The open section effect in a long bone with a longitudinal defect - a theoretical modeling study.
A longitudinal defect dramatically alters the stress distribution within a long bone. The altered stress distribution can influence the structural properties of the bone and the stimulus for repair and remodeling of the defect and the surrounding bone. For applied torsion, the defect interrupts the normal shear flow around the bone. Reversal of the shear flow along the inner cortex of the bone is the primary characteristic of the "open-section" effect. Stress concentration effects also produce large stresses at the defect corners. A finite element model of a femur mid-diaphysis with a rectangular defect in the posterior cortex was developed to quantify the femur stress distribution and torsional stiffness for defect widths ranging from one-tenth of the femur outer diameter (0.1 OD) to 0.3 OD, and defect lengths ranging from 0.5 to 5 OD. Defects with a length of 1 OD or shorter had little influence on the femur torsional stiffness or the femur shear-stress distribution. The torsional stiffness decreased most dramatically as the defect length increased from 2 to 3 OD, but began to approach an asymptote near 5 OD. Shear flow reversal peaked at the center of the defect for defects longer than 1 OD, and the magnitude of the reversal began to approach an asymptote near 5 OD. For each defect, the largest stresses within the bone, developed at the defect corners. The results indicate that the open-section effect decreases the torsional stiffness and stress concentration effects decrease the torsional strength of a long bone with a longitudinal defect.


Utility of 3D Printed Models Versus Cadaveric Pathology for Learning: Challenging Stated Preferences.
3D printing has recently emerged as an alternative to cadaveric models in medical education. A growing body of research supports the use of 3D printing in this context and details the beneficial educational outcomes. Prevailing studies rely on participants' stated preferences, but little is known about actual student preferences. A mixed methods approach, consisting of structured observation and computer vision, was used to investigate medical students' preferences and handling patterns when using 3D printed versus cadaveric models in a cardiac pathology practical skills workshop. Participants were presented with cadaveric samples and 3D printed replicas of congenital heart deformities. Analysis with computer vision found that students held cadaveric hearts for longer than 3D printed models (7.71 vs. 6.73 h), but this was not significant when comparing across the four workshops. Structured observation found that student preferences changed over the workshop, shifting from 3D printed to cadaveric over time. Interactions with the heart models (e.g., pipecleaners) were comparable. We found that students had a slight preference for cadaveric hearts over 3D printed hearts. Notably, our study contrasts with other studies that report student preferences for 3D printed learning materials. Given the relative equivalence of the models, there is opportunity to leverage 3D printed learning materials (which are not scarce, unlike cadaveric materials) to provide equitable educational opportunities (e.g., in rural settings, where access to cadaveric hearts is less likely).


Evolutionary relationship between translation initiation factor eIF-2gamma and selenocysteine-specific elongation factor SELB: change of function in translation factors.
Eubacterial and eukaryotic translation initiation systems have very little in common, and therefore the evolutionary events that gave rise to these two disparate systems are difficult to ascertain. One common feature is the presence of initiation, elongation, and release factors belonging to a large GTPase superfamily. One of these initiation factors, the gamma subunit of initiation factor 2 (eIF-2gamma), is found only in eukaryotes and archaebacteria. We have sequenced eIF-2gamma gene fragments from representative diplomonads, parabasalia, and microsporidia and used these new sequences together with new archaebacterial homologues to examine the phylogenetic position of eIF-2gamma within the GTPase superfamily. The archaebacterial and eukaryotic eIF-2gamma proteins are found to be very closely related, and are in turn related to SELB, the selenocysteine-specific elongation factor from eubacteria. The overall topology of the GTPase tree further suggests that the eIF-2gamma/SELB group may represent an ancient subfamily of GTPases that diverged prior to the last common ancestor of extant life.


The virulence factors of Bordetella pertussis: talented modulators of host immune response.
Approximately 40 million whooping cough cases and between 200,000 and 400,000 pertussis-linked deaths are recorded each year. Although several types of vaccines are licensed and widely used, Bordetella pertussis continues to circulate in populations with high vaccine coverage of infants and children due to the waning of protection induced by the vaccination. B. pertussis typically expresses a wide array of virulence factors which promote bacterial adhesion and invasion by altering the local environment, including pertussis toxin, tracheal cytotoxin, adenylate cyclase toxin, filamentous hemagglutinin, and the lipooligosaccharide. The virulence factors of B. pertussis also possess immunomodulatory properties, exerted through their enzymatic and receptor-binding activities. Both pro- and anti-inflammatory effects are mediated, that can subvert host innate and adaptive immunity and favor the onset of a long-term infection. This review describes the capacities of B. pertussis virulence factors to modulate host immune responses and the mechanisms employed, which have been the subject of extensive research in the recent years, both in murine and human experimental systems. Knowledge of these mechanisms is gaining increasing importance, since it could provide in the near future the basis for the identification of therapeutic agents for modulating the immune system as well as novel molecular targets to treat pertussis.


Size and Substitution Effect on Antimicrobial Activity of Polythiophene Polyelectrolyte Derivatives Under Photolysis and Dark Conditions.
Cationic polythiophenes have been shown to be potent antimicrobial compounds due to their ability to absorb visible light and sensitize the production of reactive oxygen species (ROS) as well as their ability to selectively associate with and damage negatively charged cell envelopes. This study demonstrates the ability of differentially sized imidazolium- and tertiary amine-functionalized poly(3-hexylthiophene) (P3HT) to inactivate Gram-negative Escherichia coli and Gram-positive Bacillus atrophaeus under photolysis and dark conditions. Flow cytometry viability assays are used to quantify cell death. Each compound shows high levels of killing at both 1 and 10 μg mL-1 polymer concentrations for each microbial species after photoactivation as well as high levels of dark inactivation in many cases. Tertiary amine-functionalized P3HT is shown to have different killing patterns, shown by transmission electron microscopy, compared to the imidazolium-functionalized derivatives.


Precipitous bradycardia induced by laryngoscopy in cardiac surgical patients.
We present three patients with severe ischaemic heart disease who developed profound bradycardia (heart rates of 15 beats.min-1, 10 beats.min-1 and asystole) at the time of laryngoscopy and spraying of the trachea with topical lidocaine. All patients had received fentanyl 20-30 micrograms.kg-1 and pancuronium 0.1-0.13 mg.kg-1 and in each case laryngoscopy was performed three minutes after the administration of these agents. We believe that in these cases the dosage of fentanyl was inadequate and since increasing the dosage of fentanyl to at least 50 micrograms.kg-1 and eliminating the manoeuvre of laryngeal spraying with topical anaesthesia, we have not encountered this problem.


Lipid permeability of the intestinal microvillus membrane may be modulated by membrane fluidity in the rat.
Fatty acids and cholesterol permeate across the intestinal microvillus membrane at rates dictated by the hydrophobicity of the permeating lipid and the permeability properties of the microvillus membrane. A theory has evolved suggesting that the chemical composition and physical properties of the microvillus membrane are important in determining microvillus membrane lipid permeability in vivo. This communication reports a test of this hypothesis. To compare in vivo membrane lipid permeability within the same intestinal region, but under conditions were membrane physical properties were radically altered, rats were fed an inhibitor of cholesterol synthesis. This resulted in the replacement of 87-90% of membrane cholesterol with its' precursor, 7-dehydrocholesterol. Marked changes in membrane physical properties were observed, including a reduction in the static and dynamic component of membrane fluidity within the jejunal microvillus membrane. These changes were limited primarily to the outer regions of the bilayer. Associated with these alterations was a pronounced reduction in membrane lipid permeability. Therefore, microvillus membrane lipid permeability, in vivo, appears to be correlated with physical properties of the bilayer, especially those of the superficial regions.


Nuclear localization of aldosterone in rat brain cells assessed by autoradiography.
Autoradiographic studies with 3H aldosterone demonstrate nuclear concentration of hormone in neurons of the hippocampus, septum, allocortical regions and brain stem reticular formation and motor nuclei of cranial nerves and in the meninges. The results suggest that mineralocorticoids have wide ranging effects on different parts of the central nervous system.


Ear, Nose, and Throat Manifestations of Vasculitis and Other Systemic Autoimmune Diseases: Otologic, Sinus, and Airway.
Auricular, nasal, and laryngeal manifestations occur frequently in rheumatic diseases. Inflammatory ear, nose, and throat (ENT) processes often result in organ damage and have profound effects on quality of life. Herein, we review the otologic, nasal, and laryngeal involvement of rheumatic diseases, focusing on their clinical presentation and diagnosis. ENT manifestations generally respond to treatment of the systemic disease, which is outside the scope of this review; however, adjunctive topical and surgical treatment approaches, as well as treatment of idiopathic inflammatory ENT manifestations will be reviewed.


Partnered, adapted argentine tango dance for cancer survivors: A feasibility study and pilot study of efficacy.
Neurotoxic cancer treatments can cause chemotherapy-induced peripheral neuropathy and postural control deficits that cancer survivors report as a concern. Exercise-based sensorimotor training has emerged as a promising treatment for symptoms including balance deficits, however, more study is needed to optimize engagement and participation. We evaluated feasibility, satisfaction, and preliminary efficacy of a novel balance training program for cancer survivors: partnered, Adapted Argentine Tango dance (Tango). Twenty-two individuals participated (n = 22). Tango classes (1 h) were offered twice/week. At baseline, midpoint (8 classes), and conclusion of the training (15 or 16 classes), we assessed postural control by measuring center-of-pressure (CoP) measures during quiet standing with eyes closed. We also documented attendance, barriers to attendance, and satisfaction (7 point scale; 1 high). At conclusion, we analyzed whether 1) attendance and satisfaction met feasibility criteria; 2) postural control improved among participants who were outside of normal range at baseline; and 3) co-enrolling with a companion increased attendance. Feasibility criteria were met: more than half of participants attended more than half the classes offered with a mean satisfaction rate of 1.2 (SD 0.4). Those who enrolled with a companion (n = 9) attended more sessions than those who did not (n = 13) (Mann-Whitney U value = 20; p = 0.012). Participants with demonstrated deficits (n = 9) improved in 3 CoP measures at midpoint (i.e., medial-lateral sway, ellipse area, medial-lateral velocity), retaining improvement in 2 CoP measures at endpoint (i.e., medial-lateral sway, ellipse area). Partnered, Adapted Argentine Tango is feasible for cancer survivors and may improve postural control. Enrolling with a companion improved attendance.


Assessment of Gastrointestinal Parasites and Productive Parameters on Sheep Fed on a Ration Supplemented with Guazuma ulmifolia Leaves in Southern Mexico.
This study aimed at evaluating the impact of a diet supplemented with Guazuma ulmifolia leaves on the productive performance and gastrointestinal parasites (GI) eggs/oocysts shedding of sheep (Pelibuey breed). Twenty-two non-lactating ewes were used. They were randomly allocated to two similar groups in terms of age, weight, body condition score (BCS), and GI parasites status. For 30 days, while the control group (G0) was given basic forage hay of Cynodon nlemfuensis, the test group (G1) received a blend of G. ulmifolia fresh foliage and C. nlemfuensis hay (respectively 30 and 70% of the diet on a DM basis). Animals were housed in separate covered pens. Quantitative coprological analysis was performed. Weight and BCS were evaluated. The daily feed amounts given and refused were measured in order to assess nutrient components intake (minerals, energy, and nitrogen). The results showed no significant differences between G1 and G0 regarding the anthelmintic and anticoccidial effects (p = 0.57, p = 0.91, respectively). Similarly, no significant overall impact on weight and BCS during the experiment (p = 0.77, p = 0.32, respectively) was observed. Nevertheless, concerning the bromatological analysis of G. ulmifolia, its use as a diet supplement to address protein and mineral deficits due to a poor-quality diet is fully justified.


Demonstration of locally synthesized borrelia antibodies in cerebrospinal fluid.
Antibodies against Borrelia burgdorferi develop slowly. Low titers can be anamnestic. In order to prove the etiology of manifestations of erythema chronicum migrans disease of the nervous system like meningopolyneuritis Garin-Bujadoux-Bannwarth or progressive borrelia encephalomyelitis we used the ELISA to measure specific IgG antibodies against Ixodes ricinus borrelia per microgram IgG in serum and cerebrospinal fluid. With the mentioned method we were able to demonstrate locally synthesized antibodies in the cerebrospinal fluid. Until the 110th day of illness a difference between serum and CSF in favour of the latter as high as five binary dilution steps could be found. Later on in time the difference decreased to four dilution steps or less.


Epidemiological tracing of Batrachochytrium salamandrivorans identifies widespread infection and associated mortalities in private amphibian collections.
The amphibian chytrid fungus Batrachochytrium salamandrivorans (Bsal) infects newts and salamanders (urodele amphibians), in which it can cause fatal disease. This pathogen has caused dramatic fire salamander population declines in Belgium, the Netherlands and Germany since its discovery in 2010. Thought to be native to Asia, it has been hypothesised that Bsal was introduced to Europe with the importation of infected amphibians for the commercial pet trade. Following the discovery of Bsal in captive amphibians in the United Kingdom in 2015, we used contact-tracing to identify epidemiologically-linked private amphibian collections in Western Europe. Of 16 linked collections identified, animals were tested from 11 and urodeles tested positive for Bsal in seven, including the identification of the pathogen in Spain for the first time. Mortality of Bsal-positive individuals was observed in five collections. Our results indicate that Bsal is likely widespread within the private amphibian trade, at least in Europe. These findings are important for informing policy regarding Bsal control strategies.


Associations among obesity, blood pressure, and left ventricular mass.
To measure resting and ambulatory systemic blood pressure (BP) and left ventricular mass (LVM) in prepubertal obese and lean children and to determine their relationships. Cross-sectional study including 44 obese and 22 lean prepubertal children (mean age 8.8 +/- 1.5 years). We measured casual and 24-hour ambulatory BP, LVM and LVM index (LVMI) by echocardiography, and whole body lean tissue and fat mass by dual-energy X-ray absorptiometry. Mean 24-hour systolic BP (124.8 +/- 14.2 vs 105.5 +/- 8.8 mm Hg), diastolic BP (72.8 +/- 7.3 vs 62.7 +/- 3.8 mm Hg), and LVMI (36.1 +/- 5.8 vs 30.9 +/- 5.7, g x m(-2.7)) were significantly higher in obese than in lean subjects. Systolic ambulatory hypertension was present in 47.6% of obese children, and casual BP was normal in 55% of those cases. Body fatness, lean tissue mass, and 24-hour BP correlated positively with LVMI. When adjusted for body fatness, LVMI was only associated with 24-hour systolic BP (adjusted R(2) = 15.9%; P = .001). Ambulatory systemic hypertension and increased LVM are found in obese children. Left ventricular mass is partially determined by systemic BP. We conclude that prevention and treatment of childhood obesity should be initiated as early as possible to prevent the premature development of hypertension and end-stage organ damage.


Faecal calprotectin, an useful marker in discriminating between inflammatory bowel disease and functional gastrointestinal disorders.
Diagnostic discrimination between inflammatory bowel disease (IBD) and functional gastrointestinal disorders is complex, as they cause similar signs and symptoms. Faecal calprotectin (FC) is a useful marker in this context, and can be used to select patients who will most benefit from colonoscopy. The aim of this study was to evaluate the utility of FC in discriminating between organic disease and functional disorders. The study included 264 patients presenting with gastrointestinal complaints consistent with an organic pathology. FC levels were determined and diagnostic accuracy was assessed using the area under the curve obtained from the final diagnosis. Calprotectin levels in organic bowel disease patients were significantly higher (median 254μg/g; 95% confidence interval [CI], interquartile range 105-588.5) than in functional disease patients (95μg/g; 95% CI, 47.25-243.92) (P<.0001). Similarly, in patients with IBD, the values obtained were higher (270.85μg/g; 95% CI, 96.85-674.00) than in those with irritable bowel syndrome (79.70μg/g; 95% CI, 36.50-117.25) (P<.0001). For a cut-off of 150μg/g, FC had an area under the ROC curve to discriminate between organic and functional disease of 0.718, and 0.872 to discriminate between irritable bowel syndrome and IBD. Our study supports the importance of FC as a marker in the evaluation of patients with IBD. The best diagnostic accuracy is obtained at a cut-off value of 150μg/g.


Graves' ophthalmopathy. A clinical and immunologic review.
Graves' thyroid disease and the orbitopathy which often accompanies it have puzzled physicians and scientists for more than 150 years. Although certain histopathological features have been documented, it is not known what mechanisms are responsible for the systemic and/or ocular disorders. The ocular condition characteristic of Graves' disease may exist in the absence of clinical or biochemical evidence of thyroid dysfunction, and when the systemic and ocular condition exist together, they may follow completely different clinical courses. Because the relationship between the thyroid disorder and the orbitopathy is not established, the authors refer not to "thyroid ophthalmopathy," but to "Graves' ophthalmopathy." In this review, histopathological features of Graves' ophthalmopathy are reviewed. The differential diagnosis of the ophthalmopathy and approaches to its evaluation are discussed, notably the T-4 radioimmunoassay, T-3 resin uptake and TSH tests, as well as CT scanning and ultrasonography. The characteristics of Classes 0-6 ophthalmopathy are outlined and the management of cases in each class is considered. The possible immunological basis for Graves' ophthalmopathy is also reviewed.


Neural cell adhesion molecules and myelin-associated glycoprotein share a common carbohydrate moiety recognized by monoclonal antibodies L2 and HNK-1.
Cell surface molecules have been implicated in cell interactions which underlie formation of the nervous system. The analysis of the functional properties of such molecules has profited from the combined use of antibodies and cell culture systems. It has been suggested that the interplay between these molecules modulates cell-to-cell interaction at critical developmental stages. In the mouse, N-CAM and L1 antigen have been shown to mediate Ca2+-independent adhesion among neural cells. N-CAM plays a role in fasciculation of neurites and formation of neuromuscular junction. L1 is apparently not involved in synaptogenesis, but in migration of granule cell neurones in the developing mouse cerebellar cortex. The two antigens are distinct molecular and functional entities which act synergistically in aggregation of neuroblastoma and early postnatal cerebellar cells. In view of a certain similarity in function between the two groups of molecules, it was not surprising to find that structural similarities are detectable by the monoclonal antibody L2. We show here that a carbohydrate moiety recognized by L2 and HNK-1 monoclonal antibodies, is present in mouse N-CAM and L1. The L2 epitope appears on all major neural cell types but not all N-CAM molecules express it. This heterogeneity points to a previously undetected molecular diversity which may have functional implications for modulating cell adhesion during development.


Systemic histoplasmosis with oesophageal obstruction due to Histoplasma granulomas. Successful treatment with rifampicin and amphotericin B.
A patient with oesophageal stenosis caused by Histoplasma granulomas is reported. He was treated with an initial combined course of intravenous amphotericin B and oral rifampicin. Complications included adrenal insufficiency, operative perforation of the oesophagus, amphotericin nephrotoxicity and tuberculosis. The histoplasmosis has not recurred for over 3 years.


Chemical and pharmacologic agents that cause hyperpigmentation or hypopigmentation of the skin.
The list of chemicals and drugs that can result in alteration of skin color is slowly growing. Inflammatory processes can lead to either post-inflammatory hyperpigmentation or hypopigmentation. In non-inflammatory situations, chemical deposition can result in hyperpigmentation, whereas chemically induced destruction of melanocytes or their products may result in hypopigmentation.


Implementation of language assessments for staff interpreters in community health centers.
Bilingual staff is used to provide interpreter services in community health centers. Little is known about the language proficiency of dual-role staff interpreters. Golden Valley Health Centers implemented a formal language assessment program to improve the number of qualified dual-role staff interpreters and ultimately improve the quality of patient care.


Rapid degradation of hypoxia-inducible factor-1alpha by KRH102053, a new activator of prolyl hydroxylase 2.
Hypoxia-inducible factor (HIF) is a transcription factor induced by hypoxia and degraded by ubiquitin-dependent proteasomes in normoxic conditions. Under hypoxic conditions, hydroxylation of HIF-1alpha subunit by prolyl hydroxylase (PHD) is suppressed, thus leading to increased levels of HIF. Although PHD2 plays a key role in regulating the levels of HIF, chemical activators of PHD2 are relatively unknown. The aim of this study was to identify small molecule activators of PHD2 that could be used, eventually, to suppress the level of HIF-1alpha. By using the overproduced PHD2 as a target, a molecular library consisting of more than 600 small molecules with a benzopyran structure was screened with an HPLC assay method. We found a potent activator of PHD2, KRH102053 (2-amino-4-methylsulphanyl-butylic acid-4-methoxy-6-(4-methoxy-benzylamino)-2,2-dimethyl-chroman-3-yl ester). The effects of KRH102053 on controlling HIF were studied in human HOS osteosarcoma, rat PC12 phaeochromocytoma and human HepG2 hepatoma cells. Under our experimental conditions, KRH102053 decreased the protein level of HIF-1alpha and the mRNA levels of HIF-regulated downstream target genes, such as vascular endothelial growth factor, aldolase A, enolase 1 and monocarboxylate transporter 4. Consistent with these results, KRH102053 also inhibited the rates of HIF-related migration and invasion of HOS cells as well as the degree of tube formation in human umbilical vein endothelium cells. These results suggest that KRH102053 and its structural analogues have the potential for use as therapeutic agents against various diseases associated with HIF.


Botulinum toxin treatment of Hertwig-Magendie sign.
Hypertropia, not due to the usual causes and associated with a central nervous system disorder, should be suspected as being a skew deviation (Hertwig-Magendie sign). We describe a new case of this supranuclear disorder, presumably related to cocaine-induced stroke. This disorder was treated by botulinum A toxin (Oculinum) injection into the superior rectus muscle. Follow-up one year later found the vertical deviation resolved.


Transcription termination factor rho mediates simultaneous release of RNA transcripts and DNA template from complexes with Escherichia coli RNA polymerase.
Dissociation of RNA and DNA from Escherichia coli RNA polymerase in transcription complexes prepared with enzyme molecules located within and near a rho-dependent transcription termination region on bacteriophage T7 D111 DNA has been studied using a membrane filter-binding assay. Rho protein with ATP present mediated rapid (half-time approximately 27 s) simultaneous dissociation of about 50% of both RNA and DNA. RNA molecules were preferentially released from enzyme molecules located within the termination region. Rapid release of RNA and DNA depended on a nucleoside triphosphate but did not depend on sigma factor. Pretreatment of complexes with ribonuclease prevented dissociation of DNA. Nearly simultaneous dissociation of both RNA and DNA was also detected after a lag of 3 min when the isolated transcription complexes were incubated with all four ribonucleoside triphosphates in the absence of rho factor. In this case, release presumably occurred at the rho-independent termination site that is 5990 nucleotides downstream from the A1 promoter. Thus, the dissociation of DNA from RNA polymerase at rho-dependent and rho-independent transcription termination sites is coupled with or occurs spontaneously soon after the release of transcripts at both sites.


[Is muscle the best coverage for leg Gustilo IIIb fractures? A retrospective comparative study].
Well-vascularized muscle flaps have been the traditional gold standard for coverage of open fracture of the lower extremity. The last 15 years have brought the fasciocutaneous and perforator flaps and raised the issue of the type of coverage required for open fracture of the lower extremity. In recent years, in selected compromised patient, we have been using nonmuscular flaps for reconstruction. The goal of this study is to compare the results of fasciocutaneous reconstruction to those of classical muscular flaps. A comparative retrospective study, including all patients from 2002 to 2006 requiring a coverage of a Gustillo III b fracture of the lower extremity, is done. The type of flaps, the fracture localization, the infection rate, the time required for consolidation of the fracture and the complication rate are reviewed. An independent university laboratory verified the statistical analysis. Twenty patients have experienced coverage by muscular flaps and 18 by fasciocutaneous flaps. We found a skin fistula and a chronic infection in the muscular-flap group, and two skin fistulae in the fasciocutaneous flaps group. The overall surgical results were comparable, except the bony union delay shorter in the fasciocutaneous flaps group. Muscle coverage is not mandatory to cover bone in the lower leg. The fasciocutaneous flaps can provide a good alternative for muscle-flap coverage. There is no significant difference as far as consolidation and infection are concerned, between the coverage by muscular or fasciocutaneous flaps.


Nucleotide sequence of the gene coding for Clostridium botulinum (Clostridium argentinense) type G neurotoxin: genealogical comparison with other clostridial neurotoxins.
The neurotoxin gene from Clostridium botulinum type G was cloned as a series of overlapping DNA fragments generated using polymerase chain reaction (PCR) technology and primers designed to conserved regions of published botulinal toxin (BoNT) sequences. The 5'-end of the gene was obtained using a primer based on a conserved region of the nontoxic-nonhaemagglutinin gene lying upstream of the toxin gene. Translation of the nucleotide sequence derived from the cloned PCR fragments demonstrated that the gene encodes a protein of 1297 amino acid residues (rmm 149, 147). Comparative alignment of the determined BoNT/G sequence with those of other clostridial neurotoxins revealed highest sequence relatedness (approx. 58% amino acid identity) with BoNT/B of proteolytic and non-proteolytic C. botulinum. Tetanus toxin (TeTx) and other BoNT types revealed lower levels of relatedness with BoNT/G (approximate range 35-42% amino acid identity).


Asymmetric lipid-polymer particles (LIPOMER) by modified nanoprecipitation: role of non-solvent composition.
Asymmetric lipid polymer nanostructures (LIPOMER) comprising glyceryl monostearate (GMS) as lipid and Gantrez AN 119 (Gantrez) as polymer, revealed enhanced splenic accumulation. In the present paper, we attempt to explain the formation of asymmetric GMS LIPOMER using real time imaging. Particles were prepared by precipitation under static conditions using different non-solvent phase compositions. The process was video recorded and the videos converted to time elapsed images using the FFmpeg 0.10.2 software at 25 frames/sec. Non-solvent compositions comprising >30% of IPA/Acetone revealed significant stranding of the solvent phase and slower onset of precipitation(2-6s). At lower concentrations of IPA and acetone, and in non-solvent compositions comprising ethanol/water the stranding phenomenon was not evident. Further, rapid precipitation(<1 s) was evident. Nanoprecipitation based on the Marangoni effect is a result of diffusion stranding, interfacial turbulence, and mass transfer of solvent and non-solvent resulting in solute precipitation. Enhanced diffusion stranding favored by high interaction of GMS and Gantrez(low ΔPol), and the low solubility parameter(Δδtotal) and high mixing enthalpy(ΔHM) of GMS in IPA resulted in droplets with random shapes analogous to an amoeba with pseudopodia, which on precipitation formed asymmetric particles. Asymmetric particles could be readily designed through appropriate selection of solutes and non-solvent phase by modified nanoprecipitation.


Factors That Contribute to Provider Decision Between Direct and Video Laryngoscopy in a Helicopter Emergency Medical Services System: A Survey.
In caring for critically ill patients in the prehospital setting, rapid, definitive airway management is a high-risk, crucial procedure. All helicopter emergency medical services (HEMS) providers must proficiently and safely perform this procedure. Little information is available about the preference and efficacy of video laryngoscopy (VL) compared with direct laryngoscopy (DL). Additionally, there is a paucity of research investigating which method of intubation is more successful in the HEMS setting. The objective of this study was to delineate factors that contribute to provider decision regarding the method of orotracheal intubation and compare the frequency of use for each method. An anonymous online survey was distributed to all providers in a single HEMS program. The survey results were deidentified and blinded to the researchers. The survey was sent to 40 HEMS providers; 29 responded, and 119 total intubations were reported. Method familiarity and patient condition were the most commonly cited reasons for choosing both DL and VL for intubation. DL accounted for 15 intubation attempts, whereas 104 attempts were completed by VL. For both laryngoscopy techniques, the top reasons cited for selecting an intubation technique were being comfortable with that technique and patient presentation. Further investigation with chart review would help confirm the reported data.


Surveillance for the safety and effectiveness of artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria in the USA: a descriptive analysis.
Data from clinical studies show that artemether-lumefantrine (AL) is effective and well tolerated in adults and children with uncomplicated Plasmodium falciparum malaria. However, data on effectiveness and safety of AL in patients in non-endemic settings are limited. A 5-year surveillance plan included all AL-treated adult and paediatric patients with confirmed or suspected P. falciparum malaria in the USA, as reported to the National Malaria Surveillance System at the Centers for Disease Control and Prevention. Descriptive analyses included demographics, baseline characteristics, clinical effectiveness, and safety. From May 2010 to April 2015, demographics and baseline characteristics were collected for 203 patients and safety data for 108 patients. Treatment effectiveness data at day 7 were collected for 117 patients and at day 28 for 98 patients. The majority of patients were male (58.6 %), Black (62.6 %), non-Hispanic (92.6 %), and likely malaria non-immune (80.8 %). The median age was 32 (range 1-88) years and the median body mass index was 25.5 (range 13.8-42.4) kg/m(2). All patients with effectiveness data had confirmed (n = 116) or suspected (n = 1) malaria. The overall cure rate for patients treated with AL was 91.5 % (95 % CI 84.8-95.8 %) at day 7 and 96.9 % (95 % CI 91.3-99.4 %) at day 28. Adverse events were reported in four (3.7 %) patients, and there were no new or unexpected safety signals. AL was effective and well tolerated in the treatment of likely non-immune patients with P. falciparum malaria.


The Effect of a General Healthy Lifestyle Intervention Delivered Around Pregnancy on Gestational Weight Gain and Infant Growth.
A life-course perspective emphasizes healthy behaviors before, during, and after pregnancy to support a multi-generational risk reduction in obesity for mothers and infants. Optimal timing, content, and dose of such interventions is not well defined. We conducted a nested cohort within a randomized trial to evaluate whether a healthy lifestyle intervention around pregnancy led to a "spill-over effect," including a healthier rate (kg/week) of maternal gestational weight gain, and infant growth during the first year. Study enrollment began in 2012, follow-up data collection completed in 2018, and the data were analyzed in 2019. The intervention focused on healthy maternal diet and physical activity but not pregnancy weight or infant feeding. Outcome data were abstracted from electronic medical records. Of the 165 women who became pregnant, 114 enrolled in the nested cohort. The average pre-pregnancy BMI was 29.6 (SD 5.1) kg/m2. Mixed effects models suggested clinically insignificant differences in both the rate of gestational weight gain (-0.02 kg/week; 95% CI -0.09, 0.06) and the rate of infant growth (difference at 1 year: -0.002 kg/cm; 95% CI -0.009, 0.005). A behavioral intervention that focused on overall maternal health delivered in the time around pregnancy did not result in a "spill-over effect" on healthy gestational weight gain or healthy infant growth during the first year of life. This study is registered at www.clinicaltrials.gov NCT01316653.


Sinusoidal high-intensity exercise does not elicit ventilatory limitation in chronic obstructive pulmonary disease.
During exercise at critical power (CP) in chronic obstructive pulmonary disease (COPD) patients, ventilation approaches its maximum. As a result of the slow ventilatory dynamics in COPD, ventilatory limitation during supramaximal exercise might be escaped using rapid sinusoidal forcing. Nine COPD patients [age, 60.2 ± 6.9 years; forced expiratory volume in the first second (FEV(1)), 42 ± 17% of predicted; and FEV(1)/FVC, 39 ± 12%] underwent an incremental cycle ergometer test and then four constant work rate cycle ergometer tests; tolerable duration (t(lim)) was recorded. Critical power was determined from constant work rate testing by linear regression of work rate versus 1/t(lim). Patients then completed fast (FS; 60 s period) and slow (SS; 360 s period) sinusoidally fluctuating exercise tests with mean work rate at CP and peak at 120% of peak incremental test work rate, and one additional test at CP; each for a 20 min target. The value of t(lim) did not differ between CP (19.8 ± 0.6 min) and FS (19.0 ± 2.5 min), but was shorter in SS (13.2 ± 4.2 min; P < 0.05). The sinusoidal ventilatory amplitude was minimal (37.4 ± 34.9 ml min(-1) W(-1)) during FS but much larger during SS (189.6 ± 120.4 ml min(-1) W(-1)). The total ventilatory response in SS reached 110 ± 8.0% of the incremental test peak, suggesting ventilatory limitation. Slow components in ventilation during constant work rate and FS exercises were detected in most subjects and contributed appreciably to the total response asymptote. The SS exercise was associated with higher mid-exercise lactate concentrations (5.2 ± 1.7, 7.6 ± 1.7 and 4.5 ± 1.3 mmol l(-1) in FS, SS and CP). Large-amplitude, rapid sinusoidal fluctuation in work rate yields little fluctuation in ventilation despite reaching 120% of the incremental test peak work rate. This high-intensity exercise strategy might be suitable for programmes of rehabilitative exercise training in COPD.


Effect of physical exercise on bone density and remodeling in egyptian type 1 diabetic osteopenic adolescents.
The study was planned to assess effect of physical exercise on bone remodeling in type I diabetics with osteopenia. Twenty-four type I diabetes mellitus (DM1) with osteopenia (10 females and 14 males) were compared to thirty-eight age- and sex-matched healthy control individuals (20 females and 18 males) for biochemical and radiologic parameters of bone mass. Laboratory investigations included serum and urinary calcium, inorganic phosphorus, alkaline phosphatase, and serum "procollagen type 1 N-terminal propeptide (P1NP). Bone densitometry was assessed at neck femur using Dual Energy X-ray Absorptiometry (DEXA). Serum P1NP and DEXA were reevaluated after a planned exercise program. Patients and controls were comparable with respect to serum as well as urinary biochemical parameters of bone mass namely; calcium, phosphorus and total serum alkaline phosphatase. Osteopenic DM1 patients displayed lower mean serum P1NP than control group (20.11 ± 6.72 ug\dL versus 64.96 ± 34.89 ug\dL; p < 0.05). A significant correlation was observed between BMD and degree of glycemic control reflected by serum glycated hemoglobin (r = -0.44, p, 0.030). Bone densitometry correlated with serum P1NP (r = -0.508, p, 0.011). After a planned regular exercise for 3 months, serum P1NP and BMD levels increased with percentage change of 40.88 ± 31.73 and 3.36 ± 2.94, respectively. Five patients resumed normal densitometry and they were all males. Diabetic osteopenic patients displayed lower serum levels of procollagen type 1 N-terminal propeptide which reflects poor bone formation. A 3-months planned exercise program was associated with improvement of bone densitometry and significant increment of serum P1NP.


[Treatment of primary disease with irradiation in case of de novo metastatic breast cancer].
Synchronous metastatic breast cancer accounts for 5 to 6% of all breast cancers in Western countries, which corresponds to nearly 2500 new cases per year in France. Irradiation of the primary tumour in cases of metastatic disease at diagnosis was historically reserved for palliative indications. However, progress in systemic treatments, a better understanding of the biological basis of metastatic dissemination, the genesis of the concept of oligometastatic disease and ablative treatments directed towards metastases are revolutionizing the management of patients with de novo stage IV breast cancer. Survival of these patients has improved markedly over the years, and several studies have investigated the carcinological benefit of local treatment of the breast tumour in patients with advanced diseases at diagnosis. This article provides an update on the role of irradiation of the primary tumour in breast cancer with synchronous metastases, and discusses its interest through published or ongoing trials.


[Effect of propofol and etomidate for anesthesia induction on plasma total cortisol concentration].
To investigate the effect of propofol and etomidate for anesthesia induction on adrenocortical function. The plasma total cortisol concentration was determined in 20 patients who were treated with propofol or etomidate. After propofol induction, the plasma total cortisol level decreased from (308.7 +/- 27.4) nmol/L to (267.7 +/- 31.2) nmol/L at post-medication 2 hours, increased to (400.2 +/- 26.9) nmol/L at postmedication 5 hours and restored to premedication level at postmedication 24 hours [(306.4 +/- 35.4) nmol/L]. After etomidate induction, the plasma total cortisol level decreased from (309.1 +/- 36.6) nmol/L to (115.9 +/- 29.7) nmol/L at postmedication 2 hours, maintained (171.1 +/- 34.7) nmol/L at postmedication 5 hours and restored to premedication level at postmedication 24 hours [(311.8 +/- 46.2) nmol/L]. Propofol induction has little effect on adrenocortical function whereas etomidate induction inhibits adrenocortical function.


Modulation of adipocytokines response and weight loss secondary to a hypocaloric diet in obese patients by -55CT polymorphism of UCP3 gene.
Decreased expression or function of UCP3 (uncoupling protein 3) could reduce energy expenditure and increase the storage of energy as fat. Some studies have pointed to a role of UCP3 in the regulation of whole body energy homeostasis, diet induced obesity, and regulation of lipids as metabolic substrates. The C/C genotype of a polymorphism in the UCP3 promoter (-55C-->T) is associated with an increased expression of UCP3 mRNA in muscle. The aim of our study was to investigate the influence of -55CT polymorphism of UCP3 gene on adipocytokines response and weight loss secondary to a hypocaloric diet in obese patients. A population of 107 obese (body mass index >30) nondiabetic outpatients was analyzed in a prospective way. Before and after three months of a hypocaloric diet, an indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure, a serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. The lifestyle modification program consisted of a hypocaloric diet (1520 kcal, 52% of carbohydrates, 25% of lipids and 23% of proteins). The exercise program consisted of aerobic exercise for at least 3 times per week (60 minutes each). The mean age was 49.5+/-34.5 years and the mean BMI 34.5+/-4.8, with 27 males (25.3%) and 80 females (74.7%). Ninety patients (25 males/65 females) (83.6%) had the genotype 55CC (wild group) and 17 patients (2 male/15 females) (16.4%) 55CT (mutant group). The percentage of responders (weight loss) was similar in both groups (wild group: 84.7% vs. mutant group: 81.8%). BMI, weight, fat mass, systolic blood pressure, LDL cholesterol, waist circumference, and waist-to-hip ratio decreased in the wild group and RMR and VO (2) were increased. In the mutant group, BMI and weight decreased. Leptin and IL-6 levels have a significant decrease in the wild group (9.6%: p<0.05) and (30.5%: p<0.05), respectively. Patients with -55CC genotype have a significant decrease in leptin, interleukin 6, BMI, weight, fat mass, systolic blood pressure, LDL cholesterol, waist circumference, waist-to-hip ratio weight, fat mass, and systolic blood pressure.


The role of the academic medical center library in training public librarians.
This project enhanced access to and awareness of health information resources on the part of public libraries in western Pennsylvania. The Health Sciences Library System (HSLS), University of Pittsburgh, conducted a needs assessment and offered a series of workshops to 298 public librarians. The National Library of Medicine-funded project "Access to Electronic Health Information" at the HSLS, University of Pittsburgh, provided Internet health information training to public libraries and librarians in sixteen counties in western Pennsylvania. Through this project, this academic medical center library identified the challenges for public librarians in providing health-related reference service, developed a training program to address those challenges, and evaluated the impact of this training on public librarians' ability to provide health information. The HSLS experience indicates academic medical center libraries can have a positive impact on their communities by providing health information instruction to public librarians. The success of this project--demonstrated by the number of participants, positive course evaluations, increased comfort level with health-related reference questions, and increased use of MEDLINEplus and other quality information resources--has been a catalyst for continuation of this programming, not only for public librarians but also for the public in general. A training needs assessment, course evaluation, and impact training survey were used in developing the curriculum and evaluating the impact of this training on public librarians' professional activities.


Long-Term Outcome of Drug-Coated Balloon vs Drug-Eluting Stent for Small Coronary Vessels: PICCOLETO-II 3-Year Follow-Up.
Native vessel coronary artery disease represents 1 of the most attractive fields of application for drug-coated balloons (DCBs). To date, several devices have been compared with drug-eluting stents (DESs) in this setting with different outcomes. The authors sought to compare the short- and long-term performance of the paclitaxel DCB with the everolimus-eluting stent in patients with de novo lesions in small coronary vessel disease. PICCOLETO II (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment) was an academic, international, investigator-driven, multicenter, open-label randomized clinical trial in which patients were allocated to a DCB (n = 118) or DES (n = 114). We previously reported the superiority of DCBs regarding in-lesion late lumen loss at 6 months. Herein we report the final 3-year clinical follow-up with the occurrence of major adverse cardiac events (MACEs), a composite of cardiac death, nonfatal myocardial infarction, target lesion revascularization, and its individual components. The 3-year clinical follow-up (median 1,101 days; IQR: 1,055-1,146 days) was available for 102 patients allocated to DCB and 101 to DES treatment. The cumulative rate of all-cause death (4% vs 3.9%; P = 0.98), cardiac death (1% vs 1.9%; P = 0.56), myocardial infarction (6.9% vs 2%; P = 0.14), and target lesion revascularization (14.8% vs 8.8%; P = 0.18) did not significantly differ between DCBs and DESs. MACEs and acute vessel occlusion occurred more frequently in the DES group (20.8% vs 10.8% [P = 0.046] and 4% vs 0% [P = 0.042], respectively). The long-term clinical follow-up of the PICCOLETO II randomized clinical trial shows a higher risk of MACEs in patients with de novo lesions in small vessel disease when they are treated with the current-generation DES compared with the new-generation paclitaxel DCB. (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment [PICCOLETO II]; NCT03899818).


Hen Egg Lysozyme Alleviates Static Mechanical Pain Via NRF1-Parkin-TACAN Signaling Axis in Sensory Neurons.
Mechanical allodynia impinges on the life quality of patients. Hen Egg Lysozyme (HEL) is a substance extracted from eggs that is commonly used to inhibit bacterial activity. The role of HEL in regulating and treating pain is unclear. Here, we find that HEL selectively attenuates static mechanical allodynia of mice induced by complete Freund's adjuvant (CFA), spinal nerve ligation (SNL) and chemotherapeutic agent. RNA-seq screening reveals that CFA significantly reduces the expression of Parkin in dorsal root ganglion (DRG) neurons of mice, while pre-administration of HEL increases the expression of Parkin and remits the static mechanical allodynia induced by Parkin-siRNA. Moreover, HEL increases the interaction between nuclear respiratory factor 1 (NRF1) and histone acetyltransferase P300 and then enhances the NRF1 mediated histone acetylation in prkn promoter region in DRGs of mice. Further, Parkin interacts with mechanotransducing ion channel TACAN (Tmem120a) and knockdown of Parkin significantly increases the membrane trafficking of TACAN in sensory neurons of mice. While pre-administration of HEL inhibits the increased membrane trafficking of TACAN in sensory neurons of mice induced by Parkin-siRNA. In addition, pre-given of HEL also significantly attenuates the static mechanical allodynia induced by overexpression of TACAN in mice, and the effect of HEL can be blocked by Parkin-siRNA. This indicates that HEL increases the expression of Parkin through epigenetic mechanisms and then decreases TACAN membrane trafficking in sensory neurons to relieve static mechanical hypersensitivity. Therefore, we reveal a novel function of HEL, which is a potential substance for the treatment of static mechanical pain.


Is There Still a Role for Digoxin in the Management of Atrial Fibrillation?
A number of recent observational analyses have assessed clinical outcomes associated with digoxin use in patients with atrial fibrillation. In this review, we review these data and provide suggestions on the contemporary use of digoxin in patients with atrial fibrillation as supported by the recent evidence. Observational data from clinical trials and registries have provided variable results on the safety and efficacy of chronic digoxin use in patients with atrial fibrillation. In general, results have been consistent with an associated increase in adverse clinical outcomes with digoxin use in atrial fibrillation patients without heart failure. In atrial fibrillation patients with heart failure, while the weight of evidence suggested an associated risk with digoxin therapy, the results are inconsistent. In patients with atrial fibrillation without heart failure, digoxin should generally be avoided. In atrial fibrillation patients with heart failure, digoxin should generally be reserved for patients that do not achieve adequate rate control or are not tolerant of other rate control therapies.


Rotavirus VP3 expressed in insect cells possesses guanylyltransferase activity.
We have examined the possible function(s) of the protein VP3 encoded by the rotavirus SA11 genomic segment 3. Viral-associated VP3 in double-shelled and single-shelled particles was shown to bind GTP covalently and reversibly. These properties are similar to the unique characteristics of eukaryotic and viral guanylyltransferases, suggesting that VP3 is associated with a capping enzyme activity. Previous studies have shown that intact viral particles are required for transcription, making it difficult to unequivocally identify the functions of individual proteins within such particles. Characterization of VP3 produced in the baculovirus expression system showed that the expressed VP3 covalently bound GTP. These studies suggest that VP3 alone is the guanylyltransferase. GTP binding also was seen in core virus-like particles and single-shelled virus-like particles that lacked viral nucleic acid and were assembled in insect cells.


Impact of corporate social responsibility on sustainable competitive advantages: The mediating role of corporate reputation.
This study investigates the relationship between corporate social responsibility (CSR) and sustainable competitive advantage (SCA). Moreover, building on the stakeholder theory, this study investigates the mediating effects of corporate reputation (CR) between the relationship of corporate social responsibility and sustainable competitive advantage. We used a questionnaire survey to collect data from the employees working in the construction industry of Pakistan. Using the sample of 239 respondents, a structural equation modeling technique was used to verify the hypothesis relationship. The findings indicated that CSR directly and positively influences sustainable competitive advantages. Moreover, corporate reputation positively mediates the connection between corporate social responsibility and sustainable competitive advantage. This research fills knowledge gaps and highlights the significance of CSR in fostering sustainable competitive advantages within the construction industry.


Hybrid liposomes inhibit growth and invasion of human osteosarcoma cells leading to apoptosis.
Marked inhibitory effects of hybrid liposomes (HL-n; n=21, 23, 25) composed of 90 mol% l-α-dimyristoylphosphatidylcholine (DMPC) and 10 mol% polyoxyethylene(n) dodecyl ethers on the growth of two human osteosarcoma cell lines (MG-63 and U-2 OS) were obtained. Furthermore, fluorescence microscopic and flow cytometric analyses revealed the induction of apoptosis by HL-n in both cells. It is noteworthy that HL-23 could inhibit the invasion and migration of U-2 OS cells on the basis of matrigel invasion assay and scratch wound assay, respectively.


Effect of myofibril architecture on the active contraction of dystrophic muscle. A mathematical model.
Duchenne muscular dystrophy (DMD) is a muscle degenerative disease caused by a mutation in the dystrophin gene. The lack of dystrophin leads to persistent inflammation, degeneration/regeneration cycles of muscle fibers, Ca2+ dysregulation, incompletely regenerated fibers, necrosis, fibrotic tissue replacement, and alterations in the fiber ultrastructure i.e., myofibril misalignment and branched fibers. This work aims to develop a comprehensive chemo-mechanical model of muscle-skeletal tissue accounting for dispersion in myofibrillar orientations, in addition to the disorders in sarcomere pattern and the fiber branching. The model results confirm a significant correlation between the myofibrillar dispersion and the reduction of isometric force in the dystrophic muscle and indicate that the reduction of contraction velocity in the dystrophic muscle seems to be associated with the local disorders in the sarcomere patterns of the myofibrils. Also, the implemented model can predict the force-velocity response to both concentric and eccentric loading. The resulting model represents an original approach to account for defects in the muscle ultrastructure caused by pathologies as DMD.


Performance of wild-Serbian Ganoderma lucidum mycelium in treating synthetic sewage loading using batch bioreactor.
The fluctuation of domestic wastewater characteristic inhibits the current conventional microbial-based treatment. The bioremediation fungi has received attention and reported to be an effective alternative to treat industrial wastewater. Similar efficient performance is envisaged for domestic wastewater whereby assessed performance of fungi for varying carbon-to-nitrogen ratios in domestic wastewater is crucial. Thus, the performance of pre-grown wild-Serbian Ganoderma lucidum mycelial pellets (GLMPs) was evaluated on four different synthetic domestic wastewaters under different conditions of initial pH (pH 4, 5, and 7) and chemical oxygen demand (COD) to nitrogen (COD/N) ratio of 3.6:1, 7.1:1, 14.2:1, and 17.8:1 (C3.6N1, C7.1N1, C14.2N1, and C17.8N1). The COD/N ratios with a constant concentration of ammonia-nitrogen (NH3-N) were chosen on the basis of the urban domestic wastewater characteristics sampled at the inlet basin of a sewage treatment plant (STP). The parameters of pH, COD, and NH3-N were measured periodically during the experiment. The wild-Serbian GLMPs efficiently removed the pollutants from the synthetic sewage. The COD/N ratio of C17.8N1 wastewater had the best COD and NH3-N removal, as compared to the lower COD/N ratio, and the shortest treatment time was obtained in an acidic environment at pH 4. The highest percentage for COD and NH3-N removal achieved was 96.0% and 93.2%, respectively. The results proved that the mycelium of GLMP has high potential in treating domestic wastewater, particularly at high organic content as a naturally sustainable bioremediation system.


Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities.
Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically 'hot' tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy.


Electron microscopic observations of a possible tubulin synthesis-polymerization complex in oocytes of a pond-skater.
Maturing oocytes of Gerris najas display, in ultrathin sections, protein fibrils extending from ribosomes, which are often arranged on ring-like cisternae of rough endoplasmic reticulum. In some cases, the fibrils apparently continue into typical microtubules. The possibility is discussed that the huge amount of microtubules of the egg cell is synthesized and polymerized in the form of specific ribosome-tubulin-filament-microtubule complexes.


Risk of bleeding and arterial cardiovascular events in patients with splanchnic vein thrombosis in Denmark: a population-based cohort study.
Little is known about adverse events following splanchnic vein thrombosis. Venous thromboembolism has been associated with increased risks of bleeding and arterial cardiovascular events. To learn more about the clinical course of splanchnic vein thrombosis, we examined the risks of bleeding and arterial cardiovascular events in patients with the disease, and compared them with the risks in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) and individuals from the general population. In this population-based cohort study, we used data for all patients with a diagnosis of splanchnic vein thrombosis recorded in the Danish National Patient Registry (DNPR) between Jan 1, 1994, and Nov 30, 2013 (cumulative source population 7 310 450 individuals). We created two comparison cohorts using data from the DNPR and the Civil Registration System for the same period: one of patients with DVT or PE and another of individuals from the general population. Comparison cohorts (ten comparators per patient with splanchnic vein thrombosis) were matched on sex, age, and calendar year of diagnosis. We calculated absolute risks and used proportional hazard regression to calculate adjusted hazard ratios (HRs) for the primary outcomes of bleeding and arterial cardiovascular events after splanchnic vein thrombosis diagnosis (or the index date for comparison cohorts). 1915 patients with splanchnic vein thrombosis, 18 373 patients with DVT or PE, and 19 150 individuals from the general population were included in the study. Patients with splanchnic vein thrombosis were followed up for a median of 1 year (IQR 0·1-3·9). These patients had a high risk of bleeding in the 30 days after diagnosis, both in absolute terms (4·3% [95% CI 3·5-5·3]) and in adjusted models (HR 9·64 [95% CI 6·46-14·40] vs DVT or PE; 39·79 [19·44-81·46] vs general population). Bleeding risk was still significantly increased in patients with splanchnic vein thrombosis up to 1 year after diagnosis (HR 3·01 [95% CI 2·28-3·97] vs DVT or PE; 6·83 [4·83-9·65] vs general population), and remained elevated for up to 10 years compared with patients with DVT or PE (1·93 [1·12-3·34]) and for up to 19 years compared with the general population (5·90 [2·22-15·64]). The risk of arterial cardiovascular events in patients with splanchnic vein thrombosis was high in the year after diagnosis (absolute risk 3·3% [95% CI 2·6-4·2] up to 30 days; 7·0% [5·8-8·4] up to 31-365 days), and in adjusted models was significantly higher than in patients with DVT or PE (HR 7·05 [95% CI 4·74-10·48] up to 30 days; 2·10 [1·62-2·72] up to 31-365 days) and individuals from the general population (15·75 [9·26-26·79] and 3·17 [2·34-4·27], respectively). However, this risk did not remain significantly elevated above that of patients with DVT or PE after 1 year or the general population after 5 years. Patients with splanchnic vein thrombosis are at increased risk of adverse outcomes, particularly bleeding but also arterial cardiovascular events, for years after diagnosis compared with patients with DVT or PE and the general population. Physicians should be cognisant of these risks in patients with splanchnic vein thrombosis. The Program for Clinical Research Infrastructure (PROCRIN), established by the Lundbeck Foundation and the Novo Nordisk Foundation.


Sleep apnea with unusual EEG changes in Jakob-Creutzfeldt disease.
Disruption of the periodic pattern in the EEG was observed in a patient with Jakob-Creutzfeldt disease. Periods of apnea (during 'sleep') were associated with abrupt cessation of the periodic complexes and their replacement by 7-9 c/sec waves which persisted throughout the apneic episode. The periodic complexes reappeared on termination of the apnea. This close temporal association between disruption of the periodicity and apneic episodes suggests proximity of respiratory neurons and the deep subcortical pacemaker.


Incarcerated fathers and parenting: importance of the relationship with their children.
This study examined the relationships of incarcerated fathers (n = 185) with their children while in a maximum security prison. Despite the attention to parental incarceration and at-risk children, the child welfare and corrections literature has focused mostly on imprisoned mothers and children. Demographic, sentence, child-related, and program participation factors were investigated for their influence on father-child relationships. Multiple regression analyses indicated race and sentence contributed to the father's positive perceptions of contacts with their children. Most important, many, though serving lengthy sentences, valued and perceived a positive father-child relationship. Results are discussed in light of implications for future research and social policy.


Metaplasia of the lung alveolar epithelium in mice repeatedly challenged with influenza virus.
Mice were repeatedly infected intranasally with increasing doses of influenza virus. A correlation was observed between the incidence of metaplasia of the lung alveolar epithelium and serum antibody levels.


What makes Sanriku waters the southernmost habitat of northern fur seals? Winter-spring habitat use in relation to oceanographic environments.
The waters off Sanriku (located on the northeastern coast of Honshu Island, Japan) provide the southernmost habitats of northern fur seals (Callorhinus ursinus) during winter and spring in the western North Pacific. The southward flowing cold Oyashio current and northward-flowing warm Kuroshio extension mix there, making the area highly productive. Northern fur seals migrate into these waters from the breeding rookeries for feeding, and the locations of the southern margins of their habitats vary yearly. The key questions for understanding the seasonal migration patterns are "why" and "how" the species utilize these waters as the southernmost habitat. We estimated the density and abundance of northern fur seals using standard line-transect theory combined with habitat modeling. The spatial patterns of animal density were analyzed using generalized additive models with seven static and dynamic environmental covariates, and those covariates were selected based on Akaike's information criterion (AIC). The lowest AIC model included depth, sea surface temperature, slope, and gradient in sea surface temperature. This model estimated well the spatial patterns of the density of the species, in which fur seals were widely distributed in the study areas, but less frequently encountered between the isobaths 100 m and 200 m. These spatially separated habitats suggest that the shelf break and offshore front play an important role in creating the feeding grounds of fur seals. On the other hand, sea surface temperature positively correlated with fur seals' density up to 14°C. This may indicate that further warm waters work as a temperature barrier, and fur seals concentrate on the edge of suitable temperature ranges.


Adverse childhood and adulthood experiences and risk of new-onset cardiovascular disease with consideration of social support: a prospective cohort study.
The relationship between adverse childhood experiences (ACEs) and adverse adulthood experiences (AAEs) and their association with incident cardiovascular disease (CVD) have not been extensively studied. Considering social support, we evaluated the complex relations of ACEs and AAEs with incident CVD. This prospective cohort study used data from the 2014 life course survey and the 2015 and 2018 surveys of the China Health and Retirement Longitudinal Study, a national survey of Chinese adults aged ≥ 45 years from 28 provinces across China. The study population included 5836 individuals (mean [SD] age, 59.59 [8.22] years, 49.7% were males). Information on ACEs, AAEs, young adulthood social support, health behavior factors, health status factors, and demographics was measured. Cox regression models, the difference method to estimate the mediation proportion, and the additive and multiplicative interactions were performed. Subgroup and sensitivity analyses were also conducted. During follow-up, 789 incident cases of CVD occurred. The fully adjusted model, including demographics, health behaviors, health status factors (e.g., depressive symptoms), and social support as control variables, demonstrated that the overall number of ACEs (Hazard ratio [HR]: 1.11, 95% CI: 1.08 to 1.14) and AAEs (HR: 1.19, 95% CI: 1.16 to 1.22) were associated with an increased risk of incident CVD. A dose-response relationship existed between the number of ACEs or AAEs and incident CVD risk. The overall AAEs were found to mediate 17.7% (95% CI: 8.2 to 34.2%) of the association between ACEs and incident CVD. Moreover, a significant additive interaction between ACEs and AAEs was detected (RERI [95% CI]: 0.32 [0.09 to 0.56]). Compared with adults without exposure to both ACE and AAE, those with exposure to both at least one ACE and one AAE indicator had the highest risk of incident CVD (HR: 1.96, 95% CI: 1.72 to 2.23). Exposure to ACEs or AAEs was independently associated with an increased risk of incident CVD among Chinese middle-aged and older adults in a dose-response manner, and the overall AAEs partially mediated the association between ACEs and incident CVD. Preventive measures aimed at addressing either ACEs or AAEs alone may not significantly reduce the risk of CVD later in life. The necessity of a comprehensive life-course health strategy targeting the prevention of adversity merits increased attention.


Comparison of efficacy and safety of two parenteral iron preparations in pregnant women.
To compare the efficacy and safety with a fixed dose of two parenteral iron preparations, iron sucrose complex and iron sorbitol citric acid as per the current practice. A prospective randomized open label study was conducted. In this study, 60 pregnant women with hemoglobin less than 8.5 g/dl received a fixed dose of either IV iron sucrose or IM iron sorbitol citric acid therapy. The efficacy of the therapy was assessed by laboratory parameters such as hemoglobin, hematocrit, MCV, MCH, and serum ferritin level after 14 and 28 days. To assess the safety, adverse drug reactions with both the therapies were recorded. Hemoglobin concentration increased significantly (P < 0.001) with respect to time in both the groups. The rise in the hemoglobin level in third and fourth weeks was significantly higher in iron sucrose (0.92 g/dl) than iron sorbitol citric acid therapy (0.56 g/dl). There was no significant change in the rise of the serum ferritin level after both the therapies. Adverse events were common with iron sorbitol citric acid therapy. However, no serious adverse drug reactions were observed. No significant difference in the efficacy of both of the therapy. However, adverse events and dropout rates were much more common in the group of pregnant women who received iron sorbitol citric acid.


Ultrastructure of differentiated malpighian tubules from cockroach nymphs during the molting cycle.
Differentiated Malpighian tubules of Periplaneta americana nymphs consist of four distinct regions. The distal, middle, and proximal regions are similar to the same regions in adult tubules. However, the transparent portion of the middle region was found to have ultrastructural characteristics different from those of the longer opaque segment of the middle region and the two other tubule regions. This newly distinguished region is called the lower middle region. Transitional zones, areas where cells show characteristics of two adjacent regions, are apparent between the distal and middle regions and between the middle and lower middle regions. The middle region of primary tubules undergoes an increase in autophagic activity and a modification of its basal infoldings and microvilli shortly before each molt. An increase in autophagic activity is also observed in the lower middle region near the time of molting.


Study on micro crack propagation mechanism of ferrite-pearlite gas transmission pipeline steel with lamellar structure.
The deformation and failure characteristics of pipeline steel depend on its atomic structure and microstructure. Based on the serial multi-scale analysis technology, the ferrite/cementite (α-Fe/Fe3C) lamellar atomic structure with Bagaryatskii orientation relationship is established. In order to obtain the experimental sample of the lowest energy state, The step-by-step relaxation method of conjugate gradient energy minimization and constant temperature and constant pressure relaxation under NPT conditions is carried out, and the energy state and atomic structure of the relaxed samples are analyzed. For the models of different cementite terminal plane structures, the tension displacement curves on the propagation path of mode I central through crack are extracted respectively, combined with the bilinear cohesion zone model, The cohesion parameters at the atomic scale are successfully transferred from bottom to top to the macro and micro scales. By simulating the reaction force and displacement response law at the loading point, the critical fracture toughness of each terminal interface of ferrite-pearlite pipeline steel at different scales is calculated, which provides a reliable path for exploring the micro mechanism of macro cracking behavior of pipeline steel.


The phosphohydrolase activity in lamellar bodies and its relationship to phosphatidylglycerol and lung surfactant formation.
Phosphohydrolase activity of a lamellar body-enriched preparation from pig lung was examined to ascertain if two separate enzymes catalyze the hydrolysis of phosphatidic acid and phosphatidylglycerol 3-phosphate. From sulfhydryl inhibition, heat inactivation and substrate specificity studies, we suggest that one phosphohydrolase may account for the hydrolysis of both substrates. The relationship of the reported experiments to the biosynthesis of the glycerophospholipids present in surfactant is discussed.


The active center of transport for phosphoenolpyruvate and inorganic phosphate in the human erythrocyte membrane.
Phosphoenolpyruvate is transported into erythrocytes by a carrier-mediated transport system. The transport is competitively inhibited by inorganic phosphate and pyridoxal phosphate, which are transported across the cell membrane by Band 3. The pH profiles for the transport of inorganic phosphate and phosphoenolpyruvate suggest that a histidine residue exposed at the inner surface of the membrane participates in both of the transport. A hydrophobic peptide which may be a part of the active center for the transport is purified from the CNBr fragments of Band 3.


Stay-green trait-antioxidant status interrelationship in durum wheat (Triticum durum) flag leaf during post-flowering.
Three independent durum wheat mutant lines that show delayed leaf senescence or stay-green (SG) phenotype, SG196, SG310 and SG504, were compared to the parental genotype, cv. Trinakria, with respect to the photosynthetic parameters and the cellular redox state of the flag leaf in the period from flowering to senescence. The SG mutants maintained their chlorophyll content and net photosynthetic rate for longer than Trinakria, thus revealing a functional SG phenotype. They also showed a better redox state as demonstrated by: (1) a lower rate of superoxide anion production due to generally higher activity of the antioxidant enzymes superoxide dismutase and catalase in all of the SG mutants and also of the total peroxidase in SG196; (2) a higher thiol content that can be ascribed to a higher activity of the NADPH-providing enzyme glucose-6-phosphate dehydrogenase in all of the SG mutants and also of the NADP(+)-dependent malic enzyme in SG196; (3) a lower pro-oxidant activity of lipoxygenase that characterises SG196 and SG504 mutants close to leaf senescence. Overall, these results show a general relationship in durum wheat between the SG phenotype and a better redox state. This relationship differs across the different SG mutants, probably as a consequence of the different set of altered genes underlying the SG trait in these independent mutant lines.


[An application of Color Doppler ultrasonography in evaluate of brachytherapy in patients with uveal melanomas].
Uveal melanomas, even those of big size, are recently more readily treated conservatively, with radiotherapy, though the efficiency of this treatment has not been yet established. Of the study was the assessment of the usefulness of Color Doppler (CD) or Power Doppler (PD) examination in monitoring the effectiveness of brachytherapy in the management of melanomas. Examination was performed in 15 patients, who were treated because of medium size or large uveal melanomas, with plaque radiation (brachytherapy). CD/PD examination of blood flow within the tumor, with the use of SonoVue contrast agent in several cases, was performed before institution of the therapy and two times after the treatment, as follow-up. Regression of the tumor and gradual atrophy of its neovascularisation was observed in all the examined patients. The enhancement of Color Doppler imaging with contrast agent helps in making decision to further therapeutic options as complex situation. Color and Power Doppler ultrasonography is a helpful method in monitoring the effectiveness of brachytherapy in patients with uveal melanomas.


Role of afferent control in maintaining structural and metabolic characteristics of stretched soleus in rats exposed to hindlimb suspension.
It is known that gravitational unloading (GU) induces atrophy of skeletal muscles and slow-to-fast muscle fiber (MF) transformation. Stretching of m. soleus prevents those changes, probably afferent information from the stretched muscle acting as triggering mechanism. It was shown that EMG of suspended animals or of stretched muscle is similar to that of control animals. Our study was aimed at revealing contribution of the afferent information from stretched m.soleus exposed to GU in maintenance of cross-sectional area (CSA) of MF and of myosine heavy chains and oxidative potential of skeletal muscles.


The yield of ophthalmoscopy as a screening tool for intracranial pathology in pediatric headache.
Headache is a common complaint in children who present at the pediatric emergency department (PED). Serious conditions such as intracranial tumors and idiopathic intracranial hypertension (IIH) should be rapidly ruled out. Ophthalmoscopy for the presence of papilledema has long been considered critical to the assessment of headaches in children; however, the yield of this procedure is poorly validated. This retrospective study implemented a computerized search of the medical records of a single tertiary center to identify all children aged 2-18 years who presented at the PED complaining of headache between 2007 and 2017. The clinical, demographic, radiographic, and laboratory data were analyzed. Of the 948 children aged 2-18 years who presented at the PED complaining of headache, 536 had an ophthalmoscopy examination carried out by an ophthalmologist. Forty-one had papilledema, of whom 7 had an intracranial tumor, 15 had IIH, and 9 had optic nerve head drusen. Of the 495 children without papilledema, 3 had intracranial tumor, and 11 had IIH. The sensitivity and specificity of papilledema for the diagnosis of intracranial tumor were 70% and 93.5%, respectively, with an NPV and PPV of 99.4% and 17.1%, respectively. The sensitivity and specificity of papilledema for the diagnosis of intracranial pathology in general were 61.1% and 96.2%, respectively, with an NPV and PPV of 97.2% and 53.7%, respectively. Conclusion: Assessment by ophthalmoscopy for papilledema in children presenting to the PED with headache had high sensitivity and high specificity, thus reinforcing the importance of ophthalmoscopy as a screening tool in these children. What is Known: • Headache is a common complaint in children. Serious intracranial pathologies need to be rapidly excluded. • Ophthalmoscopy for the presence of papilledema is commonly used as a screening tool for intracranial pathology, but this procedure is poorly validated. What is New: • Ophthalmoscopy for the assessment of papilledema in children who present with headache to the pediatric emergency department is shown to exhibit sensitivity and specificity for the diagnosis of intracranial pathology.


Is HbA1c associated with birth weight? A multivariable analysis of Pakistani pregnant women.
Globally, one in seven infants is born with low birth weight and 3%-7% of infants are born with high birth weight, with the greatest burden noted in low- and middle-income countries. This study investigated the association between maternal prenatal glucose regulation and birth weight and the moderating effect of fetal sex among Pakistani women. Secondary data from a prospective longitudinal study of healthy pregnant women from Pakistan (N = 189) was used. Participants provided a blood sample (12-19 weeks' gestational age) for the assessment of HbA1c (%). Birth weight (g) was collected following delivery. Higher maternal HbA1c was associated with higher birth weight (b = 181.81, t[189] = 2.15, p = 0.03), which was moderated by fetal sex (b = -326.27, t[189] = -2.47, p = 0.02), after adjusting for gestational age at birth, ethnicity, and pregnancy weight. Among women carrying a male fetus, every 1% increase in HbA1c predicted a 182 g increase in birth weight (b = 181.81, t[189] = 2.15, p = 0.03). Results extend research from high-income countries and indicate that fetal sex may have implications for glucose regulation in early to mid-pregnancy. Future research should examine sociocultural factors, which could elucidate potential mediating factors in the relation between HbA1c and birth weight in healthy pregnancies.


Cardiopulmonary function in very preterm lambs during liquid ventilation.
Cardiopulmonary function was evaluated in very preterm lambs (106 +/- 0.7 S.E. days gestation, 1.66 +/- 0.12 S.E. kg birth weight) during fluorocarbon ventilation. Lambs were delivered by cesarean section after epidural anesthesia. Indwelling arterial, venous, and tracheal cannulae were placed before clamping the cord. Lambs were then mechanically ventilated with oxygenated fluorocarbon for approximately 2 h. During this period it was possible to maintain adequate gas exchange and stable cardiac function. Transpulmonary pressure, liquid flow, and tidal volume tracings enabled determination of lung compliance, CL = 0.58 +/- 0.12 S.E. ml X cmH2O-1 X kg-1, inspiratory resistance, RI = 3600 +/- 604 S.E. cmH2O X liter-1 X sec-1, and expiratory resistance, RE = 4034 +/- 2183 S.E. cmH2O/liter/sec. Lung compliance of the 106-day-old fluorocarbon-filled lung is similar to the more mature 138-143-day-old air-filled lung in preterm lambs. Based on the data presented herein we have extended the viability of the preterm lamb to the limit of pulmonary capillary development rather than that of the pulmonary surfactant system.


Operation for ascending aortic aneurysm and aortic regurgitation--pathological influence on survival.
The author briefly reviews the early operations of treatment of aortic aneurysm and aortic regurgitation leading to his description, in 1968, of the first composite graft replacement of the ascending aorta and aortic valve, with anastomosis of the coronary arteries into the graft. The original operation is described with reference to modifications suggested by a number of authors throughout the last 20 years. Methods of achieving coronary artery continuity by Carrel patch and pull-through by saphenous vein interposition and by synthetic graft techniques are discussed. While any of these methods may be needed in individual cases the preference of the author remains for simplicity. The arguments for and against excision of the aneurysmal sac are considered in relation to the control of haemorrhage. The early and medium term results of operation are good but in comparing results world-wide a lack of uniform diagnostic criteria is apparent. The full clinical Marfan syndrome presents little difficulty but the status of "annuloaortic ectasia", Erdheim's medionecrosis, "cystic medial necrosis" and many other pathological descriptions are not defined: "forme fruste" of Marfan's disease has been used for any of the above. Interpretation of surgical results remains difficult and often impossible in the absence of clear definitions. Recent work on elastic tissue and on the chemistry of collagen together with the hope of identification of the genetic background now offers real hope of clearer understanding.


Molecular mechanisms for generation of neural diversity and specificity: roles of polypeptide factors in development of postmitotic neurons.
Development of postmitotic neurons is influenced by two groups of polypeptide factors. Neurotrophic factors promote neuronal survival both in vivo and in vitro. Neuronal differentiation factors influence transmitter phenotypes without affecting neuronal survival. The list of neurotrophic factors is increasing partly because certain growth factors and cytokines have been shown to possess neurotrophic activities and also because new neurotrophic factors including new members of the nerve growth factor (NGF) family have been identified at the molecular level. In vitro assays using recombinant neurotrophic factors and distributions of their mRNAs and proteins have indicated that members of a neurotrophic gene family may play sequential and complementary roles during development and in the adult nervous system. Most of the receptors for neurotrophic factors contain tyrosine kinase domains, suggesting the importance of tyrosine phosphorylation and subsequent signal transduction for their effects. Molecules such as LIF (leukemia inhibitory factor) and CNTF (ciliary neurotrophic factor) have been identified as neuronal differentiation factors in vitro. At the moment, however, it remains to be determined whether or not the receptors for a group of neuronal differentiation factors constitute a gene family or contain domains of kinase or phosphatase activity. Synergetic combinations of neurotrophic and neuronal differentiation factors as well as their receptors may contribute to the generation of neural specificity and diversity.


Immunosuppressive syndrome in juvenile black-faced ibises (Theristicus melanopis melanopis) in southern Chile.
In the austral summer of 2011, in the rural area of Villarrica county, southern Chile (39 degrees 16'S, 72 degrees 19'W), seven black-faced ibis juveniles (approximately 4 mo old) were observed in the field with weakness; they were unable to follow the group and struggling to take flight. Three of these birds were euthanatized, and complete necropsies were performed. Gross examination showed severe infestation with Colpocephalum trispinum and Ardeicola melanopis lice, moderate emaciation, pale musculature, bursal atrophy, and severe hemorrhagic enteritis due to a heavy proventricular and intestinal infection with Porrocaecum heteropterum nematodes. Fungal pneumonia and severe lymphoid depletion on thymus, spleen, and bursa were diagnosed by microscopic examination. Bursal lesions included apoptosis and necrosis of lymphoid cells, and several cystic follicles. The presence of severe lymphoid depletion associated with fungal pneumonia and severe external and internal parasite infections suggest the presence of an immunosuppressive syndrome in these birds that caused the death of several black-faced ibis juveniles in southern Chile during the summer of 2011.


Sequential loading of inclusion complex/nanoparticles improves the gastric retention of Vladimiriae Radix essential oil to promote the protection of acute gastric mucosal injury.
The essential oil from Vladimiriae Radix (VEO) is a medicinal natural product with anti-ulcer activity. A novel gastroretentive drug delivery system was developed by preparing the hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex incorporated into chitosan nanoparticles (V-CD/NPs), to improve the bioavailability of VEO and its protective effect on gastric mucosa. The optimum preparation process of V-CD/NPs was obtained by Plackett-Burman and Box-Behnken response surface methodology. The resulting V-CD/NPs gained a suitable positive potential and small particle size, and showed stability in simulated gastric fluid, whose morphology and in vitro drug release profiles had a pH-sensitivity. Besides, V-CD/NPs was proved to strongly bind with mucin, and in vivo imaging revealed that it could be retained in the stomach for more than 8 h. The results of drug concentration in gastric tissues showed that the sequential loading of inclusion complex/nanoparticles promoted the local absorption of VEO in gastric tissues, which was favorable to reach the effective therapeutic concentration in the lesioned mucosa area. In comparison to VEO and V-CD, the callback effect of V-CD/NPs on 1L-1β, 1L-6, TNF-α, NF-κB, MDA and SOD was comparable to cimetidine, and V-CD/NPs outperformed in gastric mucosal protection. Therefore, the gastroretentive drug delivery system developed in our study effectively enhanced the anti-ulcer activity of VEO, which could be a promising strategy for the prevention and treatment of the acute gastric mucosal injury.


Micro-PET imaging and small animal models of disease.
Positron emission tomography (PET) has been used clinically to measure enzyme reactions, ligand-receptor interactions, cellular metabolism and cell proliferation. Until recently, however, PET has not been suitable for small animal models because of resolution limitations. Development of micro-PET instrumentation for small animal imaging and the availability of positron-emitting tracers has made this technology accessible for the non-invasive, quantitative and repetitive imaging of biological function in living animals. The development of new probes and positron-imaging based reporter genes has extended micro-PET applications to investigations of metabolism, enzyme activity, receptor-ligand interactions, protein-protein interactions, gene expression, adoptive cell therapy and somatic gene therapy. Because small animal PET is immediately extrapolatable to the clinic, laboratory advances should rapidly be translated to clinical practice.


[Pyogenic granuloma: report of a case].
An instance of pyogenic granuloma in a nine years old boy is reported as well as clinical features, hystology, radiographic report and post-operative result.


Genetic analysis of the bacteriocin-encoding plasmids pRJ6 and pRJ9 of Staphylococcus aureus by transposon mutagenesis and cloning of genes involved in bacteriocin production.
pRJ6 and pRJ9, small Staphylococcus aureus plasmids which code for bacteriocins, exhibited a bactericidal activity against several lactic acid bacteria and strains of Listeria monocytogenes, an important food-borne pathogen. Filter-mating experiments using plasmid derivatives tagged with either Tn551 or Tn917-lac showed that pRJ6, but not pRJ9, could be mobilized by staphylococcal conjugative plasmids. Transposon mutagenesis of both plasmids was also performed. The bacteriocin and immunity structural genes of pRJ6 are part of the same operon, which is located around co-ordinate 4.0, being transcribed from right to left. However, gene cloning experiments using a staphylococcal vector showed some evidence for the involvement of additional functions of pRJ6 in bacteriocin expression. One function involved in pRJ6 mobilization mapped around co-ordinate 5.2, and it appears to be transcribed from left to right. The bactericidal action exerted by strains harbouring pRJ9 appears to reflect the activity of at least two bacteriocins, whose combined action results in a broader spectrum of activity and in a higher antagonistic activity. Gene cloning experiments also supported these assumptions.


Decreased total MKP-1 protein levels predict poor prognosis in breast cancer.
MKP-1 dephosphorylates and inactivates MAPKs, whose constitutive activations have been associated with human cancers. We found that total MKP-1 protein levels were decreased in 63.7 % of breast cancer tissues compared with the paired noncancerous breast tissues. Decreased MKP-1 protein levels were correlated with increased tumor stage and positive recurrence and were associated with poor survival, even when using a multivariate Cox regression model. Intriguingly, nuclear MKP-1 staining was positively correlated with ER status. In vitro, tamoxifen increased MKP-1 expression in ER-positive but not ER-negative breast cancer cells. ER-specific siRNA was able to attenuate tamoxifen-induced MKP-1 expression. Furthermore, tamoxifen prolonged the duration of MKP-1 elevation and the binding time of ER to the promoter of the MKP-1/DUSP-1 gene compared with estrogen. Our results suggest that alterations of MKP-1 may serve as a prognostic factor in breast cancer. In addition, the regulation of MKP-1 may be related to the ER.


Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer.
Treatment stratification in stage IV NSCLC is guided by identification of oncogene driver mutations. Actionable mutations with current licenced therapeutic agents include epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), ROS-1 and BRAF V600. Alongside progress with small molecule therapy, developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and stage IV NSCLC. The success of CPIs has led to evaluation with small molecule therapy in both concurrent and sequential settings. In this review we summarise recent results of combination CPIs and tyrosine kinase inhibitors (TKIs) in stage IV NSCLC, detailing significant toxicity and its potential mechanisms with both concurrent and sequential approaches. As more therapeutic targets are being discovered it is becoming increasingly important for clinicians to correctly sequence therapy for delivery of safe and effective treatment. In addition to stage IV disease we suggest that comprehensive molecular profiling of key NSCLC drivers, particularly in stage III disease, will help to inform optimal treatment sequencing and minimise potential toxicity.


Addressing Neisseria gonorrhoeae Treatment Resistance With the DNA Gyrase A Assay: An Economic Study, United States.
Targeted antibiotics could delay emergence of resistant Neisseria gonorrhoeae. The DNA gyrase subunit A assay predicts susceptibility to ciprofloxacin. A model found that adding a $50 gyrase subunit A test for asymptomatic patients screened for N. gonorrhoeae resulted in cost neutrality. When ciprofloxacin susceptibility was high, a $114 test resulted in savings.


Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support.
The effects of nonphysiological flow generated by continuous-flow (CF) left ventricular assist devices (LVADs) on the aorta remain poorly understood. The authors sought to quantify indexes of fibrosis and determine the molecular signature of post-CF-LVAD vascular remodeling. Paired aortic tissue was collected at CF-LVAD implant and subsequently at transplant from 22 patients. Aortic wall morphometry and fibrillar collagen content (a measure of fibrosis) was quantified. In addition, whole-transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD-mediated changes in aortic mRNA and protein expression. The mean age was 52 ± 12 years, with a mean duration of CF-LVAD of 224 ± 193 days (range 45-798 days). There was a significant increase in the thickness of the collagen-rich adventitial layer from 218 ± 110 μm pre-LVAD to 410 ± 209 μm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 ± 11 a.u. pre-LVAD to 41 ± 24 a.u. post-LVAD (P < 0.0001). The magnitude of this increase in fibrosis was greater among patients with longer durations of CF-LVAD support. CF-LVAD led to profound down-regulation in expression of extracellular matrix-degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, whereas no evidence of fibroblast activation was noted. There is aortic remodeling and fibrosis after CF-LVAD that correlates with the duration of support. This fibrosis is due, at least in part, to suppression of extracellular matrix-degrading enzyme expression. Further research is needed to examine the contribution of nonphysiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes.


Effects of short vs. prolonged mechanical ventilation on antioxidant systems in piglet diaphragm.
Prolonged controlled mechanical ventilation (MV) is known to induce diaphragmatic oxidative stress that seems to be an important factor reducing force-generating capacity. To better understand the cellular mechanisms involved, this work examined the effect of short vs. prolonged MV on antioxidant defense in the diaphragm. Prospective, randomized, controlled animal study in a university laboratory. Eleven piglets (15-20 kg) were assigned to one of two groups: a long-MV group (n=6) ventilated for 3 days or a short-MV group (n=5) ventilated for 3 h. Force frequency curves of the transdiaphragmatic pressure (Pdi) were obtained in vivo by phrenic nerve pacing. Oxidative stress was evaluated by thiobarbituric reactive substance (TBARs) content and the enzymatic antioxidant activity of both superoxide dismutase (SOD) and glutathione peroxidase (GPx) in samples of diaphragm. Pdi decreased in the long-MV group by 30-35% over the 3 days at all frequencies compared to the short-MV group. Diaphragm TBARs content was significantly higher and SOD activity lower in long-MV animals than in short-MV animals after 72 h. GPx activity tended to be lower in diaphragms from long-MV animals, but this difference was not significant. This study shows that 3 days of MV in piglets is associated with a decrease in antioxidant activity which could emphasize oxidative stress and both contribute to the diaphragm dysfunction caused by MV.


Metabolic syndrome among diabetics and pre-diabetics of Jenu Kuruba tribe in Mysore district (JKDHS-2)--An evidence of metabolic abnormalities leading to increase in CVD's among Jenu Kuruba tribal population.
Metabolic syndrome is a cluster of clinical and metabolic abnormalities. In diabetics, other components of metabolic syndrome are an added risk factor for cardiovascular disease and all these cause mortality. Epidemiological transition is happening all over the world and tribes are not spared either. Identifying the extent of metabolic syndrome and its components in diabetics is vital for the prevention of cardiovascular diseases and other morbidities. To estimate the prevalence of Metabolic Syndrome among diabetics and pre-diabetics of Jenu Kuruba tribe and compare the mean values of various components of metabolic syndrome among diabetics and pre-diabetics. A community based cross sectional study was carried out among 7500 Jenu Kuruba tribal population in two phases. In phase I, total of 7500 subjects were screened for diabetes and hypertension and in phase II, a total of 249 diabetics and 310 pre-diabetics were identified and evaluated for metabolic syndrome. Prevalence of metabolic syndrome was estimated using NCEP ATP-III criteria. Metabolic syndrome was found in 84 (33.7%) of diabetics and 113 (36.4%) of pre-diabetic study subjects. Metabolic syndrome was highest in the 41-50 year age group. Lipid parameters such as total cholesterol, triglycerides and VLDL were significantly higher and HDL levels were significantly lower among subjects with metabolic syndrome as compared to subjects without metabolic syndrome. One third of diabetics and pre-diabetics had definable metabolic syndrome. Dyslipidemia is a significant component of metabolic syndrome. Epidemiological transitions are happening among Jenu Kuruba tribes and non-communicable diseases are on the raise among them.