pressures (-10±3 and -5±2mmHg, p=0.001 and p=0.01, respectively), cardiac output (-0.37±0.24l/min, p=0.03), heart rate (-4±2bpm, p=0.001), forearm vascular resistance (-8.5±2.8U, p=0.02) and LF/HF (-1.24±0.99, p=0.001). No change was observed in the CG. In addition to increasing walking capacity, WT improved cardiovascular function and autonomic regulation in patients with IC.


The Rarest of the Rare: A Case of Primary Cardiac Osteosarcoma With a Review of the Literature.
A 54-year-old female presented with shortness of breath and cyanosis. Work up with chest X-ray and subsequent echocardiogram revealed an intracardiac bi-atrial mass leading to emergent cardiothoracic resection. Pathology was consistent with a primary cardiac high-grade osteosarcoma. Post-resection staging positron emission tomography-computed tomography (PET-CT) showed hypermetabolic mixed lytic and sclerotic lesion of T10 concerning for metastasis. She received five cycles of adriamycin and ifosfamide chemotherapy before discontinuation due to systolic dysfunction. Nine months later, she developed a high tumor burden with progressive disease and was treated with second-line gemcitabine/docetaxel with disappointing results. She is currently on treatment with cyclophosphamide and topotecan as third-line treatment with an excellent clinico-radiographic response. Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Fewer than 50 cases of primary cardiac osteosarcomas have been reported in the literature. Even though complete resection can be achieved in some cases, long-term results are usually poor. No standard therapy has been established.


Salt, arterial pressure, and cardiovascular and renal damage.
This brief review deals with some novel developments regarding the possible role of salt in the pathogenesis of cardiovascular and renal disorders. Studies in both humans and experimental animals are discussed. Increased salt intake is usually associated with an increase in arterial pressure although some controversies still exist. Salt sensitivity of arterial pressure (defined as an increase in arterial pressure on dietary salt overload) was demonstrated in many animal species as well as in humans. However, findings in rats, the most often used animal model, also demonstrated that this salt sensitivity was not uniform; some strains are salt sensitive, while other strains are salt resistant. Salt sensitivity of arterial pressure in humans is also not uniform; less than one-third of normotensive individuals and less than one-half of hypertensive individuals are salt sensitive. Of great importance are findings that excessive salt intake may damage target organs (cardiovascular system and kidneys) irrespective of arterial pressure. Together with an ever-growing consensus that sodium intake in acculturated societies is high, these findings also emphasize the need for reduction in salt intake. Therefore, the adverse cardiovascular and renal effects of salt continue to be a subject of intense study. Current data indicate that a reduction in salt intake should ameliorate, if not prevent, cardiovascular and renal morbidity and mortality, particularly among individuals with hypertension.


What is the "normal" wound bed temperature? A scoping review and new hypothesis.
Wound bed temperature measurement holds the potential to be a safe, easy to use, and low-cost tool to aid objective wound bed assessment, clinical decision making and improved patient outcomes. However, there is no consensus on the normal range of wound bed temperature in chronic wounds. We conducted a scoping review including any study type, from 2010 to 2020 in which chronic wound bed temperature was reported. Thirteen studies including 477 patients met our criteria. Venous ulcers (VLU) accounted for 46.5% (n = 222) of wounds; diabetic foot ulcers (DFU) for 25.4% (n = 121) with pressure ulcers (PU), mixed arterial venous ulcers (MAVLU) and unknown aetiology accounting for the remainder. The weighted mean of means for wound bed temperature was 31.7°C (n = 395) for all wound types; 31.7°C for VLU; 31.6°C for DFU; 33.3°C for PU; 30.9°C for MAVLU; and 32.0°C for those with unknown aetiology. Based on our review, we hypothesise that normal wound bed temperature is within a range of 30.2-33.0°C.


[A double blind study of the treatment of threatened abortion with fenoterol hydrobromide (author's transl)].
To study the effectiveness of Fenoterol Hydrobromide in the treatment of threatened abortion a double blind trial was performed. A total of 112 patients was examined. A comprehensive statistical analysis was made including Chi square and Student's t-test to provide a valid comparison of both, trial and control groups, in order to eliminate any possible statistical bias, as seen in many of the former studies of this topic. 1. The number of surviving children during the perinatal period did not differ significantly in the placebo and Fenoterol groups. 2. Fenoterol did not influence the course of pregnancy, full term delivery or fetal outcome, unless early abortion occurred. 3. Pregnancies resulting in abortions obviously were not prolonged by Fenoterol treatment. 4. Histology of aborted pregnancies revealed major pathological findings in more than 99% of the cases. So it may be presumed, that pharmacological treatment was bound to fail in these cases.


Peritonsillar abscess following tonsillectomy.
Peritonsillar abscess is an unusual complication following tonsillectomy. A series of five such patients is herein reported. Proper treatment begins with the initial tonsillectomy ensuring complete removal of the tonsils. Should a late peritonsillar abscess following tonsillectomy be found, the patient may be treated with needle aspiration of the affected area plus antibiotics. Removal of the remaining tonsillar tissue and surgical capsule of the tonsil is also advocated.


Erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus.
Complement activation and ineffective clearance of complement-bearing immune complexes via erythrocytes contribute to the pathogenesis of systemic lupus erythematosus (SLE). Abnormally high levels of erythrocyte C4d and low levels of complement receptor 1 (CD35) have been reported in SLE and might have diagnostic utility. We investigated whether erythrocyte C4d and complement receptor 1 were specific for SLE and whether there was any association with disease activity. Expression of complement receptor 1 (CD35) and complement protein C4d on erythrocytes was measured by indirect immunofluorescence and flow cytometry on the same day as the blood draw, in patients with SLE, patients with rheumatic disease, and in normal controls. Within the SLE population, there was no association with disease activity measured by the physician's global assessment or SELENA SLE Disease Activity Index, nor with past or current lupus nephritis. Assays were not specific for SLE, with higher levels also seen in antiphospholipid syndrome. Overlap of erythrocyte C4d and CD35 between SLE and other rheumatic diseases limits their utility as diagnostic tests. However, longitudinal investigation of these assays is warranted, especially given the higher levels in some patients with primary antiphospholipid syndrome.


A quantitative survey of anophelines in six villages of Kheda District, Gujarat.
Sampling of anophelines from six villages of Kheda district, Gujarat was done using four different methods viz. indoor resting, outdoor resting, bovine bait trap and immature collections. A total of 113,487 specimens representing 17 species were collected. An. subpictus (66.51 per cent) was most abundant species followed by An. culicifacies (14.12 per cent) and An. tessellatus (5.24 per cent). Bovine bait collections were found most productive yielding maximum species and highest number of anophelines per unit of collection efforts. Indoor resting collections yielded poorest diversity and greater number of specimens per unit of collection effort than outdoor resting collections. Maximum diversity was observed in outdoor collections. Most of the species exhibited unimodal prevalence.


Effectiveness of the Bactiseal Universal Shunt for reducing shunt infection in a sub-Saharan African context: a retrospective cohort study in 160 Ugandan children.
Antibiotic-impregnated shunts have yet to find widespread use in the developing world, largely due to cost. Given potential differences in the microbial spectrum, their effectiveness in preventing shunt infection for populations in low-income countries may differ and has not been demonstrated. This study is the first to compare the efficacy of a Bactiseal shunt system with a non-antibiotic-impregnated system in a developing country. The Bactiseal Universal Shunt (BUS) was placed in 80 consecutive Ugandan children who required a shunt. In this retrospective cohort study, the outcome for that group was compared with the outcome for the immediately preceding 80 consecutive children in whom a Chhabra shunt had been placed. The primary end points were shunt failure, shunt infection, and death. Shunt survival was analyzed using the Kaplan-Meier method. Significance of differences between groups was tested using the log-rank test, chi-square analysis, Fisher's exact test, and t-test. There was no difference between groups in regard to age, sex, or etiology of hydrocephalus. Mean follow-up for cases of nonfailure was 7.6 months (median 7.8 months, interquartile range 6.5-9.5 months). There was no significant difference between groups for any end point. The BUS group had fewer infections (4 vs 11), but the difference was not significant (p = 0.086, log-rank test). Gram-positive cocci were the most common culturable pathogens in the Chhabra group, while the only positive culture in the BUS group was a gram-negative rod. These results provide equipoise for a randomized controlled trial in the same population and this has been initiated. It is possible that the observed trends may become significant in a larger study. The more complex task will involve determining not only the efficacy, but also the cost-effectiveness of using antibiotic-impregnated shunt components in limited-resource settings.


Central and peripheral relationships between morphine and glucose on antinociception in rats.
Previous research from our laboratory has determined that in the absence of a gustatory response or taste hedonics, intraperitoneal (i.p.) glucose administration enhanced morphine-mediated analgesia in rats and had antinociceptive actions on its own. Two experiments examined the potential of a central mechanism for glucose's actions on morphine-mediated antinociception. Morphine (2.5 µg) was infused into the periaqueductal gray (PAG) while glucose (300 mg/kg) was injected into the peritoneal cavity, or glucose (32 nmol) was infused into the PAG while morphine (3.2 mg/kg) was injected i.p. Doses of morphine and glucose were selected based on our own prior research for being below the threshold for analgesic efficacy. Antinociception was assessed using the hot-water tail-withdrawal procedure. Tail-withdrawal latency was tested at baseline (before), and 12, 24 and 36 minutes after the i.p. injection. The results indicated that 300 mg/kg glucose, administered i.p. effectively increased the antinociceptive potency of a low dose of centrally administered morphine, while central infusion of glucose enhanced peripheral morphine-mediated antinociception. These outcomes support previous evidence of glucose's influence on the antinociception actions of opioid drugs. Furthermore, they suggest that glucose produces its enhancing actions on morphine-mediated antinociception in the brain. These results support the hypothesis that glucose does not need to go through a gustatory mechanism or taste hedonics to alter morphine's antinociceptive actions.


Loss of virulence associated with absence of flagellum in an isogenic mutant of Pseudomonas aeruginosa in the burned-mouse model.
To test the importance of flagella as a virulence factor, virulent strain Pseudomonas aeruginosa M-2 was mutagenized, and a Fla mutant was isolated. An M-2 Fla spontaneous motile revertant was isolated from M-2 Fla. The three strains were biochemically and morphologically identical. Assay of Fla in the burned-mouse model showed a severe loss of virulence. The Fla revertant was fully virulent. The importance of P. aeruginosa motility (flagella) for virulence in burns infections is indicated.


[Optimizing a system of medical rehabilitation for vibration disease patients].
The study was aimed to reveal efficiency of extracorporeal shock-wave therapy in complex treatment of vibration disease patients. Examination covered 92 patients with varying severity of vibration disease, 58 of which received extracorporeal shock-wave therapy with Piezo Wave device produced by Richard Wolf in addition to traditional treatment. The treatment efficiency was evaluated through its influence on intensity and regression of pain syndrome. Comparative analysis showed that extracorporeal shockwave therapy in the treatment complex considerably increases efficiency and leads to earlier and more stable regression of pain in distal parts of hands. Two variants of chronic pain response to extracorporeal shock-wave therapy were revealed. Marked analgetic potential, good tolerance and stability of the results obtained enable to recommend extracorporeal shock-wave therapy in rehabilitation complex for vibration disease patients.


Impact of home-delivered meal programs on diet and nutrition among older adults: a review.
Poor diet quality and insufficient nutrient intake is of particular concern among older adults. The Older Americans Act of 1965 authorizes home-delivered meal services to homebound individuals aged 60 years and older. The purpose of this study was to review scientific evidence on the impact of home-delivered meal services on diet and nutrition among recipients. Keyword and reference searches were conducted in Cochrane Library, Google Scholar, PubMed and Web of Science. Inclusion criteria included: study design (randomized controlled trials, cohort studies, pre-post studies, or cross-sectional studies); main outcome (food and nutrient intakes); population (home-delivered meal program participants); country (US); language (articles written in English); and article type (peer-reviewed publications or theses). Eight studies met the inclusion criteria, including two randomized controlled trial studies (from the same intervention), one cohort study, two pre-post studies, and three cross-sectional studies. All but two studies found home-delivered meal programs to significantly improve diet quality, increase nutrient intakes, and reduce food insecurity and nutritional risk among participants. Other beneficial outcomes include increased socialization opportunities, improvement in dietary adherence, and higher quality of life. Home-delivered meal programs improve diet quality and increase nutrient intakes among participants. These programs are also aligned with the federal cost-containment policy to rebalance long-term care away from nursing homes to home- and community-based services by helping older adults maintain independence and remain in their homes and communities as their health and functioning decline.


Rett Syndrome, a Neurodevelopmental Disorder, Whole-Transcriptome, and Mitochondrial Genome Multiomics Analyses Identify Novel Variations and Disease Pathways.
Rett syndrome (RTT) is a severe neurodevelopmental disorder reported worldwide in diverse populations. RTT is diagnosed primarily in females, with clinical findings manifesting early in life. Despite the variable rates across populations, RTT has an estimated prevalence of ∼1 in 10,000 live female births. Among 215 Saudi Arabian patients with neurodevelopmental and autism spectrum disorders, we identified 33 patients with RTT who were subsequently examined by genome-wide transcriptome and mitochondrial genome variations. To the best of our knowledge, this is the first in-depth molecular and multiomics analyses of a large cohort of Saudi RTT cases with a view to informing the underlying mechanisms of this disease that impact many patients and families worldwide. The patients were unrelated, except for 2 affected sisters, and comprised of 25 classic and eight atypical RTT cases. The cases were screened for methyl-CpG binding protein 2 (MECP2), CDKL5, FOXG1, NTNG1, and mitochondrial DNA (mtDNA) variants, as well as copy number variations (CNVs) using a genome-wide experimental strategy. We found that 15 patients (13 classic and two atypical RTT) have MECP2 mutations, 2 of which were novel variants. Two patients had novel FOXG1 and CDKL5 variants (both atypical RTT). Whole mtDNA sequencing of the patients who were MECP2 negative revealed two novel mtDNA variants in two classic RTT patients. Importantly, the whole-transcriptome analysis of our RTT patients' blood and further comparison with previous expression profiling of brain tissue from patients with RTT revealed 77 significantly dysregulated genes. The gene ontology and interaction network analysis indicated potentially critical roles of MAPK9, NDUFA5, ATR, SMARCA5, RPL23, SRSF3, and mitochondrial dysfunction, oxidative stress response and MAPK signaling pathways in the pathogenesis of RTT genes. This study expands our knowledge on RTT disease networks and pathways as well as presents novel mutations and mtDNA alterations in RTT in a population sample that was not previously studied.


Pathogenesis of diabetic neuropathy: bad to the bone.
Insulin and proinsulin are normally produced only by the pancreas and thymus. We detected in diabetic rodents the presence of extra pancreatic proinsulin-producing bone marrow-derived cells (PI-BMDCs) in the BM, liver, and fat. In mice and rats with diabetic neuropathy, we also found proinsulin-producing cells in the sciatic nerve and neurons of the dorsal root ganglion (DRG). BM transplantation experiments using genetically marked donor and recipient mice showed that the proinsulin-producing cells in the DRG, which morphologically resemble neurons, are actually polyploid proinsulin-producing fusion cells formed between neurons and PI-BMDCs. Additional experiments indicate that diabetic neuropathy is not simply the result of nerve cells being damaged directly by hyperglycemia. Rather, hyperglycemia induces fusogenic PI-BMDCs that travel to the peripheral nervous system, where they fuse with Schwann cells and DRG neurons, causing neuronal dysfunction and death, the sine qua non for diabetic neuropathy. Poorly controlled diabetes is indeed bad to the bone.


The new HLA.
The application of molecular genetics and biochemical techniques to the study of the HLA system over the past few years has resulted in tremendous advances in our knowledge of this area of the human genome. In this article, we describe the "new HLA" that has been pieced together recently through the combined efforts of molecular geneticists, biochemists, and HLA serologists, as well as developments in attempts to elucidate the associations of HLA antigens and disease.


Purification and characterization of hydrolytic haloalkane dehalogenase from Xanthobacter autotrophicus GJ10.
A new enzyme, haloalkane dehalogenase, was isolated from the 1,2-dichloroethane-utilizing bacterium Xanthobacter autotrophicus GJ10. The purified enzyme catalyzed the hydrolytic dehalogenation of n-halogenated C1 to C4 alkanes, including chlorinated, brominated, and iodinated compounds. The highest activity was found with 1,2-dichloroethane, 1,3-dichloropropane, and 1,2-dibromoethane. The enzyme followed Michaelis-Menten kinetics, and the Km for 1,2-dichloroethane was 1.1 mM. Maximum activity was found at pH 8.2 and 37 degrees C. Thiol reagents such as p-chloromercuribenzoate and iodoacetamide rapidly inhibited the enzyme. The protein consists of a single polypeptide chain of a molecular weight of 36,000, and its amino acid composition and N-terminal sequence are given.


What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport. German Dystonia Study Group.
Botulinum toxin injections have become a first line therapeutic approach in cervical dystonia. Nevertheless, published dosing schedules, responder rates, and frequency of adverse events vary widely. The present prospective multicentre placebo controlled double blind dose ranging study was performed in a homogenous group of previously untreated patients with rotational torticollis to obtain objective data on dose-response relations. Seventy five patients were randomly assigned to receive treatment with placebo or total doses of 250, 500, and 1000 Dysport units divided between one splenius capitis (0, 175, 350, 700 units) and the contralateral sternocleidomastoid (0, 75, 150, 300 units) muscle. Assessments were obtained at baseline and weeks 2, 4, and 8 after treatment and comprised a modified Tsui scale, a four point pain scale, a checklist of adverse events, global assessment of improvement, and a global rating taking into account efficacy and adverse events. At week 8 the need for retreatment was assessed and then the code was unblinded. For those still responding, there was an open follow up until retreatment to assess the duration of effect. Seventy nine per cent reported subjective improvement at one or more follow up visits. Decreases in the modified Tsui score were significant at week 4 for the 500 and 1000 unit groups versus placebo (p<0.05). Additionally positive dose-response relations were found for the degree of subjective improvement, duration of improvement, improvement on clinical global rating, and need for reinjection at eight weeks. A significant dose relation was also established for the number of adverse events overall and for the incidence of neck muscle weakness and voice changes. Magnitude and duration of improvement was greatest after injections of 1000 units Dysport; however, at the cost of significantly more adverse events. Therefore a lower starting dose of 500 units Dysport is recommended in patients with cervical dystonia, with upward titration at subsequent injection sessions if clinically necessary.


Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor.
The highly conserved, ubiquitously expressed, zinc finger protein CTCF is involved in enhancer blocking, a mechanism crucial for shielding genes from illegitimate enhancer effects. Interestingly, CTCF-binding sites are often flanked by thyroid hormone response elements (TREs), as at the chicken lysozyme upstream silencer. Here we identify a similar composite site positioned upstream of the human c-myc gene. For both elements, we demonstrate that thyroid hormone abrogates enhancer blocking. Relief of enhancer blocking occurs even though CTCF remains bound to the lysozyme chromatin. Furthermore, chromatin immunoprecipitation analysis of the lysozyme upstream region revealed that histone H4 is acetylated at the CTCF-binding site. Loss of enhancer blocking by the addition of T3 led to increased histone acetylation, not only at the CTCF site, but also at the enhancer and the promoter. Thus, when TREs are adjacent to CTCF-binding sites, thyroid hormone can regulate enhancer blocking, thereby providing a new property for what was previously thought to be constitutive enhancer shielding by CTCF.


Programming the immune checkpoint to treat hematologic malignancies.
Hematologic malignancies manipulate the immune suppressive pathways involving CTLA-4, PD-1, and others to promote immune tolerance of cancer. New monoclonal antibodies targeting immune checkpoints are showing meaningful responses in the treatment of relapsed and refractory Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. The basis for success of anti-PD-1 therapy appears to be expression of PD-L1 on tumor cells and cells of the tumor microenvironment (TME). While adverse events associated with immune checkpoint inhibitors are capable of generating auto-immune phenomena, in general these therapies are well tolerated. In this review, the authors discuss the development of immune checkpoint inhibitors and activators which hold promise as useful therapies in malignancies of hematologic origin, since many exploit endogenous pathways to induce tolerance. By programming the immune response to attack hematologic malignancies, unique regimens can be developed to optimally treat patients with curative potential. The utilization of immune checkpoint targeting agents to boost the innate and acquired immune systems to eradicate human malignancies represents a unique opportunity to develop novel therapies with increased clinical efficacy. Side effects of these therapies come with the price of auto-immune phenomena that require appropriate management.


Palliative care: a challenge for nurses.
There is an ever-growing number of cancer patients in the world today. Of the estimated nine million new cancer cases diagnosed in 1997 worldwide, 52% occurred in developing countries (WHO, 1998). The mortality from cancer is expected to rise around the globe. About 7 million deaths per year occur in the world due to cancer, of which, approximately 0.8 million occur in India (WHO, 1994). There is no cure to date for this disease but definitely a lot can be done to make the lives of these people meaningful and productive. With this idea the concept of hospice and palliative care was initiated.


Web-Based Interventions to Improve Mental Health, General Caregiving Outcomes, and General Health for Informal Caregivers of Adults With Chronic Conditions Living in the Community: Rapid Evidence Review.
Most adults with chronic conditions live at home and rely on informal caregivers to provide support. Caregiving can result in negative impacts such as poor mental and physical health. eHealth interventions may offer effective and accessible ways to provide education and support to informal caregivers. However, we know little about the impact of Web-based interventions for informal caregivers of community-dwelling adults with chronic conditions. The purpose of this rapid evidence review was to assess the impact of Web-based interventions on mental health, general caregiving outcomes, and general health for informal caregivers of persons with chronic conditions living in the community. A rapid evidence review of the current literature was employed to address the study purpose. EMBASE, MEDLINE, PsychInfo, CINAHL, Cochrane, and Ageline were searched covering all studies published from January 1995 to July 2016. Papers were included if they (1) included a Web-based modality to deliver an intervention; (2) included informal, unpaid adult caregivers of community-living adults with a chronic condition; (3) were either a randomized controlled trial (RCT) or controlled clinical trial (CCT); and (4) reported on any caregiver outcome as a result of use or exposure to the intervention. A total of 20 papers (17 studies) were included in this review. Study findings were mixed with both statistically significant and nonsignificant findings on various caregiver outcomes. Of the 17 included studies, 10 had at least one significant outcome. The most commonly assessed outcome was mental health, which included depressive symptoms, stress or distress, and anxiety. Twelve papers examined the impact of interventions on the outcome of depressive symptoms; 4 found a significant decrease in depressive symptoms. Eight studies examined the outcome of stress or distress; 4 of these found a significant reduction in stress or distress as a result of the intervention. Three studies examined the outcome of anxiety; 2 of these found significant reductions in anxiety. Other significant results of the interventions were seen in the outcomes of caregiver gain (ie, positive aspects of caregiving), knowledge, bonding, reduction of anger-hostility, and negative mood. Based on this review, it is not possible to determine which interventions were most effective since studies differed in their design, sample, and intervention. Study results suggest that Web-based interventions may result in reduced depressive symptoms, anxiety, and stress or distress among informal caregivers of adults with chronic conditions in the community. This is the first review assessing the impact of Web-based technologies on mental health, general caregiving outcomes, and general health for caregivers of adults with chronic conditions living in the community. Further rigorous research is needed that includes adequately powered studies examining the critical components of the intervention and the dosage needed to have an effect.


Sulfated polysaccharide-based scaffolds for orthopaedic tissue engineering.
Given their native-like biological properties, high growth factor retention capacity and porous nature, sulfated-polysaccharide-based scaffolds hold great promise for a number of tissue engineering applications. Specifically, as they mimic important properties of tissues such as bone and cartilage they are ideal for orthopaedic tissue engineering. Their biomimicry properties encompass important cell-binding motifs, native-like mechanical properties, designated sites for bone mineralisation and strong growth factor binding and signaling capacity. Even so, scientists in the field have just recently begun to utilise them as building blocks for tissue engineering scaffolds. Most of these efforts have so far been directed towards in vitro studies, and for these reasons the clinical gap is still substantial. With this review paper, we have tried to highlight some of the important chemical, physical and biological features of sulfated-polysaccharides in relation to their chondrogenic and osteogenic inducing capacity. Additionally, their usage in various in vivo model systems is discussed. The clinical studies reviewed herein paint a promising picture heralding a brave new world for orthopaedic tissue engineering.


Comparative analysis of the protective effects of melatonin and caffeic acid phenethyl ester (CAPE) on mobile phone-induced renal impairment in rat.
Melatonin and caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, were recently found to be potent free radical scavengers and antioxidants. There are a number of reports on the effects induced by electromagnetic radiation (EMR) in various cellular systems. Mechanisms of adverse effects of EMR indicate that reactive oxygen species may play a role in the biological effects of this radiation. The present study was carried out to compare the protective effects of melatonin and CAPE against 900 MHz EMR emitted mobile phone-induced renal tubular injury. Melatonin was administered whereas CAPE was given for 10 days before the exposure. Urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury) and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in rats exposed to EMR. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Urinary NAG and renal MDA were increased in EMR exposed rats while both melatonin and CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD and GSH-Px activities were decreased in EMR exposed animals while melatonin caused a significant increase in the activities of these antioxidant enzymes but CAPE did not. Melatonin caused a significant decrease in urinary NAG activity and MDA levels which were increased because of EMR exposure. CAPE also reduced elevated MDA levels in EMR exposed renal tissue, but the effect of melatonin was more potent than that of CAPE. Furthermore, treatment of EMR exposed rats with melatonin increased activities of SOD and GSH-Px to higher levels than those of control rats. In conclusion, melatonin and CAPE prevent renal tubular injury by reducing oxidative stress and protect the kidney from oxidative damage induced by 900 MHz mobile phone. Nevertheless, melatonin seems to be a more potent antioxidant compared with CAPE in kidney.


Collagen defect induced by penicillamine.
Collagen synthesis, as judged by the accumulation of collagen in a subcutaneous, induced granuloma, was significantly decreased by penicillamine. Penicillamine also caused a marked increase in the amount of soluble collagen in skin and a sharp drop in insoluble material. These findings, which reflect an abnormal pattern of collagen metdbolism, are accompanied by an inhibition of wound-healing and by skin fragility.


SS18 Break-Apart Fluorescence In Situ Hybridization is a Practical and Effective Method for Diagnosing Microsecretory Adenocarcinoma of Salivary Glands.
Molecular analysis has allowed for refinement of salivary gland tumor classification and, in some cases, the recognition of entirely new tumor types. Microsecretory adenocarcinoma (MSA) is a salivary gland tumor described in 2019 characterized by microcystic growth, bland cytomorphology, luminal secretions, fibromyxoid stroma, and S100/p63 positivity with negative p40. Most important, MSA is defined by MEF2C-SS18 fusion. While this fusion has, to this point, been detected by next-generation sequencing, this is a technique that is currently inaccessible in most diagnostic laboratories. On the other hand, SS18 break-apart fluorescence in situ hybridization (FISH) is widely available and frequently used as an adjunct for diagnosing synovial sarcoma. It is not known if SS18 break-apart FISH is positive in tumors with MEF2C-SS18, or if it is entirely specific for MSA. Break apart FISH for SS18 was performed on 4 cases of MSA, as well as 8 tissue microarrays (TMAs) containing 423 various salivary gland carcinomas: 26 acinic cell carcinomas, 35 adenocarcinomas not otherwise specified, 96 adenoid cystic carcinomas, 3 basal cell adenocarcinomas, 20 epithelial-myoepithelial carcinomas, 15 hyalinizing clear cell carcinomas, 3 intraductal carcinomas, 12 myoepithelial carcinomas, 117 mucoepidermoid carcinomas, 30 polymorphous adenocarcinomas, 45 salivary duct carcinomas, 19 secretory carcinomas, and 2 undifferentiated carcinomas. SS18 break-apart FISH was also performed on whole slides of 2 tumors from the TMAs. All MSA cases demonstrated classic split patterns on SS18 break-apart FISH. On the TMAs, 374 cases were evaluable by FISH, and 372 cases were clearly negative for SS18 rearrangement. Two cases, both mucoepidermoid carcinomas, had rare split signals below the positivity threshold of 12% on their TMA cores, so FISH was performed on whole sections. On the whole sections both tumors were unequivocally negative for SS18 rearrangement. Taken together, SS18 break-apart FISH was 100% sensitive and 100% specific for a diagnosis of MSA. SS18 break-apart FISH, a diagnostic tool widely available in pathology laboratories, appears to be a highly accurate method for diagnosing MSA of salivary glands. Accordingly, this new tumor type may be molecularly confirmed without needing to resort to highly specialized techniques like next-generation sequencing.


Cerebrospinal fluid neurofilament light chains predicts early disease-activity in Multiple Sclerosis.
Among biomarkers of axonal damage, neurofilament light chains (NFL) seem to play a major role, representing a promising and interesting tool in Multiple Sclerosis (MS). Our aim was to explore the predictive role of cerebrospinal fluid (CSF) NFL in patients with a recent diagnosis of MS, naïve to any MS therapy. We retrospectively collected data of patients diagnosed with MS, referred to the Neurology Clinic of the University-Hospital G. Rodolico of Catania between January 1st 2005 and December 31st 2015. All patients underwent CSF collection at the time of MS diagnosis and were followed-up for at least three years afterwards. NFL levels were measured in CSF samples with Simoa NFLight advantage kit at the CRESM (University Hospital San Luigi Gonzaga, Orbassano, Torino). NFL levels were expressed as LogNFL. Symbol Digit Modalities test (SDMT) was performed at baseline, at 1-year and at 3-year follow-up. Multivariate logistic regression analysis was performed to investigate LogNFL as a potential risk factor of different clinical outcomes. 244 MS patients (230 relapsing-remitting, RRMS; 94.3 %), with a mean age at diagnosis of 37.0 ± 11.1 years, were recruited. LogNFL did not correlate neither with EDSS score at diagnosis and at subsequent follow-up up to 12 years, nor with SDMT performed at diagnosis, at 1 year and at 3 years. LogNFL were an independent factor for the occurrence of at least one relapse during the first two years after MS diagnosis (OR = 2.75; 95 % CI 1.19-6.31; p = 0.02) and for the occurrence of gadolinium-enhanced (Gd+) lesions during the first 2 years from diagnosis at brain and spine MRI scans (OR = 3.45, 95 % CI 1.81-6.57; p < 0.001). The detection of CSF NFL at the time of MS diagnosis can be a useful support to predict the two-year risk of clinical and radiological relapses, thus affecting therapeutic choices in the very early phases of the disease.


[The joker function of glucose in the development of main non-communicable human diseases].
Glucose is one of the basic components of the internal milieu; it fulfills two principal functions: an endocrine one (the ability to induce insulin secretion) and another function, consisting in DNA-damaging associated with forming of reactive oxygen species. The joker glucose function, determined by individual balance between the mentioned functions, can be an important modifier of human pathology and, at the same time, a target for correcting measures implying the combination of insulin-sensitizing and antigenotoxic measures. The "glucose problem" and the "estrogenic problem" show some resemblance; the latter is based on the shifting of estrogen effects in the direction of genotoxicity domination in the course of aging and under the influence of some exogenic/environmental agents. Thus, both problems should be taken into account when discussing mechanisms of appearance of main non-communicable human diseases and the measures for their prevention.


The dynamics of a neuronal culture of dissociated cortical neurons of neonatal rats.
Neuronal networks of dissociated cortical neurons from neonatal rats were cultured over a multielectrode dish with 64 active sites, which were used both for recording the electrical activity and for stimulation. After about 4 weeks of culture, a dense network of neurons had developed and their electrical activity was studied. When a brief voltage pulse was applied to one extracellular electrode, a clear electrical response was evoked over almost the entire network. When a strong voltage pulse was used, the response was composed of an early phase, terminating within 25 ms, and a late phase which could last several hundreds of milliseconds. Action potentials evoked during the early phase occurred with a precise timing with a small jitter and the electrical activity initiated by a localized stimulation diffused significantly over the network. In contrast, the late phase was characterized by the occurrence of clusters of electrical activity with significant spatio-temporal fluctuations. The late phase was suppressed by adding small amounts of D(-)-2-amino-5-phosphonovaleric acid to the extracellular medium, or by increasing the amount of extracellular Mg2+. The electrical activity of the network was substantially increased by the addition of bicuculline to the extracellular medium. The results presented here show that the neuronal network may exist in two different dynamical states: one state in which the neuronal network behaves as a non-chaotic deterministic system and another state where the system exhibits large spatio-temporal fluctuations, characteristic of stochastic or chaotic systems.


Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans.
Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes. Clinical Trial Registration: ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31.


Recent advances in nicotine and tobacco research. Ninth SRNT annual meeting. New Orleans, Louisiana, USA. 19-22 February 2003.
The ninth annual meeting of the Society for Research on Nicotine and Tobacco (SRNT) was held February 19-22, 2003, in New Orleans, Louisiana. With over 800 registered attendees, this year's meeting was the largest to date. The 3-day scientific program included C. Everett Koop as the keynote speaker, four exemplary plenary speakers, 10 symposia, nine oral paper sessions, and four poster sessions that contained nearly 100 presentations per session. The meeting content emphasized three major areas of SRNT's scientific focus: Epidemiology/public health research, preclinical research, and clinical research. Thus, the meeting was an outstanding opportunity to interact with and learn from colleagues engaged in the broad area of nicotine and tobacco research around the globe. Additional events included pre- and postconference meetings, evening workshops that ranged from future directions for global tobacco research to grant writing for the new investigator, several scientific and travel awards, a members' meeting, and an opening reception. The scientific excellence and innovation presented at this year's meeting signifies SRNT's continued contributions to advancing our understanding of nicotine addiction and tobacco use.


The Relationship Between Posterior Pituitary Bright Spot on Magnetic Resonance Imaging (MRI) and Postoperative Diabetes Insipidus for Pituitary Adenoma Patients.
BACKGROUND This study is to investigate the predictive value of posterior pituitary bright spot (PPBS) on magnetic resonance imaging (MRI) for postoperative diabetes insipidus (DI) in patients with pituitary adenoma. MATERIAL AND METHODS This was a retrospective study. In total, 65 patients with pituitary adenoma who underwent transsphenoidal surgery were enrolled. Before surgery, all patients had MRI examinations. The length of pituitary stalk and position of PPBS in T1WI sagittal and coronal sections were analyzed. The volume and height of the tumor was calculated in enhanced T1WI. Urine volume was monitored to analyze the clinical factors contributing to DI. RESULTS Among the 65 cases of pituitary adenoma, there were 54 cases of positive PPBS and 11 cases of negative PPBS. There were 32 cases of transient DI, and among these, 22 cases were positive PPBS and 10 cases were negative PPBS. However, there were 33 cases without DI, and among these, 32 cases were positive PPBS and one case was negative PPBS. The negative PPBS was significantly higher in cases with DI, compared with positive PPBS (P<0.05). Logistic regression showed that preoperative negative PPBS was an important predictor for postoperative DI (P<0.05). CONCLUSIONS Postoperative DI should be considered when there is negative preoperative PPBS on MRI. Also, severe pituitary stalk compression indicates higher risk of postoperative DI.


Shallow dynamic overshoot and energetic deep rupture in the 2011 Mw 9.0 Tohoku-Oki earthquake.
Strong spatial variation of rupture characteristics in the moment magnitude (M(w)) 9.0 Tohoku-Oki megathrust earthquake controlled both the strength of shaking and the size of the tsunami that followed. Finite-source imaging reveals that the rupture consisted of a small initial phase, deep rupture for up to 40 seconds, extensive shallow rupture at 60 to 70 seconds, and continuing deep rupture lasting more than 100 seconds. A combination of a shallow dipping fault and a compliant hanging wall may have enabled large shallow slip near the trench. Normal faulting aftershocks in the area of high slip suggest dynamic overshoot on the fault. Despite prodigious total slip, shallower parts of the rupture weakly radiated at high frequencies, whereas deeper parts of the rupture radiated strongly at high frequencies.


Current perspectives on the management of refractory or relapsed classic hodgkin lymphoma in brazil: Balancing efficacy, safety, and tolerability.
Classic Hodgkin lymphoma (CHL), which accounts for 90-95% of all cases of Hodgkin lymphoma, is the most frequent cancer in adolescents and the most frequent lymphoma in adolescents and young adults. Despite progressive improvements over past decades and the general sensitivity of CHL to frontline chemotherapy, approximately 10-15% of patients have refractory disease that either does not respond to such therapy or progresses after an initial partial response. In patients with refractory or relapsed disease, standard treatment until recently consisted mainly of salvage chemotherapy, in many cases followed by high-dose chemotherapy and autologous stem-cell transplantation. However, improved understanding of the pathobiology of CHL, coupled with the introduction of novel agents, has markedly changed the treatment landscape in the past decade. Although refractory or relapsed CHL continues to be challenging, the therapeutic landscape is undergoing profound changes brought about by novel agents, particularly brentuximab vedotin and immunotherapy. In this review, we discuss the most salient treatment options for adult patients with refractory or relapsed CHL, with a special focus on the Brazilian healthcare setting, which is constrained by inherent characteristics of this system. In the attempt to balance efficacy, safety and tolerability, practicing physicians must rely on clinical trials and on results from real-world studies, and use their own point of view and experience, as well as patient characteristics and previous therapy, to make treatment decisions for refractory or relapsed CHL.


Amino acid and peptide requirement of Fusiformis necrophorus.
Uptake of individual amino acids and peptides by Fusiformis necrophorus was studied in growing cultures and resting cell suspensions. The cells were able to incorporate 16 of 17 (14)C-labeled amino acids into cell protein, the exception being proline. Proline could neither be formed by the cells from any of the other tested amino acids nor be synthesized from glucose or serine when these were used as energy sources. The addition of di- and tripeptides, the octapeptides vasopressin and oxytocin, and the poly (24) peptide ACTH did not stimulate cell growth, but a marked stimulatory effect was noted after the addition of poly-l-proline (mean molecular weight 2,000). It is concluded that cells of F. necrophorus (i) possess transport systems for most amino acids but not for proline, (ii) are dependent on exogenous proline in the form of proline-containing peptides for growth, and (iii) may be cultivated in a defined amino acid medium provided the proline requirement is met by the addition of a proline-containing peptide.


The impact of a history of psychotic symptoms on cognitive function in euthymic bipolar patients: a comparison with schizophrenic patients and healthy controls.
About two-thirds of patients with bipolar disorder (BD) have a lifetime history of at least one psychotic symptom. To compare the neurocognitive performance of four groups: BD patients with and without a history of psychotic symptoms (BD HPS+ and BD HPS-, respectively); patients with schizophrenia (SZ); and healthy control (HC) subjects. In this cross-sectional study, 35 stabilized patients with SZ, 79 euthymic (44 HPS+ and 35 HPS-) patients with BD, and 50 HC were administered a comprehensive battery of neuropsychological tests. There was worse neurocognitive functioning in both BD and SZ patients compared to HC. Overall, data from both groups of BD patients did not differ on sociodemographic, clinical, or neurocognitive variables. However, BD HPS+ patients had significantly more negative symptoms, as measured by the Positive and Negative Syndrome Scale (PANSS), and showed a trend toward worse performance on executive functions compared to BD HPS- patients. Moreover, both BD groups had better performance on all neurocognitive tests compared to SZ group. Neurocognitive dysfunction may be more marked in SZ than in BD, yet qualitatively similar. A history of past psychotic symptoms in BD was not associated with more severe cognitive impairment during euthymia. Therefore, BD with psychotic symptoms does not appear to be a distinct neurocognitive phenotype.


Hierarchical assembly of Ti(IV)/Sn(II) co-doped SnO₂ nanosheets along sacrificial titanate nanowires: synthesis, characterization and electrochemical properties.
Hierarchical assembly of Ti(IV)/Sn(II)-doped SnO₂ nanosheets along titanate nanowires serving as both sacrificial templates and a Ti(IV) source is demonstrated, using SnCl2 as a tin precursor and Sn(II) dopants and NaF as the morphology controlling agent. Excess fluoride inhibits the hydrolysis of SnCl2, promoting heterogeneous nucleation of Sn(II)-doped SnO₂ on the titanate nanowires due to the insufficient oxidization of Sn(II) to Sn(IV). Simultaneously, titanate nanowires are dissolved forming Ti(4+) species under the etching effect of in situ generated HF resulting in spontaneous Ti(4+) ion doping of SnO₂ nanosheets formed under hydrothermal conditions. Compositional analysis indicates that Ti(4+) ions are incorporated by substitution of Sn sites at a high level (16-18 at.%), with uniform distribution and no phase separation. Mössbauer spectroscopy quantified the relative content of Sn(II) and Sn(IV) in both Sn(II)-doped and Ti(IV)/Sn(II) co-doped SnO₂ samples. Electrochemical properties were investigated as an anode material in lithium ion batteries, demonstrating that Ti-doped SnO₂ nanosheets show improved cycle performance, which is attributed to the alleviation of inherent volume expansion of the SnO₂-based anode materials by substituting part of Sn sites with Ti dopants.


Orthograde retreatment and apexification after unsuccessful endodontic treatment, retreatment and apicectomy.
To describe a case where a second orthograde retreatment was successful in the management of an infected mandibular right first molar that previously had received both orthograde and retrograde treatments. Periapical surgery is unlikely to be successful unless the root canal system has been adequately debrided and sealed. A case is described where orthograde endodontic treatment, retreatment and apicectomy were unsuccessful in the management of and infected mandibular right first molar. The periapical radiolucency eventually disappeared following a second orthograde retreatment. Teh second retreatment included 12 months of intracanal calcium hydroxide placement to promote apexification, thus allowing subsequent controlled obturation with gutta percha and AH26. At a 5-year review following completion of treatment, the tooth remained asymptomatic and was in normal function. Orthograde retreatment is a treatment option to manage refractory lesions in teeth that have previously received endodontic treatment, retreatment and apicectomy. Orthograde retreatment using long-term intracanal calcium hydroxide can help promote root-end closure of a resected apex.


Geographical patterns of male circumcision practices in Africa: association with HIV seroprevalence.
To ascertain whether male circumcision might explain some of the geographical variation in human immunodeficiency virus (HIV) seroprevalence in Africa, we investigated the association between the practice of male circumcision at a societal level and HIV seroprevalence. Male circumcision practices for over 700 African societies were identified, and HIV seroprevalence in general adult populations from 140 distinct locations in 41 countries was obtained. In locations where male circumcision is practised, HIV seroprevalence was considerably lower than in areas where it is not practised. This study supports the hypothesis that lack of circumcision in males is a risk factor for HIV transmission.


Soluble CD163: a novel independent prognostic biomarker in patients with metastatic renal cell carcinoma.
The hemoglobin-haptoglobin scavenger receptor CD163 is present in both a membrane-bound form on monocytes and macrophages (mCD163) and a shed soluble circulating form (sCD163). CD163 is a well-described marker of M2-like tumor-associated macrophages, but in patients with metastatic renal cell carcinoma (mRCC), monocyte mCD163 and serum sCD163 levels have not previously been investigated and associated with patient overall survival (OS). Here, we report mCD163 expression on peripheral blood monocytes, as well as sCD163 serum levels, in samples from 89 patients newly diagnosed with mRCC and 20 healthy controls. We found that in mRCC patients, compared to healthy controls, monocyte mCD163 levels were reduced (P < 0.001) whereas serum sCD163 levels were increased (P = 0.004). Moreover, an inverse correlation between mCD163 and sCD163 levels (P = 0.04) was shown. In survival analyses, intermediary levels of monocyte mCD163 were associated with longest OS, compared to both lower and higher mCD163 levels, which were both associated with worse outcomes (P < 0.01). Further, higher levels of sCD163 at diagnosis were associated with poor OS in both univariate (P < 0.001) and multivariate analysis (HR = 1.28; 95%CI 1.09-1.50, P = 0.002). Importantly, stratification by low vs. high sCD163 was able to separate patients with International Metastatic RCC Database Consortium (IMDC) intermediate risk (IMDCINT) into two subgroups with different OS (P = 0.03): IMDCINT-sCD163LOW showed survival similar to IMDCFAV patients, and IMDCINT-sCD163HIGH showed survival similar to IMDCPOOR patients. Thus, baseline sCD163 is a novel independent biomarker of OS in mRCC, and using sCD163 as an add-on biomarker may improve prognostic value for patients in the heterogenous IMDC intermediate group.


HMDD v4.0: a database for experimentally supported human microRNA-disease associations.
MicroRNAs (miRNAs) are a class of important small non-coding RNAs with critical molecular functions in almost all biological processes, and thus, they play important roles in disease diagnosis and therapy. Human MicroRNA Disease Database (HMDD) represents an important and comprehensive resource for biomedical researchers in miRNA-related medicine. Here, we introduce HMDD v4.0, which curates 53530 miRNA-disease association entries from literatures. In comparison to HMDD v3.0 released five years ago, HMDD v4.0 contains 1.5 times more entries. In addition, some new categories have been curated, including exosomal miRNAs implicated in diseases, virus-encoded miRNAs involved in human diseases, and entries containing miRNA-circRNA interactions. We also curated sex-biased miRNAs in diseases. Furthermore, in a case study, disease similarity analysis successfully revealed that sex-biased miRNAs related to developmental anomalies are associated with a number of human diseases with sex bias. HMDD can be freely visited at http://www.cuilab.cn/hmdd.


Articular cartilage changes seen with magnetic resonance imaging-detected bone bruises associated with acute anterior cruciate ligament rupture.
Occult osteochondral lesions (bone bruises) have been documented on magnetic resonance images in more than 80% of patients sustaining acute anterior cruciate ligament ruptures. Despite the high prevalence of these lesions, little is known about the histologic changes in the adjacent articular cartilage. Ten patients with acute anterior cruciate ligament ruptures who had a preoperatively documented (by magnetic resonance imaging) geographic bone bruise at the sulcus terminalis on the lateral femoral condyle underwent a 3-mm diameter trephine biopsy of the articular cartilage and subchondral bone overlying the bone bruise at the time of anterior cruciate ligament reconstruction. Biopsy samples of the articular cartilage and subchondral bone were stained with hematoxylin and eosin and toluidine blue. All patients had significant arthroscopic and histologic articular cartilage irregularity in the area overlying the bone bruise. Arthroscopic findings of the articular cartilage included softening (dimpling), fissuring, or overt chondral fracture. Histologic examination revealed degeneration of the chondrocytes and loss of toluidine blue staining in the articular cartilage (loss of proteoglycan). There was necrosis of osteocytes in the subchondral bone, and empty lacuna were visible. This study defines the exact histologic changes of the articular cartilage overlying a geographic bone bruise secondary to an acute anterior cruciate ligament tear. Our findings suggest that a geographic bone bruise found on magnetic resonance imaging indicates substantial damage to normal articular cartilage homeostasis.


Turkish Tombul hazelnut (Corylus avellana L.) protein concentrates: functional and rheological properties.
Turkish Tombul hazelnut consumed as natural or processed forms were evaluated to obtain protein concentrate. Defatted hazelnut flour protein (DHFP) and defatted hazelnut cake protein (DHCP) were produced from defatted hazelnut flour (DHF) and defatted hazelnut cake (DHC), respectively. The functional properties (protein solubility, emulsifying properties, foaming capacity, and colour), and dynamic rheological characteristics of protein concentrates were measured. The protein contents of samples varied in the range of 35-48 % (w/w, db) and 91-92 % (w/w, db) for DHF/DHC and DHFP/DHCP samples, respectively. The significant difference for water/fat absorption capacity, emulsion stability between DHF and DHC were determined. On the other hand, the solubility and emulsion activity of DHF and DHC were not significantly different (p > 0.05). Emulsion stability of DHFP (%46) was higher than that of DHCP (%35) but other functional properties were found similar. According to these results, the DHCP could be used as DHFP in food product formulations. The DHFP and DHCP samples showed different apparent viscosity at the same temperature and concentration, the elastic modulus (G' value) of DHPC was also found higher than that of DHFP samples.


Cemented or cementless humeral fixation in reverse total shoulder arthroplasty? a systematic review.
To date, there is insufficient evidence available to compare the outcome of cemented and uncemented fixation of the humeral stem in reverse shoulder arthroplasty (RSA). A systemic review comprising 41 clinical studies was performed to compare the functional outcome and rate of complications of cemented and uncemented stems in RSA. These included 1455 cemented and 329 uncemented shoulders. The clinical characteristics of the two groups were similar. Variables were compared using pooled frequency-weighted means and relative risk ratios (RR). Uncemented stems had a significantly higher incidence of early humeral stem migration (p < 0.001, RR 18.1, 95% confidence interval (CI) 5.0 to 65.2) and non-progressive radiolucent lines (p < 0.001, RR 2.4, 95% CI 1.7 to 3.4), but a significantly lower incidence of post-operative fractures of the acromion compared with cemented stems (p = 0.004, RR 14.3, 95% CI 0.9 to 232.8). There was no difference in the risk of stem loosening or revision between the groups. The cemented stems had a greater relative risk of infection (RR 3.3, 95% CI 0.8 to 13.7), nerve injury (RR 5.7, 95% CI 0.7 to 41.5) and thromboembolism (RR 3.9, 95% CI 0.2 to 66.6). The functional outcome and range of movement were equivalent in the two groups. RSA performed with an uncemented stem gives them equivalent functional outcome and a better complication profile than with a cemented stem. The natural history and clinical relevance of early stem migration and radiolucent lines found with uncemented stems requires further long-term study. This study demonstrates that uncemented stems have at least equivalent clinical and radiographic outcomes compared with cemented stems when used for reverse total shoulder arthroplasty.


A Bayesian model for evaluating influenza antiviral efficacy in household studies with asymptomatic infections.
Antiviral agents are an important component in mitigation/containment strategies for pandemic influenza. However, most research for mitigation/containment strategies relies on the antiviral efficacies evaluated from limited data of clinical trials. Which efficacy measures can be reliably estimated from these studies depends on the trial design, the size of the epidemics, and the statistical methods. We propose a Bayesian framework for modeling the influenza transmission dynamics within households. This Bayesian framework takes into account asymptomatic infections and is able to estimate efficacies with respect to protecting against viral infection, infection with clinical disease, and pathogenicity (the probability of disease given infection). We use the method to reanalyze 2 clinical studies of oseltamivir, an influenza antiviral agent, and compare the results with previous analyses. We found significant prophylactic efficacies in reducing the risk of viral infection and infection with disease but no prophylactic efficacy in reducing pathogenicity. We also found significant therapeutic efficacies in reducing pathogenicity and the risk of infection with disease but no therapeutic efficacy in reducing the risk of viral infection in the contacts.