Reduced levels of stromal sex hormone-binding globulin and androgen receptor dysfunction in the sperm storage region of the rat epididymis.
The cauda epididymidis is the major sperm storage region whose androgenic supply, essential for the sperm viability, is provided by the vasculature and is dependent upon testosterone diffusion through the stromal tissue to reach the epithelial cells. We have focused our efforts on examining the regulation of this important epididymal region by evaluating the impact of the androgen disrupter cimetidine on the epithelial-stromal androgenic microenvironment. Male rats received 100 mg/kg cimetidine (CMTG) or saline (CG) for 50 days, serum testosterone levels were measured and the epididymal cauda region was processed for light and transmission electron microscopy. In the proximal cauda region, the duct diameter was measured and birefringent collagen in the stroma was quantified. TUNEL-labeled epithelial cells were quantified, and androgen receptor (AR), karyopherin alpha (KPNA) and sex hormone-binding globulin (SHBG) levels were analyzed by immunofluorescence and Western blot. CMTG showed reduced duct diameter and high number of apoptotic epithelial cells. In the epithelium, the total AR concentration and the KPNA immunoreactivity were reduced, and a weak/absent AR nuclear immunofluorescence was observed in contrast to the enhanced AR immunolabeling observed in the cytoplasm of the epithelial cells. A significant reduction of collagen and SHBG levels in the stroma was also observed. Cimetidine treatment impairs AR nuclear import in the epithelium, causing androgenic dysfunction and subsequent epithelial cell apoptosis and duct atrophy. The connective tissue atrophy and reduction of SHBG stromal levels associated with epithelial androgenic dysfunction indicate a possible role of stromal SHBG in the androgenic supply of the sperm storage region of the epididymis.


Androgen metabolites impact CSF amines and axonal serotonin via MAO-A and -B in male macaques.
A number of studies have shown that mutations or deletions of the monoamine oxidase-A (MAO-A) gene cause elevated CNS serotonin and elevated impulsive aggression in humans and animal models. In addition, low cerebrospinal fluid (CSF) 5-hydroxyindole acetic acid (5HIAA) has been documented in a limited number of violent criminal populations and in macaques that exhibit impulsive aggression. To reconcile these different analyses, we hypothesized that CSF 5HIAA reflected degradation of serotonin by the activity of MAO-A; and that low MAO-A activity would result in lower CSF 5HIAA, but overall higher serotonin in the CNS. To test this hypothesis, male Japanese macaques (Macaca fuscata) were castrated, rested for 5-7months, and then treated for 3months with [1] placebo, [2] testosterone (T), [3] dihydrotestosterone (DHT; non-aromatizable androgen) and 1,4,6-androstatriene-3,17-dione (ATD) (steroidal aromatase inhibitor), or [4] flutamide (FLUT; androgen antagonist) and ATD (n=5/group). These treatments enable isolation of androgen and estrogen activities. In the dorsal raphe, MAO-A and MAO-B expressions were determined with in situ hybridization (ISH) and protein expression of aromatase was determined with immunohistochemistry (IHC). CSF concentrations of 5HIAA, 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were determined with liquid chromatography/mass spectrometry (LC/MS). From the same animals, previously published data on serotonin axon density were used as a proxy for CNS serotonin. Aromatase conversion of T to estrogen (E) suppressed MAO-A (positive pixel area, p=0.0045), but androgens increased MAO-B (positive pixel area, p=0.014). CSF 5HIAA was suppressed by conversion of T to E (Cohen's d=0.6). CSF 5HIAA was positively correlated with MAO-A-positive pixel area (r(2)=0.78). CSF 5HIAA was inversely correlated with serotonin axon-positive pixel area (r(2)=0.69). In summary, CSF 5HIAA reflects MAO-A activity rather than global serotonin. Low CSF 5HIAA may, in this paradigm, reflect higher serotonin activity. Androgens lower MAO-A activity via metabolism to E, thus elevating CNS serotonin and decreasing CSF 5HIAA. Since androgens increase certain types of aggression, these data are consistent with studies demonstrating that lower MAO-A activity is associated with elevated serotonin and increased aggression.


Influence of pH on the Motion of Catalytic Janus Particles and Tubular Bubble-Propelled Micromotors.
Self-propelled miniaturized machines harness the chemical potential of their environment for movement. Locomotion of chemically powered micromotors have been hugely dependent on the surroundings. The use of pH to alter the mobility of micromotors is demonstrated in this work through the manipulation of hydrogen peroxide chemistry in different acidity/alkalinity. The sequential addition of sodium hydroxide to increase the pH of the solution led to a consequent increase in activity of micromotors. Meanwhile, addition of hydrochloric acid compromised the structural integrity of the microstructures, culminating in locomotive changes. Such dramatic changes in activity and velocities of the micromotors allow the usage of this behavior for pH detection. This concept was illustrated with Janus silver micromotors and tubular bimetallic Cu/Pt micromotors. Alteration of pH serves as a useful general strategy for increasing hydrogen peroxide decomposition for enhanced oxygen-bubble propulsion in catalytic micromotors.


Being parents with epilepsy: thoughts on its consequences and difficulties affecting their children.
Parents with epilepsy can be concerned about the consequences of epilepsy affecting their children. The aim of this paper is to describe aspects of what it means being a parent having epilepsy, focusing the parents' perspectives and their thoughts on having children. Fourteen adults aged 18-35 years with epilepsy and subjective memory decline took part in focus-group interviews. The interviews were conducted according to a semi-structured guideline. Material containing aspects of parenthood was extracted from the original interviews and a secondary analysis was done according to a content-analysis guideline. Interviews with two parents for the Swedish book Leva med epilepsi [To live with epilepsy] by AM Landtblom (Stockholm: Bilda ide; 2009) were analyzed according to the same method. Four themes emerged: (1) a persistent feeling of insecurity, since a seizure can occur at any time and the child could be hurt; (2) a feeling of inadequacy - of not being able to take full responsibility for one's child; (3) acknowledgment that one's children are forced to take more responsibility than other children do; and (4) a feeling of guilt - of not being able to fulfill one's expectations of being the parent one would like to be. The parents with epilepsy are deeply concerned about how epilepsy affects the lives of their children. These parents are always aware that a seizure may occur and reflect on how this can affect their child. They try to foresee possible dangerous situations and prevent them. These parents were sad that they could not always take full responsibility for their child and could not live up to their own expectations of parenthood. Supportive programs may be of importance since fear for the safety of the child increases the psychosocial burden of epilepsy. There were also a few parents who did not acknowledge the safety issue of their child - the authors believe that it is important to identify these parents and provide extra information and support to them.


Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis.
Dose-dependant gastrointestinal and cardiovascular side-effects limit the use of NSAIDs in the management of RA. The n-3 essential fatty acids (EFAs) have previously demonstrated some anti-inflammatory and NSAID-sparing properties. The objective of this study was to determine whether cod liver oil supplementation helps reduce daily NSAID requirement of patients with RA. Dual-centre, double-blind placebo-controlled randomized study of 9 months' duration. Ninety-seven patients with RA were randomized to take either 10 g of cod liver oil containing 2.2 g of n-3 EFAs or air-filled identical placebo capsules. Documentation of NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake. Relative reduction of daily NSAID requirement by >30% after 9 months was the primary outcome measure. Fifty-eight patients (60%) completed the study. Out of 49 patients 19 (39%) in the cod liver oil group and out of 48 patients 5 (10%) in the placebo group were able to reduce their daily NSAID requirement by >30% (P = 0.002, chi-squared test). No differences between the groups were observed in the clinical parameters of RA disease activity or in the side-effects observed. This study suggests that cod liver oil supplements containing n-3 fatty acids can be used as NSAID-sparing agents in RA patients.


Nucleotide excision repair efficiencies of bulky carcinogen-DNA adducts are governed by a balance between stabilizing and destabilizing interactions.
The nucleotide excision repair (NER) machinery, the primary defense against cancer-causing bulky DNA lesions, is surprisingly inefficient in recognizing certain mutagenic DNA adducts and other forms of DNA damage. However, the biochemical basis of resistance to repair remains poorly understood. To address this problem, we have investigated a series of intercalated DNA-adenine lesions derived from carcinogenic polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites that differ in their response to the mammalian NER apparatus. These stereoisomeric PAH-derived adenine lesions represent ideal model systems for elucidating the effects of structural, dynamic, and thermodynamic properties that determine the recognition of these bulky DNA lesions by NER factors. The objective of this work was to gain a systematic understanding of the relation between aromatic ring topology and adduct stereochemistry with existing experimental NER efficiencies and known thermodynamic stabilities of the damaged DNA duplexes. For this purpose, we performed 100 ns molecular dynamics studies of the lesions embedded in identical double-stranded 11-mer sequences. Our studies show that, depending on topology and stereochemistry, stabilizing PAH-DNA base van der Waals stacking interactions can compensate for destabilizing distortions caused by these lesions that can, in turn, cause resistance to NER. The results suggest that the balance between helix stabilizing and destabilizing interactions between the adduct and nearby DNA residues can account for the variability of NER efficiencies observed in this class of PAH-DNA lesions.


Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 8: Nicotine bridging--estimating smoke constituent exposure by their relationships to both nicotine levels in mainstream cigarette smoke and in smokers.
A modeling approach termed 'nicotine bridging' is presented to estimate exposure to mainstream smoke constituents. The method is based on: (1) determination of harmful and potentially harmful constituents (HPHC) and in vitro toxicity parameter-to-nicotine regressions obtained using multiple machine-smoking protocols, (2) nicotine uptake distributions determined from 24-h excretion of nicotine metabolites in a clinical study, and (3) modeled HPHC uptake distributions using steps 1 and 2. An example of 'nicotine bridging' is provided, using a subset of the data reported in Part 2 of this supplement (Zenzen et al., 2012) for two conventional lit-end cigarettes (CC) and the Electrically Heated Cigarette Smoking System (EHCSS) series-K6 cigarette. The bridging method provides justified extrapolations of HPHC exposure distributions that cannot be obtained for smoke constituents due to the lack of specific biomarkers of exposure to cigarette smoke constituents in clinical evaluations. Using this modeling approach, exposure reduction is evident when the HPHC exposure distribution curves between the MRTP and the CC users are substantially separated with little or no overlap between the distribution curves.


Toric orthokeratology for highly astigmatic children.
To determine the efficacy of toric orthokeratology (ortho-k) in correcting myopia and astigmatism in myopic children with moderate to high astigmatism. Asymptomatic subjects aged 6 to 12 years with myopia of 0.50 to 5.00 D and astigmatism of 1.25 to 3.50 D of axes 180 ± 20° were fitted with Menicon Z Night Toric Lens (NKL Contactlenzen B.V., Emmen, The Netherlands). Data collection was performed at baseline and 1 night, 1 week, and 1 month after the commencement of lens wear. The results from the right eye or the eye with higher astigmatism were reported. The first lens fit success rate was 95%. Two subjects had to be refitted due to lens decentration and inadequate central clearance after one overnight lens wear and were successfully fitted with a second pair of lenses. Toric ortho-k significantly reduced the manifest myopia from 2.53 ± 1.31 D to 0.41 ± 0.43 D and astigmatism from 1.91 ± 0.64 D to 0.40 ± 0.39 D (paired t-tests, p < 0.02) after 1 month of lens wear. The unaided visual acuity (logMAR) was 0.11 ± 0.13 after 1 month of lens wear. No significant lens binding, corneal staining, or other adverse events were observed during this period of lens wear. This toric lens design lens, with a first lens fit success rate of 95%, was effective in correcting low-moderate myopic children who had moderate-high astigmatism. It has the potential to be used in myopic control studies for myopic children who have high astigmatism.


Size-Matched Radical Multivalency.
Persistent π-radicals such as MV+• (MV refers to methyl viologen, i.e., N,N'-dimethyl-4,4'-bipyridinum) engage in weak radical-radical interactions. This phenomenon has been utilized recently in supramolecular chemistry with the discovery that MV+• and [cyclobis(paraquat-p-phenylene)]2(+•) (CBPQT2(+•)) form a strong 1:1 host-guest complex [CBPQT⊂MV]3(+•). In this full paper, we describe the extension of radical-pairing-based molecular recognition to a larger, square-shaped diradical host, [cyclobis(paraquat-4,4'-biphenylene)]2(+•) (MS2(+•)). This molecular square was evaluated for its ability to bind an isomeric series of possible diradical cyclophane guests, which consist of two radical viologen units that are linked by two ortho-, meta-, or para-xylylene bridges to provide different spacing between the planar radicals. UV-Vis-NIR measurements reveal that only the m-xylylene-linked isomer (m-CBPQT2(+•)) binds strongly inside of MS2(+•), resulting in the formation of a tetraradical complex [MS⊂m-CBPQT]4(+•). Titration experiments and variable temperature UV-Vis-NIR and EPR spectroscopic data indicate that, relative to the smaller trisradical complex [CBPQT⊂MV]3(+•), the new host-guest complex forms with a more favorable enthalpy change that is offset by a greater entropic penalty. As a result, the association constant (Ka = (1.12 ± 0.08) × 105 M-1) for [MS⊂m-CBPQT]4(+•) is similar to that previously determined for [CBPQT⊂MV]3(+•). The (super)structures of MS2(+•), m-CBPQT2(+•), and [MS⊂m-CBPQT]4(+•) were examined by single-crystal X-ray diffraction measurements and density functional theory calculations. The solid-state and computational structural analyses reveal that m-CBPQT2(+•) is ideally sized to bind inside of MS2(+•). The solid-state superstructures also indicate that localized radical-radical interactions in m-CBPQT2(+•) and [MS⊂m-CBPQT]4(+•) disrupt the extended radical-pairing interactions that are common in crystals of other viologen radical cations. Lastly, the formation of [MS⊂m-CBPQT]4(+•) was probed by cyclic voltammetry, demonstrating that the radical states of the cyclophanes are stabilized by the radical-pairing interactions.


pH-Mediated molecular differentiation for fluorimetric quantification of chemotherapeutic drugs in human plasma.
At present, drug dosage is based on standardised approaches that disregard pharmakokinetic differences between patients and lead to non-optimal efficacy and unnecessary side effects. In this work, we demonstrate the potential of pH-mediated fluorescence spectroscopy for therapeutic drug monitoring in complex media. We apply this principle to the simultaneous quantification of the chemotherapeutic prodrug Irinotecan and its active metabolite SN-38 from human plasma across the clinically relevant concentration range, i.e. from micromolar to nanomolar at molar ratios of up to 30 : 1.


Effects of ventricular insertion sites on rotational motion of left ventricular segments studied by cardiac MR.
Obtaining new details for rotational motion of left ventricular (LV) segments using velocity encoding cardiac MR and correlating the regional motion patterns to LV insertion sites. Cardiac MR examinations were performed on 14 healthy volunteers aged between 19 and 26 years. Peak rotational velocities and circumferential velocity curves were obtained for 16 ventricular segments. Reduced peak clockwise velocities of anteroseptal segments (i.e. Segments 2 and 8) and peak counterclockwise velocities of inferoseptal segments (i.e. Segments 3 and 9) were the most prominent findings. The observations can be attributed to the LV insertion sites into the right ventricle, limiting the clockwise rotation of anteroseptal LV segments and the counterclockwise rotation of inferoseptal segments as viewed from the apex. Relatively lower clockwise velocities of Segment 5 and counterclockwise velocities of Segment 6 were also noted, suggesting a cardiac fixation point between these two segments, which is in close proximity to the lateral LV wall. Apart from showing different rotational patterns of LV base, mid ventricle and apex, the study showed significant differences in the rotational velocities of individual LV segments. Correlating regional wall motion with known orientation of myocardial aggregates has also provided new insights into the mechanisms of LV rotational motions during a cardiac cycle. LV insertion into the right ventricle limits the clockwise rotation of anteroseptal LV segments and the counterclockwise rotation of inferoseptal segments adjacent to the ventricular insertion sites. The pattern should be differentiated from wall motion abnormalities in cardiac pathology.


Timed Up and Go predicts functional decline in older patients presenting to the emergency department following minor trauma†.
there is no standardised test for assessing mobility in the Emergency Department (ED). we wished to evaluate the relationship between the Timed Up and Go (TUG) and frailty, functional decline and falls in community dwelling elders that present to the ED following minor trauma. this was a secondary analysis of a prospective cohort study conducted at eight Canadian hospitals. Evaluations included: TUG; Study of Osteoporotic Fractures Frailty Index; Older American Resources and Service Functional Scale; and self-reported falls. Of note, 3- and 6-month follow-up was conducted. Generalised linear model with log-binomial distribution was utilised. Relative risks (RR) and 95% CI were calculated. TUG scores were available for 911/2918 patients, mean age 76.2 (SD 7.8) and 57.9% female. There was an association between TUG scores and frailty (P < 0.05) and functional decline at 3 (P < 0.05) and 6 (P < 0.05) months but not self-reported falls. For TUG scores 10-19 seconds, 20-29 seconds and ≥30 seconds, respectively: (i) frailty RR (95% CI): 1.8 (1.3-2.4), 3.0 (2.2-4.2) and 3.7 (2.6-5.1); (ii) functional decline RR (95% CI): 2.7 (1.1-6.4), 5.5 (2.1-14.3) and 8.9 (3.0-25.8); (iii) falls RR (95% CI): 0.9 (0.5-1.5), 1.3 (0.6-2.5) and 1.1 (0.4-3.5). in community dwelling elders presenting to the ED following minor trauma, TUG scores were associated with frailty and strongly associated with functional decline at 3 and 6 months post injury. TUG scores were not associated with self-reported falls. Use of the TUG in the ED will help identify frail patients at risk of functional decline.


Taurine enhances the sexual response and mating ability in aged male rats.
It has been demonstrated that taurine is abundant in male reproductive organs, and can be biosynthesized by testis, but the taurine concentration will reduce with aging. The levels of serum LH, T, NOS, and NO were found to be obviously increased by taurine supplementation in aged rats in our previous study. In addition, aging will result in a significant decline in sexual response and function, which may be attributed to the androgen deficiency. Furthermore, NO has been proposed as a crucial mediator of penile erection. That makes us hypothesize that there is potential relationship between taurine decline and erection dysfunction in aged males. So the primary aim of the present study was to investigate the effect of taurine on male sexuality in rats. Taurine was offered in water to male aged (20 months old) rats for 110 days. The effects of taurine on the sexual response, mating ability, levels of serum reproductive hormones, and penile NOS and NO levels were investigated. The results showed that taurine can significantly reduce the EL and ML; obviously increase the ERF, MF, IF, and EJF; stimulate the secretion of GnRH, LH, and T; and elevate penis NOS and NO level in aged rats. The results indicated that taurine can enhance the sexual response and mating ability in aged male rats by increasing the level of testosterone and NO, but the exact mechanism of which needs to be further investigated.


Growth hormone decreases the response to anti-lipolytic agonists and decreases the levels of Gi2 in rat adipocytes.
The effect of growth hormone (GH) in vivo on the Gi-mediated anti-lipolytic signalling system of rat adipocytes has been investigated. Lowering of serum GH levels, by treatment of rats with an antiserum (anti-rGH) specific for rat GH, increased the sensitivity of adipocytes to the anti-lipolytic agonists N6-phenylisopropyladenosine (PIA) and prostaglandin E1. This occurred in the absence of any change in PIA binding to adipocyte membranes. Immunoblot analysis of adipocyte membranes revealed that lowering of serum GH resulted in at least a 3-fold increase in the levels of alpha-subunit of Gi2, but had no effect on the alpha-subunits of Gi1 and Gi3 nor on the 42 and 45 kDa forms of the alpha-subunit of Gs. Replenishment of serum GH, by concurrent administration of ovine GH to rats, prevented all of these effects of anti-rGH. It is concluded that GH down-regulates the amount of Gi2 alpha-subunit in adipocyte membranes, resulting in a decrease in the sensitivity of the cells to anti-lipolytic agonists.


Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system.
The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered. A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.


Numerical Simulation of Particle Distribution in Capillary Membrane during Backwash.
The membrane filtration with inside-out dead-end driven UF-/MF- capillary membranes is an effective process for particle removal in water treatment. Its industrial application increased in the last decade exponentially. To date, the research activities in this field were aimed first of all at the analysis of filtration phenomena disregarding the influence of backwash on the operation parameters of filtration plants. However, following the main hypothesis of this paper, backwash has great potential to increase the efficiency of filtration. In this paper, a numerical approach for a detailed study of fluid dynamic processes in capillary membranes during backwash is presented. The effect of particle size and inlet flux on the backwash process are investigated. The evaluation of these data concentrates on the analysis of particle behavior in the cross sectional plane and the appearance of eventually formed particle plugs inside the membrane capillary. Simulations are conducted in dead-end filtration mode and with two configurations. The first configuration includes a particle concentration of 10% homogeneously distributed within the capillary and the second configuration demonstrates a cake layer on the membrane surface with a packing density of 0:6. Analyzing the hydrodynamic forces acting on the particles shows that the lift force plays the main role in defining the particle enrichment areas. The operation parameters contribute in enhancing the lift force and the heterogeneity to anticipate the clogging of the membrane.


Selective Activation of Cortical Columns Using Multichannel Magnetic Stimulation With a Bent Flat Microwire Array.
Cortical neural prostheses that aim to restore useful vision, hearing, and tactile sensations require the ability to selectively target different cortical regions simultaneously. Electrical stimulation via intracortical electrodes has been used to create spatial patterns of cortical activation. However, their efficacy remains limited due to the inability of conventional electrodes to confine activation to specific cortical regions around each electrode. Magnetic stimulation from single bent wires can selectively activate pyramidal neurons while avoiding passing axons, thereby confining activation to small cortical regions. This paper presents a novel bent flat microwire array and demonstrates its effectiveness for selective activation of cortical columns in mouse brain slices. A computational model was developed to compare the spatial resolution of magnetic stimulation from bent wire arrays with 280 and 530 μm tip spacings. The same array designs were fabricated for use in electrophysiological experiments, i.e., calcium imaging (GCaMP6s) of mouse brain slices. All fabricated array designs reliably produced spatially discrete cortical activations at low stimulus amplitudes, but the 280-μm-spacing produced strong interference (constructive or destructive) at high stimulus amplitudes, thereby resulting in single strong activations or two asymmetric activations. 4-channel bent wire arrays with spacing of 340 μm avoided the interference and produced clearer spatial patterns of activation than electrodes. Bent wire array designs can influence the strength or the spatial resolution of multichannel magnetic stimulation. These results suggest that bent microwire arrays can enhance the selectivity of multichannel stimulation of brain and therefore may help to develop reliable and effective cortical neural prostheses.


A comparative study of bloodstream infections in acute myeloid leukemia according to different phases of treatment: Can we predict the organism?
The treatment of acute myeloid leukemia (AML) consists of induction therapy with anthracyclines and cytarabine followed by two to four cycles of consolidation therapy with high-dose cytarabine after achieving remission. There have been very few studies comparing infections during induction and consolidation. We have analyzed blood cultures of patients with AML during episodes of fever occurring during induction and consolidation, for comparing the bloodstream infections in both the phases. Blood cultures of patients during febrile episodes were collected from central venous catheters and peripheral blood, both during induction and consolidation therapy of AML. The study population included 52 AML patients. During induction, there were 52 episodes of fever and 25 (48%) blood cultures were positive, 15 of these blood cultures reported Gram-negative organisms, 9 reported Gram-positive organisms and 1 as yeast. During consolidation, 47 episodes of fever were recorded and blood cultures were positive in 12, of which 7 were Gram-negative, 5 were Gram-positive. The incidence of blood culture positive infections during therapy of AML at our center was higher. The predominant organism isolated was Gram-negative both during induction and consolidation. The incidence of blood culture positive infections had decreased by 50% during consolidation.


Astrin is required for the maintenance of sister chromatid cohesion and centrosome integrity.
Faithful chromosome segregation in mitosis requires the formation of a bipolar mitotic spindle with stably attached chromosomes. Once all of the chromosomes are aligned, the connection between the sister chromatids is severed by the cysteine protease separase. Separase also promotes centriole disengagement at the end of mitosis. Temporal coordination of these two activities with the rest of the cell cycle is required for the successful completion of mitosis. In this study, we report that depletion of the microtubule and kinetochore protein astrin results in checkpoint-arrested cells with multipolar spindles and separated sister chromatids, which is consistent with untimely separase activation. Supporting this idea, astrin-depleted cells contain active separase, and separase depletion suppresses the premature sister chromatid separation and centriole disengagement in these cells. We suggest that astrin contributes to the regulatory network that controls separase activity.


The detrimental influence of bacteria (E. coli, Shigella and Salmonella) on the degradation of organic compounds (and vice versa) in TiO2 photocatalysis and near-neutral photo-Fenton processes under simulated solar light.
TiO2 photocatalytic and near-neutral photo-Fenton processes were tested under simulated solar light to degrade two models of natural organic matter - resorcinol (R) (which should interact strongly with TiO2 surfaces) and hydroquinone (H) - separately or in the presence of bacteria. Under similar oxidative conditions, inactivation of Escherichia coli, Shigella sonnei and Salmonella typhimurium was carried out in the absence and in the presence of 10 mg L(-1) of R and H. The 100% abatement of R and H by using a TiO2 photocatalytic process in the absence of bacteria was observed in 90 min for R and in 120 min for H, while in the presence of microorganisms abatement was only of 55% and 35% for R and H, respectively. Photo-Fenton reagent at pH 5.0 completely removed R and H in 40 min, whereas in the presence of microorganisms their degradation was of 60% to 80%. On the other hand, 2 h of TiO2 photocatalytic process inactivated S. typhimurium and E. coli cells in three and six orders of magnitude, respectively, while S. sonnei was completely inactivated in 10 min. In the presence of R or H, the bacterial inactivation via TiO2 photocatalysis was significantly decreased. With photo-Fenton reagent at pH 5 all the microorganisms tested were completely inactivated in 40 min of simulated solar light irradiation in the absence of organics. When R and H were present, bacterial photo-Fenton inactivation was less affected. The obtained results suggest that in both TiO2 and iron photo-assisted processes, there is competition between organic substances and bacteria simultaneously present for generated reactive oxygen species (ROS). This competition is most important in heterogeneous systems, mainly when there are strong organic-TiO2 surface interactions, as in the resorcinol case, suggesting that bacteria-TiO2 interactions could play a key role in photocatalytic cell inactivation processes.


Treatment-seeking and recovery among young undernourished children post-hospital discharge in Bangladesh: A qualitative study.
Post-hospital discharge mortality is high among undernourished children in many low and middle-income countries. Although a number of quantitative studies have highlighted a range of potential socio-cultural, economic and health system factors influencing paediatric post-discharge treatment-seeking and recovery, few studies have explored family and provider perspectives of the post-discharge period in-depth. This work was part of a large, multi-country prospective cohort study, the Childhood Acute Illness and Nutrition (CHAIN) Network. We conducted a qualitative sub-study to understand the post-discharge treatment-seeking and recovery experiences of families of undernourished children aged 2-23 months admitted in a rural and urban icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh) hospital. Methods included repeat in-depth interviews (73 interviews in total) with 29 family members of 17 purposively selected children. These data were supplemented by interviews with 33 health workers, and by observations in hospitals and homes. Important drivers of treatment-seeking perceived to support recovery included advice provided to family members while in hospital, media campaigns on hygiene practice, availability of free treatment, and social and financial support from family members, relatives and neighbours. Key perceived challenges included low household incomes, mothers having to juggle multiple responsibilities in addition to caring for the sick child, lack of support (sometimes violence) from the child's father, and family members' preference for relatively accessible drug shops, physicians or healers over hospital admission. Development of interventions that address the challenges that families face is essential to support post-discharge adherence to medical advice and recovery. Potential interventions include strengthening information giving during hospitalization on what post-discharge care is needed and why, reducing direct and indirect costs associated with hospital visits, engaging fathers and other 'significant others' in post-discharge advice, and building mobile phone-based support for follow-up care.


Cognitive Tests to Detect Dementia: A Systematic Review and Meta-analysis.
Dementia is a global public health problem. The Mini-Mental State Examination (MMSE) is a proprietary instrument for detecting dementia, but many other tests are also available. To evaluate the diagnostic performance of all cognitive tests for the detection of dementia. Literature searches were performed on the list of dementia screening tests in MEDLINE, EMBASE, and PsychoINFO from the earliest available dates stated in the individual databases until September 1, 2014. Because Google Scholar searches literature with a combined ranking algorithm on citation counts and keywords in each article, our literature search was extended to Google Scholar with individual test names and dementia screening as a supplementary search. Studies were eligible if participants were interviewed face to face with respective screening tests, and findings were compared with criterion standard diagnostic criteria for dementia. Bivariate random-effects models were used, and the area under the summary receiver-operating characteristic curve was used to present the overall performance. Sensitivity, specificity, and positive and negative likelihood ratios were the main outcomes. Eleven screening tests were identified among 149 studies with more than 49,000 participants. Most studies used the MMSE (n = 102) and included 10,263 patients with dementia. The combined sensitivity and specificity for detection of dementia were 0.81 (95% CI, 0.78-0.84) and 0.89 (95% CI, 0.87-0.91), respectively. Among the other 10 tests, the Mini-Cog test and Addenbrooke's Cognitive Examination-Revised (ACE-R) had the best diagnostic performances, which were comparable to that of the MMSE (Mini-Cog, 0.91 sensitivity and 0.86 specificity; ACE-R, 0.92 sensitivity and 0.89 specificity). Subgroup analysis revealed that only the Montreal Cognitive Assessment had comparable performance to the MMSE on detection of mild cognitive impairment with 0.89 sensitivity and 0.75 specificity. Besides the MMSE, there are many other tests with comparable diagnostic performance for detecting dementia. The Mini-Cog test and the ACE-R are the best alternative screening tests for dementia, and the Montreal Cognitive Assessment is the best alternative for mild cognitive impairment.


The impact of telemental health use on healthcare costs among commercially insured adults with mental health conditions.
To determine the impact of telemental health (TMH) use on total healthcare costs and mental health (MH)-related costs paid by a third party among adults with mental health conditions (MHC). This study employed a pre-post design with a non-equivalent control group. The cohort comprised adults with MHCs identified using diagnosis codes from de-identified claims data of the Optum Clinformatics DataMart (2010 January 01 to 2017 June 30). We identified mental health (MH) service users and TMH users (N = 348) based on procedure codes. Non-users (N = 238,595) were defined as those who only used in-person MH services. A Difference-in-Differences (DID) analysis was performed within a multivariable two-part model (TPM) framework to examine the impact of TMH use on adjusted standardized costs (2018 US $) of all healthcare services and MH services. Patient-level and state-level factors were adjusted in TPM. TMH use was associated with significantly higher MH-related costs [Marginal effect = $461.3, 95% confidence interval: $142.4-$780.2] and an excess of $370 increase in MH-related costs at follow-up as compared to baseline. However, TMH use was not associated with an increase in total third-party healthcare costs nor with changes in total costs from baseline to follow-up. Despite having a higher likelihood of MH services use and MH-related costs, TMH users did not have higher total costs as compared to adults using only in-person MH services. Our findings suggest that TMH can increase access to MH care without increasing total healthcare costs among adults with MHC. Future studies exploring whether TMH use can lead to cost-savings over a longer period are warranted.


Orbital angular momentum of entangled counterpropagating photons.
We elucidate the paraxial orbital angular momentum of entangled photon pairs generated by spontaneous parametric downconversion in different noncollinear geometries in which the entangled photons counterpropagate. We find, in particular, the orbital angular momentum of entangled pairs generated in transverse-emitting configurations, in which none of the known rules for selecting orbital angular momentum holds.


Design of stable nanocrystalline alloys.
Nanostructured metals are generally unstable; their grains grow rapidly even at low temperatures, rendering them difficult to process and often unsuitable for usage. Alloying has been found to improve stability, but only in a few empirically discovered systems. We have developed a theoretical framework with which stable nanostructured alloys can be designed. A nanostructure stability map based on a thermodynamic model is applied to design stable nanostructured tungsten alloys. We identify a candidate alloy, W-Ti, and demonstrate substantially enhanced stability for the high-temperature, long-duration conditions amenable to powder-route production of bulk nanostructured tungsten. This nanostructured alloy adopts a heterogeneous chemical distribution that is anticipated by the present theoretical framework but unexpected on the basis of conventional bulk thermodynamics.


Cod and God: Dr Wilfred Grenfell in Newfoundland.
Wilfred Thomason Grenfell (1865-1940) began his medical career working for the National Mission for Deep Sea Fishermen on the North Sea. In 1892, the Mission sent him to Newfoundland to invesitigate the living and working conditions of the fishermen there. He spent most of his life improving conditions for the settlers on the coasts of Newfoundland and Labrador. His unorthodox methods and difficult personality brought him into conflict with the authorities. In spite of this, he achieved significant changes for the Newfoundlanders in medical care, education and economic prospects.


Impact of Hot Yoga on Arterial Stiffness and Quality of Life in Normal and Overweight/Obese Adults.
Obesity is associated with arterial stiffening and diminished quality of life. Bikram yoga may be a feasible alternative to traditional exercise among obese individuals. Accordingly, the purpose of this study was to investigate the impact of Bikram yoga, a heated style of hatha yoga, on arterial stiffness in normal and overweight/obese adults. Forty-three (23 normal body mass index or BMI; 20 overweight/obese) apparently healthy participants completed an 8-week Bikram yoga intervention. Body composition was estimated via dual energy x-ray absorptiometry, arterial stiffness was measured via brachialankle pulse wave velocity, and health-related quality of life was assessed via RAND 36-Item Short Form survey at baseline and at the end of the 8-week intervention. After the intervention, brachial-ankle pulse wave velocity decreased (P < .05) in overweight/obese participants while no such changes were observed in normal BMI participants. In the quality of life measures, emotional well-being improved (P < .05) in both groups, and general health improved (P < .05) only in the normal weight BMI group. Bikram yoga ameliorates arterial stiffness in overweight/obese adults and can positively impact quality of life regardless of BMI.


Is low cognitive functioning a predictor or consequence of major depressive disorder? A test in two longitudinal birth cohorts.
Cognitive impairment has been identified as an important aspect of major depressive disorder (MDD). We tested two theories regarding the association between MDD and cognitive functioning using data from longitudinal cohort studies. One theory, the cognitive reserve hypothesis, suggests that higher cognitive ability in childhood decreases risk of later MDD. The second, the scarring hypothesis, instead suggests that MDD leads to persistent cognitive deficits following disorder onset. We tested both theories in the Dunedin Study, a population-representative cohort followed from birth to midlife and assessed repeatedly for both cognitive functioning and psychopathology. We also used data from the Environmental Risk Longitudinal Twin Study to test whether childhood cognitive functioning predicts future MDD risk independent of family-wide and genetic risk using a discordant twin design. Contrary to both hypotheses, we found that childhood cognitive functioning did not predict future risk of MDD, nor did study members with a past history of MDD show evidence of greater cognitive decline unless MDD was accompanied by other comorbid psychiatric conditions. Our results thus suggest that low cognitive functioning is related to comorbidity, but is neither an antecedent nor an enduring consequence of MDD. Future research may benefit from considering cognitive deficits that occur during depressive episodes from a transdiagnostic perspective.


The physical state of water in bacterial spores.
The bacterial spore, the hardiest known life form, can survive in a metabolically dormant state for many years and can withstand high temperatures, radiation, and toxic chemicals. The molecular basis of spore dormancy and resistance is not understood, but the physical state of water in the different spore compartments is thought to play a key role. To characterize this water in situ, we recorded the water (2)H and (17)O spin relaxation rates in D(2)O-exchanged Bacillus subtilis spores over a wide frequency range. The data indicate high water mobility throughout the spore, comparable with binary protein-water systems at similar hydration levels. Even in the dense core, the average water rotational correlation time is only 50 ps. Spore dormancy therefore cannot be explained by glass-like quenching of molecular diffusion but may be linked to dehydration-induced conformational changes in key enzymes. The data demonstrate that most spore proteins are rotationally immobilized, which may contribute to heat resistance by preventing heat-denatured proteins from aggregating irreversibly. We also find that the water permeability of the inner membrane is at least 2 orders of magnitude lower than for model membranes, consistent with the reported high degree of lipid immobilization in this membrane and with its proposed role in spore resistance to chemicals that damage DNA. The quantitative results reported here on water mobility and transport provide important clues about the mechanism of spore dormancy and resistance, with relevance to food preservation, disease prevention, and astrobiology.


The cell adhesion molecule, connectin, and the development of the Drosophila neuromuscular system.
The connectin gene of Drosophila has been identified as a candidate direct target of homeotic gene control and has also been implicated in the formation of specific neuromuscular connections. The gene product, connectin, is a member of the leucine-rich repeat protein family and we show that it is attached to the cell surface via a glycosylphosphatidylinositol linkage and that it can mediate homotypic cell-cell adhesion in vitro. The expression of connectin protein during Drosophila embryogenesis provides support for a role in adhesion in vivo. In the central nervous system, it is initially expressed on longitudinal glia and on a few identified neurons. These cells extend processes and connect up to form a continuous scaffold of connectin-expressing cells, presaging the development of axonal pathways. Later, connectin is expressed on specific axons as they track along the connectin scaffold. Glial expression then declines and connectin appears on axons that fasciculate with pre-existing connectin-positive bundles. Thus scaffold formation, axon pathfinding and fasciculation involve specific contacts between connectin-positive cells. The timing and pattern of connectin expression suggest that it may play an important role in mediating specific interactions through homotypic cell adhesion.


Case studies of food shopping, cooking and eating habits in older women with Parkinson's disease.
The principal aim of this study was to investigate how married and single-living older women diagnosed with Parkinson's disease managed to shop for food, cook and carry out their meals; and to observe whether their nutritional needs were satisfied. A secondary aim was to identify women with severe motor problems and describe their food-related situation. Parkinson's disease is associated with motor and eating problems, which, combined with age-related declines in physical functioning, may affect activities of daily living and dietary intake. Qualitative interviews and food survey were carried out in the homes of 10 women aged 67-80 years. The sample was recruited from outpatient registers. Decreased sense of smell, appetite and taste in combination with problems transporting food to the mouth and swallowing were risks for nutritional well-being. Food shopping was most difficult to manage, but six cooked even if their cooking style was changed. Married women with healthy husbands received support from their spouses. Single-living women suffering from motor problems had to call for help, which represented a threat to their well-being. Independence was given high priority. The whole situation - including psychosocial and stress factors - must be taken into account when discussing shopping, cooking and eating among old women with Parkinson's disease. A home-helper should not take over but facilitate procedures so that the woman can manage as long as possible. This gave them self-esteem.


Involvement of a Rac1-Dependent Macropinocytosis Pathway in Plasmid DNA Delivery by Electrotransfection.
Electrotransfection is a widely used method for delivering genes into cells with electric pulses. Although different hypotheses have been proposed, the mechanism of electrotransfection remains controversial. Previous studies have indicated that uptake and intracellular trafficking of plasmid DNA (pDNA) are mediated by endocytic pathways, but it is still unclear which pathways are directly involved in the delivery. To this end, the present study investigated the dependence of electrotransfection on macropinocytosis. Data from the study demonstrated that electric pulses induced cell membrane ruffling and actin cytoskeleton remodeling. Using fluorescently labeled pDNA and a macropinocytosis marker (i.e., dextran), the study showed that electrotransfected pDNA co-localized with dextran in intracellular vesicles. Furthermore, electrotransfection efficiency could be decreased significantly by reducing temperature or treatment of cells with a pharmacological inhibitor of Rac1 and could be altered by changing Rac1 activity. Taken together, the findings suggested that electrotransfection of pDNA involved Rac1-dependent macropinocytosis.


Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro.
This study evaluated the effects of acute psychological stress (cat exposure) in adult male rats on electrophysiological plasticity subsequently assessed in the hippocampus in vitro. Two physiological models of memory were studied in CA1 in each recording session: (1) primed burst potentiation (PBP), a low-threshold form of plasticity produced by a total of five physiologically patterned pulses; and (2) long-term potentiation (LTP), a suprathreshold form of plasticity produced by a train of 100 pulses. Three groups of rats were studied: (1) undisturbed rats in their home cage (home cage); (2) rats placed in a chamber for 75 min (chamber); and (3) rats placed in a chamber for 75 min in close proximity to a cat (chamber/stress). At the end of the chamber exposure period, blood samples were obtained, and the hippocampus was prepared for in vitro recordings. Only the chamber/stress group had elevated (stress) levels of corticosterone. The major finding was that PBP, but not LTP, was blocked in the chamber/stress group. Thus, the psychological stress experienced by the rats in response to cat exposure resulted in an inhibition of plasticity, which was localized to the intrinsic circuitry of the hippocampus. This work provides novel observations on the effects of an ethologically relevant stressor on PBP in vitro and of the relative insensitivity of LTP to being modulated by psychological stress. We discuss the relevance of these electrophysiological findings to our behavioral work showing that predator stress impairs spatial memory.


The protofilament substructure of amyloid fibrils.
Tissue deposition of normally soluble proteins, or their fragments, as insoluble amyloid fibrils causes the usually fatal, acquired and hereditary systemic amyloidoses and is associated with the pathology of Alzheimer's disease, type 2 diabetes and the transmissible spongiform encephalopathies. Although each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. We have previously demonstrated that transthyretin amyloid fibrils contain four constituent protofilaments packed in a square array. Here, we have used cross-correlation techniques to average electron microscopy images of multiple cross-sections in order to reconstruct the sub-structure of ex vivo amyloid fibrils composed of amyloid A protein, monoclonal immunoglobulin lambda light chain, Leu60Arg variant apolipoprotein AI, and Asp67His variant lysozyme, as well as synthetic fibrils derived from a ten-residue peptide corresponding to the A-strand of transthyretin. All the fibrils had an electron-lucent core but the packing arrangement comprised five or six protofilaments rather than four. The structural similarity that defines amyloid fibres thus exists principally at the level of beta-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular assembly of their protofilaments.


Can one blood draw replace transrectal ultrasonography-estimated prostate volume to predict prostate cancer risk?
To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting. The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (≥3 ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam (n = 2914) and Göteborg (n = 740). A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome. The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Göteborg. Adding digital rectal examination (DRE) or DRE plus transrectal ultrasonography (TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high-grade cancer. There was a strong correlation between the blood measurements and TRUS-estimated prostate volume (Spearman's correlation 0.60 in Rotterdam and 0.57 in Göteborg). In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to-day clinical practice. Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches.


Bacterial genes in the aphid genome: absence of functional gene transfer from Buchnera to its host.
Genome reduction is typical of obligate symbionts. In cellular organelles, this reduction partly reflects transfer of ancestral bacterial genes to the host genome, but little is known about gene transfer in other obligate symbioses. Aphids harbor anciently acquired obligate mutualists, Buchnera aphidicola (Gammaproteobacteria), which have highly reduced genomes (420-650 kb), raising the possibility of gene transfer from ancestral Buchnera to the aphid genome. In addition, aphids often harbor other bacteria that also are potential sources of transferred genes. Previous limited sampling of genes expressed in bacteriocytes, the specialized cells that harbor Buchnera, revealed that aphids acquired at least two genes from bacteria. The newly sequenced genome of the pea aphid, Acyrthosiphon pisum, presents the first opportunity for a complete inventory of genes transferred from bacteria to the host genome in the context of an ancient obligate symbiosis. Computational screening of the entire A. pisum genome, followed by phylogenetic and experimental analyses, provided strong support for the transfer of 12 genes or gene fragments from bacteria to the aphid genome: three LD-carboxypeptidases (LdcA1, LdcA2,psiLdcA), five rare lipoprotein As (RlpA1-5), N-acetylmuramoyl-L-alanine amidase (AmiD), 1,4-beta-N-acetylmuramidase (bLys), DNA polymerase III alpha chain (psiDnaE), and ATP synthase delta chain (psiAtpH). Buchnera was the apparent source of two highly truncated pseudogenes (psiDnaE and psiAtpH). Most other transferred genes were closely related to genes from relatives of Wolbachia (Alphaproteobacteria). At least eight of the transferred genes (LdcA1, AmiD, RlpA1-5, bLys) appear to be functional, and expression of seven (LdcA1, AmiD, RlpA1-5) are highly upregulated in bacteriocytes. The LdcAs and RlpAs appear to have been duplicated after transfer. Our results excluded the hypothesis that genome reduction in Buchnera has been accompanied by gene transfer to the host nuclear genome, but suggest that aphids utilize a set of duplicated genes acquired from other bacteria in the context of the Buchnera-aphid mutualism.


Comparison of Combinatorial Signatures of Global Network Dynamics Generated by Two Classes of ODE Models.
Modeling the dynamics of biological networks introduces many challenges, among them the lack of first principle models, the size of the networks, and difficulties with parameterization. Discrete time Boolean networks and related continuous time switching systems provide a computationally accessible way to translate the structure of the network to predictions about the dynamics. Recent work has shown that the parameterized dynamics of switching systems can be captured by a combinatorial object, called a Dynamic Signatures Generated by Regulatory Networks (DSGRN) database, that consists of a parameter graph characterizing a finite parameter space decomposition, whose nodes are assigned a Morse graph that captures global dynamics for all corresponding parameters. We show that for a given network there is a way to associate the same type of object by considering a continuous time ODE system with a continuous right-hand side, which we call an L-system. The main goal of this paper is to compare the two DSGRN databases for the same network. Since the L-systems can be thought of as perturbations (not necessarily small) of the switching systems, our results address the correspondence between global parameterized dynamics of switching systems and their perturbations. We show that, at corresponding parameters, there is an order preserving map from the Morse graph of the switching system to that of the L-system that is surjective on the set of attractors and bijective on the set of fixed-point attractors. We provide important examples showing why this correspondence cannot be strengthened.


Medicaid Expansion: Effects On Hospital Finances And Implications For Hospitals Facing COVID-19 Challenges.
States' decisions to expand Medicaid may have important implications for their hospitals' financial ability to weather the coronavirus disease 2019 (COVID-19) pandemic. This study estimated the effects of the Affordable Care Act (ACA) Medicaid expansion on hospital finances in 2017 to update earlier findings. The analysis also explored how the ACA Medicaid expansion affects different types of hospitals by size, ownership, rurality, and safety-net status. We found that the early positive financial impact of Medicaid expansion was sustained in fiscal years 2016 and 2017 as hospitals in expansion states continued to experience decreased uncompensated care costs and increased Medicaid revenue and financial margins. The magnitude of these impacts varied by hospital type. As COVID-19 has brought hospitals to a time of great need, findings from this study provide important information on what hospitals in states that have yet to expand Medicaid could gain through expansion and what is at risk should any reversal of Medicaid expansions occur.


Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors.
A family of histone deacetylases (HDACs) mediates chromatin remodeling, and repression of gene expression. Deacetylation of histones within the HIV-1 long terminal repeat (LTR) by HDACs plays a key role in the maintenance of latency, whereas acetylation of histones about the LTR is linked to proviral expression and escape of HIV from latency. Global HDAC inhibition may adversely affect host gene expression, leading to cellular toxicities. Potent inhibitors selective for HDACs that maintain LTR repression could be ideal antilatency therapeutics. We investigated the ability of selective HDAC inhibitors to de-repress the HIV-1 LTR in both a cell line model of latency and in resting CD4 T cells isolated from patients who were aviremic on antiretroviral therapy (ART). We found that inhibition of class I HDACs increased acetylation of histones at the LTR, but that LTR chromatin was unaffected by class II HDAC inhibitors. In a latently infected cell line, inhibitors selective for class I HDACs were more efficient activators of the LTR than inhibitors that target class II HDACs. Class I HDAC inhibitors were strikingly efficient inducers of virus outgrowth from resting CD4 T cells of aviremic patients, whereas HIV was rarely recovered from patient's cells exposed to class II HDAC inhibitors. Further development of selective HDAC inhibitors as part of a clinical strategy to target persistent HIV infection is warranted.


Morphometric criteria for sexing juvenile human skeletons using the ilium.
Previous attempts to sex juvenile skeletons have focused on the application of qualitative or semi-quantitative techniques. This study applies a variety of geometric morphometric methods, including eigenshape analysis, to this problem. Six metric criteria for the ilia were tested with the aim of investigating previous ideas concerning sexually diagnostic characters. This study uses 25 ilia from juveniles of known age and sex from Christ Church, Spitalfields, London. Ninety-six percent of juvenile ilia were correctly identified as male or female using the shape of the greater sciatic notch. Identification accuracy is shown to improve with age for several criteria. Males were identified to a higher accuracy than females. Application of geometric techniques improves the understanding of the relationship between age, sex, and shape and the clarity with which these relationships can be quantified. Archaeological and forensic relevance of the results are discussed with recommendations for future application.


Probiotics in irritable bowel syndrome: an immunomodulatory strategy?
The clear delineation of a post-infective variety of IBS, as well as the description, in a number of studies, of evidence of low-grade inflammation and immune activation in IBS, suggest a role for a dysfunctional relationship between the indigenous flora and the host in IBS and, accordingly, provide a clear rationale for the use of probiotics in this disorder. Other modes of action, including bacterial displacement and alterations in luminal contents, are also plausible. While clinical evidence of efficacy is now beginning to emerge, a review of available trials emphasizes the importance of a clear definition of strain selection, dose and viability. The possible roles of co-therapy or sequential therapy with antibiotics, probiotics, prokinetics, or other agents also deserves further study. The role of the enteric flora is evidently an area of great potential in IBS; we are on the threshold of a new era of research and therapy for this common disorder.


An approach to monitoring influenza vaccination uptake across Europe.
Currently, the monitoring of influenza vaccination uptake is mainly a national issue. As influenza infection easily crosses international borders, it is in the interest of all countries to have a high vaccine uptake in people who may be vulnerable when influenza spreads. A Europe-wide monitoring system can provide insight into the strengths and weaknesses of uptake rates in countries and, on ce sufficient levels are achieved, can safeguard the continuation of the achieved levels. This paper aims to address the following issues: a) How is influenza vaccination uptake monitored in Europe? b) What methods to monitor vaccination uptake are available and what are their limitations? c) What steps should be taken to implement a European-wide influenza vaccination uptake monitoring system? Based on existing literature and experiences in monitoring influenza vaccination uptake, an approach to set up a European-wide monitoring system is proposed. The following issues were identified as relevant for influenza vaccination uptake monitoring: a) Agreement on the population groups in which vaccination uptake should be monitored; b) The frequency of data collection; c) The importance of sharing experiences regarding existing influenza vaccination campaigns in order to learn from each other, and develop 'best practices'; d) The need to publish uptake data in close relation with influenza surveillance data and other European efforts on dissemination of vaccination knowledge. To stimulate the discussion on implementing a pan-European influenza uptake monitoring scheme the following recommendations were suggested : a) Develop a common set of variables; b) Build on experience from individual countries; c) Create a coordinating body; d) Create or identify a platform to publish the data; e) Start small and expand rapidly.


Abnormalities in muscle density and muscle function in hypophosphatemic rickets.
Animal studies suggest that hypophosphatemic rickets (HPR) is associated with muscle function deficits, but it is unknown whether humans with HPR have a muscle disorder. Our objective was to assess calf muscle size and density (an indicator of muscle quality) and lower extremity muscle function in patients with HPR. The study was carried out in the outpatient department of a pediatric orthopedic hospital. Participants included 34 individuals with HPR (6-60 yr; nine males) and 34 age- and gender-matched controls. Calf muscle parameters (muscle cross-sectional area and density) were measured by peripheral quantitative computed tomography. Lower extremity muscle function (peak force per body weight and peak power per body mass) was measured by jumping mechanography through five tests with different levels of difficulty: multiple two-legged hopping, multiple one-legged hopping, single two-legged jump, chair-rise test, and heel-rise test. Compared with age- and gender-matched controls, patients with HPR had normal muscle size (P = 0.58) but lower muscle density (P = 0.008) and lower peak muscle force and power (P < 0.001 in each test). Muscle function tests were also lower in the subgroup of patients with straight legs (n = 13) than in controls, even though patients with straight legs had higher muscle function test results than patients with severe leg deformities. The present study suggests that muscle weakness is a clinical feature of HPR. Lower muscle quality and limb deformities contribute to this functional deficit.


Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease.
The numbers and distribution of the neurofibrillary tangles and neuritic plaques have been determined in several areas of the neocortex in brains affected by various degrees of severity of Alzheimer disease. The homotypical cortex of the "association" areas of the temporal, parietal, and frontal lobes are severely involved, whereas the motor, somatic sensory, and primary visual areas are virtually unaffected. The neurofibrillary tangles are mainly in the supra- and infragranular layers, particularly in layers III and V. In all areas except area 18 in the occipital lobe, there are approximately twice as many tangles in layer V as in layer III. The tangles are arranged in definite clusters, and those in the supra- and infragranular layers are in register. The neuritic plaques occur in all layers but predominantly affect layers II and III and do not show clustering. These data on the severity of the pathological involvement in different areas of the neocortex and the laminar distribution and the clustering of the tangles support the suggestion that the pathological changes in Alzheimer disease affect regions that are interconnected by well-defined groups of connections and that the disease process may extend along the connecting fibers. The invariable and severe involvement of the olfactory areas of the brain in this disease is in striking contrast to the minimal changes in the somatic sensory and primary visual areas and raises the possibility that the olfactory pathway may be initially involved.


Kidney injury molecule-1 expression is closely associated with renal allograft damage.
The aim of our study was to investigate the expression of kidney injury molecule-1 (KIM-1) in renal allograft biopsy samples and assess the clinical significance of its use as a biomarker for tissue damage. A total of 69 renal allograft biopsy samples from 17 patients with normal serum creatinine and 52 cases of increased serum creatinine were collected. They were divided into different groups according to the Banff 2007 diagnostic criteria. KIM-1 expression was detected by immunohistochemical methods and the association of KIM-1 and blood biochemical indexes was analyzed. KIM-1 expression increased as Banff 2007 classification grade increased and was positively correlated with tubular inflammation severity in the acute T-cell rejection group. Moreover, KIM-1 expression was strongly positive in the chronic active antibody-mediated rejection group. Interestingly, KIM-1 was weakly positive in the normal group without obvious acute rejection and injury of immunosuppressant toxicity. In this group, 27.3% (3/11) of the cases with normal serum creatinine level showed weakly positive KIM-1 expression in their renal tissues. KIM-1 expression level is positively correlated with renal allograft damage and tubular cell injury. KIM-1 is expressed in tubular epithelial cells before blood biochemical indexes become elevated and morphological changes occur. KIM-1 expression is an early, sensitive, and specific biomarker to determine renal tubular epithelial cell injury in renal allograft tissue.


Comprehensive and comparative exploration of the Atp7b-/- mouse plasma proteome.
Wilson's disease (WD), a rare genetic disease caused by mutations in the ATP7B gene, is associated with altered expression and/or function of the copper-transporting ATP7B protein, leading to massive toxic accumulation of copper in the liver and brain. The Atp7b-/- mouse, a genetic and phenotypic model of WD, was developed to provide new insights into the pathogenic mechanisms of WD. Many plasma proteins are secreted by the liver, and impairment of liver function can trigger changes to the plasma proteome. High standard proteomics workflows can identify such changes. Here, we explored the plasma proteome of the Atp7b-/- mouse using a mass spectrometry (MS)-based proteomics workflow combining unbiased discovery analysis followed by targeted quantification. Among the 367 unique plasma proteins identified, 7 proteins were confirmed as differentially abundant between Atp7b-/- mice and wild-type littermates, and were directly linked to WD pathophysiology (regeneration of liver parenchyma, plasma iron depletion, etc.). We then adapted our targeted proteomics assay to quantify human orthologues of these proteins in plasma from copper-chelator-treated WD patients. The plasma proteome changes observed in the Atp7b-/- mouse were not confirmed in these samples, except for alpha-1 antichymotrypsin, levels of which were decreased in WD patients compared to healthy individuals. Plasma ceruloplasmin was investigated in both the Atp7b-/- mouse model and human patients; it was significantly decreased in the human form of WD only. In conclusion, MS-based proteomics is a method of choice to identify proteome changes in murine models of disrupted metal homeostasis, and allows their validation in human cohorts.


Insulin-like growth factor axis and risk of type 2 diabetes in women.
IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses' Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR](q5-q1) = 0.17 [95% CI 0.08-0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (OR(q5-q1) = 0.37 [0.18-0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (OR(q5-q1) = 2.05 [1.20-3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (OR(q5-q1) = 0.48 [0.26-0.90]; P trend = 0.0001) versus below the median (OR(q5-q1) = 2.52 [1.05-6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.


Alterations in serum fatty acid concentrations and desaturase activities in Bietti crystalline dystrophy unaffected by CYP4V2 genotypes.
To evaluate the serum fatty acid changes in Chinese patients with Bietti crystalline dystrophy (BCD) in association with CYP4V2 mutation. Sixteen Chinese patients with BCD confirmed with CYP4V2 mutation were recruited. Peripheral venous blood was obtained after fasting and serum fatty acid concentrations were measured and compared with those in 13 control subjects. Delta-9-desaturase and Delta-5-desaturase activities were estimated based on serum fatty acid compositions. Serum insulin and glucagon concentrations and their correlations with fatty acid and desaturase activities were also evaluated. Fatty acid concentrations were compared among patients with BCD with different genotypes or phenotypes. Patients with BCD were found to have a significantly higher concentration of octadecanoic acid (18:0) than that in control subjects (18.28% versus 13.52%, P = 0.007), as well as a lower concentration of octadecadienoic acid (18:1n-9) than that in control subjects (10.97% vs. 14.88%, P = 0.007). The total monounsaturated fatty acid concentration was significantly lower in BCD than in the control (11.82% vs. 15.85%, P = 0.012). The activity of Delta-9-desaturase was also significantly lower in BCD (0.71 vs. 1.14, P = 0.004). Serum glucagon was significantly associated with increased total unsaturated fatty acid and decreased polyunsaturated fatty acid in control subjects but not in patients with BCD. No significant difference in the fatty acid concentration and desaturase activities was found in patients with different genotypes or phenotypes. Abnormal serum fatty acid composition with reduced Delta-9-desaturase activity was detected in patients with BCD, and the metabolic derangement was unaffected by CYP4V2 mutations. The findings suggest that systemic abnormality in fatty acid metabolism occurs in patients with BCD independent of CYP4V2 genotype.


Murine cutaneous responses to the rocky mountain spotted fever vector, Dermacentor andersoni, feeding.
Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, cutaneous responses at Dermacentor andersoni bite-sites were analyzed using Affymetrix mouse genome arrays and histopathology at 12, 48, 96 and 120 h post- infestation (hpi) during primary infestations and 120 hpi during secondary infestations. The microarray data suggests: (1) chemotaxis of neutrophils, monocytes, and other cell types; (2) production and scavenging of reactive oxygen species; and, (3) keratin- based wound healing responses. Histological analysis supported the microarray findings. At 12 hpi, a mild inflammatory infiltrate was present in the dermis, especially concentrated at the junction between dermal connective tissue and underlying adipose tissue. A small lesion was located immediately under the hypostome and likely represents the feeding "pool." Surprisingly, at 48 hpi, the number of inflammatory cells had not increased from 12 hpi, perhaps mirroring the reduction in gene expression seen at this time point. The feeding lesion is very well defined, and extravasated erythrocytes are readily evident around the hypostome. By 96 hpi, the inflammatory infiltrate has increased dramatically and the feeding lesion appears to have moved deeper into the dermis. At 120 hpi, most of the changes at 96 hpi are intensified. The infiltrate is very dense, the epidermis is markedly thickened, the feeding lesion is poorly defined and the dermal tissue near the hypostome appears to be loosing its normal architecture. In conclusion, during D. andersoni feeding infiltration of inflammatory cells increases across time concurrent with significant changes in the epidermal and dermal compartments near the feeding tick. The importance of changes in the epidermal layer in the host response to ticks is not known, however, it is possible the host attempts to "slough off" the tick by greatly increasing epithelial cell replication.


A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas.
While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution's Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, stratified by the most recent WHO classification. Thirty-one patients with atypical and 4 patients with malignant meningiomas treated with Gamma Knife radiosurgery between July 2000 and July 2011 were retrospectively reviewed. All patients underwent prior surgical resection. Overall survival was the primary endpoint and rate of disease recurrence in the brain was a secondary endpoint. Patients who had previous radiotherapy or prior surgical resection were included. Kaplan-Meier and Cox proportional hazards models were used to estimate survival and identify factors predictive of recurrence and survival. Post-Gamma Knife recurrence was identified in 11 patients (31.4%) with a median overall survival of 36 months and progression-free survival of 25.8 months. Nine patients (25.7%) had died. Three-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 65.0%, respectively. WHO grade II 3-year OS and PFS were 83.4% and 70.1%, while WHO grade III 3-year OS and PFS were 33.3% and 0%. Recurrence rate was significantly higher in patients with a prior history of benign meningioma, nuclear atypia, high mitotic rate, spontaneous necrosis, and WHO grade III diagnosis on univariate analysis; only WHO grade III diagnosis was significant on multivariate analysis. Overall survival was adversely affected in patients with WHO grade III diagnosis, prior history of benign meningioma, prior fractionated radiotherapy, larger tumor volume, and higher isocenter number on univariate analysis; WHO grade III diagnosis and larger treated tumor volume were significant on multivariate analysis. Atypical and anaplastic meningiomas remain difficult tumors to treat. WHO grade III diagnosis and treated tumor volume were significantly predictive of recurrence and survival on multivariate analysis in aggressive meningioma patients treated with radiosurgery. Larger tumor size predicts poor survival, while nuclear atypia, necrosis, and increased mitotic rate are risk factors for recurrence. Clinical and pathologic predictors may help identify patients that are at higher risk for recurrence.


Assessing water-quality changes in US rivers at multiple geographic scales using results from probabilistic and targeted monitoring.
Two commonly used approaches for water quality monitoring are probabilistic and targeted. In a probabilistic approach like the US Environmental Protection Agency's National Rivers and Streams Assessment, monitoring sites are selected using a statistically representative approach. In a targeted approach like that used by many monitoring organizations, monitoring sites are chosen individually to answer specific questions. One important goal of both approaches is documenting long-term changes in water quality. Here, we compare chloride change results in US rivers and streams between the early 2000s and early 2010s from both approaches. The probabilistic approach provided an unbiased representation of change in all US rivers and streams, but was designed to measure low-streamflow conditions within a spring/summer index period during periodic survey years. The targeted approach was focused on larger, more developed watersheds but samples were collected frequently throughout the assessment period in different seasons and streamflows. The probabilistic results showed a small decrease in chloride concentrations in rivers and streams with the lowest concentrations, but no consistent increase or decrease in the remainder. The increased granularity of the targeted results showed that there was, in fact, a mix of changes occurring, with increases at 132 sites, decreases at 112 sites, and relatively stable conditions at 55 sites. The combined results suggest that chloride is not responding to a widespread, common driver across the USA and that management of chloride would be most effective when targeted regionally or locally.


Clb6/Cdc28 and Cdc14 regulate phosphorylation status and cellular localization of Swi6.
Nuclear export of the transcription factor Swi6 during the budding yeast Saccharomyces cerevisiae cell cycle is known to require phosphorylation of the Swi6 serine 160 residue. We show that Clb6/Cdc28 kinase is required for this nuclear export. Furthermore, Cdc28 combined with the S-phase cyclin Clb6 specifically phosphorylates serine 160 of Swi6 in vitro. Nuclear import of Swi6 occurs concomitantly with dephosphorylation of serine 160 in late M phase. We show that Cdc14 phosphatase, the principal effector of the mitotic exit network, can trigger nuclear import of Swi6 in vivo and that Cdc14 dephosphorylates Swi6 at serine 160 in vitro. Taken together, these observations show how Swi6 dephosphorylation and phosphorylation are integrated into changes of Cdc28 activity governing entry and exit from the G1 phase of the cell cycle.


Assessment of technical skills of orthopaedic surgery residents performing open carpal tunnel release surgery.
Motor skills assessment is an important part of validating surgical competency. The need to test surgical skills competency has gained acceptance; however, assessment methods have not yet been defined or validated. The purpose of the present study was to evaluate the reliability and validity of four testing measures for the integrated assessment of orthopaedic surgery residents with regard to their competence in performing carpal tunnel release. Twenty-eight orthopaedic residents representing six levels of surgical training were tested for competence in performing carpal tunnel release on cadaver specimens. Four measures were used to assess competency. First, a web-based knowledge test of surgical anatomy, surgical indications, surgical steps, operative report dictation, and surgical complications was administered. Second, residents participated in an Objective Structured Assessment of Technical Skills; each resident performed surgery on a cadaver specimen. All residents were evaluated independently by two board-certified orthopaedic surgeons with a subspecialty certificate in hand surgery with use of a detailed checklist score, a global rating scale, and a pass/fail assessment. The time for completion of the surgery was also recorded. Each assessment tool was correlated with the others as well as with the resident's level of training. Significant differences were found between year of training and knowledge test scores (F = 7.913, p < 0.001), year of training and detailed checklist scores (F = 5.734, p = 0.002), year of training and global rating scale (F = 2.835, p = 0.040), and year of training and percentage pass rate (F = 26.3, p < 0.001). No significant differences were found between year of training and time to completion of the carpal tunnel release (F = 2.482, p < 0.063). The results of the present study suggest that both knowledge and cadaver testing discriminate between novice and accomplished residents. However, although failure of the knowledge test can predict failure on technical skills testing, the presence of knowledge does not necessarily ensure successful performance of technical skills, as cognitive testing and technical skills testing are separate domains.


Understanding the determinants of patient satisfaction with surgical care using the Consumer Assessment of Healthcare Providers and Systems surgical care survey (S-CAHPS).
Patient satisfaction has been emphasized increasingly in all aspects of medicine, including the imposition of financial penalties for underperformance. Current measures of patient satisfaction, however, do not address aspects specific to the care of operative patients. Therefore, our aim was to examine the recently validated Consumer Assessment of Healthcare Providers and Systems (S-CAHPS) to determine which aspects of perioperative care are predictive of satisfaction with the surgeon. All patients undergoing a general surgery operation at our institution during a 5-month period were sent a modified S-CAHPS within 3 days of discharge. Patients were then divided into 2 groups: those who rated their surgeon as the best possible and those giving a lower rating. Univariate and multivariate analyses were used to determine predictors of satisfaction with operative care. S-CAHPS results were then compared with other satisfaction measures in a subset of patients. The response rate was 45.3% (456/1,007). The average age was 59 ± 16 years, duration of stay was 4.1 ± 6.6 days, and 23% underwent unscheduled operations. A total of 72% of patients rated their surgeon as the best surgeon possible. On multivariate analysis, preoperative communication and attentiveness on the day of operation were the most important determinants of overall surgeon rating. S-CAHPS scores correlated with other standard measures of satisfaction (HCAHPS scores). S-CAHPS is a novel operative satisfaction tool and is feasible to administer to patients undergoing general operative procedures. Surgeon characteristics most predictive of high patient satisfaction are effective preoperative communication and attentiveness on the day of operation.


Experimental Research of Blood Collected From the Peripheral Side of the Fluid Infusion Site That Is Not Affected by Fluid Infusion.
The objective of this study was to determine a safe blood sample collection site for clinical investigations, in patients with an in situ intravenous line, which would minimize distress to the patient and provide accurate blood data. An intravenous line was established in the left upper limb for administration of Solita T3G (84 mL/h). After 5 min of infusion, two nurses simultaneously collected venous blood samples (vacuum blood collection method) from a site on dorsum of the left hand located 15 cm distal to the site of fluid infusion (the peripheral side), and the cubital fossa of the contralateral upper limb (the opposite side). The results obtained from the blood samples of the contralateral side served as the standard reference. Testing of 41 blood-cell tests and biochemical parameters were outsourced to a specialized company. Between-group differences in test results for the two locations were assessed using the paired t-test, with a significance level of < 5%. No significant differences in mean values (± standard deviation) of blood parameters were observed between the distal site and the contralateral side. Blood samples collected from a venous site located 15 cm distal to the fluid-infusion site did not show any effect of fluid infusion on the results.


Pure motor hemiplegia: CT study of 30 cases.
Pure motor hemiplegia (PMH) is a well defined syndrome usually caused by ischemic lesions of lacunar type located either in the internal capsule or in the pons. Angiography and isotope scanning are usually normal. CT scan reveals small deep infarcts and appears to be the most reliable investigative method. The CT scan findings are described of thirty patients with PMH of rapid onset (less than 36 hours). In 29 of the 30 cases a lesion was found which could explain the PMH. Small hemorrhages (2 cm in diameter) in the posterior limb of the internal capsule were noted in two cases. Ischemic lesions were found in 27 patients, 22 patients had a single lesion (20 capsular and 2 pontine), while 5 patients had 2 lesions (2 bi-capsular, 3 capsular and pontine). Three varieties of ischemic capsular lesions were observed. We found in 15 cases a capsulo-putamine-caudate infarct (type I); in 8 cases a capsulo-pallidal infarct (type II); and in 2 cases an anterior capsulo-caudate infarct (type III). Type I corresponded to the area of the lateral lenticulostriate branches of the middle cerebral artery. Type II involved the territory of the perforating branches of the anterior choroidal artery. We suggest that type III involves the territory of the internal lenticulostriate branches of the anterior cerebral artery. Lacunes are generally linked to arterial systemic hypertension. However, only 16 of 30 patients in this series were chronically hypertensive.


Discovery and Validation of Prognostic Biomarker Models to Guide Triage among Adult Dengue Patients at Early Infection.
Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue disease in 2009. However, WS is limited in stratifying adult dengue patients at early infection (Day 1-3 post fever), who require close monitoring in hospitals to prevent severe dengue. The aim of this study is to identify and validate prognostic models, built with differentially expressed biomarkers, that enable the early identification of those with early dengue infection that require close clinical monitoring. RNA microarray and protein assays were performed to identify differentially expressed biomarkers of severity among 92 adult dengue patients recruited at early infection from years 2005-2008. This comprised 47 cases who developed WS after first presentation and required hospitalization (WS+Hosp), as well as 45 controls who did not develop WS after first presentation and did not require hospitalization (Non-WS+Non-Hosp). Independent validation was conducted with 80 adult dengue patients recruited from years 2009-2012. Prognostic models were developed based on forward stepwise and backward elimination estimation, using multiple logistic regressions. Prognostic power was estimated by the area under the receiver operating characteristic curve (AUC). The WS+Hosp group had significantly higher viral load (P<0.001), lower platelet (P<0.001) and lymphocytes counts (P = 0.004) at early infection compared to the Non-WS+Non-Hosp group. From the RNA microarray and protein assays, the top single RNA and protein prognostic models at early infection were CCL8 RNA (AUC:0.73) and IP-10 protein (AUC:0.74), respectively. The model with CCL8, VPS13C RNA, uPAR protein, and with CCL8, VPS13C RNA and platelets were the best biomarker models for stratifying adult dengue patients at early infection, with sensitivity and specificity up to 83% and 84%, respectively. These results were tested in the independent validation group, showing sensitivity and specificity up to 96% and 54.6%, respectively. At early infection, adult dengue patients who later presented WS and require hospitalization have significantly different pathophysiology compared with patients who consistently presented no WS and / or require no hospitalization. The molecular prognostic models developed and validated here based on these pathophysiology differences, could offer earlier and complementary indicators to the clinical WHO 2009 WS guide, in order to triage adult dengue patients at early infection.


PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils.
Acute lung injury (ALI) can cause acute respiratory distress syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19. ARDS secondary to transfusion-related ALI (TRALI) has been recapitulated preclinically by anti-MHC-I antibody administration to LPS-primed mice. In this model, we demonstrate that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI and was associated with release of myeloperoxidase, suppression of neutrophil extracellular trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of PI3Kγ/AKT/mTOR, was essential for these effects, linking PTP1B inhibition to promoting an aged-neutrophil phenotype. Considering that dysregulated activation of neutrophils has been implicated in sepsis and causes collateral tissue damage, we demonstrate that PTP1B inhibitors improved survival and ameliorated lung injury in an LPS-induced sepsis model and improved survival in the cecal ligation and puncture-induced (CLP-induced) sepsis model. Our data highlight the potential for PTP1B inhibition to prevent ALI and ARDS from multiple etiologies.


Characterization of a sialate pyruvate-lyase in the cytosol of human erythrocytes.
Sialate pyruvate-lyases, also known as sialate aldolases (EC 184.108.40.206), reversibly catalyse the cleavage of free N-acetylneuraminic acids to form pyruvate and N-acetylmannosamine. These enzymes are widely distributed and are present in numerous pro- and eukaryotic cells, in which they are localized only in the cytosol. They play an important role in the regulation of sialic acid metabolism by controlling the intracellular concentration of sialic acids of biosynthetic or exogenous origin, thus preventing the accumulation of toxic levels of this sugar. Application of an original colorimetric micromethod for N-acetylmannosamine determination, as well as the use of [4,5,6,7,8,9-14C]N-acetylneuraminic acid, led us to evidence a cytosolic neuraminate aldolase activity in human red blood cells (RBCs) and then to define the main characteristics of this enzyme: Michaelis-Menten type, K(m:) 1.4 +/- 0.05 mM, optimal pH: 7.6 +/- 0.2, optimal temperature: 70 +/- 2 degrees C, inhibition by heavy metals: Ag(+) and Hg(++). These enzyme parameters are close to those of the bacterial and mammalian aldolases described up to now. At the moment, the presence of sialate pyruvate-lyase in the cytosol of red blood cells remains an enigma.