Immunomodulatory effects of probiotics in different stages of life.
The immunomodulatory properties of lactic acid bacteria (LAB) and foods containing them (e.g., fermented milks) is a topic currently under investigation. Individuals could potentially benefit from the inclusion of LAB in the diet at different times during the life cycle. One of the most accepted specific uses of probiotic bacteria is the prevention of atopic eczema in infants with family history of the disease who receive the probiotic bacteria early, through supplementation of the gestating mother and orally after birth. Immune enhancing effects have also been suggested to be beneficial in diarrhoea treatment, especially in children infected with rotavirus and in malnourished patients, infants and adolescents, whose capacity to produce IFN-gamma can be increased after LAB-containing yoghurt intake. Regarding young people and adults, investigations have been conducted exploring the immunomodulation by LAB in subjects under stressful situations, in the prevention of urinary tract infections in fertile women and in the treatment of allergy. However, the beneficial effects of probiotics in these conditions remain controversial and the scientific evidence provided so far is not considered to be conclusive. The elderly population has been the focus of investigations aimed at identifying the capacity of probiotics to counteract the immunosenescence process by increasing phagocytic and natural killer (NK) cell activities and to protect against infection. The mechanisms involved in the different effects attributed to LAB remain to be clarified. Moreover, considering that the immunomodulatory properties are strain-specific, defining the optimal dose of a certain bacteria or combination of bacteria strains and the duration of treatment for a desired effect in a target population group is essential in order to substantiate health claims.


CRISPR-based self-cleaving mechanism for controllable gene delivery in human cells.
Controllable gene delivery via vector-based systems remains a formidable challenge in mammalian synthetic biology and a desirable asset in gene therapy applications. Here, we introduce a methodology to control the copies and residence time of a gene product delivered in host human cells but also selectively disrupt fragments of the delivery vehicle. A crucial element of the proposed system is the CRISPR protein Cas9. Upon delivery, Cas9 guided by a custom RNA sequence cleaves the delivery vector at strategically placed targets thereby inactivating a co-expressed gene of interest. Importantly, using experiments in human embryonic kidney cells, we show that specific parameters of the system can be adjusted to fine-tune the delivery properties. We envision future applications in complex synthetic biology architectures, gene therapy and trace-free delivery.


Relationships between bone morphology and bone elastic properties can be accurately quantified using high-resolution computer reconstructions.
It would be advantageous if the mechanical properties of trabecular bone could be directly inferred from stereomorphometric parameters. For that purpose, apparent density and mean intercept length, as measures of bone mass and directionality (fabric), are commonly correlated with the elastic characteristics of bone samples, as determined in compression tests. However, complete and accurate relationships have not yet been established in this way. This may be due not only to the occurrence of artifacts in both the stereomorphometric and the mechanical assessments but also to an inherent inadequacy of mean intercept length in characterizing the full mechanical significance of bone architecture or nonhomogeneities in trabecular tissue properties not accounted for in stereomorphometry. In this study, we introduce a computer modeling approach allowing these biases to be eliminated. With use of high-resolution three-dimensional computer reconstructions of trabecular bone specimens for stereomorphometry and for microstructural finite element models to simulate mechanical tests, unbiased comparisons become feasible. The purpose was to investigate if accurate and complete relationships can be established in this way. Four different fabric measures were considered: mean intercept length and three volume-based ones. Compliance matrices were calculated from fabric tensors, with use of the mathematical relationship proposed by Cowin for 29 vertebral whale-bone specimens. These were correlated with the compliance constants determined directly from the microstructural finite element model simulation. The nine orthotropic elastic constants of all 29 specimens were well predicted from their stereomorphometric fabric and volume fraction values, with correlation coefficients ranging from R2adj = 0.9934 to 0.9963. When individual compliance components were considered (1/Ei, 1/Gij, or -v[ij]/Ei), correlation coefficients ranged from R2adj = 0.924 to 0.982. All four fabric measures performed equally well. It is concluded that volume fraction and fabric measures correlate highly with the apparent elastic properties of bone samples, provided that anisotropy and nonhomogeneity in the elastic properties of the trabecular tissue itself have negligible effects on the apparent properties. Whether this is true for bone in general remains to be seen, as only a subset was analyzed here. These methods, however, can be valuable in similar assessments of other subsets.


Calcipotriol/betamethasone foam for proactive management of plaque psoriasis: four case reports.
Psoriasis is a chronic inflammatory disease affecting about 100 million people worldwide. Around 80% of patients can be treated with topical agents, most commonly corticosteroids and vitamin D analogues. A topical foam formulation of calcipotriol (50 μg/g) and betamethasone dipropionate (0.5 mg/g) (Cal/BD foam; Enstilar®) is approved for the daily treatment of psoriasis for up to 4 weeks and twice-weekly thereafter as maintenance treatment (after initial 4-week treatment success). Long-term proactive maintenance with Cal/BD foam for plaque psoriasis has been shown to prolong the time to first relapse, reduce the number of relapses and increase days in remission in the PSO-LONG trial. Four case studies of proactive management with Cal/BD foam for the treatment of plaque psoriasis for up to 12 months from initial presentation are described. These case studies provide real-world evidence on the long-term effectiveness of proactive management with Cal/BD foam as well as the improvement and maintenance of health-related quality of life. Cal/BD foam was well tolerated.


Acute appendicitis - new diagnostic algorithm using RIPASA score and non-contrast Computeed Tomography Scan.
To compare the accuracy of Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) and modified Alvarado scores with that of non-contrast computed tomography scan and ultrasound of abdomen and pelvis. The observational correlational study was conducted at Manipal Hospital, Bengaluru, India, from April 1, 2014, to April 30, 2016, and comprised patients aged 18-60 years presenting with right lower quadrant pain to the emergency department. Modified Alvarado, RIPASA scores and ultrasound of abdomen and pelvis with optional non-contrast computed tomography scan reports were collected. Subjects underwent laparoscopic appendectomy, followed by histopathological analysis of specimen. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of diagnostic modalities in question were computed using SPSS 15. Of the 206 patients, 126(61%) were males and 80(39%) were females. Overall mean mean age was 27.81±9.23 years. The diagnostic accuracy was 92.72% for RIPASA score and 59.22% for the modified Alvarado score. Ultrasound showed a high sensitivity of 94.65% but specificity of only 5.26%. Of the total, 25 patients underwent non-contrast computed tomography scan, and among them, 10(40%) were reported as cases of acute appendicitis. Diagnostic accuracy of non-contrast computed tomography scan was 100%. Non-contrast computed tomography scan and RIPASA score were the most accurate diagnostic modalities..


Highly conducting wire gratings in the resonance region.
We present a theoretical approach for calculating the fields diffracted by gratings made of highlyconducting wires that have a rectangular shape. The fields between the wires are represented in terms of modal expansions that satisfy the approximated impedance boundary condition. Our results show thatthis procedure is particularly suited to dealing with gold gratings used in the infrared range, a spectral region where the assumption of a perfect conductor does not hold, and where the rigorous modal method assuming penetrable wires exhibits numerical instabilities linked with the high conductivity of gold. Numerical results are presented, and the theory is used to determine wire parameters by fitting theoretical and experimental data.


Venous thromboembolic disease in trauma and surveillance ultrasonography.
The literature reports a wide variation in the incidence of venous thromboembolic (VTE) disease in trauma patients. The performance of routine surveillance venous duplex ultrasound of bilateral lower extremities is controversial. Furthermore, recent examinations of the national trauma databank registry have suggested that routine duplex surveillance is associated with higher deep venous thrombosis (DVT) detection rates. We examined the incidence and risk factors for VTE disease in 2827 trauma patients admitted over a 2-y period to a state-verified level I trauma center. Detailed chart review was carried out for patients with VTE disease. We then evaluated the effects of a routine bilateral lower extremity duplex surveillance guideline on VTE detection in the subset of injury patients admitted to the trauma service. We found an approximately 2% incidence of venous thromboembolic disease in a mostly blunt trauma population. Amongst patients with VTE disease, the most common risk factors were obesity and significant head injury. We then evaluated the 998 patients with injury who were admitted to the trauma service 1 y before and after surveillance guideline implementation. Despite a nearly 5-fold increase in the number of duplex scans, with a substantial increase in cost, we found no significant difference in the incidence of DVT. Our preliminary data argue against the use of routine duplex surveillance of lower extremities for DVT in trauma patients. A larger, prospective analysis is necessary to confirm these findings.


Random sequence libraries displayed on phage: identification of biologically important molecules.
Phage display has become a widely used tool for the identification of proteins or peptides with affinity for a variety of biomolecules. The versatility, simplicity and cost effectiveness of this application has pervaded a wide variety of research areas. Although not without its limitations, phage display has provided a convenient methodology for obtaining ligands to study the function, structure and diagnostic or therapeutic potential of various macromolecules. This review highlights some recent research employing this technology that serves to illustrate its utility in various research and clinical applications.


Implementing telestroke to reduce the burden of stroke in Louisiana.
Cardiovascular diseases (heart diseases and stroke) are the leading cause of death in the United States. People living in rural areas have disproportionately high mortality rates due to stroke mainly due to lack of specialty services. Timely intervention is a critical factor in determining the prognosis for acute stroke and thousands of lives can be saved by recognizing/treating a stroke patient within an hour. This paper deals with telestroke, a unique intervention implemented in Louisiana that incorporated latest technology to integrate with advanced clinical protocols in treating acute stroke. People living in remote and rural areas of Louisiana were greatly benefited from this initiative and several lives saved as a result of timely intervention. Expanding these initiatives to larger populations and other states will greatly reduce the stroke mortality.


Corneal Cross-Linking With Verteporfin and Nonthermal Laser Therapy.
To test whether verteporfin with a nonthermal laser increases corneal mechanical stiffness and resistance to enzymatic degradation ex vivo. Thirty human corneas (n = 5 per group) were treated with verteporfin alone (V), irradiated with nonthermal laser therapy (689 nm) alone (NTL), or received combined treatment of verteporfin with nonthermal laser therapy for 1 sequence (V+NTL1) or 6 sequences (V+NTL6) of 1 minute of NTL exposure. Positive controls were pretreated with 0.1% riboflavin/20% dextran every 3 to 5 minutes for 30 minutes and irradiated with ultraviolet light type A (λ = 370 nm, irradiance = 3 mW/cm) for 30 minutes using the Dresden protocol (R+UVA). Untreated corneas were used as negative controls. The corneal biomechanical properties were measured with enzymatic digestion, compression, creep, and tensile strength testing. V+NTL6- and R+UVA-treated corneas acquired higher rigidity and more pronounced curvature than untreated corneas. The stress-strain tests showed that V+NTL6 and R+UVA corneas became significantly stiffer than controls (P < 0.005). The V+NTL6 group seemed to be slightly stiffer than the R+UVA group, although the differences were not statistically significant. V+NTL6 corneas were found to have a significantly lower absolute creep rate (-1.87 vs. -3.46, P < 0.05) and significantly higher maximum stress values (7.67 vs. 3.02 P < 0.05) compared with untreated corneas. Verteporfin-NTL (V+NTL6) increases corneal mechanical stiffness and resistance to enzymatic collagenase degradation. Although a clinical study is needed, our results suggest that V+NTL6 induces corneal cross-linking and corneal biomechanical changes that are similar to those induced by standard corneal collagen cross-linking.


Development of recombinant Salmonellae expressing hybrid hepatitis B virus core particles as candidate oral vaccines.
This paper provides a review on the development of hepatitis core antigen as a vaccine carrier moiety and the use of recombinant Salmonella vaccine strains expressing hybrid HBcAg particles as live oral vaccines. Salmonella spp. can be attenuated by defined genetic means so that they become avirulent, yet preserve invasiveness after oral uptake. Oral immunization of mice with such avirulent candidate Salmonella typhimurium vaccine strains elicited serum antibody responses against a limited number of bacterial antigens. A highly immunogenic viral nucleocapsid antigen, hepatitis B virus core antigen (HBcAg) that can be expressed in prokaryotes was used as a carrier moiety for B-cell epitopes. Insertion sites with an enhanced immunogenicity for the carried epitopes were defined using HBV envelope protein virus neutralizing epitopes. An internal insertion site in HBcAg was found that drastically enhanced the immunogenicity of the foreign (pre-S1) epitope while reducing the immunogenicity of the carrier protein. Internally fused HBc/pre-S hybrid particles were expressed in Salmonella typhimurium and S. typhi vaccine strains. A single oral immunization of mice with such live recombinant S. typhimurium strains elicited a high titred serum anti-pre-S1 IgG response. Similarly, circumsporozoite repeat epitopes of three different malaria parasites were expressed as HBcAg/CS hybrids in recombinant S. spp. and were found to be highly immunogenic.


Stereological study of the synaptic profiles belonging to interneurons in the dorsal lateral geniculate nucleus of the rabbit.
This study is concerned with some characteristics of the interneurons belonging to the dLGN (dorsal Lateral Geniculate Nucleus) of the rabbit. The work deals with the distribution of such cells in the alpha E sector of the nucleus and their F1 and F2 presynaptic contacts. The F1 and the F2 profiles are present in all three of the alpha E zones studied. The F1 profiles are significantly more numerous in the upper zone (57 +/- 2 profiles per 10(4) microns2 of section) and the middle zone (59 +/- 3 profiles per 10(4) microns2 of section) than in the lower one (41 +/- 2 profiles per 10(4) microns2 of section). The F2 profiles are more abundant in the alpha E sector than the F1 ones are, particularly in the lower zone, where F2 profiles (104 +/- 4 profiles per 10(4) microns2 of section) are not only significantly more numerous than F1 profiles but also more abundant than the F2 profiles in the middle zone (84 +/- 3 profiles per 10(4) microns2 of section) and upper zone (88 +/- 2 profiles per 10(4) microns2 of section). These results and their comments reveal diverse density of the element distribution from the dorsal to the ventral part of the alpha E sector as well as the possible relationship or independence from the extranuclear afferent inputs.


Viable cell yield from active dry yeast products and effects of storage temperature and diluent on yeast cell viability.
Active dry yeast (ADY) products are commonly fed in the dairy industry, but research regarding quality control for such products is limited. The objectives of this study were to determine yeast viability in field samples relative to manufacturers' guarantees (experiment 1), measure the effects of high-temperature storage on yeast viability (experiment 1), and determine the effect of vitamin-trace mineral (VTM) premix on yeast viability (experiment 2). Commercially available ADY products were acquired in triplicate through normal distribution channels and stored at 4°C upon receipt. Initial samples were evaluated for colony-forming units and compared with product label guarantees. Only 1 of the 6 products sampled in experiment 1 met product guarantees for all 3 samples. To determine effects of storage temperature and duration on viability, ADY samples were stored in an incubator at 40°C with ambient humidity for 1, 2, and 3 mo. High-temperature storage significantly decreased viability over the 3-mo period; approximately 90% of viable cells were lost each month. Three of the 5 products sampled in experiment 2 met product guarantees. Fresh samples of 4 of these 5 ADY products were mixed in duplicate with ground corn (GC) or a VTM premix to achieve a target concentration of 2.2×10(8) cfu/g. For each product, GC and VTM samples were stored at ambient temperature (22°C) and at an elevated temperature (40°C) for 2 wk. No differences in viable yeast count were observed between GC and VTM samples immediately after mixing or after storage at ambient temperature. Yeast viability in GC and VTM samples decreased during storage at an elevated temperature. There also was a significant interaction of diluent and storage temperature; VTM samples had higher cell viability than GC samples when subjected to high-temperature storage. Results suggest that (1) ADY products failed to consistently meet product guarantees; (2) viability of ADY products was greatly diminished during storage at 40°C for 2 wk; and (3) the loss in viability at elevated temperatures may be attenuated when ADY products are diluted with a premix containing VTM.


Rapid methods for determining decarboxylase activity: ornithine and lysine decarboxylases.
A rapid biochemical method for the determination of ornithine and lysine decarboxylase (EC 184.108.40.206) activity has been developed for use in the routine clinical laboratory. It is based on the detection of the amine end product produced in response to the single key amino acid added to a synthetic medium. A modified ninhydrin reagent is used to detect the amine after a chloroform extraction. This procedure can be used with a 1- to 4-hr incubation period (utilizing an initial concentrated inoculum) or with an overnight culture. Thus, measurements based on the alkalinization of the medium after a lengthy incubation period are avoided. Optimal parameters for enzyme activity are discussed.


The occipital lobe convexity sulci and gyri.
The anatomy of the occipital lobe convexity is so intricate and variable that its precise description is not found in the classic anatomy textbooks, and the occipital sulci and gyri are described with different nomenclatures according to different authors. The aim of this study was to investigate and describe the anatomy of the occipital lobe convexity and clarify its nomenclature. The configurations of sulci and gyri on the lateral surface of the occipital lobe of 20 cerebral hemispheres were examined in order to identify the most characteristic and consistent patterns. The most characteristic and consistent occipital sulci identified in this study were the intraoccipital, transverse occipital, and lateral occipital sulci. The morphology of the transverse occipital sulcus and the intraoccipital sulcus connection was identified as the most important aspect to define the gyral pattern of the occipital lobe convexity. Knowledge of the main features of the occipital sulci and gyri permits the recognition of a basic configuration of the occipital lobe and the identification of its sulcal and gyral variations.


Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation.
Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.


CheX is a phosphorylated CheY phosphatase essential for Borrelia burgdorferi chemotaxis.
Motility and chemotaxis are believed to be important in the pathogenesis of Lyme disease caused by the spirochete Borrelia burgdorferi. Controlling the phosphorylation state of CheY, a response regulator protein, is essential for regulating bacterial chemotaxis and motility. Rapid dephosphorylation of phosphorylated CheY (CheY-P) is crucial for cells to respond to environmental changes. CheY-P dephosphorylation is accomplished by one or more phosphatases in different species, including CheZ, CheC, CheX, FliY, and/or FliY/N. Only a cheX phosphatase homolog has been identified in the B. burgdorferi genome. However, a role for cheX in chemotaxis has not been established in any bacterial species. Inactivating B. burgdorferi cheX by inserting a flgB-kan cassette resulted in cells (cheX mutant cells) with a distinct motility phenotype. While wild-type cells ran, paused (stopped or flexed), and reversed, the cheX mutant cells continuously flexed and were not able to run or reverse. Furthermore, swarm plate and capillary tube chemotaxis assays demonstrated that cheX mutant cells were deficient in chemotaxis. Wild-type chemotaxis and motility were restored when cheX mutant cells were complemented with a shuttle vector expressing CheX. Furthermore, CheX dephosphorylated CheY3-P in vitro and eluted as a homodimer in gel filtration chromatography. These findings demonstrated that B. burgdorferi CheX is a CheY-P phosphatase that is essential for chemotaxis and motility, which is consistent with CheX being the only CheY-P phosphatase in the B. burgdorferi chemotaxis signal transduction pathway.


Competition increases binding errors in visual working memory.
When faced with maintaining multiple objects in visual working memory, item information must be bound to the correct object in order to be correctly recalled. Sometimes, however, binding errors occur, and participants report the feature (e.g., color) of an unprobed, non-target item. In the present study, we examine whether the configuration of sample stimuli affects the proportion of these binding errors. The results demonstrate that participants mistakenly report the identity of the unprobed item (i.e., they make a non-target response) when sample items are presented close together in space, suggesting that binding errors can increase independent of increases in memory load. Moreover, the proportion of these non-target responses is linearly related to the distance between sample items, suggesting that these errors are spatially specific. Finally, presenting sample items sequentially decreases non-target responses, suggesting that reducing competition between sample stimuli reduces the number of binding errors. Importantly, these effects all occurred without increases in the amount of error in the memory representation. These results suggest that competition during encoding can account for some of the binding errors made during VWM recall.


Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging. MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.


Meningioma and schwannoma risk in adults in relation to family history of cancer.
Relatively little is known about factors that contribute to the development of meningioma and vestibular schwannoma, two intracranial nervous system tumors. We evaluated the risk of these tumors in relation to family history of malignant or benign tumors. Incident cases of meningioma (n = 197) or schwannoma (n = 96) were identified at three U. S. referral hospitals between June 1994 and August 1998. Controls (n = 799) admitted to the same hospitals for nonmalignant conditions were matched to cases on age, sex, race/ethnicity, hospital, and proximity of residence to hospital. We found that risk of meningioma was increased among persons reporting a family history of a benign brain tumor (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.0-21.0; n = 5) or melanoma (OR, 4.2; 95% CI, 1.2-15.0; n 5). A family history of breast cancer was associated with an elevated meningioma risk among participants aged 18 to 49 years (OR, 3.9; 95% CI, 1.4-11.0; n = 8) but a reduced risk among older respondents (OR, 0.2; 95% CI, 0.1-0.7; n = 3). Family history of cancer did not differ between schwannoma cases and controls, although the statistical power to detect associations was limited. Some relative risk estimates were based on a small number of observations and may have arisen by chance. Inheritance of predisposing genes, shared environmental factors, or both within families with a history of benign brain tumors, melanoma, or possibly breast cancer may be related to altered meningioma risk.


A Composite Chitosan-Reinforced Scaffold Fails to Provide Osteochondral Regeneration.
Several biomaterials have recently been developed to address the challenge of osteochondral regeneration. Among these, chitosan holds promises both for cartilage and bone healing. The aim of this in vivo study was to evaluate the regeneration potential of a novel hybrid magnesium-doped hydroxyapatite (MgHA), collagen, chitosan-based scaffold, which was tested in a sheep model to ascertain its osteochondral regenerative potential, and in a rabbit model to further evaluate its ability to regenerate bone tissue. Macroscopic, microtomography, histology, histomorphometry, and immunohistochemical analysis were performed. In the sheep model, all analyses did not show significant differences compared to untreated defects (p > 0.05), with no evidence of cartilage and subchondral bone regeneration. In the rabbit model, this bone scaffold provided less ability to enhance tissue healing compared with a commercial bone scaffold. Moreover, persistence of scaffold material and absence of integration with connective tissue around the scaffolds were observed. These results raised some concerns about the osteochondral use of this chitosan composite scaffold, especially for the bone layer. Further studies are needed to explore the best formulation of chitosan-reinforced composites for osteochondral treatment.


Fulminant Type 1 Diabetes Mellitus Developed about Half a Year after Discontinuation of Immune Checkpoint Inhibitor Combination Therapy with Nivolumab and Ipilimumab: A Case Report.
The cytotoxic T-lymphocyte antigen-4 and programmed cell death 1 pathways are novel therapeutic targets in immune checkpoint inhibitor (ICI) therapy for cancer. However, they may cause endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis and type 1 diabetes mellitus (DM). Moreover, delayed immune-related adverse events (irAEs) after discontinuation of ICI therapy have been reported. Here we report a 60-year-old female patient with advanced renal cell carcinoma with brain metastasis who was treated with nivolumab, ipilimumab and prednisolone. At the 3rd course of combination therapy, the administration was discontinued due to the onset of colitis and the dosage of prednisolone was increased. About half a year after discontinuation, she was admitted to the hospital with general malaise, hyperglycemia (330 mg/dL) and diabetic ketoacidosis. Glycated hemoglobin level was 6.5%. Islet-related autoantibodies were negative. The glucagon tolerance test showed complete depletion of insulin. Therefore, we diagnosed fulminant type 1 DM and treated with multiple daily injections of insulin. The onset of type 1 DM was rapid in many cases treated with combination therapy of ICIs. The present case is a rare case in which fulminant type 1 DM developed about half a year after discontinuation of nivolumab and ipilimumab. The literature shows two cases of type 1 DM occurring 4 months after discontinuation of ICI therapy by nivolumab or atezolizumab. The present case indicates that regular monitoring is mandatory for fulminant type 1 DM and other delayed irAEs after discontinuation of ICI therapy even under the low-dose prednisolone treatment.


Comparative Effectiveness of Intralesional Therapy for Peyronie's Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis.
Medical treatment of Peyronie's disease (PD) in terms of intralesional therapy is still a matter of debate. To compare the efficacy of different classes of intralesional therapy with a network meta-analysis (NMA) method. The search was conducted using documents published in PubMed, Scopus, and Web of Science databases until September 30, 2017. We included randomized controlled trials comparing at least 1 intralesional therapy with a placebo therapy or with another drug for the treatment of PD. All intralesional therapies have been considered: collagenase Clostridium histolyticum (CCH), hyaluronic acid, verapamil, and interferon α-2b. Outcomes of the study are the mean change in penile curvature (PC) and in erectile function (EF) assessed with the International Index of Erectile Function questionnaire. In total, 8 comparisons matched with the inclusion criteria, which includes 1,050 patients. With regard to PC (degree) improvement, hyaluronic acid and verapamil showed worse outcomes when compared with CCH (-6.66 and -2.30) and interferon α-2b (-6.75 and -2.38). When considering improvement in EF, hyaluronic acid, verapamil and interferon α-2b showed a slight increase in mean change when compared with CCH (+2.39, +1.77, and +0.65). Moreover, verapamil and interferon α-2b showed slightly worse mean change in comparison to hyaluronic acid (+0.62 and +1.74), whereas interferon α-2b was worse than verapamil (-1.12). Based on this NMA, empirical therapy for PD should be avoided to offer the patients the best treatment in terms of level of evidence. In this NMA, we have provided, for the first time, evidence of the efficacy between different intralesional therapies for the treatment of PD. We were not able to compare all specific outcomes (ie, pain, plaque size, patient satisfaction) of PD, because of the lack of homogeneity across relevant studies. Moreover, because of the few included studies, a meta-regression analysis of predictive factors of treatment response was not calculated. This is the first meta-analysis comparing all available intralesional treatments for PD. CCH and interferon α-2b showed the best outcome in terms of PC, whereas hyaluronic acid was most efficient in relation to EF. Russo GI, Cacciamani G, Cocci A, et al. Comparative Effectiveness of Intralesional Therapy for Peyronie's Disease in Controlled Clinical Studies: A Systematic Review and Network Meta-Analysis. J Sex Med 2019;16:289-299.


Comparison of real-time PCR with conventional PCR and culture to assess the efficacy of a live attenuated Salmonella enterica serovar Typhimurium vaccine against Salmonella enterica serovar Enteritidis in commercial leghorn chicks vaccinated under field and laboratory conditions.
The efficacy of a live attenuated Salmonella Typhimurium Megan Vac 1 vaccine (MV1) was evaluated against Salmonella Enteritidis in chicken pullets with the use of PCR and culture methods. Two hundred Hyline W-32 white leghorn chicks were obtained from a local hatchery and divided into four treatment groups. Two of the groups served as positive and negative controls. The MV1 vaccine was administered to the chicks in the remaining two groups at 1 and 35 days old by either the coarse spray (field) or the oral route (laboratory) method. The chicks were challenged with a high dose of a Salmonella Enteritidis strain at 10 wk old and euthanatized 3 days postinoculation. Samples for PCR analysis were collected prior to enrichment, after pre-enrichment in buffered peptone water (BPW) and after primary enrichment from the ceca, liver, and spleen. None of the samples tested yielded positive results for the Salmonella Typhimurium vaccine strain by either the culture or PCR methods. Results from the standard culture method showed that vaccinating the birds with MV1 reduced the counts of Salmonella Enteritidis recovered from the challenged birds. In addition, fewer pre-enriched samples tested positive for Salmonella Enteritidis among the challenged groups that were vaccinated when compared to the unvaccinated challenged group. Under the conditions of this study, MV1 was unable to prevent colonization of other internal organs such as the liver and spleen. Real-time PCR was significantly more sensitive than conventional PCR (C-PCR) prior to enrichment, but after enrichment the sensitivities of the two methods were similar. Enrichment significantly increased the sensitivity of both PCR methods for the detection of Salmonella Enteritidis in cecal samples, but did not significantly increase the sensitivity for detection of Salmonella Enteritidis in liver and spleen samples that were pre-enriched in BPW. There was no significant difference between the laboratory or field vaccination methods with respect to either the prevalence of Salmonella Enteritidis isolation or the bacterial loads in culture-positive samples. Collectively, the data suggest that MV1 offered some protection against Salmonella Enteritidis in commercial layer chick pullets under the conditions of this study. Given the labor and time required to perform the C-PCR and culture methods, the real-time PCR method may prove to be a more useful method to use in diagnostics.


Laparoscopic conversion of laparoscopic gastric banding to Roux-en-Y gastric bypass: a review of 70 patients.
The feasibility and outcomes of conversion of laparoscopic adjustable gastric banding (LAGB) to laparoscopic Roux-en-Y gastric bypass (LRYGBP) was evaluated. From November 2000 to March 2004, all patients who underwent laparoscopic conversion of LAGB to LRYGBP were retrospectively analyzed. The procedure included adhesiolysis, resection of the previous band, creation of an isolated gastric pouch, 100-cm Roux-limb, side-to-side jejuno-jejunostomy, and end-to-end gastro-jejunostomy. 70 patients (58 female, mean age 41) with a median BMI of 45+/-11 (27-81) underwent attempted laparoscopic conversion of LAGB to an RYGBP. Indications for conversion were insufficient weight loss or weight regain after band deflation for gastric pouch dilatation in 34 patients (49%), inadequate weight loss in 17 patients (25%), symptomatic proximal gastric pouch dilatation in 15 patients (20%), intragastric band migration in 3 patients (5%), and psychological band intolerance in 1 patient. 3 of 70 patients (4.3%) had to be converted to a laparotomy because of severe adhesions. Mean operative time was 240+/-40 SD min (210-280). Mean hospital length of stay was 7.2 days. Early complication rate was 14.3% (10/70). Late major complications occurred in 6 patients (8.6%). There was no mortality. Median excess body weight loss was 70+/-20%. 60% of patients achieved a BMI of <33 with mean follow-up 18 months. Laparoscopic conversion of LAGB to RYGBP is a technically challenging procedure that can be safely integrated into a bariatric treatment program with good results. Short-term weight loss is very good.


Different Outcomes According to Needling Point Location Used in Sham Acupuncture for Cancer-Related Pain: A Systematic Review and Network Meta-Analysis.
Numerous acupuncture studies have been conducted on cancer-related pain; however, its efficacy compared to sham acupuncture remains controversial. We confirmed whether the outcome of acupuncture differs according to the needling points of sham acupuncture for cancer-related pain. We searched 10 databases on 23 May 2023 to screen acupuncture trials using sham acupuncture or waiting list as controls for cancer-related pain. Sham acupuncture was classified into two types, depending on whether the needling was applied at the same locations as verum acupuncture (SATV) or not (SATS). A network meta-analysis (NMA) was performed on the basis of a frequentist approach to assess pain severity. Eight studies (n = 574 participants) were included in the review, seven of which (n = 527 participants) were included in the NMA. The pain severity was not significantly different between SATV and verum acupuncture, but verum acupuncture significantly improved pain severity compared to SATS. The risk of bias affecting the comparisons between the verum and sham acupuncture was generally low. Previous acupuncture trials for cancer-related pain showed differing outcomes of sham and verum acupuncture, depending on the needling points of sham acupuncture. The application of SATV cannot be considered a true placebo, which leads to an underestimation of the efficacy of verum acupuncture.


Safety Run-in of Intramuscular pNGVL4a-Sig/E7(detox)/HSP70 DNA and TA-CIN Protein Vaccination as Treatment for HPV16+ ASC-US, ASC-H, or LSIL/CIN1.
Patients with human papillomavirus type 16 (HPV16) infection and low-grade cervical dysplasia [low-grade squamous intraepithelial lesion (LSIL)/CIN1] or atypical squamous cells [atypical squamous cells of undetermined significance (ASC-US)/atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion (ASC-H)] require active surveillance for disease progression. A safe and effective immunotherapy to clear HPV16 is an unmet medical need. The safety run-in cohort of a randomized double-blind, placebo-controlled phase II trial of PVX2 [vaccination twice with HPV16-targeting pNGVL4a-Sig/E7(detox)/HSP70 plasmid and once with the HPV16 L2E7E6 fusion protein "TA-CIN"] as immunotherapy for patients with HPV16+ ASC-US, ASC-H, or LSIL/CIN1 (NCT03911076) was recently completed. The primary objective of this cohort was to determine the safety and tolerability of PVX2 vaccination. Subjects were confirmed to have HPV16 infection and LSIL/CIN1, ASC-US, or ASC-H. Adverse events were evaluated using Common Terminology Criteria for Adverse Events v5.0. HPV typing by HPV16 18/45 Aptima Assay was done at baseline, month 6, and month 12, with simultaneous cytology analysis. Cervical biopsies and endocervical curettage were performed at baseline and month 6. In the safety run-in cohort 12 eligible patients were enrolled. Each received three monthly immunizations. One was lost to follow-up after week 12. There were no serious adverse events. A total of five adverse events were noted by 4 patients; 4 were considered not vaccine-related, and one 'unlikely related' by the investigator. At month 6, 45% (5/11) of participants converted to HPV16-negative and 2 others developed CIN2+ and received a loop electrosurgical excision procedure. At month 12, 64% (7/11) were HPV16-negative, including those HPV16-negative at month 6. In conclusion, PVX2 immunotherapy was well tolerated and associated with viral regression, supporting further testing. This safety run-in study cohort suggests that PVX2 immunotherapy is well tolerated in the target population and is sufficiently safe to warrant further clinical testing in a randomized study. The combined vaccines may facilitate higher-than-expected rate of human papillomavirus type 16 viral clearance 6 and 12 months after treatment, although this requires validation.


Cognitive impairment and risk factor prevalence in a population over 60 in Argentina.
Epidemiological data on dementia and cognitive impairment are scarce in South America. In Argentina, no dementia/cognitive impairment population-based epidemiological studies are available. The Ceibo Study is a population-based epidemiological study of dementia and cognitive impairment in individuals over 60 to be conducted. The present paper reports the results of the pilot phase (survey of cognitive impairment) conducted in Cañuelas (province of Buenos Aires). In a door-to-door survey, trained high school students evaluated 1453 individuals aged 60 years and over in one day using a demographic data and risk factors questionnaire, the Mini-Mental State Examination (MMSE) and the 15-item Geriatric Depression Scale (GDS). Mean age of the individuals was 70.9 (±7.5) years, 61.4% were women, mean schooling was 5.5 (±3.5) years. Mean MMSE score was 24.5 (±4.7) and mean GDS 3.1 (±2.7). Risk factors of higher prevalence in the population under study were: hypertension (40.6%), smoking (35.1%), alcohol consumption (32.8%), high cholesterol (16.1%), diabetes (12.5%), cranial trauma with loss of consciousness (12.5%), 7 points or more on the GDS (11.7%). Prevalence of cognitive impairment for the whole sample was 23%, and 16.9% in subjects aged 60-69, 23.3% in 70-79 and 42.5% in subjects aged 80 or over . A significant correlation of cognitive impairment with age, functional illiteracy, cranial trauma, high blood pressure, inactivity and depression was found. In this pilot study, the prevalence of cognitive impairment was comparable with previous international studies.


Sprinting Toward Fitness.
Intense intermittent exercise, or interval training, is a powerful stimulus to induce many of the physiological adaptations typically associated with traditional, moderate-intensity continuous training. While coaches and athletes have recognized the value of interval training to enhance performance for over a century, recent scientific interest has focused on the application of this training method for health promotion. Despite renewed attention, the mechanistic basis for the physiological remodeling that occurs after interval training and the role that the stochastic nature of this type of exercise plays in mediating adaptive responses remains to be elucidated.


Presenting clinical pharmacology and therapeutics: evaluation of a problem based approach for choosing drug treatments.
Between 1983 and 1989 three studies were conducted to determine whether the ability of senior medical students to choose drug treatments rationally had improved. This period spanned the implementation of a course in pharmacotherapeutics which trained students to use a systematic problem-based approach to choosing and prescribing drugs. The results show that in the short-term students remembered how to choose drugs rationally for cases known to them (retention effect), but had difficulties in transferring what had been learned to similar but different problems (transfer effect). In the medium-term a retention effect was shown for all three aspects of choice (drug, dosage and duration), and a transfer effect for choosing a dosage and duration when solving almost all types of patient problems used in the study. Transfer of the ability to choose a drug was less easily demonstrable. Compared with control students rational choices of trained students increased significantly for all aspects of drug choice, and almost all patient problems used in the study, whether or not they had been discussed. Possible causes for not finding a full transfer effect are: the intervention (course) may have been too short; there was sufficient knowledge about drugs but a lack of understanding of basic pharmacological concepts; or there was no reinforcement of the problem-based approach during clinical clerkships.


Minoxidil reduces pulmonary vascular resistance in dogs and cattle.
Minoxidil has a direct dilator effect on the systemic arterial smooth muscle. It is potentially an important drug in the treatment of systemic hypertension, especially when combined with beta blockade, which is used to control the associated tachycardia and increase in cardiac output. However, recent observations have suggested that minoxidil might cause pulmonary hypertension. Consequently, we examined the acute effect of monoxidil and propranolol, separately and in combination, on the pulmonary vasculature of the anesthetized dog and the awake calf during normoxia and hypoxia. In both species minoxidil reduced pulmonary vascular resistance. In the dogs this appeared to be the result of a direct action on the pulmonary vascular smooth muscle and in the cattle it was secondary to beta-receptor stimulation. Propranolol alone in the cattle increased the pulmonary pressor response to hypoxia. While we have not examined the possibility that chronic administration of minoxidil might cause pulmonary hypertension by some other mechanism, our acute studies suggest that it reduces, rather than increases, pulmonary vascular resistance. Furthermore, there seems to be a species difference in the mode of its action in dogs and cattle.


Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features.
MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.


Do primary afferent cell numbers change in relation to increasing weight and surface area in adult rats?
Adult mammalian primary afferent neurogenesis implies considerably more plasticity for the adult nervous system than is presently envisioned. One hypothesis is that such neurogenesis does not occur, because no tritiated-thymidine-labeled or mitosing neurons are observed in adults, and no increase in cells can be found in young as compared to old adults. The other hypothesis is that adult primary afferent neurogenesis does occur, but that it has not been observed because it is correlated with changes in the size of the animals. This has not been tested, and because of the implications of adult neurogenesis, it is important to see whether dorsal root ganglion (DRG) cell numbers increase with animal size. This is particularly pertinent because of recent advances in the technology for counting neurons and improved methods for resolving the cells in question. The present results indicate that DRG cell numbers are approximately the same in animals whose sizes are different by a factor of approximately 5. Thus our data are consistent with the hypothesis that numbers of adult DRG cells are stable, and we cannot demonstrate a change in relation to age or body size in our animals. Therefore, we do not find evidence of adult neurogenesis in our animals.


Is there a learning curve for photodynamic diagnosis of bladder cancer with hexaminolevulinate hydrochloride?
To assess the learning curve for fluorescence cystoscopy using hexaminolevulinate hydrochloride (HAL) in patients with bladder cancer. Fifty patients underwent bladder instillation with HAL. Two senior residents inspected separately the bladder using white light cystoscopy, followed by fluorescence cystoscopy and mapped the lesions. An experienced with photodynamic diagnosis (PDD) urologist also performed both cystoscopies, mapped, resected or cold biopsied suspect lesions under the supervision of another experienced urologist. To evaluate the learning curve, patients were divided into five subgroups, including group 1 (patients 1-10), group 2 (11-20), group 3 (21-30), group 4 (31-40) and group 5 (41-50). The kappa statistics was calculated to assess interobserver agreement between the physicians and the false positive rates of urologists and residents were also compared. Histologically verified tumors were diagnosed in 103 of 142 lesions identified by PDD. The interobserver agreement between urologists and residents was moderate, moderate, good, excellent, and excellent for group 1, 2, 3, 4, and 5, respectively. Both residents had increased false positive rates compared to urologists in all subgroups of patients but this difference did not reach statistical significance. In addition, false positive rate of residents was declining as the number of procedures was increasing. Our data suggest that 20 cases of HAL PDD are required to achieve a good interobserver agreement between inexperienced and experienced operator, and excellent agreement is achieved after 30 cases. The false positive rate of inexperienced operators was comparable to the experts and showed a gradual decrease.


Sleep/wake firing patterns of human genioglossus motor units.
Although studies of the principal tongue protrudor muscle genioglossus (GG) suggest that whole muscle GG electromyographic (EMG) activities are preserved in nonrapid eye movement (NREM) sleep, it is unclear what influence sleep exerts on individual GG motor unit (MU) activities. We characterized the firing patterns of human GG MUs in wakefulness and NREM sleep with the aim of determining 1) whether the range of MU discharge patterns evident in wakefulness is preserved in sleep and 2) what effect the removal of the "wakefulness" input has on the magnitude of the respiratory modulation of MU activities. Microelectrodes inserted into the extrinsic tongue protrudor muscle, the genioglossus, were used to follow the discharge of single MUs. We categorized MU activities on the basis of the temporal relationship between the spike train and the respiration cycle and quantified the magnitude of the respiratory modulation of each MU using the eta (eta(2)) index, in wakefulness and sleep. The majority of MUs exhibited subtle increases or decreases in respiratory modulation but were otherwise unaffected by NREM sleep. In contrast, 30% of MUs exhibited marked sleep-associated changes in discharge frequency and respiratory modulation. We suggest that GG MUs should not be considered exclusively tonic or phasic; rather, the discharge pattern appears to be a flexible feature of GG activities in healthy young adults. Whether such flexibility is important in the response to changes in the chemical and/or mechanical environment and whether it is preserved as a function of aging or in individuals with obstructive sleep apnea are critical questions for future research.


Rib fracture fixation in a South African public trauma service.
Rib fractures and flail chests have traditionally been treated nonoperatively. Current literature suggests that it is not only safe and feasible but also desirable to perform fixation of severe rib fractures. Our unit in the Pietermaritzburg public sector adopted rib fracture fixation in 2014 and in this audit we assess its feasibility in our setting. We audited our first nine cases of rib fracture fixation performed to date, of which seven were males. The age range was 29 to 67 years. All patients had multiple rib fractures with severe displacement; one had bilateral flail segments and one had severely displaced unilateral single fractures without flail; all others had unilateral flail chests. Time from injury to operation ranged from 3 to 20 days. Of six ventilator dependent patients, all but one were liberated from the ventilator within 3 days after fixation (1-3 days). The remaining patient remained ventilator dependent for 10 days while recovering from traumatic brain injury. This patient aside, all were discharged from ICU within 5 days. Patients with no other significant injuries were discharged from hospital within five to eight days; all being mobile within five days. Procedure-related complications included accidental pleural breach during rib mobilization necessitating intercostal drain placement (2 patients) and superficial wound infection (1 patient). All patients were discharged well. Rib fracture fixation is safe and feasible in our unit and is feasible in the South African public sector.


Masting in whitebark pine (Pinus albicaulis) depletes stored nutrients.
• In masting trees, synchronized, heavy reproductive events are thought to deplete stored resources and to impose a replenishment period before subsequent masting. However, direct evidence of resource depletion in wild, masting trees is very rare. Here, we examined the timing and magnitude (local vs individual-level) of stored nutrient depletion after a heavy mast event in Pinus albicaulis. • In 2005, the mast year, we compared seasonal changes in leaf and sapwood nitrogen (N) and phosphorus (P) concentrations and leaf photosynthetic rates in cone-bearing branches, branches that never produced cones, and branches with experimentally removed cones. We also compared nutrient concentrations in cone branches and branches that had never had cones between 2005 and 2006, and measured tree ring width and new shoot growth during 2005. • During the mast year, N or P depletion occurred only in tissue fractions of reproductive branches, where photosynthetic rates were reduced. However, by the end of the following year, nutrients were depleted in all branches, indicating individual-level resource depletion. New shoot and radial growth were not affected by masting. • We provide direct evidence that mast events in wild trees deplete stored nutrients. Our results highlight the importance of evaluating reproductive costs over time and at the individual level.


Minimal clinically important differences in the EORTC QLQ-C30 and brief pain inventory in patients undergoing re-irradiation for painful bone metastases.
The EORTC QLQ-C30 and the Brief Pain Inventory (BPI) are validated tools for measuring quality of life (QOL) and the impact of pain in patients with advanced cancer. Interpretation of these instrument scores can be challenging and it is difficult to know what numerical changes translate to clinically significant impact in patients' lives. To address this issue, our study sought to establish the minimal clinically important differences (MCID) for these two instruments in a prospective cohort of patients with advanced cancer and painful bone metastases. Both anchor-based and distribution-based methods were used to estimate the MCID scores from patients enrolled in a randomized phase III trial evaluating two different re-irradiation treatment schedules. For the anchor-based method, the global QOL item from the QLQ-C30 was chosen as the anchor. Spearman correlation coefficients were calculated for all items and only those items with moderate or better correlation (|r| ≥ 0.30) with the anchor were used for subsequent analysis. A 10-point difference in the global QOL score was used to classify improvement and deterioration, and the MCID scores were calculated for each of these categories. These results were compared with scores obtained by the distribution-method, which estimates the MCID purely from the statistical characteristics of the sample population. A total of 375 patients were included in this study with documented pain responses and completed QOL questionnaires at 2 months. 9/14 items in the QLQ-C30 and 6/10 items in the BPI were found to have moderate or better correlation with the anchor. For deterioration, statistically significant MCID scores were found in all items of the QLQ-C30 and BPI. For improvement, statistically significant MCID scores were found in 7/9 items of the QLQ-C30 and 2/6 items of the BPI. The MCID scores for deterioration were uniformly higher than the MCIDs for improvement. Using the distribution-based method, there was good agreement between the 0.5 standard deviation (SD) values and anchor-based scores for deterioration. For improvement, there was less agreement and the anchor-based scores were lower than the 0.5 SD values obtained from the distribution-based method. We present MCID scores for the QLQ-C30 and BPI instruments obtained from a large cohort of patients with advanced cancer undergoing re-irradiation for painful bone metastases. The results from this study were compared to other similar studies which showed larger MCID scores for improvement compared to deterioration. We hypothesize that disease trajectory and patient expectations are important factors in understanding the contrasting results. The results of this study can guide clinicians and researchers in the interpretation of these instruments.


The Place and Prognostic Value of TERT Promoter Mutation in Molecular Classification in Grade II-III Glial Tumors and Primary Glioblastomas.
Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class II-IV gliomas. After 2016, two mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were identified in addition to the IDH, 1p / 19q, and ATRX status. We identified 84 patients with grade II-IV glioma with IDH, ATRX, 1p / 19q and TERT status. All tumor samples were subjected to molecular genetic screening (Sanger sequencing for IDH and TERT mutations, fluorescence in situ hybridization for 1p/19q status) after histological diagnosis (immunohistochemistry for IDH1 R132H, ATRX, and p53) for a more precise molecular diagnosis. The confidence intervals were calculated at the 95% confidence level, and differences at p < 0.05 were considered statistically significant. Primary glioblastomas had the highest frequency of TERT promoter mutations (25 of 28, 89.2%, p=0.006) followed by oligodendrogliomas (29 of 35, 82.8%, p < 0.001) while astrocytomas showed the lowest frequency (3 of 15, 20%, p=0.107), and the positivity significantly differed among these three groups (p < 0.001). TERT promoter mutations were more frequent in patients older than 55 years of age at diagnosis (p=0.023). The group with TERT promoter mutations, and without IDH mutations showed the worst overall survival. However, the presence of both TERT promoter and IDH mutations, which resembled oligodendroglial progression, showed best overall survival (p=0.042). The discovery of TERT promoter mutations in numerous gliomas has opened the door for a better molecular classification of gliomas, and TERT status is associated with survival. Further studies will help in elucidating the value of TERT promoter mutations as biomarkers in clinical practice, and eventual therapeutic targets.


Species-specific responses of constitutively active receptor (CAR)-CYP2B coupling: lack of CYP2B inducer-responsive nuclear translocation of CAR in marine teleost, scup (Stenotomus chrysops).
The mammalian constitutively active receptor (CAR) is a novel ligand-activated transcription factor that participates in controlling the expression of cytochrome P450 2B (CYP2B) genes in response to pharmaceutical agents (phenobarbital) and halogenated aromatic hydrocarbons (ortho-substituted PCBs). The occurrence and physiological function of this protein are as yet unknown in marine animals, where there has been a paradoxical lack of induction by PB-type chemicals. One approach to understanding CAR function is to study the evolutionary history of processes such as CAR-CYP2B coupling. In this study, CAR function was evaluated in a representative teleost fish (scup, Stenotomus chrysops). Treatment of scup with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is one of the most potent CYP2B inducers in mouse, caused no increase in hepatic alkoxyresorufin O-dealkylase activity nor in immunodetectable CYP2B-like protein levels. Western blot analyses of scup livers using anti-human CAR antisera revealed the occurrence of a putative CAR homologue in nuclear and cytoplasmic fractions, but no nuclear accumulation of CAR following TCPOBOP treatment, which is a first step regulating the transcriptional activation of CYP2B genes in mouse. Immunohistochemical study also showed no translocation of CAR into nucleus in the hepatocytes of TCPOBOP-treated scup. These results suggest that there may be species-specific differences in CAR activation or CAR-CYP2B coupling signaling transduction in fish from those in mouse.


Public perceptions of obesity and bariatric surgery in Singapore: a pilot study.
Obesity is a real and dangerous problem with rising incidence. This study aimed to examine public perceptions of obesity as a disease, as well as the community's impression of the various modalities in the management of obesity, particularly bariatric surgery, in Singapore. Volunteers from the public were approached in 2010 to complete a questionnaire that collected both their demographic data and perceptions on obesity, management of obesity and bariatric surgery. The perceptions of the respondents were analysed based on various demographic factors. The incidence of obesity was 16.8%. Consistent with previous studies in developed countries, the highest mean body mass index was noted in the age range of 41-50 years. 95.6% of the population surveyed were aware that obesity was related to significant medical conditions. 60% of the population surveyed had attempted weight loss in the past, with 41.7% expressing lack of success, and 58.4% expressed that they had not heard of surgery as a modality. This study shows that the majority of the population understands the significance of obesity as a medical problem and would take steps to combat it. However, there is suboptimal knowledge of the various modalities of managing obesity as a disease, especially with regard to surgical options. More education on the modalities available and access to them would help in the combat of this obesity epidemic.


Genome-Scale Metabolic Modeling Enables In-Depth Understanding of Big Data.
Genome-scale metabolic models (GEMs) enable the mathematical simulation of the metabolism of archaea, bacteria, and eukaryotic organisms. GEMs quantitatively define a relationship between genotype and phenotype by contextualizing different types of Big Data (e.g., genomics, metabolomics, and transcriptomics). In this review, we analyze the available Big Data useful for metabolic modeling and compile the available GEM reconstruction tools that integrate Big Data. We also discuss recent applications in industry and research that include predicting phenotypes, elucidating metabolic pathways, producing industry-relevant chemicals, identifying drug targets, and generating knowledge to better understand host-associated diseases. In addition to the up-to-date review of GEMs currently available, we assessed a plethora of tools for developing new GEMs that include macromolecular expression and dynamic resolution. Finally, we provide a perspective in emerging areas, such as annotation, data managing, and machine learning, in which GEMs will play a key role in the further utilization of Big Data.


Wilms' tumor and paternal occupation.
A case-control study was conducted to examine the relationship between Wilms' tumor and paternal occupational exposures. The case group consisted of 200 children diagnosed as having Wilms' tumor who were registered at selected National Wilms' Tumor Study institutions during the period June 1, 1984, to May 31, 1986. Disease-free controls were matched to each case using a random digit dialing procedure. The parents of cases and controls completed a self-administered questionnaire. There was no consistent pattern of increased risk for paternal occupational exposure to hydrocarbons or lead found in this study. However, certain paternal occupations were found to have an elevated odds ratio (OR) of Wilms' tumor, including vehicle mechanics, auto body repairmen, and welders. Offspring of fathers who were auto mechanics had a 4- to 7-fold increased risk of Wilms' tumor for all 3 time periods. The largest increased odds ratio for auto mechanics was in the preconception period [OR = 7.58; 95% confidence interval (CI) = 0.90-63.9]. Welders had a 4- to 8-fold increased odds ratio, with the strongest association during pregnancy (OR = 8.22; CI = 0.95-71.3). Although chance cannot be excluded as a possible explanation, association of Wilms' tumor with these occupations has been reported in previous studies. Further study is needed to provide data on the specific occupational exposures involved.


Electron microscopy of Listeria monocytogenes-infected mouse spleen.
Armstrong, B. A. (The University of Kansas, Lawrence), and C. P. Sword. Electron microscopy of Listeria monocytogenes-infected mouse spleen. J. Bacteriol. 91:1346-1355. 1966.-Mouse spleen infected with Listeria monocytogenes was observed during the acute phase of infection; 72 hr after infection, organisms were usually found within phagocytic vacuoles in the cytoplasm of macrophages. These vacuoles, which resembled phagosomes, often contained several organisms as well as varying amounts of amorphous electron-dense material, ferritin-like particles, membrane fragments, and vesicles of varying density. Breakdown of vacuolar membranes appeared to be accompanied by damage to the host cell cytoplasm. Nuclear membrane damage was occasionally observed when phagocytic vacuoles were close to the nucleus.


Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients.
Ablation of androgen receptor (AR) signaling by androgen deprivation is the goal of the first line of therapy for prostate cancer that initially results in cancer regression. However, in a significant number of cases, the disease progresses to advanced, castration-resistant prostate cancer (CRPC), which has limited therapeutic options and is often aggressive. Distant metastasis is mostly observed at this stage of the aggressive disease. CRPC is treated by a second generation of AR pathway inhibitors that improve survival initially, followed by the emergence of therapy resistance. Neuroendocrine prostate cancer (NEPC) is a rare variant of prostate cancer (PCa) that often develops as a result of therapy resistance via a transdifferentiation process known as neuroendocrine differentiation (NED), wherein PCa cells undergo a lineage switch from adenocarcinomas and show increased expression of neuroendocrine (NE) lineage markers. In addition to the genomic alterations that drive the progression and transdifferentiation to NEPC, epigenetic factors and microenvironmental cues are considered essential players in driving disease progression. This manuscript provides a detailed protocol to identify the epigenetic drivers (i.e., small non-coding RNAs) that are associated with advanced PCa. Using purified microRNAs from formalin-fixed paraffin-embedded (FFPE) metastatic tissues and corresponding serum-derived extracellular vesicles (EVs), the protocol describes how to prepare libraries with appropriate quality control for sequencing microRNAs from these sample sources. Isolating RNA from both FFPE and EVs is often challenging because most of it is either degraded or is limited in quantity. This protocol will elaborate on different methods to optimize the RNA inputs and cDNA libraries to yield most specific reads and high-quality data upon sequencing.


Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden Early Arthritis cohort.
The performance of spondyloarthritis (SpA) classification criteria is not well-established in general early arthritis cohorts. Therefore, the authors tested their performance in the Leiden Early Arthritis Clinic (EAC) cohort and assessed whether these criteria can assist rheumatologists in diagnosing patients. The authors identified all SpA and psoriatic arthritis (PsA) patients in the EAC cohort according to the diagnosis of the treating rheumatologist. A control group consisting of arthritis patients with other diagnoses was matched to the SpA and PsA patients on gender, age and symptom duration. The authors assessed the fulfilment of SpA criteria in all three groups. Of the patients in the EAC cohort (n=2011), 7.5% was diagnosed with PsA and 3.8% with SpA. In the PsA group, the ClASsification criteria for Psoratic ARthritis (CASPAR) criteria had the highest sensitivity (88.7%). In the SpA group, the Assessment of SpondyloArthritis international Society (ASAS) peripheral SpA and European Spondylarthropathy Study Group (ESSG) criteria had the highest sensitivity (both 48.7%). Specificity of all criteria sets was good: ranging from 88.5% (ESSG) to 100% (Amor). In early arthritis, sensitivity of SpA classification criteria is modest except for the CASPAR criteria in PsA. However, specificity of classification criteria, including the new ASAS-peripheral SpA criteria, is high.


Combinatorial invariant for Morse-Smale diffeomorphisms on surfaces with orientable heteroclinic.
In this paper, we consider a class of orientation-preserving Morse-Smale diffeomorphisms defined on an orientable surface. The papers by Bezdenezhnykh and Grines showed that such diffeomorphisms have a finite number of heteroclinic orbits. In addition, the classification problem for such diffeomorphisms is reduced to the problem of distinguishing orientable graphs with substitutions describing the geometry of a heteroclinic intersection. However, such graphs generally do not admit polynomial discriminating algorithms. This article proposes a new approach to the classification of these cascades. For this, each diffeomorphism under consideration is associated with a graph that allows the construction of an effective algorithm for determining whether graphs are isomorphic. We also identified a class of admissible graphs, each isomorphism class of which can be realized by a diffeomorphism of a surface with an orientable heteroclinic. The results obtained are directly related to the realization problem of homotopy classes of homeomorphisms on closed orientable surfaces. In particular, they give an approach to constructing a representative in each homotopy class of homeomorphisms of algebraically finite type according to the Nielsen classification, which is an open problem today.


Immunization against serogroup B meningococci. Opsonin response in vaccinees as measured by chemiluminescence.
One hundred and thirteen healthy volunteers were immunized twice (six weeks apart) with four different doses (12.5, 25, 50 and 100 micrograms, measured as protein content) of an outer membrane vesicle vaccine from a serogroup B meningococcal strain (44/76, B:15:P1.16) complexed to serogroup C meningococcal polysaccharide and/or Al(OH)3 i.e. 12 different vaccines. Serum opsonic activity against the serogroup B strain was measured using a chemiluminescence method. A significant rise in serum opsonic activity was demonstrated in 84 volunteers (74%) six weeks after the first injection and in 97 (86%) six weeks after the second. All vaccinees with low preimmunization values (less than 25 mVs) experienced a significant increase in opsonic activity. A dose-related response was most evident for the vaccines containing adjuvant, and these vaccines were associated with a maximum response six weeks after the second injection, while the vaccines without Al(OH)3 induced a peak response six weeks after the first injection. The postimmunization opsonic activity was similar to that found in convalescent sera, indicating that the vaccines may protect against serogroup B meningococcal disease.


Mechanical properties of primary cilia regulate the response to fluid flow.
The primary cilium is a ubiquitous organelle present on most mammalian cells. Malfunction of the organelle has been associated with various pathological disorders, many of which lead to cystic disorders in liver, pancreas, and kidney. Primary cilia have in kidney epithelial cells been observed to generate intracellular calcium in response to fluid flow, and disruption of proteins involved in this calcium signaling lead to autosomal dominant polycystic kidney disease, implying a direct connection between calcium signaling and cyst formation. It has also been shown that there is a significant lag between the onset of flow and initiation of the calcium signal. The present study focuses on the mechanics of cilium bending and the resulting calcium signal. Visualization of real-time cilium movements in response to different types of applied flow showed that the bending is fast compared with the initiation of calcium increase. Mathematical modeling of cilium and surrounding membrane was performed to deduce the relation between bending and membrane stress. The results showed a delay in stress buildup that was similar to the delay in calcium signal. Our results thus indicate that the delay in calcium response upon cilia bending is caused by mechanical properties of the cell membrane.


Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins.
The aim of this study was to assess and to compare the role of HFE polymorphisms and other genetic factors in variation in iron stores. Blood samples were obtained from 3,375 adult male and female twins (age range 29-82 years) recruited from the Australian Twin Registry. There were 1,233 complete pairs (562 monozygotic and 571 dizygotic twins). Serum iron, transferrin, transferrin saturation with iron, and ferritin were measured, and the HFE C282Y and H63D genotypes were determined. The frequency of the C282Y allele was.072, and that of the H63D allele was.141. Significant sources of variation in the indices of iron status included age, sex, age-sex interaction, body-mass index, and both the C282Y and H63D genotypes. The iron, transferrin, and saturation values of CC and CY subjects differed significantly, but the ferritin values did not. After correction for age and body-mass index, 23% and 31% of the variance in iron, 66% and 49% of the variance in transferrin, 33% and 47% of the variance in transferrin saturation, and 47% and 47% of the variance in ferritin could be explained by additive genetic factors, for men and women, respectively. HFE C282Y and H63D variation accounted for <5% of the corrected phenotypic variance, except for saturation (12% in women and 5% in men). We conclude that HFE CY and HD heterozygotes differ in iron status from the CC and HH homozygotes and that serum transferrin saturation is more affected than is serum ferritin. There are highly significant effects of other as-yet-unidentified genes on iron stores, in addition to HFE genotype.


Correlation of FISH and PRAME Immunohistochemistry in Ambiguous Superficial Cutaneous Melanocytic Proliferations.
Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated repressor of retinoic acid signaling which is expressed in melanoma and has emerged as a potential biomarker for malignant behavior in melanocytic neoplasms. Although ancillary molecular techniques such as fluorescence in situ hybridization (FISH) are established techniques in the diagnosis of problematic cutaneous melanocytic proliferations, they are expensive, time-consuming, and require appropriate infrastructure, which places them out of reach of some laboratories. The advent of readily available commercial antibodies to PRAME has the potential to provide a more accessible alternative. The aim of this study was to determine whether immunohistochemistry for PRAME could serve as a surrogate for FISH analysis in a subgroup of challenging superficial melanocytic proliferations. Cases which had previously been submitted for FISH analysis were stained for PRAME and interpreted by a panel of at least 3 dermatopathologists is a blinded fashion. Of a study set of 55 cases, 42 (76%) showed a pattern of PRAME immunostaining which was concordant with the cytogenetic interpretation, with an unweighted kappa of 0.42 (representing mild-to-moderate agreement). Thus, although there was a correlation between positive immunohistochemistry for PRAME and abnormal findings on FISH analysis, in our view, the concordance was not sufficient to enable PRAME immunohistochemistry to act as a surrogate for FISH testing. Our findings reiterate the principle that interpretation of problematic superficial melanocytic proliferations requires a synthesis of all the available data, including clinical scenario, morphological features, immunohistochemistry, and ancillary molecular investigations.


Patient perceptions of virtual reality for pain relief in labor: A qualitative study.
Labor represents the most common reason for hospitalization, and most patients will use some form of pain management during their labor. While some studies have suggested that virtual reality (VR) may be an effective option for managing pain, more study is necessary to understand the patient experience of VR. The aim of this study is to characterize the effect of VR on patient perceptions of coping in labor and their descriptions of the VR experience. A nested prospective, descriptive study within a randomized controlled trial of VR in laboring patients. We included nulliparous, term patients, having contractions at least every 5 min, a pain score on the Wong-Baker pain scale of 4-7, and who had been randomized to receive the 30 min virtual reality intervention in the trial. Subjects completed a childbirth self-efficacy inventory prior to the intervention. After the intervention, they completed a modified childbirth self-efficacy inventory related to VR and underwent a structured interview. Self-efficacy scores were compared using t-tests and qualitative, thematic analysis was performed using Dedoose. Twenty-one subjects received the VR intervention. Twenty subjects completed the post-intervention survey and structured interview; one declined due to discomfort. Subjects noted a significant increase in perceived degree to which VR could improve their self-efficacy in managing pain during labor. Thematic analysis revealed that subjects described the VR experience as allowing them to connect with their breathing, feeling more relaxed, and being distracted from pain. In total, 70% believed VR reduced their pain, 60% felt it reduced their anxiety, and 100% would recommend VR availability for laboring patients. VR can improve patient self-efficacy for managing pain in labor. Future studies should focus on the content of the visualizations, optimized user experience and design, and effectiveness with ongoing exposure to VR content in labor.


The Close Link of Pancreatic Iron With Glucose Metabolism and With Cardiac Complications in Thalassemia Major: A Large, Multicenter Observational Study.
We systematically explored the link of pancreatic iron with glucose metabolism and with cardiac complications in a cohort of 1,079 patients with thalassemia major (TM) enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. MRI was used to quantify iron overload (T2* technique) and cardiac function (cine images) and to detect macroscopic myocardial fibrosis (late gadolinium enhancement technique). Glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Patients with normal glucose metabolism showed significantly higher global pancreas T2* values than patients with impaired fasting glucose, impaired glucose tolerance, and diabetes. A pancreas T2* <13.07 ms predicted an abnormal OGTT. A normal pancreas T2* value showed a 100% negative predictive value for disturbances of glucose metabolism and for cardiac iron. Patients with myocardial fibrosis showed significantly lower pancreas T2* values. Patients with cardiac complications had significantly lower pancreas T2* values. No patient with arrhythmias/heart failure had a normal global pancreas T2*. Pancreatic iron is a powerful predictor not only for glucose metabolism but also for cardiac iron and complications, supporting the close link between pancreatic iron and heart disease and the need to intensify iron chelation therapy to prevent both alterations of glucose metabolism and cardiac iron accumulation.


[Protraction--it's use and abuse].
1. Protraction devices can be used to close excess spaces by moving posterior teeth forward, to protract maxillas, to rotate arch segments in cleft palate patients and to remove hyper anterior contacts in patients with TMJ derangements. 2. There are three types of protraction headgears: Chin support with cranial straps (Hickham), chin support with a forehead pad (Face mask) and zygoma support with a headband (Suborbital). They all have specific advantages and disadvantages. 3. The force magnitude from a protraction gear varies according to the desired effect from between app. 400 grams/side to move the maxillary anterior teeth forward and 800 grams/side to encourage maxillary sutural expansion. 4. The centers of rotation of the jaws and the dentition are located apically to the attachment of the protraction device. Therefore not only the intended mesially oriented force is produced but also the undesired side effect of both jaws moving around their centers of rotation. To avoid these negative effects the protraction elastics should always leave the arch in the canine area. 5. Basically Class III cases are due to either a short maxilla and/or a long mandible with variations in the vertical. App. 60% of all Class III cases have a short maxilla indicating the need for protraction. About 50% of the total Class III patient population would need surgery to finish with an ideal occlusion. However, many types of compromise treatments can be acceptable. 6. A good occlusion can only be accomplished in the presence of normal function. In Class III patients special attention should be given to possible nasal obstruction as well as to tongue posture and function. ENT cooperation and tongue spikes are often necessary to resolve these problems. 7. Class III elastics tend to rotate the maxilla and mandible counterclockwise. The resulting change in molar relationship is only due to the rotation of the occlusal plane which is unstable. Also because of the extrusional side effect there is an increase in vertical dimension which usually is undesirable. 8. Intraorally the protraction device can either be attached to a bonded acrylic expansion appliance or to a cemented Hyrax depending on the developmental stage of the dentition. To avoid traumatic occlusion conditions a modified splint should be used with the protraction gear in adults. 9. In all growing Class III patients overcorrection of overjet and overbite is very important. This way not only possible relapse is prevented but also the change of a posteriorly displaced mandible is avoided which could be a later cause for TMJ derangement. 10. When deciding whether the deformity is in the maxilla or in the mandible--the individualized Jacobson templates are very helpful.


Current and future directions of deep brain stimulation for neurological and psychiatric disorders.
Deep brain stimulation (DBS) has evolved considerably over the past 4 decades. Although it has primarily been used to treat movement disorders such as Parkinson's disease, essential tremor, and dystonia, recently it has been approved to treat obsessive-compulsive disorder and epilepsy. Novel potential indications in both neurological and psychiatric disorders are undergoing active study. There have been significant advances in DBS technology, including preoperative and intraoperative imaging, surgical approaches and techniques, and device improvements. In addition to providing significant clinical benefits and improving quality of life, DBS has also increased the understanding of human electrophysiology and network interactions. Despite the value of DBS, future developments should be aimed at developing less invasive techniques and attaining not just symptom improvement but curative disease modification.


The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes.
The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung abnormalities (ILA) in white participants from the general population; whether these findings are replicated and influenced by the ILA subtype is not known. We evaluated the associations between the MUC5B genotype and ILA in cohorts with extensive imaging characterisation.We performed ILA phenotyping and MUC5B promoter genotyping in 5308 and 9292 participants from the AGES-Reykjavik and COPDGene cohorts, respectively.We found that ILA was present in 7% of participants from the AGES-Reykjavik, 8% of non-Hispanic white participants from COPDGene and 7% of African-American participants from COPDGene. Although the MUC5B genotype was strongly associated (after correction for multiple testing) with ILA (OR 2.1, 95% CI 1.8-2.4, p=1×10-26), there was evidence of significant heterogeneity between cohorts (I2=81%). When narrowed to specific radiologic subtypes, (e.g. subpleural ILA), the MUC5B genotype remained strongly associated (OR 2.6, 95% CI 2.2-3.1, p=1×10-30) with minimal heterogeneity (I2=0%). Although there was no evidence that the MUC5B genotype influenced survival, there was evidence that MUC5B genotype improved risk prediction for possible usual interstitial pneumonia (UIP) or a UIP pattern in non-Hispanic white populations.The MUC5B promoter polymorphism is strongly associated with ILA and specific radiologic subtypes of ILA, with varying degrees of heterogeneity in the underlying populations.


Inhibition of Pancreatic Cancer Cells by Different Amyloid Proteins Reveals an Inverse Relationship between Neurodegenerative Diseases and Cancer.
Neurodegenerative diseases and cancers are considered to be two families of diseases caused by completely opposite cell-death mechanisms: the former caused by premature cell death, with the latter due to the increased resistance to cell death. Growing epidemiologic evidence appear to suggest an inverse correlation between neurodegenerative diseases and cancers. However, pathological links, particularly from a protein-cell interaction perspective, between these two families of diseases remains to be proven. Here, a fundamental study investigates the effects of three amyloid proteins of Aβ (associated with AD), hIAPP (associated with T2D), and hCT (associated with MTC) on pancreatic cancer (PANC-1) cells. Collective results demonstrate a general inhibitory activity of all of three amyloid proteins on cancer cell proliferation, but inhibition efficiencies are strongly dependent on amyloid sequence (Aβ, hIAPP, hCT), concentration (IC25, IC50, IC75), and aggregation states (monomers, oligomers). Amyloid proteins exhibit two pathways against cancer cells: amyloid monomer-induced ROS production to inhibit cell growth and amyloid oligomer-induced membrane disruption to kill cells. Collectively, the results demonstrate a general inhibition function of amyloid proteins to induce cancer cell death by preventing cell proliferation, suppressing cell migration, promoting reactive oxygen species production, and disrupting cell membranes.


A review of fabrication and applications of carbon nanotube film-based flexible electronics.
Flexible electronics offer a wide-variety of applications such as flexible circuits, flexible displays, flexible solar cells, skin-like pressure sensors, and conformable RFID tags. Carbon nanotubes (CNTs) are a promising material for flexible electronics, both as the channel material in field-effect transistors (FETs) and as transparent electrodes, due to their high intrinsic carrier mobility, conductivity, and mechanical flexibility. In this feature article, we review the recent progress of CNTs in flexible electronics by describing both the processing and the applications of CNT-based flexible devices. To employ CNTs as the channel material in FETs, single-walled carbon nanotubes (SWNTs) are used. There are generally two methods of depositing SWNTs on flexible substrates-transferring CVD-grown SWNTs or solution-depositing SWNTs. Since CVD-grown SWNTs can be highly aligned, they often outperform solution-processed SWNT films that are typically in the form of random network. However, solution-based SWNTs can be printed at a large-scale and at low-cost, rendering them more appropriate for manufacturing. In either case, the removal of metallic SWNTs in an effective and a scalable manner is critical, which must still be developed and optimized. Nevertheless, promising results demonstrating SWNT-based flexible circuits, displays, RF-devices, and biochemical sensors have been reported by various research groups, proving insight into the exciting possibilities of SWNT-based FETs. In using carbon nanotubes as transparent electrodes (TEs), two main strategies have been implemented to fabricate highly conductive, transparent, and mechanically compliant films-superaligned films of CNTs drawn from vertically grown CNT forests using the "dry-drawing" technique and the deposition or embedding of CNTs onto flexible or stretchable substrates. The main challenge for CNT based TEs is to fabricate films that are both highly conductive and transparent. These CNT based TEs have been used in stretchable and flexible pressure, strain, and chemical and biological sensors. In addition, they have also been used as the anode and cathode in flexible light emitting diodes, solar cells, and supercapacitors. In summary, there are a number of challenges yet to overcome to optimize the processing and performance of CNT-based flexible electronics; nonetheless, CNTs remain a highly suitable candidate for various flexible electronic applications in the near future.


Impact of a commercial order entry system on prescribing errors amenable to computerised decision support in the hospital setting: a prospective pre-post study.
In this UK study, we investigated the impact of computerised physician order entry (CPOE) and clinical decision support (CDS) implementation on the rate of 78 high-risk prescribing errors amenable to CDS. We conducted a preintervention/postintervention study in three acute hospitals in England. A predefined list of prescribing errors was incorporated into an audit tool. At each site, approximately 4000 prescriptions were reviewed both pre-CPOE and 6 months post-CPOE implementation. The number of opportunities for error and the number of errors that occurred were collated. Error rates were then calculated and compared between periods, as well as by the level of CDS. The prescriptions of 1244 patients were audited pre-CPOE and 1178 post-CPOE implementation. A total of 28 526 prescriptions were reviewed, with 21 138 opportunities for error identified based on 78 defined errors. Across the three sites, for those prescriptions where opportunities for error were identified, the error rate was found to reduce significantly post-CPOE implementation, from 5.0% to 4.0% (P<0.001). CDS implementation by error type was found to differ significantly between sites, ranging from 0% to 88% across clinical contraindication, dose/frequency, drug interactions and other error types (P<0.001). Overall, 43/78 (55%) of the errors had some degree of CDS implemented in at least one of the hospitals. Implementation of CPOE with CDS was associated with clinically important reductions in the rate of high-risk prescribing errors. Given the pre-post design, these findings however need to be interpreted with caution. The occurrence of errors was found to be highly dependent on the level of restriction of CDS presented to the prescriber, with the effect that different configurations of the same CPOE system can produce very different results.


[The differential staining of murine metaphase chromosomes in early embryogenesis after treatment with restrictase AluI in situ].
The picture of differential staining of early mouse embryogenesis metaphasic chromosomes, from the first cleavage up to 10 days of gestation, after digestion by restriction endonuclease AluI was studied. It was shown that depending on the degree of digestion by endonuclease differential bandings of G+C- or C-type were observed. After the least digestion only the first cleavage chromosomes were differently stained. A slight difference in intensity of staining between paternal and maternal chromosomes of the zygote was observed. All the mouse chromosomes were identified after AluI digestion and staining after Giemsa.


Designing intervention scheme for vaccine market: a bilevel programming approach.
Public-interest goods benefit consumers and also generate external benefits boosting societal welfare. Despite this characteristic of these goods, their level of consumption or production are generally well below the socially desirable levels without intervention. Motivated by influenza vaccine market, this paper examines the intervention design problem for a public-interest good facing yield uncertainty in production as well as inefficiencies in distribution and allocation. The proposed mechanism considers two intervention tools with the aim of resolving the inefficiencies in the system and allowing the actors to take socially desirable decisions. The first tool is to intervene so that demand level for the good is increased; we call it demand increasing strategy. The second tool aims to support the production, allocation, and distribution by investing in research and development and better planning and enhances the availability; we call this as availability increasing strategy. The intervention design problem is based on stylized demand and availability models that take into account investments made to improve them. The model suggested is experimented by a numerical study to analyze the impact of applying proposed joint mechanism in US influenza vaccine market. The results show that proposed strategy is very effectual in terms of vaccination percentages achieved and budget savings realized beyond the current practices, and the improvement in vaccination percentages is even greater when uncertainty in the system is higher. Besides, the results suggest that as long as the parameter calibration and decision problems are solved consistently, availability can be approximated by its average value when necessary.