Mitochondrial fusion, division and positioning in plants.
Mitochondria are involved in many fundamental processes underpinning plant growth, development and death. Owing to their multiple roles, as the sites of the tricarboxylic acid cycle and oxidative phosphorylation, as harbourers of their own genomes and as sensors of cell redox status, amongst others, mitochondria are in a unique position to act as sentinels of cell physiology. The plant chondriome is typically organized as a population of physically discrete organelles, but visualization of mitochondria in living tissues has shown that the mitochondrial population is highly interactive. Mitochondria are highly motile and movement on the cytoskeleton ensures that the physically discrete organelles come into contact with one another, which allows transient fusion, followed by division of the mitochondrial membranes. This article serves to review our current knowledge of mitochondrial fusion and division, and link this to recent discoveries regarding a putative mitochondrial 'health-check' and repair process, whereby non-repairable dysfunctional mitochondria can be removed from the chondriome. It is proposed that the unequal distribution of the multipartite plant mitochondrial genome between discrete organelles provides the driver for transient mitochondrial fusion that, in turn, is dependent on mitochondrial motility, and that both fusion and motility are necessary to maintain a healthy functional chondriome.


Evaluation of Salivary Profile among Adult Type 2 Diabetes Mellitus Patients in South India.
A lack of consensus on the possible association between diabetes and salivary dysfunction motivated us to conduct this investigation on the salivary parameters in diabetic and non diabetic subjects. This could also make the use of saliva as an alternative to that of blood in the diagnosis/monitoring of diabetes mellitus. To compare the salivary flow rates and the salivary physical and biochemical parameters of diabetic (D) and non diabetic (ND) subjects. The participants in this study included 30 non diabetic subjects and 30 diabetic volunteers who had Type 2 Diabetes mellitus for a minimum of 2 years. Unstimulated whole saliva was collected in the fasting state. Salivary pH, flow rate and organic and inorganic constituents were evaluated. Data which was collected was statistically analysed and interpreted. Salivary pH (ND=7.09±0.29, D=6.69±0.35), flow rate (ND=0.67±0.07, D=0.46±0.02) and salivary amylase (ND=92.51±13.74, D=19.20±1.8) were significantly lower in diabetics. They had significantly higher levels of salivary glucose (ND=4.33 ± 0.29, D=17.31±2.05), total proteins (ND=424.46±237.34, D=877.29±603.84), sodium (ND=4.31±0.65, D=14.42±1.83) and potassium (ND=20.84±0.71, D=25.95±1.56) and lower levels of calcium (ND=6.39±0.5, D=4.22±0.12) in comparison to those in the non-diabetic group. Significant variations were observed in salivary physical and biochemical parameters between diabetics and non diabetics. Evaluation of salivary parameters can be a cost effective and a non invasive alternative for screening, diagnosis and monitoring of diabetes, to blood.


Rail-gap switch with a multistep high-voltage triggering system.
A rail-gap switch with a multistep triggering system was developed. The rail-gap switch consisted of two rail-like electrodes and a knife-edge electrode parallel to each other. It was assembled from many pieces and filled with unpressurized-flowing dry air. Good alignments between all electrodes were achieved by using a special jig and the knife-edge electrode as the spatial reference. Furthermore, to trigger the rail-gap switch, a multistep triggering system was used. The triggering system consisted of three components: an optical trigger-pulse generator, a slow high-voltage trigger-pulse generator using an ignition coil for a car, and finally, a fast high-voltage trigger-pulse generator using a three-stage Marx generator. The triggering system generated a negative high-voltage trigger pulse of less than -40 kV with a falling speed of -6.6 ± 0.4 kV/ns. The falling speed was fast enough to initiate multichannel discharges in the rail-gap switch. Finally, the rail-gap switch was tested using a test bench consisting of a 0.5-μF capacitor bank charged to 20 kV. The rail-gap switch was triggered by the multistep triggering system robustly with a delay of 180 ns. The delay between the time, when the peak current of the test bench occurred, and the trigger pulse was 890 ns with a jitter of 20 ns, i.e., ∼2% uncertainty in time. The inductance of the rail-gap switch was ∼80 nH obtained from the discharge tests. The rail-gap switch with the multistep high-voltage triggering system is suitable for any pulsed-power systems with current rise times in the order of 1 µs.


Photoreduction of oxoisoaporphine dyes by amines: transient-absorption and semiempirical quantum-chemical studies.
Photoreduction by amines of oxoisoaporphine dyes occurs via a stepwise mechanism of electron-proton-electron transfer that leads to the metastable N-hydrogen oxoisoaporphine anion. During photoreduction that occurs from the triplet manifold of the oxoisoaporphine, a radical ion A(-)(*), a neutral-hydrogenated radical A-NH(*), and the metastable ion A-NH(-) of the oxoisoaporphine are formed. We present time-resolved spectroscopic data and quantum mechanical semiempirical PM3 and ZINDO/S results for the transient species formed during the flash photolysis of oxoisoaporphines in the presence of amines. These calculations reproduce adequately the experimental spectra of the triplet-triplet absorption near 450 nm, and that of neutral hydrogenated radical of the studied oxoisoaporphines centered at 390 nm. A transient absorption observed near 490 nm, for all of the studied systems, was explained by considering the formation of radical ion pair between the radical anion of the oxoisoaporphine, A(-)(*), and the radical cation of the amine, whose ZINDO/S calculated spectra generate the strongest transition near the experimentally observed absorption maximum at 490 nm, supporting the formation of a radical ion pair complex as the first step of the photoreduction.


Drug treatment and novel drug target against Cryptosporidium.
Cryptosporidiosis emergence triggered the screening of many compounds for potential anti-cryptosporidial activity in which the majority were ineffective. The outbreak of cryptosporidiosis which occurred in Milwaukee in 1993 was not only the first significant emergence of Cryptosporidium spp. as a major human pathogen but also a huge waterborne outbreak thickening thousands of people from a major city in North America. Since then, outbreaks of cryptosporidiosis are regularly occurring throughout the world. New drugs against this parasite became consequently urgently needed. Among the most commonly used treatments against cryptosporidiosis are paromomycin, and azithromycin, which are partially effective. Nitazoxanide (NTZ)'s effectiveness was demonstrated in vitro, and in vivo using several animal models and finally in clinical trials. It significantly shortened the duration of diarrhea and decreased mortality in adults and in malnourished children. NTZ is not effective without an appropriate immune response. In AIDS patients, combination therapy restoring immunity along with antimicrobial treatment of Cryptosporidium infection is necessary. Recent investigations focused on the potential of molecular-based immunotherapy against this parasite. Others tested the effects of probiotic bacteria, but were unable to demonstrate eradication of C. parvum. New synthetic isoflavone derivatives demonstrated excellent activity against C. parvum in vitro and in a gerbil model of infection. Newly synthesized nitro- or non nitro- thiazolide compounds, derived from NTZ, have been recently shown to be at least as effective as NTZ against C. parvum in vitro development and are promising new therapeutic agents.


Medical dominance and strategic action: the fields of nursing and psychotherapy in the German health care system.
The paper seeks to identify and explain shifts in dominance relationships between the medical profession and allied health professions in Germany, taking the occupational fields of nursing and psychotherapy as examples. It suggests an actor-based perspective which focuses on the strategic interplay between collective actors in the fields in question, namely professional associations and unions, state actors, sickness funds, universities, polytechnics and associations of work organisations. It considers the context of governance of the German health care system and an awareness of a changed demand. The thesis is that the interplay between the actors has led to a small reduction of medical dominance. It is examined whether changes in governance structures of the health care system have led to a more favourable context for shifts in the dominance relationships. Moreover, the possible effects of the recent re-organisation of health provision are considered. Based on an empirical investigation using the method of document analysis, the paper shows that there has been a small reduction of medical dominance which is essentially the outcome of the interrelated strategic actions of various collective actors in the fields. A public perception of a new kind of health care demand has facilitated this development.


Synergistic interactions among beta-laminarinase, beta-1,4-glucanase, and beta-glucosidase from the hyperthermophilic archaeon Pyrococcus furiosus during hydrolysis of beta-1,4-, beta-1,3-, and mixed-linked polysaccharides.
The synergistic interaction among three beta-specific glycosidases from the hyperthermophilic archaeon Pyrococcus furiosus, namely two endoglucanases (EglA and LamA) and an exo-acting beta-glucosidase (Bgl), on barley-glucan and laminarin, was examined. In addition to following glucose release and the generation of reducing sugar ends, the distribution and amounts of oligomeric products from beta-1,3- and beta-1,4-linked substrates were determined as a function of extent of hydrolysis at 98 degrees C. Positive interactions were noted between endo/exo glucanase combinations, leading to enhanced and rapid degradation of the larger complex carbohydrates to oligosaccharides. The EglA/LamA endo-acting combination was also synergistic in degrading barley-glucan. However, hydrolysis was most efficient when a blend of all three hydrolases was used, possibly due to the relief of product inhibition by the exoglyosidase. Furthermore, by monitoring the distribution of oligosaccharides present during hydrolysis, patterns of enzymatic attack could be followed in addition to determining the specific contributions of each hydrolase to the overall process.


Impact of impaired glucose regulation on the functions of large and small fibers of peripheral nerves
This article analyzes the incidence and characteristics of peripheral neuropathy in patients with impaired glucose regulation (IGR). A total of 120 IGR patients and 60 healthy controls were enrolled. All subjects underwent nerve conduction study (NCS) of large fibers and skin sympathetic response (SSR) and contact heat pain evoked potential (CHEP) testing of small fibers with a Medtronic Keypoint machine (Medoc Ltd., Israel). IGR patients were evaluated using the Michigan Neuropathy Screening Instrument (MNSI). The abnormal rates (MNSI >2) in IGR patients and NCS and SSR evaluations were 18.3%, 22.5%, and 39.2%, respectively. All abnormal NCS findings were accompanied with abnormal SSR findings. Compared with the control group, the sensory nerve action potential wave of the posterior tibial and sural nerve was decreased in the IGR group (P = 0.01, P = 0.00), the SSR wave was reduced in the upper and lower limbs (P = 0.002, P = 0.00), and the CHEP wave was decreased in opisthenar and shank (P = 0.00). Compared with the control group, the CHEP wave was decreased in the shank in the normal SSR group (P < 0.05) and in the opisthenar and shank in the normal NCS group (P < 0.05). IGR patients have peripheral neuropathy characterized by impaired functions of large and small fibers focused on small fiber and lower limb sensory nerves. CHEP can detect small fiber damage earlier than SSR and NCS.


Mechanistic studies of catechol generation from secondary quinone amines relevant to indole formation and tyrosinase activation.
The biological significance of the spontaneous cyclization and redox reactions of ortho-quinone amines is that these appear to be the mechanism of formation of the indolic components of melanin and are also involved in the autoactivation of tyrosinase. We have previously shown that activation of tyrosinase is prevented by the formation of a cyclic betaine from a tertiary amine analogue. Evidence is presented to show that cyclization of ortho-quinones by Michael addition also occurs in the oxidation of secondary catecholamines. Three varieties of cyclic product have been detected and their formation is influenced by the nature of the N-substituent. Five-membered betaine rings form directly and, although six- and seven-membered rings also form, a transient spiro isomer of the ortho-quinone was in some cases detected as an intermediate. The heterocyclic products formed as betaines undergo redox exchange with residual quinone to form the corresponding aminochromes. We have established the kinetic constants of these reactions, either directly by pulse radiolysis measurements or by inference using a computer model of the reaction pathway to fit the observed data. To investigate the potential biological applications of this chemistry the system was also examined by tyrosinase-catalysed oxidation of the catecholamine substrates in which there is re-oxidation of the catechol formed by the redox exchange reaction and enables measurement of oxygen utilization stoichiometry. We show that the redox exchange reaction is unaffected by side-chain modification whereas cyclization is dependent on both electronic and steric factors. In the light of these studies we conclude that the failure of tertiary amine-derived betaines to undergo redox exchange, and thus block in vitro activation of tyrosinase, is due to the absence of a second exchangeable proton.


Riluzole improves functional recovery after ischemia in the rat retina.
Retinal ischemia leads to neuronal death. The effects of riluzole, a drug that protects against the deleterious effect of cerebral ischemia by acting on several types of ion channels and blocking glutamatergic neurotransmission, were investigated in a rat model of retinal ischemic injury. Retinal ischemia was induced by increasing intraocular pressure above systolic blood pressure for 30 minutes. Electroretinograms were recorded before ischemia and at different periods of reperfusion. Riluzole was injected or topically applied to the eye before or after ischemia and twice daily during the reperfusion period. Retinas were harvested for histopathology (toluidine blue and silver-impregnation stainings, Tdt-dUTP terminal nick-end labeling [TUNEL] method) and immunohistochemistry for cytoskeletal glial fibrillary acid protein and c-jun NH2-terminal kinase (p-JNK). Ischemia for 30 minutes caused a reduction of a- and b-waves of the electroretinogram. Systemic and topical treatments with riluzole significantly enhanced the recovery of the reduced a- and b-waves after defined reperfusion times. Riluzole also prevented or attenuated ischemia-induced retinal cell death (necrosis and apoptosis) and reduced the activation of p-JNK, c-jun phosphorylation, and the increase of cytoskeletal proteins induced by ischemic injury. Riluzole acted in vivo as a potent neuroprotective agent against pressure-induced ischemia. Therefore, riluzole may be a major drug for use in protection against retinal injury.


Catalytic Reductive Recyclization of Functionalized Isoxazoline N-Oxides to Pyrrolizidine-3-ones.
Pyrrolizidine is among the saturated N-heterocyclic scaffolds most frequently found in natural products and pharmaceutically relevant substances. Herein, a strategy for the synthesis of polysubstituted pyrrolizidine-3-ones by catalytic reductive domino-type recyclization of properly functionalized isoxazoline N-oxides was developed. The process is diastereoselective, and one diastereomer (out of four possible ones) is predominant in many of the studied cases. Using the developed method, modifications of potent GSK's PDE4 inhibitor and MSD's potent hNK1 antagonist were prepared.


Pharmacomicrobiomics and Drug-Infection Interactions: The Impact of Commensal, Symbiotic and Pathogenic Microorganisms on a Host Response to Drug Therapy.
Microorganisms have a close relationship with humans, whether it is commensal, symbiotic, or pathogenic. Recently, it has been documented that microorganisms may influence the response to drug therapy. Pharmacomicrobiomics is an emerging field that focuses on the study of how variations in the microbiome affect the disposition, action, and toxicity of drugs. Two additional sciences have been added to complement pharmacomicrobiomics, namely toxicomicrobiomics, which explores how the microbiome influences drug metabolism and toxicity, and pharmacoecology, which refers to modifications in the microbiome as a result of drug administration. In this context, we introduce the concept of "drug-infection interaction" to describe the influence of pathogenic microorganisms on drug response. This review analyzes the current state of knowledge regarding the relevance of microorganisms in the host's response to drugs. It also highlights promising areas for future research and proposes the term "drug-infection interaction" as an extension of pharmacomicrobiomics.


Nontraumatic perforation of the bile duct treated with laparoscopic surgery.
Nontraumatic perforation of the bile duct (NPB), which has also been reported as spontaneous perforation of the bile duct, is a disease in which spontaneous perforation occurs in the wall of the extrahepatic or intrahepatic duct without any traumatic or iatrogenic injury. Although NPB in adults is extremely rare, we have treated two such patients using a laparoscopic technique. Both cases presented with intra-abdominal abscesses associated with common bile duct stones, and laparoscopic surgery for those conditions was initially performed. During the procedure, NPB was identified in the right intrahepatic duct in one case and in the left intrahepatic duct in the other case. Laparoscopic surgery consisting of common bile duct exploration, T-tube placement, cholecystectomy, and abscess drainage was safely performed in both cases. Both patients eventually recovered without major complications. Although NBP is an uncommon disease, it can be treated successfully with a laparoscopic procedure.


A study on the bronchial innvervation of the male Perdicula asiatica (Uungle Bush quail) by cholinesterase technique.
Ganglia of various shapes (rounded and oval) and sizes (large, medium and smaller) either arranged in chain like fashion or in free form, lying on the wall of the bronchi and their branches, were recorded. The preganglionic and postganglionic nerve fibres formed the meshwork on the bronchi. The postganglionic fibres of the bronchial ganglia and the fibres of the peribronchial plexus, were either connected with the fibres of the plexus on air cavities or with the myelinated fibres of the plexus of muscles in the intraparenchyma. Groups of AChE-positive nerve cells were recorded in the lung lobule.


BIRD'S-EYE VIEW OF GnRH ANALOG USE IN A PEDIATRIC ENDOCRINOLOGY REFERRAL CENTER.
Gonadotropin-releasing hormone analogs (GnRHa) are standard of care for the treatment of central precocious puberty (CPP). GnRHa have also been prescribed in other clinical settings with the hope of increasing adult stature, although evidence to support this practice is lacking. The degree to which GnRHa are being prescribed for indications other than CPP in routine clinical care has not been described. We sought to systematically examine GnRHa prescribing practices among the pediatric endocrinologists at our academic medical center. We reviewed medical records of children treated with GnRHa during a 6-year interval. Variables analyzed included gender, age at start of treatment, indication for therapy, and use of growth hormone as adjunctive treatment. Nonparametric analyses were utilized to compare treatment characteristics of those with CPP versus those without. A total of 260 patients (82% female) aged 8.06 ± 2.68 years were identified. Of these, 191 (73.5%) were treated for CPP, whereas 69 (26.5%) were treated for normally timed puberty in the context of idiopathic short stature/poor predicted height (n = 37), growth hormone deficiency (n = 17), congenital adrenal hyperplasia (n = 10), primary hypothyroidism (n = 4), and developmental delay (n = 1). Of the 161 girls with CPP, GnRHa therapy was initiated at ≥8 years of age in 62 (39%). Whereas most patients were treated for CPP, ~27% were treated for other indications. Of girls with CPP, 39% were treated at an age when benefit in terms of height is unlikely. This highlights the need for rigorous studies of GnRHa use for indications beyond CPP.


Limited Intrahost Diversity and Background Evolution Accompany 40 Years of Canine Parvovirus Host Adaptation and Spread.
Canine parvovirus (CPV) is a highly successful pathogen that has sustained pandemic circulation in dogs for more than 40 years. Here, integrating full-genome and deep-sequencing analyses, structural information, and in vitro experimentation, we describe the macro- and microscale features that accompany CPV's evolutionary success. Despite 40 years of viral evolution, all CPV variants are more than ∼99% identical in nucleotide sequence, with only a limited number (<40) of substitutions becoming fixed or widespread during this time. Notably, most substitutions in the major capsid protein (VP2) gene are nonsynonymous, altering amino acid residues that fall within, or adjacent to, the overlapping receptor footprint or antigenic regions, suggesting that natural selection has channeled much of CPV evolution. Among the limited number of variable sites, CPV genomes exhibit complex patterns of variation that include parallel evolution, reversion, and recombination, compromising phylogenetic inference. At the intrahost level, deep sequencing of viral DNA in original clinical samples from dogs and other host species sampled between 1978 and 2018 revealed few subconsensus single nucleotide variants (SNVs) above ∼0.5%, and experimental passages demonstrate that substantial preexisting genetic variation is not necessarily required for rapid host receptor-driven adaptation. Together, these findings suggest that although CPV is capable of rapid host adaptation, a relatively low mutation rate, pleiotropy, and/or a lack of selective challenges since its initial emergence have inhibited the long-term accumulation of genetic diversity. Hence, continuously high levels of inter- and intrahost diversity are not necessarily required for virus host adaptation.IMPORTANCE Rapid mutation rates and correspondingly high levels of intra- and interhost diversity are often cited as key features of viruses with the capacity for emergence and sustained transmission in a new host species. However, most of this information comes from studies of RNA viruses, with relatively little known about evolutionary processes in viruses with single-stranded DNA (ssDNA) genomes. Here, we provide a unique model of virus evolution, integrating both long-term global-scale and short-term intrahost evolutionary processes of an ssDNA virus that emerged to cause a pandemic in a new host animal. Our analysis reveals that successful host jumping and sustained transmission does not necessarily depend on a high level of intrahost diversity nor result in the continued accumulation of high levels of long-term evolution change. These findings indicate that all aspects of the biology and ecology of a virus are relevant when considering their adaptability.


Design of an organic chromophore for p-type dye-sensitized solar cells.
A successful model for the design of efficient dyes for p-type dye-sensitized solar cells (DSSCs) is presented. As an example, a novel and efficient organic dye containing a triphenylamine chromophore has been synthesized and successfully applied in a p-type DSSC. The highest incident photon-to-current conversion efficiency (IPCE) of 18% in the visible region has been obtained, which is the highest value so far in p-type DSSCs. This is remarkably high, considering that only 600 nm thin NiO mesoporous films were used as p-type DSSC electrodes.


Auxiliary Atomic Relay Center Facilitates Enhanced Magnetic Couplings in Blatter's Radical.
The recent accomplishments in obtaining strong ferromagnetic exchange interactions in organic diradicals have made the field quite fascinating and even more promising toward its technological applications. In this context, herein, we report a unique combination of remarkably strong ferromagnetic exchange interactions coupled with molecular rigidity, utilizing superstable Blatter's radical as a spin source. The planar analogues of the parent Blatter's radical obtained by annulation with a chalcogen coupled to nitronyl nitroxide (NN) are investigated using density functional theory along with the wave function-based multiconfigurational self-consistent field methods, for example, complete active space self-consistent field (CASSCF)-N-electron valence state perturbation theory (NEVPT2). The calculations reveal phenomenal modulation in exchange couplings upon annulation such that remarkably strong ferromagnetic interactions are realized especially for a certain class of the Blatter-NN diradicals. The modulation of spin-spin interactions is rationalized by variation in spin density distribution and molecular torsional angles. We demonstrate that annulation in OMMs opens an additional coupling pathway via auxiliary X-atom acting as the atomic relay center which strongly manipulates the magnitude of exchange couplings.


Incidence and outcome of surgical procedures after coronary artery bypass grafting compared with those after percutaneous coronary intervention: a report from the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG Registry Cohort-2.
Noncardiac surgery after percutaneous coronary intervention (PCI) has been reported to be carrying high risk for both ischemic and bleeding complications. However, there has been no report comparing the incidence and outcomes of surgical procedures after coronary artery bypass grafting (CABG) with those after PCI. Among 14 383 patients undergoing first coronary revascularization (PCI, n=12 207; CABG, n=2176) enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG Registry Cohort-2, surgical procedures were performed more frequently after CABG (n=560) than after PCI (n=2398; cumulative 3-year incidence: 27% versus 22%; unadjusted P<0.0001), particularly <6 months of coronary revascularization. The risk for the primary ischemic outcome measure (death/myocardial infarction) at 30-day postsurgical procedures was not significantly different between the CABG and PCI groups (cumulative incidence: 3.1% versus 3.2%; unadjusted P=0.9; adjusted hazard ratio, 0.97; 95% confidence interval, 0.47-1.89; P=0.9). The risk for the primary bleeding outcome measure (moderate or severe bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification) was lower in the CABG groups than in the PCI group (cumulative incidence: 1.3% versus 2.6%; unadjusted P=0.07; adjusted hazard ratio, 0.36; 95% confidence interval, 0.12-0.87; P=0.02). There were no interactions between the timing of surgery and the types of coronary revascularization (CABG/PCI) for both ischemic and bleeding outcomes. Surgical procedures were performed significantly more frequently after CABG than after PCI, particularly <6 months after coronary revascularization. Surgical procedures after CABG as compared with those after PCI were associated with similar risk for ischemic events and lower risk for bleeding events, regardless of the timing after coronary revascularization.


Recent advances of simulation in obstetric anesthesia.
Simulation training in obstetric anesthesia has become widespread in recent years. Simulations are used to train staff and trainees, assess and improve team performance, and evaluate the work environment. This review summarizes current research in these categories. Simulation to improve individual technical skills has focused on induction of general anesthesia for emergent cesarean delivery, an infrequently encountered scenario by anesthesia trainees. Low- and high-fidelity simulation devices for the learning and practicing neuraxial and non-neuraxial procedures have been described, and both are equally effective. The use of checklists in obstetric emergencies has become common as and post-scenario debriefing techniques have improved. Although participant task performance improves, whether participants retain learned skills or whether simulation improves patient outcomes has not yet been established. Tools to assess teamwork during simulation have been developed, but none have been rigorously validated. In-situ vs. offsite simulations do not differ in effectiveness. Simulation allows for practice of tasks and teamwork in a controlled manner. There is little data whether simulation improves patient outcomes and metrics to predict the long-term retention of skills by simulation participants have not been developed.


Pharmacokinetic study of radioactive antineoplaston A10 in rats and mice.
Fifteen Wistar rats were divided into three groups: low dose--150 mg/kg, medium dose--300 mg/kg and high dose--600 mg/kg. 3H-labelled antineoplaston A10 (3H-A10) was administered to the rats in all three groups. Blood was withdrawn from the tail vein, while urine and faeces were collected at different time intervals for the determination of radioactivity. The volume of distribution (Vd) was evaluated in the rats by intravenous dosage of 150 mg/kg of 3H-A10 dissolved in dimethyl sulfoxide. Thirty mice were divided into six groups and sacrificed at 1, 3, 6, 12, 24 and 36 h respectively after oral administration of H3-A10 for the study of radioactivity in various organs. It was observed that the concentration-time curves of A10 in the blood support a dicompartmental model of pharmacokinetics, and calculated values are very close to experimental values. The binding rate of A10 to plasma protein is 5.05% at 3 h after oral administration. Organ distribution studies indicated the highest accumulation of radioactivity in the bladder, followed by kidney, stomach, genitals and liver, whereas there was lower accumulation of radioactivity in the spleen, heart, brains and lungs.


Evaluation of Fertility Preservation Counseling and Treatments for Female Oncology Patients in an Urban Pediatric Canadian Center.
Purpose: Several international organizations and guidelines have recommended implementation of structured fertility preservation (FP) discussions with patients and their families before initiation of chemotherapy and radiation treatments in children. This study aimed to identify current trends and rates in FP counseling and treatments at a Canadian pediatric tertiary care center. Objectives were to measure guideline adherence for FP counseling at our institution by determining (1) the frequency of FP counseling in pediatric female oncological patients at our institution, (2) the frequency of FP treatment in this study population, and (3) the factors associated with FP pre-treatment counseling. Methods: A retrospective chart review was performed, including all pediatric and adolescent female patients (age <18) seen in consultation by the oncology team. Demographic data, as well as documentation of FP counseling and referral to a reproductive endocrinology and infertility (REI) specialist and subsequent FP treatment were collected. Results: A total of 89 female pediatric patients were included in our study. Forty-two patients received fertility counseling (47.2%; 95% confidence interval [CI] 37.2-57.5). Only 29/42 (69.0%; 95% CI: 54-80.9) received counseling before onset of treatment. A 12/42 (41.4%; 95% CI: 25-59.3) of the patients who received FP counseling were referred to an REI specialist and 11/12 proceeded with FP treatment (37.9%, 95% CI: 22.7-56). Conclusion: This study presents contemporary data on the rates of FP counseling in Canadian pediatric female oncological patients and demonstrates low rates of FP counseling in our patient population.


A novel procedure for pattern analysis of features present on freeze-fractured plasma membranes.
We have used statistical methods for the analysis of two-dimensional point patterns to derive quantitative descriptions of the distributions of caveolae on freeze-fractured muscle fibre membranes. One method was based on a quadrat analysis while the second was a new procedure that we have called the interpoint distance analysis. We show that the latter analysis can unambiguously distinguish random, clustered and dispersed patterns and that a single parameter can be derived that can be used to compare different distributions. It is readily applicable to patterns containing several hundred points. Practical details of the method are given and a simple algorithm that can be implemented on a microcomputer is provided. The interpoint distance analysis should prove generally useful in situations where the two-dimensional distribution of objects has to be quantified.


Ischemic Lesions in Acute and Subacute Perimesencephalic Subarachnoid Hemorrhage.
Perimesencephalic hemorrhage (PMH) is a subtype of nonaneurysmal subarachnoid hemorrhage (SAH). In patients with aneurysmal SAH, the occurrence of acute ischemic lesions is associated with severity and poor outcome. We investigated the frequency of ischemic lesions on DWI in patients with PMH and compared it with the frequency of ischemic lesions in patients with aneurysmal SAH. From a prospective cohort of 80 patients with acute spontaneous SAH, we included 15 patients with PMH and 39 patients with aneurysmal SAH who were matched on the basis of their clinical condition (World Federation of Neurological Societies grade 1 or 2). MRI was performed less than 72 hours after SAH, 8-10 days after SAH, or at both points in time. The number and distribution of lesions previously seen on DWI that were also seen on a second MRI examination were assessed. Nonparametric tests were used to compare groups. Early acute ischemic lesions (those identified < 72 hours after SAH) were found in 46.2% of patients with PMH and in 62.9% of patients with aneurysmal SAH. No significant differences in the number of acute ischemic lesions between groups were noted less than 72 hours after SAH (median, 0.5 lesion [interquartile range {IQR}, two lesions] in patients with PMH vs one lesion [IQR, three lesions] in patients with aneurysmal SAH [p = 0.48] or 8-10 days after SAH (median, 0.5 lesion [IQR, four lesions] in patients with PMH vs 1.5 lesions [IQR, three lesions] in patients with aneurysmal SAH [p = 0.26]). However, 58.3% of patients with aneurysmal SAH had new infarcts at 8-10 days, compared with 7.1% of patients with PMH. Patients with PMH had diffuse ischemic lesions, whereas patients with aneurysmal SAH in the anterior circulation had mainly supratentorial lesions. Early ischemic lesions appeared on DWI both in patients with PMH and in patients with aneurysmal SAH. The number of lesions increased during the time window for vasospasm, mainly in patients with aneurysmal SAH. Further studies are required to better understand the pathophysiologic mechanisms behind early ischemia in patients with PMH and their impact on prognosis.


[Distribution of Tick Species Spread in Kütahya Vicinity].
This study was performed to determine the tick species infested to the cattle and small ruminants in Kütahya Province and their seasonal activity and prevalence. Examination was performed in terms of infestation in 2402 farm animals and their shelters in 10 villages between October 2010 and October 2011. The infestation rate of animals was detected as 9.55%. A total of 657 adult ticks were collected. A total of 11 tick species consisting of Ixodes ricinus, Ixodes hexagonus, Rhipicephalus (Boophilus) annulatus, Dermacentor marginatus, Hyalomma marginatum, Haemaphysalis parva, Haemaphysalis sulcata, Haemaphysalis punctata, Rhipicephalus bursa, Rhipicephalus sanguineus and Rhipicephalus turanicus were determined. Seasonal fluctuations of tick species were also determined. Ixodes ricinus and R. (Boophilus) annulatus species were encountered mostly during fall and winter months. Dermacentor marginatus was usually found in winter time. Hyalomma marginatum, was found between April and July. Haemaphysalis parva was found in October, November and March. Haemaphysalis sulcata was found in November and March. Haemaphysalis punctata was found only in March and November. Rhipicephalus species were generally found in late spring and summer. Finally, these results will be helpful for the determination of control methods of tick infestations and tick-borne diseases in the region.


Assessment of prognostic value of semiquantitative parameters on gated single photon emission computed tomography myocardial perfusion scintigraphy in a large middle eastern population.
Coronary artery disease is the leading cause of mortality worldwide. The goal of this study is to determine the prognostic value of semiquantitative parameters of electrocardiogram-gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a large Middle Eastern (Iranian) population. This study was a prospective study including all patients referred to our center for myocardial perfusion scan. The patients were followed annually up to 24 months and their survival information was collected. From 1148 patients, 473 (41.2%) men and 675 (58.8%) women, 40.6% had normal MPI, 13.3% near normal and 46.1% abnormal MPI. After follow-up of 929 patients, 97.4% of patients were alive, and 2.6% succumbed to cardiac deaths. Abnormal ejection fraction was related with cardiac events (P = 0.001), but neither transient ischemic dilation (TID) (P = 0.09) nor lung/heart ratio (P = 0.92) showed such relationship. Association between summed difference score (SDS) and soft cardiac events (P < 0.001) was significant. Summed motion score (SMS) and summed thickening score (STS) showed a significant relation with hard cardiac events, including myocardial infarction and cardiac death (P < 0.001 and P = 0.001, respectively). Totally, risk of all cardiac events was significantly higher in abnormal MPI group than normal group (P < 0.001, 0.02, and 0.025, respectively). No significant relationship was found between TID and total cardiac events (P = 0.478). Semiquantitative variables derived from gated SPECT MPI have independent prognostic value. Rate of total cardiac events is higher in patients with higher summed stress score and SDS. Total and hard cardiac events are higher in upper scores of functional parameters (SMS and STS). Total cardiac events are higher in patients with lower left ventricular ejection fraction.


Polar features in the flagellar propulsion of E. coli bacteria.
E. coli bacteria swim following a run and tumble pattern. In the run state all flagella join in a single helical bundle that propels the cell body along approximately straight paths. When one or more flagellar motors reverse direction the bundle unwinds and the cell randomizes its orientation. This basic picture represents an idealization of a much more complex dynamical problem. Although it has been shown that bundle formation can occur at either pole of the cell, it is still unclear whether these two run states correspond to asymmetric propulsion features. Using holographic microscopy we record the 3D motions of individual bacteria swimming in optical traps. We find that most cells possess two run states characterized by different propulsion forces, total torque, and bundle conformations. We analyze the statistical properties of bundle reversal and compare the hydrodynamic features of forward and backward running states. Our method is naturally multi-particle and opens up the way towards controlled hydrodynamic studies of interacting swimming cells.


Idiopathic optic neuritis of childhood.
I saw two children who had painless unilateral visual loss due to papillitis of unknown cause. Loss of visual acuity was moderate to severe and was accompanied by a central scotoma and color vision impairment. In each case the optic disks were pale and swollen, and retinal exudates formed a partial star figure in the macula. Previous diagnostic considerations in one patient had led to an unnecessary neuroradiologic search for an intracranial lesion. Unilateral neuroretinitis is less common than the bilateral papillitis that usually occurs in children, but should not be mistaken for unilateral papilledema. The visual prognosis for unilateral optic neuritis is excellent; both patients improved to normal or nearly normal visual acuity without treatment, although subtle signs of previous optic neuritis persisted.


Modulite technology in the development of formoterol HFA pMDI: clinical evidence and future opportunities.
This article is based on published safety and efficacy data on formoterol pressurized metered-dose inhalers (pMDIs) developed with the Modulite technology. This technology allows the development of ozone-friendly inhaled drugs that replace the same doses of chlorofluorocarbon (CFC)-formulated products and enables the attainment of new formulations with extra-fine particles and improved lung deposition. Clinical pharmacology, as well as clinical studies against comparators, have demonstrated that formoterol Modulite and the existing dry powder inhaler and CFC formoterol formulations have a similar pharmacokinetic profile, are clinically equivalent in bronchodilating effects and exhibit a similar potential for systemic side effects. Therefore, the Modulite formoterol hydrofluoroalkane-based formulation in extra-fine particles is a valuable therapeutic option for both patients and physicians in the management of asthma and chronic obstructive pulmonary disease.


Major cardiovascular risk factors in Latin America: a comparison with the United States. The Latin American Consortium of Studies in Obesity (LASO).
Limited knowledge on the prevalence and distribution of risk factors impairs the planning and implementation of cardiovascular prevention programs in the Latin American and Caribbean (LAC) region. Prevalence of hypertension, diabetes mellitus, abnormal lipoprotein levels, obesity, and smoking were estimated from individual-level patient data pooled from population-based surveys (1998-2007, n=31,009) from eight LAC countries and from a national survey of the United States (US) population (1999-2004) Age and gender specific prevalence were estimated and age-gender adjusted comparisons between both populations were conducted. Prevalence of diabetes mellitus, hypertension, and low high-density lipoprotein (HDL)-cholesterol in LAC were 5% (95% confidence interval [95% CI]: 3.4, 7.9), 20.2% (95% CI: 12.5, 31), and 53.3% (95% CI: 47, 63.4), respectively. Compared to LAC region's average, the prevalence of each risk factor tended to be lower in Peru and higher in Chile. LAC women had higher prevalence of obesity and low HDL-cholesterol than men. Obesity, hypercholesterolemia, and hypertriglyceridemia were more prevalent in the US population than in LAC population (31 vs. 16.1%, 16.8 vs. 8.9%, and 36.2 vs. 26.5%, respectively). However, the prevalence of low HDL-cholesterol was higher in LAC than in the US (53.3 vs. 33.7%). Major cardiovascular risk factors are highly prevalent in LAC region, in particular low HDL-cholesterol. In addition, marked differences do exist in this prevalence profile between LAC and the US. The observed patterns of obesity-related risk factors and their current and future impact on the burden of cardiovascular diseases remain to be explained.


Spindle poisons and cell fate: a tale of two pathways.
Spindle poisons, such as paclitaxel and vinblastine, exert their potent anti-neoplastic effects through activation of the spindle assembly checkpoint (SAC), thereby arresting cells in mitosis. Unfortunately, only certain cancers are susceptible to these drugs, and many patients fail to respond to treatment. We review the pathways that are triggered by spindle poisons and highlight recent studies that describe the great variability of tumor cells in responding to these drugs. We also describe the recent identification of an apoptotic pathway that is activated by mitotic arrest in response to spindle poisons. Emerging from these studies is not only a greater understanding of how these classic antimitotic agents bring about cell death, but also a wealth of potential new targets of anticancer therapeutics.


[Quantitative analysis of chlorophyll-a reflectance spectrum in red spectral region of water].
The chlorophyll-a concentration in waters is one of the main parameters of water color remote sensing in case II waters. There is a reflectance peak in red band region because of inherent optical properties. Based on the coefficients of absorption and backscattering of waters, colored dissolved organic matter (CDOM), tripton and chlorophyll-a, the reflectance of remote sensing was simulated according to the forward radiation transfer model without the consideration of fluorescence peak. The reflectance peak intensity and reflectance peak position at different wavelengths in red band region were analyzed with different chlorophyll-a concentration. There is a good linear relationship between the red reflectance peak intensity and chlorophyll-a concentration when the chlorophyll-a concentration is 1-50 microg x L(-1). But the linear relationship between the reflectance peak intensity and chlorophyll-a concentration will decrease with the increasing chlorophyll-a concentration. When chlorophyll-a concentration is up to 1 000 microg x L(-1), the logarithm relationship between the reflectance peak intensity and chlorophyll-a concentration is better than linear relationship. The wavelength position of reflectance peak in red band region will shift towards larger wave-length at logarithmic growth rate with increasing chlorophyll-a concentration, and the logarithm relationship will be more apparent with the inoreasing chlorophyll-a concentration. The same trend happens to the reflectance peak intensity and the wavelength position of peak in red region with different in-water constituents, such as CDOM, tripton and so on. Furthermore, according to the comparison with fluorescence peak, the authors also found that the reflectance peak intensity and the wavelength position of peak in red region are different from those of the fluorescence peak.


Laparoscopy staging of early ovarian cancer: our experience and review of the literature.
We report our experience with laparoscopic staging of apparent early ovarian cancer, and we critically review the current literature on this issue. Potential limits of laparoscopic technique and theoretical concerns of using pneumoperitoneum-based surgery in this setting are addressed. Surgical, pathological, and oncological outcome data of consecutive patients undergoing comprehensive laparoscopic staging for presumed early ovarian cancer at our institution were prospectively collected. The median operative time was 348 minutes (range, 255-450 minutes). The median estimated blood loss was 250 mL (range, 50-3000 mL). The mean number of pelvic and paraaortic lymph nodes harvested was 24.5 (SD, 6.3) and 9.8 (SD, 7.1), respectively. The disease was upstaged in 6 women (23.1%). No conversion to laparotomy and no intraoperative complication occurred. One patient had a retroperitoneal hematoma recognized in the postoperative period, and this required laparotomy and ligature of the hypogastric arteries to achieve hemostasis. The median follow-up period was 26.7 months (range, 2-83 months). Recurrence-free survival was 96.1%. Our results suggest that laparoscopic comprehensive surgical staging is a valuable treatment option for ovarian cancer patients with apparent early disease. Evidence is beginning to accumulate suggesting that minimally invasive surgery is at least equivalent in surgicopathological outcomes and middle-range oncological results to the conventional treatment approach, and early concerns are proving largely unfounded.


Hyperhemolysis Syndrome in a Patient with Sickle Cell Disease: A Case Report.
Hyperhemolysis syndrome (HHS) is a rare complication of repeat blood transfusions in sickle cell disease (SCD). This can occur acutely or have a delayed presentation and often goes unrecognized in the emergency department (ED) due to its rapid progression and similarity to acute chest syndrome and other common complications of SCD. We present a case of a 20-year-old male with SCD who presented to the ED with pain and tenderness in his lower extremities one day after discharge for a crisis. Unbeknownst to the ED team, during his admission he had received a blood transfusion. On presentation he was noted to have hyperkalemia, hyperbilirubinemia, anemia, and uncontrolled pain, and was admitted for sickle cell pain crisis. Over the next 36 hours, his hemoglobin dropped precipitously from 8.9 grams per deciliter (g/dL) to 4.2 g/dL (reference range: 11.5-14.5 g/dL), reticulocyte count from 11.7 % to 3.8% (0.4-2.2%), and platelets from 318,000 per cubic centimeter (K/cm3) to 65 K/cm3 (140-350 K/cm3). He also developed a fever, hypoxia, transaminitis, a deteriorating mental status, and severe lactic acidosis. Hematology was consulted and he was treated with methylprednisolone, intravenous immunoglobulin, two units of antigen-matched red blood cells, fresh frozen plasma, and cryoprecipitate. He was transferred to an outside hospital for exchange transfusion and remained hospitalized for 26 days with acute liver failure, bone marrow necrosis, and a fever of unknown origin. Because of the untoward outcomes associated with delay in HHS diagnosis and the need for early initiation of steroids, it is important for emergency providers to screen patients with hemoglobinopathies for recent transfusion at ED presentation. Asking the simple question about when a patient's last transfusion occurred can lead an emergency physician to include HHS in the differential and work-up of patients with sickle cell disease complications.


The effect of physical exercise on physical and psychological problems.
Despite therapeutic effect of hemodialysis in end stage renal disease (ESRD) patients, these patients encounter different physical and psychological tensional factors. Physical exercises have beneficial physical and psychological effects on patients under hemodialysis as one of the accessory therapeutic methods. As few studies have been done about the effects of physical exercise on physical and psychological problems in Iran than other countries, we assessed the effect in patients under hemodialysis. For this purpose, 43 qualified hemodialysis patients receiving hemodialysis in hospitals of Tabriz University of Medical Sciences were included, but only 35 patients did the exercises for 8 weeks completely. Exercise program was done for 1 hour every session and was composed of ergometer, treadmill and ball playing. Before and after intervention data were collected by interview through a synthetic and adjusted questionnaire. At the end of the intervention, two special questions were added about the improvement of physical and psychological problems. Paired t-test was used to compare the scores of before and after intervention. There were significant differences between scores of before and after intervention considering physical problems including sleep, pain and discomfort, daily activities, and physical function; but about sexual activity, there was not a significant difference between scores of before and after intervention. Psychological problems improved after doing exercises too. About first special question, 85.6% of patients expressed an improvement in physical conditions and about second special question, 91.4% of patients expressed an improvement in psychological conditions. Since physical exercise improves the physical (physical function, daily activities, pain and discomfort, sleep), and psychological problems, it is suggested that responsible people prepare equipment for these patients, until they do exercise forever. Nurses would present them the ways of a correct exercise, and doing it in days after hemodialysis, in order to improve physical, and psychological problems in hemodialysis patients, and finally to enhance their quality of life.


Prostatic disorders: MR imaging at 1.5 T.
Pelvic magnetic resonance (MR) images obtained at 1.5 T of 31 men with known genitourinary disease were reviewed retrospectively. In most, peripheral and central prostatic zones could be seen on axial images obtained with long repetition times/echo times (TRs/TEs). The prostate had no specific signal intensity that enabled differentiation between benign and malignant changes. Each patient with known extracapsular prostatic carcinoma had a peripheral zone defect--1 cm or greater in diameter with ill-defined borders and relatively lower signal intensity than that of the remainder of the peripheral zone--that correlated with the site of clinical-pathologic involvement. Correlation of a peripheral zone defect on long TR/TE images as a sign for extracapsular spread of prostatic cancer was 100% sensitive, yet 54% specific, with excellent interobserver agreement. Stage A2 and B1 prostatic carcinoma was not detected. Benign prostatic hyperplasia was seen as centrally located proliferation and nodularity, usually with discrete margins and a wide spectrum of low- to high-signal-intensity features. MR imaging may have a role in differentiating between intracapsular and extracapsular prostatic carcinoma.


NMR of glycogen in exercise.
Natural-abundance 13C NMR spectroscopy is a non-invasive technique that enables in vivo assessments of muscle and/or liver glycogen concentrations. Over the last several years, 13C NMR has been developed and used to obtain information about human glycogen metabolism with diet and exercise. Since NMR is non-invasive, more data points are available over a specified time course, dramatically improving the time resolution. This improved time resolution has enabled the documentation of subtleties of muscle glycogen re-synthesis following severe glycogen depletion that were not previously observed. Muscle and liver glycogen concentrations have been tracked in several different human populations under conditions that include: (1) muscle glycogen recovery from intense localized exercise with normal insulin and with insulin suppressed; (2) muscle glycogen recovery in an insulin-resistant population; (3) muscle glycogen depletion during prolonged low-intensity exercise; (4) effect of a mixed meal on postprandial muscle and liver glycogen synthesis. The present review focuses on basic 13C NMR and gives results from selected studies.


A parametric study of prefrontal cortex involvement in human working memory.
Although recent neuroimaging studies suggest that prefrontal cortex (PFC) is involved in working memory (WM), the relationship between PFC activity and memory load has not yet been well-described in humans. Here we use functional magnetic resonance imaging (fMRI) to probe PFC activity during a sequential letter task in which memory load was varied in an incremental fashion. In all nine subjects studied, dorsolateral and left inferior regions of PFC were identified that exhibited a linear relationship between activity and WM load. Furthermore, these same regions were independently identified through direct correlations of the fMRI signal with a behavioral measure that indexes WM function during task performance. A second experiment, using whole-brain imaging techniques, both replicated these findings and identified additional brain regions showing a linear relationship with load, suggesting a distributed circuit that participates with PFC in subserving WM. Taken together, these results provide a "dose-response curve" describing the involvement of both PFC and related brain regions in WM function, and highlight the benefits of using graded, parametric designs in neuroimaging research.


[Computed tomography and magnetic resonance angiography of brain meningiomas].
The article analyzes magnetic resonance angiography and computed tomography angiography for diagnosis of blood vessels in the brain. 215 patients with brain meningiomas were examined in 2006-2013 years. Among them 206 adults: 90 (43,3%) men, 119 (56,7%) weman from 19 to 76 years (mean age - 51,4 yrs) and 6 children (4 boys, 2 girls) from 6 to 16 years (mean age - 12 yrs). Adult patients with atypical and malignant meningiomas were 13,6%, children - 0,4%. All patients underwent MR-angiography (100%), CT angiography - 122 (56.7%). Based on the article data, it's obvious, that malignant meningiomas are characterized by a rather specific vasculature. Contrast-enhanced CT angiography makes possible to examine blood vessels, get sliced visualization of their images and, with the help of computer processing of the obtained data, to make a 3D image of the vascular system, to detect morphological and functional changes of brain blood vessels. From the informative point of view contrast-enhanced CT angiography dramatically changes digital angiography. MR tomography gives possibility to make a complete evaluation the brain vasculature in different parts, including small-caliber arteries and veins. The advantage of MRI examination is that it gives the possibility to manifest not only anatomical, but also functional characteristics of blood circulation. In case of localization of meningiomas close to main arterial and veins it's necessary to perform both non-contrast and contrast-enhanced MR angiography, because this method gives us the proper information about the damage of blood vessels and their involvement in the process. MR angiography makes possible to diagnose the involvement of arterial or venous vasculature in the tumor process, dislocation and extravasal compression of arterial branches, the degree of venous sinus damage and evaluation of draining collateral branches, thus enables us to provide prophylaxis of intra and postoperative hemorrhagic and ischemic complications.


Properdin has an ascendancy over factor H regulation in complement-mediated renal tubular damage.
Urinary (U)-complement components have been detected in patients with proteinuric renal diseases, and complement activation via the alternative pathway (AP) is believed to play a role in renal tubular damage. The present study aimed to examine the regulation of complement AP activation in patients with renal tubular damage by focusing on the balance between properdin (P) and factor H (fH). In the in vivo studies, U concentrations of P, fH and membrane attack complex (MAC) were measured in patients with renal diseases using an enzyme-linked immunosorbent assay (ELISA), and their relationships with the clinical data were evaluated. In the in vitro studies, human proximal tubular epithelial cells (PTECs) were incubated with normal human serum (NHS), P-depleted serum (PDS), purified P and/or fH. Changes in cell morphology and phenotype were assessed by microscopy, real-time polymerase chain reaction (PCR), immunostaining and a cell viability assay. The U-P, fH and MAC concentrations were significantly higher in patients with renal disease than in normal controls and correlated with the U-protein and tubular damage markers. Furthermore, multivariate analysis revealed a relationship between P levels and tubular damage markers. There were no significant changes in morphology and mRNA expression in the AP components (P, fH, fB, C3, C5 and C9) after the addition of up to 25% NHS. Dose-dependent depositions of P or fH were observed after the addition of P or fH on PTECs. Depositions of P were not inhibited by fH in a mixture of a fixed concentration of P and a variable concentration of fH, and vice versa. Preincubation with the fixed concentration of P before the addition of NHS or PDS increased the depositions of P, C3 and MAC compared with incubation with intact NHS or intact PDS only; the depositions of C3 and MAC showed a serum-dependent trend. Preincubation with P before NHS addition significantly suppressed cell viability without causing morphological changes. In the pathogenesis of renal tubular damage, P can directly bind to PTECs and may accelerate AP activation by surpassing fH regulation.


Biogenic carbon dots: a novel mechanistic approach to combat multidrug-resistant critical pathogens on the global priority list.
This study delves into investigating alternative methodologies for anti-microbial therapy by focusing on the mechanistic assessment of carbon dots (CDs) synthesized from F. benghalensis L. extracts. These biogenic CDs have shown remarkable broad-spectrum anti-bacterial activity even against multi-drug resistant (MDR) bacterial strains, prompting a deeper examination of their potential as novel anti-microbial agents. The study highlights the significant detrimental impact of CDs on bacterial cells through oxidative damage, which disrupts the delicate balance of ROS control within the cells. Notably, even at low doses, the anti-bacterial activity of CDs against MDR strains of P. aeruginosa and E. cloacae is highly effective, demonstrating their promise as potent antimicrobial agents. The research sheds light on the capacity of CDs to generate ROS, leading to membrane lipid peroxidation, loss of membrane potential, and rupture of bacterial cell membranes, resulting in cytoplasmic leakage. SEM and TEM analysis revealed time-dependent cell surface, morphological, and ultrastructural changes such as elongation of the cells, irregular surface protrusion, cell wall and cell membrane disintegration, internalization, and aggregations of CDs. These mechanisms offer a comprehensive explanation of how CDs exert their anti-bacterial effects. We also determined the status of plasma membrane integrity and evaluated live (viable) and dead cells upon CD exposure by flow cytometry. Furthermore, comet assay, biochemical assays, and SDS PAGE identify DNA damage, carbohydrate and protein leakage, and distinct differences in protein expression, adding another layer of understanding to the mechanisms behind CDs' anti-bacterial activity. These findings pave the way for future research on managing ROS levels and developing CDs with enhanced anti-bacterial properties, presenting a breakthrough in anti-microbial therapy.


Protective effect of caffeic acid phenethyl ester against imidacloprid-induced hepatotoxicity by attenuating oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis.
Imidacloprid (IMI) is a widely used neonicotinoid pesticide in the world, its environmental and human health risk has particularly attracted the attention of researchers. Caffeic acid phenethyl ester (CAPE), an active polyphenol of propolis, has many pharmacological activities including free radical scavenger, anti-inflammatory, and anti-oxidant. In this study, protective effect of CAPE against IMI induced liver injury in mice was performed. Administration of 1 and 2.5 mg/kg CAPE markedly prevented serum AST and ALT increase in 5 mg/kg IMI-induced mice. CAPE significantly downregulated liver NO generation and lipid peroxidation, and upregulated glutathione, catalase, superoxide dismutase and glutathione peroxidase in a dose-dependent manner in liver of IMI-induced mice. Endoplasmic reticulum stress represented by the swelling of endoplasmic reticulum was observed by transmission electron microscope in IMI group. Pretreatment of 2.5 mg/kg CAPE significantly attenuated the endoplasmic reticulum stress induced by IMI in liver. Western blot analysis illustrated that pretreatment of CAPE downregulated the upregulation of TNF-α and IFN-γ induced by IMI in liver of mice. Moreover, the increase of positive apoptotic hepatocytes further suggested apoptosis might be involved in IMI-induced hepatotoxicity. Pretreatment of 1 and 2.5 mg/kg CAPE significantly decreased positive apoptotic hepatocytes, suggested that CAPE prevented apoptosis in liver of IMI-induced mice. In conclusion, CAPE prevented liver injury in IMI-induced mice via attenuation of oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis. Our findings may have broad biological and environmental implications for future research on the therapeutic strategy to prevent liver injury induced by pesticides.


Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies.
The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNF alpha), lymphotoxin-alpha (LT alpha) and interleukin-10 (IL-10) genes on stimulated TNF alpha and IL-10 production was studied in ulcerative colitis (UC) patients, Crohn's disease (CD) patients and in healthy controls. A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF alpha, LT alpha and IL-10 genes. Production of the TNF alpha and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNF alpha gene, three haplotypes of LT alpha and three haplotypes of IL-10 were identified. No significant differences in haplotype frequencies were found between patients and controls overall. On subgroup analysis however, haplotype TNF-2 was more frequent in women with extensive colitis compared to distal colitis (31% vs 12%; P = 0.028). This difference was even greater for the combined TNF-2-LT alpha-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LT alpha-2 haplotypes were associated with higher TNF alpha production in CD patients, and the TNF-4 haplotype was associated with lower TNF alpha production in UC patients. The A allele in the IL-10 promoter region at position -1082 was associated with decreased IL-10 production in CD patients and controls (P = 0.005, P = 0.015 respectively). These data provide evidence that the effect of TNF alpha, LT alpha and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls.


'The normal' as a culture-related concept: historical considerations.
Three definitions of 'normal' are recognized: the normative or ideal, the average or statistical, and the medical or freedom from illness. We still retain from our historical past the notion that mental or emotional illness bespeaks, if not possession by spirits, at least an irreversible condition. A person who has once sought medical treatment for mental sickness is forever after viewed as suspect, as one who may relapse at any time. The modern norm of reason, as against unreason, reinforces distaste for mental illness. The withdrawal of the Eagleton candidacy in 1972 attests that our society is not yet ready to accept mental illness as treatable and curable. To aspire to the presidency or other high office is probably not 'normal' in the sense of not being 'average', and it is entirely possible that the norm of adaptive behavior is incongruent with ambition and exceptional ability. Should the eligibility requirement for leadership then be 'normal' in the sense of free from illness? Abraham Lincoln was subject to periods of acute depression, Winston Churchill was to a degree manic-depressive, and Woodrow Wilson suffered a series of 'nervous breakdowns' before serving as President. History has vindicated the mental ability and leadership qualities of these men. By modern psychiatric criteria for mental health, many creative scientists and artists would be considered abnormal. On the other hand, the concept of normalcy has recently been used to rationalize political misbehavior. Is it possible, then, to develop a viewpoint of 'normal' that is consistent with our culture, and yet at the same time is broad enough to encompass the uncommon?


Incorporating variations in pesticide catabolic activity into a GIS-based groundwater risk assessment.
The catabolic activity of incumbent microorganisms in soil samples of eleven dissimilar soil series was investigated, with respect to the herbicide isoproturon. Soils were collected from a 30x37 km area of river catchment to the north-west of London, England. Catabolic activity in each soil type during a 500 h assay was determined by 14C-radiorespirometry. Results showed four soils that exhibited high levels of catabolic activity (33-44% mineralisation) while the remaining seven soils showed lower levels of catabolic activity (12-16% mineralisation). There was evidence to suggest that soils exhibiting high catabolic activity had low (<22%) clay content and tended towards lower organic carbon content (<2.7%), but that these higher levels of catabolic activity were also related to pre-exposure to isoproturon. The 14C-radiorespirometric results were used to produce a GIS layer representing levels of catabolic activity for the dissimilar soils across the study area. This layer was combined with other GIS layers relating to pesticide attenuation, including soil organic carbon content, depth to groundwater and hydrogeology, to produce a map showing risk of groundwater contamination by isoproturon. The output from this approach was compared with output from an attenuation-only approach and differences appraised. Inclusion of the catabolism layer resulted in a lowering of risk in the model in 15% of the study area. Although there appears to be limited benefit in including pesticide catabolic activity in this regional-scale groundwater risk model, this type of addition could be useful in a site-specific risk assessment.


Therapy of acute myeloid leukemia: towards a patient-oriented, risk-adapted approach.
The successful use of differentiating treatment for patients with acute promyelocytic leukemia (APL) suggests that other acute myeloid leukemias (AML) may benefit from tailored and subtype-specific therapy. Despite the fact that new drugs specifically targeting AML genetic lesions have not yet been developed, distinct karyotypic categories have been identified which may deserve differentiated treatment. In addition, molecular assays to assess response to therapy more sensitively are now available for several AML subsets. In this review, we discuss the role of genetic characterization in the therapy of AML, and the investigative efforts which we believe are still needed for the design of tailored treatment for each and every patient with this disease. The authors have been working in this field for many years and have contributed original papers, the data of which are incorporated in this article. In addition, the material analyzed in this overview includes articles and reviews covered by the Science Citation Index and Medline as well as some more recent unpublished personal observations. Modern therapeutic approaches to AML tend to differentiate post-induction treatment intensity according to cytogenetically defined risk categories. Such prognostic categorization is largely unsatisfactory. In fact, following the advent of newly developed molecular assays (e.g. RT-PCR and FISH), specific and prognostically relevant lesions are frequently found in patients with an apparently normal karyotype, and these patients are, therefore, re-assigned to more appropriate prognostic categories. In addition, recent studies suggest that some patients may benefit from an increase in induction intensity; rapid genetic characterization will be needed for future differentiation of initial therapy. However, preliminary investigation of AML by integrated karyotypic/molecular analyses show that no specific abnormalities are detectable in at least half of the cases. Therefore, use of genetic criteria for prognostic stratification is currently feasible in only a proportion of patients. The prognostic role of genetic lesions, currently identified by karyotypic studies, needs to be validated in large series of AML patients prospectively characterized by advanced molecular/cytogenetic analyses and treated uniformly. In addition, searches for new clinically relevant genetic abnormalities, and diagnostic tools for their rapid identification are urgently needed to identify prognostic categories better. Elucidation of AML gene alterations should foster basic investigation aimed at developing new drugs targeted to the specific lesion in the individual patient. Before these more specific therapeutic agents are developed, diagnostic genetic characterization should add to other well-established prognostic factors to optimize the use of the presently available therapies.


Toward an ecological synthesis: a case for habitat selection.
Habitat selection, and its associated density and frequency-dependent evolution, has a profound influence on such vital phenomena as population regulation, species interactions, the assembly of ecological communities, and the origin and maintenance of biodiversity. Different strategies of habitat selection, and their importance in ecology and evolution, can often be revealed simply by plots of density in adjacent habitats. For individual species, the strategies are closely intertwined with mechanisms of population regulation, and with the persistence of populations through time. For interacting species, strategies of habitat selection are not only responsible for species coexistence, but provide one of the most convenient mechanisms for measuring competition, and the various community structures caused by competitive interactions. Other kinds of interactions, such as those between predators and prey, demonstrate that an understanding of the coevolution of habitat-selection strategies among strongly interacting species is essential to properly interpret their spatial and temporal dynamics. At the evolutionary scale, the frequency dependence associated with habitat selection may often allow populations to diverge and diversify into separate species. Habitat selection thereby demonstrates how we can map microevolutionary strategies in behavior onto their population and community consequences, and from there, onto macroevolutionary patterns of speciation and adaptive radiation. We can anticipate that future studies of habitat selection will not only help us complete those maps, but that they will also continue to enrich the panoply of ideas that shape evolutionary ecology.


[Portuguese-language translation and cross-cultural adaptation of the Fatigue domain of Patient-Reported-Outcomes Measurement Information System (PROMIS)].
The items bank of the Fatigue domain is part of an American system developed for evaluation of results reported by patients, called Patient-Reported-Outcomes Measurement Information System (PROMIS). This study aimed to translate and cross-culturally adapt this item bank for the Brazilian population, as a promising new tool for evaluating health-related quality of life. The items in this bank were translated using rigorous translation and back-translation protocols. The translated version was pre-tested in twenty Brazilians with a brief cognitive and retrospective interview in order to test the items' conceptual, cultural, and semantic equivalences. In the translation and back-translation process, only three of the 82 items had to be reworded due to the culturally inadequate content. In the pretest, only four items needed to be reworded, but without conceptual and semantic alterations. The results showed that the translated version of this item bank is conceptually, culturally, and semantically equivalent to the original version.


The growth promoting effects of bFGF, PD-ECGF and VEGF on cultured postimplantation rat embryos deprived of serum fractions.
Serum components in which embryos are cultured in vitro are very important for normal embryonic development. In this study, rat serum was fractionated using Macrosep filters to study the effect of a single growth factor. The fractionated serum, both that containing only material greater than 30 kDa molecular weight (> 30 kDa) and that from which material between 30 kDa and 50 kDa had been removed (< 30 kDa+ > 50 kDa), caused significant embryonic growth retardation. Addition of different concentrations of basic fibroblast growth factor (bFGF, 18 kDa), vascular endothelial growth factor (VEGF, 45 kDa) and platelet-derived endothelial growth factor (PD-ECGF, 45 kDa), to fractionated serum (bFGF to > 30 kDa serum and VEGF or PD-ECGF to < 30 kDa+ > 50 kDa serum) partially restored embryonic growth and development according to a morphological scoring system and protein assay. This restoration was clear by all criteria, as well as in yolk sac vascularisation and heart development. The growth promoting effects of all 3 factors were significant but did not reach the level seen in embryos grown in whole rat serum. The effect of these growth factors was also investigated on anembryonic yolk sac development using a concentration for which maximum whole embryonic growth was seen (128 ng/ml bFGF, 1.6 ng/ml VEGF and 4 ng/ml PD-ECGF), and significant anembryonic yolk sac development was found. These findings suggest that the angiogenic factors may have a growth promoting effect on total embryonic development and vascularisation.


Transmission of Resistant Gram-Negative Bacteria to Health Care Worker Gowns and Gloves during Care of Nursing Home Residents in Veterans Affairs Community Living Centers.
The objectives of the study were to estimate the risk of transmission of antibiotic-resistant Gram-negative bacteria (RGNB) to gowns and gloves (G&G) worn by health care workers (HCWs) when providing care to nursing home residents and to identify the types of care and resident characteristics associated with transmission. A multicenter, prospective observational study was conducted with residents and HCWs from Veterans Affairs (VA) nursing homes. Perianal swabs to detect RGNB were collected from residents. HCWs wore G&G during usual care activities, and the G&G were swabbed at the end of the interaction in a standardized manner. Transmission of RGNB from a colonized resident to G&G by type of care was measured. Odds ratios (ORs) associated with type of care or resident characteristics were estimated. Fifty-seven (31%) of 185 enrolled residents were colonized with ≥1 RGNB. RGNB transmission to HCW gloves or gowns occurred during 9% of the interactions (n = 905): 7% to only gloves and 2% to only gowns. Bathing the resident and providing hygiene and toilet assistance were associated with a high risk of transmission. Glucose monitoring and assistance with feeding or medication were associated with a low risk of transmission. In addition, antibiotic use by the resident was strongly associated with greater transmission (OR, 2.51; P < 0.01). RGNB were transferred to HCWs during ∼9% of visits. High-risk types of care were identified for which use of G&G may be prioritized. Antibiotic use was associated with 2.5 times greater risk of transmission, emphasizing the importance of antibiotic stewardship. (This study has been registered at ClinicalTrials.gov under registration no. NCT01350479.).


Principal component analysis under population genetic models of range expansion and admixture.
In a series of highly influential publications, Cavalli-Sforza and colleagues used principal component (PC) analysis to produce maps depicting how human genetic diversity varies across geographic space. Within Europe, the first axis of variation (PC1) was interpreted as evidence for the demic diffusion model of agriculture, in which farmers expanded from the Near East approximately 10,000 years ago and replaced the resident hunter-gatherer populations with little or no interbreeding. These interpretations of the PC maps have been recently questioned as the original results can be reproduced under models of spatially covarying allele frequencies without any expansion. Here, we study PC maps for data simulated under models of range expansion and admixture. Our simulations include a spatially realistic model of Neolithic farmer expansion and assume various levels of interbreeding between farmer and resident hunter-gatherer populations. An important result is that under a broad range of conditions, the gradients in PC1 maps are oriented along a direction perpendicular to the axis of the expansion, rather than along the same axis as the expansion. We propose that this surprising pattern is an outcome of the "allele surfing" phenomenon, which creates sectors of high allele-frequency differentiation that align perpendicular to the direction of the expansion.


Immunoglobulin E antibodies to pollens augmented in dogs by virus vaccines.
An inbred "atopic dog colony" was established to study the effect of viruses on immunoregulation of immunoglobulin (Ig) E antibodies. Dogs were selected for high skin reactivity to grass and weed pollens. Their offspring were inoculated with pollen extracts in alum immediately after routine vaccinations (attenuated live-virus vaccines for canine distemper and infectious canine hepatitis, and a killed bacterin for Leptospira). Heat labile antipollen IgE antibodies were measured by passive cutaneous anaphylaxis. Pups vaccinated for canine distemper before being given pollen extracts had many more IgE antibodies than did their control littermates who were not vaccinated until after the last pollen extract injection. This may be a natural example of the "allergic break-through phenomenon."


[Electrocardiographic changes and cardiovascular risk factors in patients with type-2 diabetes].
To determine the most frequent alterations in rhythm and cardiac conduction in patients with type 2 diabetes without previous cardiopathy, and to establish the association of this disease with cardiovascular risk factors. Subjects with type 2 diabetes, without cardiopathy antecedents were included in the study. Cardiovascular risk factors, body mass index and serum glucose, cholesterol and trygliceride levels were determined. A resting electrocardiogram was recorded. The association between the variables under study and arrhythmia was calculated with a multivariate analysis adjusted by sex. A total of 199 patients were included: 113 women (56.8%) and 86 men (43.2%). Arrhythmia was registered in 29.1% of the subjects. Anterior hemiblock (AH) and right bundle branch block (RBBB) constituted 75.9% of the identified alterations. Patients with arrhythmia and conduction disorders have higher levels of cholesterol and triglycerides. Appearance of arrhythmia is directly related to aging (r = 0.75, p = 0.01). The multivariate analysis adjusted by sex revealed that hypercholesterolemia and aging are significantly associated with arrhythmia and conduction alterations: OR 1.5, CI 95%, 1.1-4.6, p < 0.05 and OR 1.3, CI 95% 1.0-5.2, p < 0.05, respectively. The most frequent arrhythmia and conduction disorders in type 2 diabetes are AH and RBBB. Hypercholesterolemia and aging are the strongest and most frequent factors associated to the presence of this disease.


Karyotypic analysis of intersexuality in Chinese from Taiyuan.
To analyze the kayrotypic patterns of 33 cases of intersexuality in Chinese from Taiyuan, China in order to further clarify its mechanism of development and the interrelationship between karyotype and phenotypic sex. High-resolution GTG-banding chromosome technique was used to analyze the karyotype patterns. In these patients, 57.58% were male pseudohermaphrodites (46,XY), 18.18%, female pseudohermaphrodites (46, XX), 12.12%, true hemaphrodites, and 12.12%, other karyotypes. Although testes can be seen in 88.8% of karyotypes with Y chromosome, 73.68% of the patients were of female social sex. In 42.82% of patients the social sex is in conformity with their karyotypes. There were 2 cases of male pseudohermaphrodites, where the sex chromosome was normal, but abnormalities were found in chromosomes 9, 13, or 14. Sex chromosomes determine the direction of gonadal and sex differentiation, while the development of the normal gonad and external genitalia should have the participation of many autosomal chromosomes as well.


Influenza virus neuraminidase alters allogeneic T cell proliferation.
Influenza virus elicits good cellular and humoral immune responses. Unlike the cytotoxic T lymphocyte response to many other antigens, the cytotoxic T lymphocyte response to influenza virus is CD4(+) T cell independent, suggesting that viral infection of antigen-presenting cells may alter their capacity to stimulate T cell responses. To clarify the role of influenza virus in these functional alterations, we compared T cell responses to uninfected and A/PR/8/34-infected dendritic cells (DC). DC were prepared from the bone marrow of C57BL/6 (H2(b)) mice and used to stimulate in vivo and in vitro alloreactive T cell responses. In both cases, influenza virus infection increased the capacity of DC to stimulate T cell proliferation. This enhancement was blocked by antibodies specific for neuraminidase (NA), but not hemagglutinin. Infection was not required to observe enhanced T cell proliferation, showing that NA from exogeneous virus particles can facilitate this effect. These results are the first to show that influenza virus alters the capacity of DC to stimulate T cell proliferation through mechanisms mediated by viral NA.


Repeated-doses and reproductive toxicity studies of the monoterpene 1,8-cineole (eucalyptol) in Wistar rats.
1,8-cineole (eucalyptol) is widely used as an excipient in the pharmaceutical industry and as a food flavoring agent, thus providing significant potential for human exposure to the compound. We investigated the preclinical toxicity and reproductive toxicity of 1,8-cineole (CIN). In the repeated-doses toxicity study for 50 days, CIN (100, 500 or 1000 mg/kg) did not produce any signs of toxicity or deaths, but affected body weight gain during the first week of treatment. The hematological and biochemical profiles did not show significant differences except for increase in the MCV, platelet and urea levels or reduction in MCHC, MPV and alkaline phosphatase. Histopathological analysis showed weak changes in the lungs, liver, kidneys and uterus. In the reproductive toxicity, CIN (250, 500 or 1000 mg/kg) produced a reduction in body weight in pregnant rats treated during the pre-implantation or organogenesis periods. The highest doses induced a reduction in the mass of fetuses (pre-implantation) and dead fetuses (both periods) of pregnant rats. The results indicate that the treatment by repeated-doses showed occasional alterations in rats of both sexes. However, provide evidence that possibly 1,8-cineole presents maternal and fetal toxicity. This requires more detailed investigation to better characterize the toxic effects of this compound.


Galectin-3: a new biomarker for differentiating periodic fever, adenitis, pharyngitis, aphthous stomatitis (PFAPA) syndrome from familial Mediterranean fever?
Differentiating PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis) syndrome from familial Mediterranean fever (FMF) could be challenging in some cases. Galectin-3 is a lectin with regulatory functions in apoptosis and inflammation. We aimed to test whether galectin-3 could be a biomarker for differentiating PFAPA syndrome from FMF. Patients with PFAPA syndrome, FMF, cryopyrin-associated periodic syndrome (CAPS), and streptococcal pharyngitis, and healthy controls were included in this study. Serum galectin-3 levels were measured using enzyme-linked immunosorbent assay. Eighty-seven patients (36 with PFAPA, 39 with FMF, 8 with CAPS, 4 with streptococcal pharyngitis), and 17 healthy controls were included. Blood samples were drawn during attacks from 20 PFAPA and 7 FMF patients and attack-free periods from 22 PFAPA, 35 FMF, and 8 CAPS patients. The median serum galectin-3 level in the PFAPA-attack group (1.025 ng/ml) was significantly lower than the levels in healthy control (2.367 ng/ml), streptococcal pharyngitis (3.021 ng/ml), FMF attack (2.402 ng/ml), and FMF-attack-free groups (2.797 ng/ml) (p = 0.006, 0.03, 0.01, and < 0.001, respectively). PFAPA-attack-free group had lower galectin-3 levels than the FMF-attack-free group (1.794 vs. 2.797 ng/ml, respectively; p = 0.01). Galectin-3 levels did not differ significantly between CAPS and attack-free PFAPA patients (1.439 ng/ml vs. 1.794 ng/ml, respectively; p = 0.63). In our study, for the first time, we defined galectin-3 as a promising biomarker that differs between PFAPA and FMF patients during both disease flares and attack-free periods. Further studies with high number of patients could validate its role as a biomarker.


Gait abnormalities in minimally impaired multiple sclerosis patients.
Subclinical evidence of gait abnormalities were identified in a group of seven patients with multiple sclerosis, EDSS scored 0 - 2, without functional limitations. A movement analysis technique was used to identify gait parameters indicative of impaired motor function during walking. Abnormalities related primarily to time-distance parameters (reduced speed of progression, shorter strides, prolonged double support phase) and muscular function (premature recruitment of gastrocnemius and late relaxation of tibialis anterior during stance phase) were identified regardless the severity of the clinical score. The gait analysis procedure was able to provide the clinician with evidence of motor abnormalities prior to functional disturbance observable by a trained physician. These minimal dysfunctions may have resulted from reflex mechanisms impaired by delayed transmission through long loop pathways or else as a result of a nonspecific protective gait strategy to improve balance control. The technique described in this study may be useful to identify earlier starting points for follow-up and physiotherapy.


Use of Thermistor Temperature Sensors for Cyber-Physical System Security.
The last few decades have seen a large proliferation in the prevalence of cyber-physical systems. This has been especially highlighted by the explosive growth in the number of Internet of Things (IoT) devices. Unfortunately, the increasing prevalence of these devices has begun to draw the attention of malicious entities which exploit them for their own gain. What makes these devices especially attractive is the various resource constraints present in these devices that make it difficult to add standard security features. Therefore, one intriguing research direction is creating security solutions out of already present components such as sensors. Physically Unclonable Functions (PUFs) are one potential solution that use intrinsic variations of the device manufacturing process for provisioning security. In this work, we propose a novel weak PUF design using thermistor temperature sensors. Our design uses the differences in resistance variation between thermistors in response to temperature change. To generate a PUF that is reliable across a range of temperatures, we use a response-generation algorithm that helps mitigate the effects of temperature variation on the thermistors. We tested the performance of our proposed design across a range of environmental operating conditions. From this we were able to evaluate the reliability of the proposed PUF with respect to variations in temperature and humidity. We also evaluated the PUF's uniqueness using Monte Carlo simulations.


Low levels of hepatitis C diagnosis and testing uptake among people who inject image and performance enhancing drugs in England and Wales, 2012-15.
People injecting image and performance enhancing drugs (IPEDs) have traditionally not been perceived as being at high risk of hepatitis C virus (HCV) infection. However, recent studies indicate the HCV antibody (anti-HCV) prevalence in this group is 10-times that in the general population. HCV testing uptake and undiagnosed infections are examined using data from a voluntary unlinked-anonymous survey. People injecting IPEDs across England and Wales completed a short bio-behavioural survey (2012-15). Anti-HCV status and self-reports of HCV testing were used in the analysis. The participants median age was 31 years, 98% were men, 14% had also injected psychoactive drugs and the anti-HCV prevalence was 4.8% (N=564). Among those who had never injected psychoactive drugs the anti-HCV prevalence was 1.4%; among those who had recently injected psychoactive drugs (preceding 12 months) prevalence was 39% and among those who had done this previously 14% (p<0.001). Overall, 37% had been tested for HCV: among those who had recently injected psychoactive drugs 78% had been tested, as had 56% of those who had injected psychoactive drugs previously; 33% of those never injecting psychoactive drugs were tested (p<0.001). Overall, 44% of those with anti-HCV were aware of this; however, only 14% of those who had never injected psychoactive drugs were aware. One-in-twenty people who inject IPEDs have anti-HCV. HCV infections among those who had never injected psychoactive drugs were mostly undiagnosed, though this group had a lower prevalence. Targeted HCV testing interventions are also needed for those injecting IPEDs.


Connecting recombination, nucleotide diversity and species divergence in Drosophila.
The association between recombination rate and nucleotide diversity provides compelling evidence for the action of natural selection across much of the Drosophila melanogaster genome. This conclusion is further supported by the lack of association between recombination rate and nucleotide divergence between species. However, studies of other species, including other Drosophila, have not always yielded the same results. Our recent study measured these parameters within the D. pseudoobscura species group using next-generation sequencing and high-throughput genotyping technologies. We documented fine-scale variation in crossover rate within D. pseudoobscura, and we observed that crossover variation was strongly associated with nucleotide diversity only when measured at a fine-scale. We also observed associations between crossover rate and sequence differences between D. pseudoobscura and its close relatives. These latter associations could have been driven in part by mutagenic effects associated with double-strand break repair, but we cannot exclude the possibility that it results primarily from shared ancestral polymorphisms. Overall, this work strongly underscores the importance of scale in testing for associations of recombination rate with other parameters, and it brings us one small step closer to understanding the role of natural selection and other evolutionary forces in shaping divergence among genomes.


Plasticity and proprioception in insects. I. Responses and cellular properties of individual receptors of the locust metathoracic femoral chordotonal organ.
The metathoracic femoral chordotonal organ is a joint angle receptor of the locust hindleg. It consists of 45-55 bipolar sensory neurones located distally in the femur and mechanically coupled to the tibia. Responses of receptors of the organ were examined by extracellular and intracellular recording. The organ as a whole encodes the angle of the femorotibial joint but shows substantial hysteresis. Tonic activity is greatest at the extremes of joint position. The organ possesses no direct linkage to tibial muscle fibres and shows no response to resisted muscle contractions in most ranges of joint angle. However, responses to extensor muscle contractions are obtained when the tibia is held in full flexion due to specializations of the femoro-tibial joint. These responses could be of importance in signalling preparedness for a jump. Intracellular soma recordings of activity in individual receptors indicate that the organ contains two types of receptors: phasic units that respond to joint movement and tonic units that encode joint position and also show some response to movement. All units are directionally sensitive and respond only in limited ranges of joint angle. Some phasic units increase firing frequency with increasing rate of movement and thus encode joint velocity. Other phasic units fire only single action potentials and can encode only the occurrence and direction of joint movement. All tonic units increase activity in the extremes of joint position and show substantial hysteresis upon return to more median positions. Direct soma depolarization produces different responses in different types of units: phasic receptors show only transient discharges to current injection; tonic receptors exhibit sustained increases in activity that are followed by periods of inhibition of background firing upon cessation of current injection. Receptors of the chordotonal organ are separable into two major groups, based upon their response characteristics, soma location and dendritic orientation: a dorsal group of receptors contains tonic units that respond in ranges of joint flexion (joint angle 0-80 degrees) and phasic units that respond to flexion movements; a ventral group of sensilla contains tonic units active in ranges of joint extension (joint angle 80-170 degrees) and phasic receptors that respond to extension movements. The response properties of these receptors are discussed with reference to the potential functions of the chordotonal organ in the locust's behavioural repertoire.


[Roaming through the methodology. VIII. Pilot studies: sense and nonsense].
A pilot study is often performed before the start of a large study. Its aim is improving the methodological quality and evaluating the feasibility. The results of a pilot study are also often used to gain an impression of the efficacy of an intervention. For this purpose a pilot is absolutely unsuited. However, the estimate of the effect of an intervention in small studies such as pilot studies is determined to a large extent by chance. When conducting small studies the chance of publication bias is large. Small studies of adequate methodological quality should be published, whether the results are positive or negative, significant or non-significant, because combination in a later cumulative meta-analysis may lead to sufficient power to assess the efficacy of an experimental intervention.