Variations of parathyroid hormone and bone biomarkers are concordant only after a long term follow-up in hemodialyzed patients.
End-stage renal disease is associated with mineral and bone disorders. Guidelines recommending therapies should be based on serial assessments of biomarkers, and thus on variations (Δ), rather than scattered values. We analyzed the correlations between ΔPTH and Δbone biomarkers such as bone-specific alkaline phosphatase (b-ALP), Beta-CrossLaps (CTX), osteocalcin, intact serum procollagen type-1 N-propeptide (P1NP), and tartrate-resistant acid phosphatase 5B (TRAP-5B) at different time-points. In this prospective observational analysis, variations of biomarkers were followed after 6-week (n = 129), 6-month (n = 108) and one-year (n = 93) period. Associations between variations were studied by univariate linear regression. Patients followed for one-year period were classified (increaser or decliner) according to variations reaching the critical difference. Over the 6-week period, only ΔCTX was correlated with ΔPTH (r = 0.38, p < 0.0001). Over the one-year period, correlations between ΔPTH and Δbone biomarkers became significant (r from 0.23 to 0.47, p < 0.01), except with ΔTRAP-5b. Correlations between Δbone biomarkers were all significant after one-year period (r from 0.31 to 0.68, p < 0.01), except between Δb-ALP and ΔTRAP-5b. In the head-to-head classifications (decliners/increasers), the percentage of concordant patients was significantly higher over the one-year than the 6-week period. A concordance between ΔPTH and Δbone biomarkers is observed in dialysis patients, but only after a long follow-up.


An adaptive technique for multiscale approximate entropy (MAEbin) threshold (r) selection: application to heart rate variability (HRV) and systolic blood pressure variability (SBPV) under postural stress.
Multiscale approximate entropy (MAE) is used to quantify the complexity of a time series as a function of time scale τ. Approximate entropy (ApEn) tolerance threshold selection 'r' is based on either: (1) arbitrary selection in the recommended range (0.1-0.25) times standard deviation of time series (2) or finding maximum ApEn (ApEnmax) i.e., the point where self-matches start to prevail over other matches and choosing the corresponding 'r' (rmax) as threshold (3) or computing rchon by empirically finding the relation between rmax, SD1/SD2 ratio and N using curve fitting, where, SD1 and SD2 are short-term and long-term variability of a time series respectively. None of these methods is gold standard for selection of 'r'. In our previous study [1], an adaptive procedure for selection of 'r' is proposed for approximate entropy (ApEn). In this paper, this is extended to multiple time scales using MAEbin and multiscale cross-MAEbin (XMAEbin). We applied this to simulations i.e. 50 realizations (n = 50) of random number series, fractional Brownian motion (fBm) and MIX (P) [1] series of data length of N = 300 and short term recordings of HRV and SBPV performed under postural stress from supine to standing. MAEbin and XMAEbin analysis was performed on laboratory recorded data of 50 healthy young subjects experiencing postural stress from supine to upright. The study showed that (i) ApEnbin of HRV is more than SBPV in supine position but is lower than SBPV in upright position (ii) ApEnbin of HRV decreases from supine i.e. 1.7324 ± 0.112 (mean ± SD) to upright 1.4916 ± 0.108 due to vagal inhibition (iii) ApEnbin of SBPV increases from supine i.e. 1.5535 ± 0.098 to upright i.e. 1.6241 ± 0.101 due sympathetic activation (iv) individual and cross complexities of RRi and systolic blood pressure (SBP) series depend on time scale under consideration (v) XMAEbin calculated using ApEnmax is correlated with cross-MAE calculated using ApEn (0.1-0.26) in steps of 0.02 at each time scale in supine and upright position and is concluded that ApEn0.26 has highest correlation at most scales (vi) choice of 'r' is critical in interpreting interactions between RRi and SBP and in ascertaining true complexity of the individual RRi and SBP series.


Efficacy and safety of supramolecular active zinc in the treatment of scalp psoriasis: a multicentre, randomized, observed-blind, parallel-group, placebo- and active-controlled noninferiority trial.
Controlling the relapses of scalp psoriasis is a clinical issue. To evaluate the efficacy and safety of a supramolecular active zinc antidandruff hair conditioner in managing scalp psoriasis (SP). This multicentre randomized, observed-blind, parallel-group, placebo- and active-controlled noninferiority trial enrolled 211 patients with SP between October 2018 and June 2019. The participants were randomized 1 : 1 : 1 to the experimental (supramolecular active zinc antidandruff hair conditioner), placebo (supramolecular hydrogel) or positive control (calcipotriol ointment) group. The primary efficacy endpoint was the disease control rate at the end of the fourth week of treatment, measured using the Investigator's Global Assessment score. This study included 70, 70 and 71 participants in the experiment, control and placebo groups, respectively. The disease control rates of SP at the end of week 4 of treatment in the full-analysis set (FAS) were 39%, 25% and 37% in the experimental, placebo and control groups. The margin of superiority between the experimental and placebo groups was > 0 [96% confidence interval (CI) 13.22% (0.43% to ∞)] in the FAS. The experimental group was superior to the placebo group. The noninferiority margin between the experiment and control groups was > -15% [96% CI -1.43% (-14.91% to ∞)] in the FAS. The experimental group was not inferior to the control group. Supramolecular active zinc antidandruff hair conditioner was helpful for the treatment of SP, and it has good clinical efficacy in maintaining therapeutic effect and assisting in preventing the recurrence of psoriasis.


Cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory drugs in the management of arthritis.
The management of arthritis pain should be individualized to the needs and characteristics of the patient. The decision to use nonsteroidal anti-inflammatory drugs (NSAIDs), and in particular the cyclooxygenase-2 (COX-2) inhibitors, is multidimensional. The challenge is to achieve optimal pain relief at the minimum dose to minimize adverse effects. Whenever possible, NSAIDs should be given as monotherapies or in combinations at the lowest effective doses. The COX-2 inhibitors are a safe choice for most patients who are at low risk for a cardiovascular event. Individuals who are at risk for thromboses should not receive unopposed COX-2 inhibitors; COX-2 should be given in combination with low-dose aspirin which is expected to be cardioprotective in high-risk patients.


Variations in tooth surface temperature in the oral cavity during fluid intake.
Measurements were made of the extremes in temperature which occur at different sites in the oral cavity during fluid intake. The results indicate that temperatures noted at the tooth surface, within the mouth, during fluid intake were less than the temperatures of the fluid imbibed. Variations in temperature were noted in different areas of the mouth. This may be associated with the position of the tongue during swallowing and the effect of the tissues of the oral cavity as heat absorbers. The range of temperatures noted at the tooth surface and the duration of the temperature changes were at variance with those utilized in many thermocycling studies. It is suggested that closer alignment with the clinical situation is desirable.


Photosensitizing properties and subcellular localisation of 3,4-dihydro-β-carbolines harmaline and harmalol.
Harmaline (1) and harmalol (2) represent two 3,4-dihydro-β-carboline (DHβCs) most frequently reported in a vast number of living systems. Fundamental aspects including the photosensitizing properties, cellular uptake, as well as the cyto- and phototoxicity of 1 and 2 were investigated herein. The molecular basis underlying the investigated processes are elucidated. Data reveal that both alkaloids show a distinctive pattern of extracellular DNA photodamage. Compound 1 induces a DNA photodamage profile dominated by oxidised purines and sites of base loss (AP sites), whereas 2 mostly induces single-strand breaks (SSBs) in addition to a small extent of purine oxidative damage. In both cases, DNA oxidative damage would occur through type I mechanism. In addition, a concerted hydrolytic attack is suggested as an extra mechanism accounting for the SSBs formation photoinduced by 2. Subcellular internalisation, cyto- and phototoxicity of 1 and 2 and the corresponding full-aromatic derivatives harmine (3) and harmol (4) also showed quite distinctive patterns in a structure-dependent manner. These results are discussed in the framework of the potential biological, biomedical and/or pharmacological roles reported for these alkaloids. The subtle structural difference (i.e., the exchange of a methoxy group for a hydroxyl substituent at C(7)) between harmaline and harmalol, gives rise to distinctive photosensitizing and subcellular localisation patterns.


Bioelectricity generation from human urine and simultaneous nutrient recovery: Role of Microbial Fuel Cells.
Urine is a 'valuable waste' that can be exploited to generate bioelectricity and recover key nutrients for producing NPK-rich biofertilizers. In recent times, improved and innovative waste management technologies have emerged to manage the rapidly increasing environmental pollution and to accomplish the goal of sustainable development. Microbial fuel cells (MFCs) have attracted the attention of environmentalists worldwide to treat human urine and produce power through bioelectrochemical reactions in presence of electroactive bacteria growing on the anode. The bacteria break down the complex organic matter present in urine into simpler compounds and release the electrons which flow through an external circuit generating current at the cathode. Many other useful products are harvested at the end of the process. So, in this review, an attempt has been made to synthesize the information on MFCs fuelled with urine to generate bioelectricity and recover value-added resources (nutrients), and their modifications to enhance productivity. Moreover, configuration and mode of system operation, and factors enhancing the performance of MFCs have been also presented.


Cell proliferation and apoptosis in rat mammary cancer after electrochemical treatment (EChT).
Several authors have recently reported encouraging results from Electrochemical treatment (EChT) in malignant tumours. However, EChT is not established and mechanisms are not completely understood. In vivo studies were conducted to evaluate the toxic changes and effectiveness of EChT on an animal tumour model. Tumours were induced by injecting cells from the R3230AC rat mammary tumour cell line clone D subcutaneously, in 28 female Fischer 344 rats. EChT was conducted by inserting a platinum electrode into the tumours. The positive and negative control groups were subjected to the same conditions but without current. The rats were kept for 0, 7 or 14 days post-treatment. Three hours prior to euthanasia an i.p. injection of Bromodioxyuridine (BrdU) was given. The rats were euthanized, the lesions extirpated and samples were collected for histopathological, and immunohistochemical examination. Significant changes in cell proliferation rate were seen both in the cathode and anode regions. Apoptosis were induced in the anodic treated area outside the primary necrosis, detected with the TUNEL method. The results suggest that secondary cell destruction was caused by necrosis with cathodic EChT and apoptosis or necrosis with anodic EChT.


Simultaneous determination of ascorbic acid and dehydroascorbic acid in fish tissues by high-performance liquid chromatography.
An high-performance liquid chromatographic method with post-column derivatization has been developed for the simultaneous determination of ascorbic acid (AA) and dehydroascorbic acid (DHAA) in fish tissues. Extracted AA and DHAA were separated by a Shim-pack SCR-1O1H column within 20 min, reacted with sodium hydroxide containing sodium borohydride and monitored at 300 nm. The detection limits for both AA and DHAA were 0.1 microgram/ml.


High Throughput Laser Process of Transparent Conducting Surfaces for Terahertz Bandpass Ultrathin Metamaterials.
Terahertz (THz) imaging has attracted much attention within the past decade as an emerging nondestructive evaluation technique. In this paper, we present a novel Laser-based Metamaterial Fabrication (LMF) process for high-throughput fabrication of transparent conducting surfaces on dielectric substrates such as glass, quartz and polymers to achieve tunable THz bandpass characteristics. The LMF process comprises two steps: (1) applying ultrathin-film metal deposition, with a typical thickness of 10 nm, on the dielectric substrate; (2) creating a ~100-micron feature pattern on the metal film using nanosecond pulsed laser ablation. Our results demonstrate the use of laser-textured ultra-thin film with newly integrated functional capabilities: (a) highly conductive with ~20 Ω/sq sheet resistance, (b) optically transparent with ~70% transmittance within visible spectrum, and (c) tunable bandpass filtering effect in the THz frequency range. A numerical analysis is performed to help determine the fundamental mechanism of THz bandpass filtering for the LMF-built samples. The scientific findings from this work render an economical and scalable manufacturing technique capable of treating large surface area for multi-functional metamaterials.


Phospholipid-sensitive Ca2+ -dependent protein kinase preferentially phosphorylates serine-115 of bovine myelin basic protein.
Phospholipid-sensitive Ca2+ -dependent protein kinase (PL-Ca-PK) and cyclic AMP-dependent protein kinase (A-PK) both preferentially phosphorylated serine residues of bovine myelin basic protein (MBP). Tryptic peptide maps of MBP phosphorylated by PL-Ca-PK or A-PK, however, revealed different phosphopeptides, suggesting a difference in the intramolecular substrate specificity for the two enzymes. Serine-115 of MBP, in the sequence (-Arg-Phe-Ser(115)-Trp-), was found to be a preferred and probably major phosphorylation site for PL-Ca-PK. Because serine-115 of bovine MBP corresponds to serine-113 of rabbit MBP, an in vivo phosphorylation site reported by Martenson et al. (1983), and PL-Ca-PK is present at a very high level in brain and myelin, it is suggested that the enzyme may be responsible for the in vivo phosphorylation of this and other sites in MBP.


Dopamine receptors and ergot drugs. Evidence that an ergolene derivative is a differential agonist at subcortical limbic dopamine receptors.
The actions of a new type of ergolene derivative, MPME ((5R, 8R)-8-(4-p-methoxyphenyl-1-piperazinyl methyl)-6-methylergolene), have been evaluated on central catecholamine (CA) neurons in the rat by means of a combined biochemical, histochemical and behavioural analysis. The evidence suggests that this ergolene derivative is a preferential agonist at subcortical limbic dopamine (DA) receptors and at DA receptors belonging to the neostriatal DA islands. (1) MPME does not change the DA and noradrenaline (NA) levels 4 h after the injection in doses ranging from 0.1 to 5 mg/kg. MPME significantly reduced DA turnover in doses from 0.5 to 5 mg/kg, whereas the NA turnover was increased in the same dose range. (2) Histochemically, using quantitative microfluorometry, DA levels were unchanged, except in the islands of the nucleus caudatus following administration of MPME. The drug selectively reduced DA turnover in the subcortical limbic regions (tuberculum olfactorium and nucleus accumbens) and in the DA terminal islands of the nucleus caudatus in doses of 1-5 mg/kg, whereas the large diffuse DA terminal systems of the nucleus caudatus were unaffected. Using this ergolene derivative the islandic small neostriatal DA system can be excellently demonstrated also in the adult rat. The effects of MPME on DA turnover, are blocked by haloperiodol but not by methergoline (which blocks 5-HT receptors). (3) Studies on uptake of tritiated DA in the nucleus caudatus and tuberculum olfactorium reveal a weak inhibition of DA uptake and retention only in high concentrations (10(-5)-10(-6) M). Such actions therefore can probably not explain the changes in DA turnover observed. (4) Behavioural effects of MPME were evaluated in the rotometer model of Ungerstedt25. This model will reveal actions on supersensitive striatal DA receptors. MPME was found to mimic the action of apomorphine and cause a prolonged rotational behaviour towards the nonoperated side in doses of 0.25-0.5 mg/kg. A marked potentiation of the action of MPME was obtained by means of pretreatment with phosphodiesterase inhibitors suggesting that the effect of MPME might be mediated by cyclic AMP. Studies with the DA receptor blocking agent pimozide indicated a high affinity of MPME for the supersensitive striatal DA receptors, since only very high doses of pimozide (15 mg/kg) were capable of blocking the actions of MPME. (5) Studies on the effect of MPME on DA sensitive adenylate cyclase in the nucleus caudatus and the subcortical limbic system (mainly tuberculum olfactorium and nucleus accumbens) suggested that MPME is a partial DA receptor agonist with different intrinsic activity on the DA receptors of the subcortical limbic system and of the nucleus caudatus, the effects in the subcortical limbic system being considerably larger than in the nucleus caudatus. Thus, the present paper gives evidence that the various DA receptor populations in the brain are sufficiently different to allow their preferential activation by drugs.


Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by delta 9-THC in the rat.
The cataleptogenic effect of delta 9-THC was compared to its discriminative stimulus effects in rats. The ED50s for the discriminative stimulus and catalepsy were 0.8 and 4.0 mg/kg, respectively, while their time courses were very similar. The ED50 of delta 9-THC for catalepsy in experimentally naive rats was not different from that in rats trained with the drug discrimination procedure, indicating that the cataleptogenic effect was not appreciably attenuated by long-term exposure to low doses of delta 9-THC. Pharmacologically, the catalepsy produced by delta 9-THC more closely resembled that of haloperidol than of morphine, since anticholinergic pretreatment eliminated the delta 9-THC-induced catalepsy while pre-treatment with naloxone had no effect. Although the cataleptogenic effect of delta 9-THC could be pharmacologically manipulated by anticholinergic pre-treatment, its discriminative stimulus effects were not changed in the same animals. These results demonstrate that distinctive mechanisms of action exist for these cannabinoid-induced behaviors.


Intra-procedural anticoagulation and post-procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants: comparisons across 4 drugs.
Thromboembolic or hemorrhagic complications related to atrial fibrillation (AF) ablation are rare, and thus, it is difficult to compare their frequency across different direct oral anticoagulants (DOACs). We aimed to compare the intra-ablation blood coagulability and post-procedural hemoglobin fall as alternatives to those complications across 4 DOACs. We enrolled AF patients younger than 65 years old in 3 cardiovascular centers who skipped a single dose of apixaban, dabigatran, edoxaban, and rivaroxaban, prior to the ablation. Endpoints included the activated clotting time (ACT), heparin requirement during the ablation, and drop in the hemoglobin level 24 h after the procedure. The time-course curves of the ACT differed significantly across the patients with apixaban (N = 113), dabigatran (N = 130), edoxaban (N = 144), and rivaroxaban (N = 81), with its highest level in the dabigatran group (P < 0.001). The average ACT was greater in the dabigatran group than in the other groups (312.3 ± 34, 334.4 ± 44, 308.1 ± 41, and 305.8 ± 34.7 s; P < 0.001). A significant difference was noted in total heparin requirement across the patient groups (3990.2 ± 1167.9, 3890.4 ± 955.3, 4423.8 ± 1051.6, and 3972 ± 978.7 U/m2/h; P < 0.001), with its greatest amount in the edoxaban group. The reduction in the hemoglobin level was similar (- 0.93 ± 0.92, - 0.88 ± 0.79, - 0.89 ± 0.97, - 0.95 ± 1.23 g/dL; P = 0.94). No inter-group difference was noted in the rate of major or minor bleedings (0.9%, 2.3%, 1.4%, and 3.7%; P = 0.51), and no thromboembolic events were encountered. A difference in DOACs may have an impact on intra-ablation anticoagulation; however, it may not be on the procedural blood loss in the setting of a single skip.


The interactions of alcohol and cocaine regulate the expression of genes involved in the GABAergic, glutamatergic and endocannabinoid systems of male and female rats.
Although the pharmacological and behavioural interactions between cocaine and alcohol are well established, less is known about how polyconsumption of these drugs affects the neurotransmitter systems involved in their psychoactive effects and in particular, in the process of addiction. Here, rats of both sexes at two stages of development were studied under a chronic regime of intravenous cocaine and/or alcohol administration. Brain samples from the medial prefrontal cortex, nucleus accumbens, hippocampus and amygdala were extracted to analyse the mRNA expression of genes encoding subunits of the GABA, NMDA and AMPA receptors, as well as the expression of the CB1 receptor, and that of enzymes related to the biosynthesis and degradation of endocannabinoids. Moreover, two synaptic scaffold proteins related to GABA and NMDA receptors, gephyrin and PSD-95, were quantified in Western blots. Significant interactions between cocaine and alcohol were common, affecting the GABAergic and endocannabinoid systems in the medial prefrontal cortex and amygdala of young adults, whereas such interactions were evident in the glutamatergic and endocannabinoid systems in adults, as well as a more pronounced sex effect. Significant interactions between these drugs affecting the scaffold proteins were evident in the medial prefrontal cortex and nucleus accumbens of young adults, and in the nucleus accumbens and amygdala of adults, but not in the hippocampus. These results highlight the importance of considering the interactions between cocaine and alcohol on neurotransmitter systems in the context of polyconsumption, specifically when treating problems of abuse of these two substances.


[Simple rapid test with carbonate/nitroprusside for the semiquantitative determination of cysteine in the urine--possible use for control of ascorbic acid therapy in cystine urolithiasis].
In this paper a method of semiquantitative cysteine determination is presented, which is based on the formation of a red cysteine-Na-nitroprusside salt. The method is a suitable rapid test for checking the process of ascorbic acid therapy in cystinuria and cystine urolithiasis patients. It guarantees acceptable reproducibility of values and can be easily carried out in every clinicochemical laboratory. With the K2CO3/nitroprusside test described and an additional cystine rapid test (Ni2+/S2O4(2-) tablet reagency) a separate semiquantitative differentiation of cysteine and cystine in fresh (!) urine is possible.


[Peritoneal dialysis catheter insertion under TAP block procedure: A pilot study].
The main objective of this study was to evaluate the feasibility of a laparotomy peritoneal dialysis insertion, under locoregional anesthesia, by transversus abdominis plane block anesthesia. This was a retrospective study of the peritoneal dialysis catheter insertion under transversus abdominis plane block anesthesia in our center between the September 1, 2011 and July 31, 2013. The transversus abdominis plane block procedure was used as an alternative to general anesthesia. Patients who underwent a peritoneal dialysis catheter insertion under transversus abdominis plane block anesthesia were included in the study. The main criterion of the study was the pain expressed by the patient during the procedure. Postoperative complications were also evaluated. The catheter function was assessed by an infusion and drainage test just after surgical procedure, 10 days after the insertion and at dialysis initiation. Thirty-seven patients who had one catheter insertion were included in the study. Among those 37 patients, 28 (75.7%), 26 (70.3%) and 31 (83.8%) respectively did not express any pain during the procedure, two and four hours after the catheter insertion. Of the 37 patients, 5 had an early postoperative complication (hematoma: 11%, hemoperitoneum: 3%). The peritoneal dialysis catheter function was estimated to be good just after the insertion and 10 days after the surgery for 35/37 (95%) patients. Among these 36 patients, 29 (81%) had a catheter function peritoneal dialysis initiation. The transversus abdominis plane block anesthesia should be considered as an alternative to general anesthesia for the peritoneal dialysis insertion in comorbid end stage renal disease patient.


Seasonal pollen flow and progeny diversity in Amianthium muscaetoxicum: ecological potential for multiple mating in a self-incompatible, hermaphroditic perennial.
The ecological potential for multiple mating is high in Amianthium muscaetoxicum. The percentage of long-distance pollinations (20-100 m) is greater than reported for most insect-pollinated systems. Estimations of neighborhood area are at least an order of magnitude larger than any previously reported for plant species. Seasonal effects on fluorescent dust dispersal indicate that neighborhood areas change during the flowering season. The number of flowers marked with fluorescent dust on an inflorescence increases with increasing inflorescence size, and the proportions of available inflorescences that are marked decrease with distance from the source. Allozyme analysis indicates that heterozygosity levels are typical of outcrossing plants. The diversity of seed genotypes is increased by increasing the size of the floral display. The present investigation is the first to consider the effects of floral display on seed diversity and adds to existing data indicating that inflorescence size is important to fecundity and/or pollen donation in some systems.


Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists.
Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H(3) receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K(+) channel and human alpha(1A)-adrenoceptor activities is the main focus of the present study.


Spatiotemporal arrangement of objects in activities with people with dementia.
This study shows how the spatial organization of objects and their use may impact locally produced order of activities and how that can affect the accomplishment of everyday activities by people with dementia. The study is based on ethnomethodological conversation analysis of eight and a half hours of video recordings in three different settings. Eighteen sequences of activities identified were multimodally transcribed and analyzed. The availability or non-availability of objects, their arrangements and manipulations play a crucial role in the management of the order of activities and may present both challenges and facilitations for people with dementia. The organizations of objects directly influence the order of the activity, and the objects' potential use may afford actions that deviate from the trajectory and the order of the main activity. One of the significant uses of objects is how they contribute to the perceptual field where attention is organized for building actions. Participants in activities modify the perceptual field by manipulating objects in the material surrounds in response to the relevancies resulting from the unfolding activities. Therefore, spatial contingency is significant in the accomplishment of activities by people with dementia. As it is not self-evident that verbal instructions may result in the instructed actions accordingly, the rearrangement of objects and making them timely available to people with dementia may increase the possibilities of keeping the order of the activities intact.


Acetazolamide and topiramate lower intracranial pressure through differential mechanisms: The effect of acute and chronic administration.
Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate. Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross-over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT-qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions. We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24-h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium-dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes. Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.


Cervical artery dissection-an easily neglected cause of stroke: a case report.
In recent years, the incidence of stroke has gradually increased in young people. There are many reasons causing stroke, including atherosclerosis, artery embolization, and cervical artery dissection and so on. However, cervical artery dissection is a major cause of stroke in young people. We present a case of ischemic stroke caused by dissection, whose distal vascular occlusion due to detachment of the thrombosis in the right internal carotid artery. A 33-year-old male patient was admitted to the hospital because of stroke. Imaging examination showed that there was no visualization of the right middle cerebral artery and there were a large number of mural thrombus in the C1 segment of the right internal carotid artery. After emergency surgery, the patient had vascular recanalization and the symptoms were significantly improved. Magnetic resonance imaging showed a high signal in the C1 segment of the right internal carotid artery, the abnormal signal disappeared after antiplatelet therapy. When a patient has symptoms of stroke, we need to explore the root cause of stroke. Especially in young people, cervical artery dissection is an important reason that can't be ignored. Through review and analysis of this case, we hope to improve the understanding of radiologists and clinicians about the cervical artery dissection, reduce the rate of misdiagnosis, and improve patients' prognosis.


[Synthesis of phenol-antigen conjugates by reacting N-hydroxysuccinimidic esters of hydroxybenzoic acids with human serum albumin and bovine gamma globulin].
Salicylic acid, beta-resorcylic acid and gentisic acid were acetylated and then reacted with N-hydroxysuccinimide according to the DDC procedure to give the corresponding activated esters. The reaction of these N-hydroxysuccinimidic esters with human serum albumin and bovine gamma globulin yielded modified proteins containing hydroxybenzoyl residues linked to amino groups, the mode of linkage being of the acid amide type.


Effect of the St. John's wort constituent hyperforin on docetaxel metabolism by human hepatocyte cultures.
St. John's wort is a commonly used herbal medication that increases cytochrome P450 3A (CYP3A) activity. Because docetaxel is inactivated by CYP3A, we studied the effects of the St. John's wort constituent hyperforin on docetaxel metabolism in a human hepatocyte model. Hepatocytes, isolated from three donor livers, were exposed to hyperforin (0.1, 0.5, or 1.5 micromol/L) or rifampin (10 micromol/L) for 48 hours. After 48 hours, hyperforin- or rifampin-containing medium was replaced with medium containing 100 micromol/L docetaxel. After 1 hour, docetaxel metabolism was characterized by liquid chromatography-tandem mass spectrometry. Subsequent incubations characterized the specific cytochrome P450s that produced the docetaxel metabolites observed in hepatocyte incubations. Rifampin induced docetaxel metabolism 6.8- to 32-fold above docetaxel metabolism in control cultures. Hyperforin induced docetaxel metabolism in all three hepatocyte preparations. Hyperforin induction was dose-dependent and, at maximum, was 2.6- to 7-fold greater than that in controls. Docetaxel metabolites identified in rifampin- and hyperforin-treated hepatocyte preparations included the previously described tert-butyl-hydroxylated metabolite and two previously unidentified metabolites involving hydroxylation on the baccatin ring. CYP3A4 produced the tert-butyl-hydroxylated metabolite and the two ring-hydroxylated metabolites. CYP2C8 produced one of the newly described ring-hydroxylated metabolites. Exposure to the St. John's wort constituent hyperforin induces docetaxel metabolism in vitro. This implies that subtherapeutic docetaxel concentrations may result when docetaxel is administered to patients using St. John's wort on a chronic basis. The results also show induction of previously undescribed metabolic pathways for docetaxel, one of which may be analogous to the known 6-alpha-hydroxylation of paclitaxel by CYP2C8.


Serosurveillance of SARS-CoV-2 in companion animals in Sarawak, Malaysia.
SARS-CoV-2 is a zoonotic betacoronavirus that was first reported at the dawn of 2019 in Wuhan, China and has since spread globally, causing an ongoing pandemic. Anthroponotic transmission was reported early, with confirmed infections reported in 26 species to date, including dogs and cats. However, there is a paucity of reports on the transmission of SARS-CoV-2 to companion animals, and thus, we aimed to estimate the seroprevalence of SARS-CoV-2 in dogs and cats in Sarawak, Malaysia. From August 2022 to 2023, we screened plasma samples of 172 companion animals in Sarawak, Malaysia, using a species-independent surrogate virus neutralization test. Our findings revealed the presence of neutralizing antibodies of SARS-CoV-2 in 24.5% (27/110) of dogs and 24.2% (15/62) of cats. To the best of our knowledge, this is the first report of the seroprevalence of SARS-CoV-2 in companion animals in Malaysia. Our findings emphasize the need for pet owners to distance themselves from their pets when unwell, and a strategy must be in place to monitor SARS-CoV-2 in companion animals to assess the potential impact of the virus on companion animals.


Totally laparoscopic associating simultaneous bile duct and portal vein ligation for planned hepatectomy for primary liver cancer: a case report.
Some patients with liver cancer lose the chance to have surgical treatment due to insufficient future remnant liver. To address this problem, individual or occlusion of both the portal vein and the bile duct was used to achieve quick hypertrophy. This is the first study reported in which simultaneous ligation of the portal vein and the bile duct was applied as the first step of planned hepatectomy of primary liver cancer. Here we report a case of a 38-year-old Asian male patient with hepatocellular carcinoma with tumor thrombus in the right anterior branch of the portal vein. Right hemihepatectomy can be curative, but patients face a high risk of liver failure because of the small volume of the remaining left liver lobe. Hence we developed a two-step liver resection strategy in which the patient underwent laparoscopic simultaneous bile duct and portal vein ligation of the right hepatic lobe prior to right hemihepatectomy under laparoscopy. Using this procedure, we achieved fast hypertrophy of the left liver lobe and successfully reversed the primary unresectability. This case report demonstrates that simultaneous bile duct and portal vein ligation may be a feasible option for those patients with liver cancer who cannot get surgical treatment due to insufficient future remnant liver.


Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
The apparent shortfall in prevention of coronary heart disease (CHD) noted in early hypertension trials has been attributed to disadvantages of the diuretics and beta blockers used. For a given reduction in blood pressure, some suggested that newer agents would confer advantages over diuretics and beta blockers. Our aim, therefore, was to compare the effect on non-fatal myocardial infarction and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril. We did a multicentre, prospective, randomised controlled trial in 19 257 patients with hypertension who were aged 40-79 years and had at least three other cardiovascular risk factors. Patients were assigned either amlodipine 5-10 mg adding perindopril 4-8 mg as required (amlodipine-based regimen; n=9639) or atenolol 50-100 mg adding bendroflumethiazide 1.25-2.5 mg and potassium as required (atenolol-based regimen; n=9618). Our primary endpoint was non-fatal myocardial infarction (including silent myocardial infarction) and fatal CHD. Analysis was by intention to treat. The study was stopped prematurely after 5.5 years' median follow-up and accumulated in total 106 153 patient-years of observation. Though not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs 474; unadjusted HR 0.90, 95% CI 0.79-1.02, p=0.1052), fatal and non-fatal stroke (327 vs 422; 0.77, 0.66-0.89, p=0.0003), total cardiovascular events and procedures (1362 vs 1602; 0.84, 0.78-0.90, p<0.0001), and all-cause mortality (738 vs 820; 0.89, 0.81-0.99, p=0.025). The incidence of developing diabetes was less on the amlodipine-based regimen (567 vs 799; 0.70, 0.63-0.78, p<0.0001). The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. On the basis of previous trial evidence, these effects might not be entirely explained by better control of blood pressure, and this issue is addressed in the accompanying article. Nevertheless, the results have implications with respect to optimum combinations of antihypertensive agents.


Animal excrement: a potential biomonitor of heavy metal contamination in the marine environment.
To assess the feasibility of using animal excrement to biomonitor the extent of heavy metal contamination in the marine environment, concentrations of mercury (Hg), lead (Pb), copper (Cu) and zinc (Zn) in the fresh excrement of seabirds and marine mammals, along with other biomaterials, from the Arctic, Antarctica (West and East), and Xisha Archipelago of the South China Sea were determined. Results show that the excrement of marine animals at higher trophic levels generally contained high levels of Hg, demonstrating the biomagnification of Hg through food chains in different remote regions. Significant variations in metal accumulation in the excrements were observed among the distinctive geographical areas, with the highest Hg concentration in Xisha Archipelago and the highest Pb concentration in the Arctic, which reflects different levels of air metal pollution at various sampling locations. Concentrations of Cu in the excrements primarily correlate to the geochemical background levels in the regions. High Cu concentrations were found near the Great Wall Station in West Antarctica where a copper mineralized belt exists. No clear spatial variation pattern was found for Zn accumulation in the excrement. This study shows that animal excrement can be used as bioindicators for the level of metal contamination in the marine environment, with the advantages of easy sampling, accurate detection (i.e., with high levels of metal accumulation), and reconstructing historical metal contamination trends by long-term monitoring of sedimentary excrements.


Impact of pneumococcal conjugate vaccines on microbial epidemiology and clinical outcomes of acute otitis media.
Acute otitis media (AOM) is the leading bacterial infection in childhood and the main reason for antibiotic prescriptions in children. The success of pneumococcal conjugate vaccines (PCVs) in reducing invasive pneumococcal disease has been demonstrated in many studies. Because Streptococcus pneumoniae is one of the two main bacterial species implicated in AOM, the incidence and characteristics of AOM might also be modified by PCVs. Pre-licensure controlled studies showed that the effect was modest. However, after PCV7 implementation, the impact on the AOM burden appeared to be more marked, despite the fact that serotype replacement in the nasopharynx was almost complete. Most data on the impact of PCVs on nasopharyngeal flora have been drawn from studies with PCV7. No difference was observed with PCV10 compared with PCV7 concerning S. pneumoniae and Haemophilus influenza carriage. For PCV13 compared with PCV7, additional reduction of carriage of serotypes 1, 6A, 7F, 6C, 19A, and 19F was observed, but for the other serotypes, the two PCVs seemed to have the same effect.


Mixed-backbone oligonucleotides as second-generation antisense agents with reduced phosphorothioate-related side effects.
Mixed-backbone oligonucleotides containing alternative phosphorothioate and phosphodiester linkages in the 2'-O-methylribonucleosides segment show increased affinity with complementary targets, increased stability towards nucleases in vitro and in vivo, and reduced phosphorothioate-related prolongation of partial thromboplastin time compared to phosphorothioate oligodeoxynucleotides, thereby providing antisense agents with reduced side effects.


Cooperation of N-Heterocyclic Carbenes on a Gold Surface.
Atomically precise tailoring of interface structures is crucial for developing functional materials. We demonstrate an N-heterocyclic carbene (NHC) based molecular tool, which modifies the structure of a gold surface with atomic accuracy by the formation of gold nanorods. After adsorption on the gold surface, individual surface atoms are pulled out by the NHCs, generating single-atom surface defects and mobile NHC-Au species. Atomistic calculations reveal that these molecular "ballbots" can act as assembling tools to dislocate individual surface atoms. The predicted functionality of these carbene-based complexes is confirmed by scanning tunneling microscopy measurements. Cooperative operation of these NHC-Au species induces a step-wise formation of gold nanorods. Consequently, the surface is re-structured by a zipper-type mechanism. Our work presents a foundation to utilize molecular-based nanotools to design surface structures.


Enhancing the physical and structural properties of poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone) copolymer fibers.
Nowadays, due to the methodological needs in the application of internal surgery new methods evolving novel design for surgical suture are recommended. In this work, the effect of cold drawing process and the thermal annealing process on the different optical and structural properties of surgical suture fibers were studied. For the thermal annealing process, samples of Monosyn monofilaments suture fibers were thermally annealed at temperatures ranging from 50 to 100 ° C for annealing time = 120 min. The thermal treatment was carried out under free end condition. For the cold drawing process, an Instron was used to mechanically draw and measures the tensile stress strain curve of Monosyn samples. Using differential scanning calorimetry, X-ray diffraction techniques, and optical polarizing microscope the different properties of the tested sutures, such as the crystallinity, sample radius, birefringence, molecular orientation, and tensile properties were measured. From the resulting data, there was a marked increase in the physical and structural properties during the thermal annealing and cold drawing processes. This means that a new reorientation of Monosyn suture molecular chains were performed and approved by calculating the different orientations f(θ) and fc . This is an important improvement for these biodegradable materials to widen their medical use and improve their clinical results. RESEARCH HIGHLIGHTS: The stress-strain curve for Monosyn surgical fiber is J shape and identical to the human tissue stress-stain curve. The different orientation calculated improve that the drawing process affect directly on the fiber chain orientations. The fiber chains orientation due to the cold drawing process causes strain induced crystallinity.


Perception of across-frequency asynchrony by listeners with cochlear hearing loss.
Cochlear hearing loss is often associated with broader tuning of the cochlear filters. Cochlear response latencies are dependent on the filter bandwidths, so hearing loss may affect the relationship between latencies across different characteristic frequencies. This prediction was tested by investigating the perception of synchrony between two tones exciting different regions of the cochlea in listeners with hearing loss. Subjective judgments of synchrony were compared with thresholds for asynchrony discrimination in a three-alternative forced-choice task. In contrast to earlier data from normal-hearing (NH) listeners, the synchronous-response functions obtained from the hearing-impaired (HI) listeners differed in patterns of symmetry and often had a very low peak (i.e., maximum proportion of "synchronous" responses). Also in contrast to data from NH listeners, the quantitative and qualitative correspondence between the data from the subjective and the forced-choice tasks was often poor. The results do not provide strong evidence for the influence of changes in cochlear mechanics on the perception of synchrony in HI listeners, and it remains possible that age, independent of hearing loss, plays an important role in temporal synchrony and asynchrony perception.


Arrhythmia-Induced Cardiomyopathies: Mechanisms, Recognition, and Management.
Arrhythmia-induced cardiomyopathy (AIC) is a potentially reversible condition in which left ventricular dysfunction is induced or mediated by atrial or ventricular arrhythmias. Cellular and extracellular changes in response to the culprit arrhythmia have been identified, but specific pathophysiological mechanisms remain unclear. Early recognition of AIC and prompt treatment of the culprit arrhythmia using pharmacological or ablative techniques result in symptom resolution and recovery of ventricular function. Although cardiomyopathy in response to an arrhythmia may take months to years to develop, recurrent arrhythmia can result in rapid decline in ventricular function with development of heart failure, suggesting residual ultrastructural abnormalities. Reports of sudden death in patients with normalized left ventricular ejection fraction cast doubt on the complete reversibility of this condition. Several aspects of AIC, including specific pathophysiological mechanisms, predisposing factors, optimal therapeutic strategies to prevent ultrastructural changes, and long-term risk of sudden death remain unresolved and need further research.


Structures, stabilities and piezoelectric properties of Janus gallium oxides and chalcogenides monolayers.
Due to losing out-of-surface symmetry and the induced built-in dipole, two-dimensional (2D) Janus structures were believed to have various potential applications in the fields of piezoelectric devices, photocatalysis and electrochemical catalysis. In this work, 2D gallium oxides and chalcogenides (GaX) derived Janus monolayers Ga2XY (X/Y = O, S, Se, and Te) were designed. Our first-principles calculations showed that apart from Ga2OTe, all the monolayers are thermodynamically, dynamically and mechanically stable. These monolayers are demonstrated to be semiconductors with the band gaps in a wide range of 1.00-3.24 eV. The calculated in-plane piezoelectric coefficients of Janus monolayers (d 11 = 3.09-5.67 pm V-1) are demonstrably enhanced with respect to the pristine monolayers (d 11 = 0.41-3.04 pm V-1). Meanwhile, the yielding additional out-of-plane piezoelectric coefficients range from 0.11 to 0.34 pm V-1. Interestingly, O-participated Janus monolayers display distinctive properties: dipole direction flipping from O to S/Se, high stabilities and moderate direct-band-gaps. Particularly, Ga2OSe monolayer was found to have the largest piezoelectric coefficient of 5.67 pm V-1, which can be ascribed to the highly imbalanced charge distribution on O and Se as well as the largest bond length differences between Ga-O and Ga-Se. Our study revealed that the Janus Ga2XY monolayers, especially O-related systems, could be pretty promising as candidates in optoelectronic, piezoelectric sensors and energy conversion devices.


Effect of citrate buffer on hydrogen production by photosynthetic bacteria.
The effect of citrate buffer on biohydrogen production using photosynthetic bacteria was studied. The study was performed in two steps. First, specific concentrations of citrate and sodium citrate as buffers were mixed into batch cultures, and the effects of these buffers on fermentation broth characteristics and biohydrogen production were analyzed. The maximum overall biohydrogen yield of 411.4 mL, which was 42% higher to the control group, was obtained with 0.05 mol/L citrate buffer. Then, the effect of 0.05 mol/L citrate buffer on biohydrogen yield at different pH values (5.5-7.5) were explored. The maximum biohydrogen yield of 429.82 mL was obtained at pH 6, and the final pH values were effectively controlled. The findings indicated that citrate buffer seriously affected the pH of the reaction liquid. The results provide technical support to stabilize the pH of photo-fermentation broth and improve biohydrogen production performance.


Serological response to pgp3 protein in animal and human chlamydial infections.
Specific antibodies to plasmid-encoded protein pgp3 are known to be encountered in human Chlamydia (C.) trachomatis infections. In order to verify whether antibodies to this protein could be developed in animals infected with plasmid-carrying chlamydial strains, 454 animal sera were examined using a home-made pgp3 protein ELISA and Western blots (WB) of recombinant pgp3 protein from Chlamydophila (Cp.) psittaci. Likewise, 50 human sera were tested by ELISA and WB of recombinant pgp3 from C. trachomatis. The reactivity against pgp3 protein was compared to the reactivity against chlamydial elementary bodies (EBs) detected by microimmunofluorescence (MIF) test. The presence of pgp3-specific antibodies was demonstrated in most ducks and pigeons with Cp. psittaci infection detected by MIF, as well as in the majority of symptomatic cats and pigs infected with Cp. felis and C. suis, respectively, which reacted at high titres to Cp. felis and C. suis EBs by MIF. Moreover, most of the sera collected from patients with C. trachomatis culture-confirmed infection and seropositive to C. trachomatis by MIF, presented antibodies specific to C. trachomatis pgp3 recombinant protein. Therefore, pgp3 protein could be a useful marker of chlamydial infections in animals, as well as in humans.


Transcription factor binding to the core promoter of the human monoamine oxidase B gene in the cerebral cortex and in blood cells.
Many studies show that monoamine oxidase B in blood cells is a biological marker for personality characteristics such as sensation seeking. The mechanism underlying this association is so far not explored. In the present study we have performed electrophoretic mobility-shift assays to investigate the pattern of protein binding to a 150 bp fragment of the proximal 5'-flanking region of the human monoamine oxidase B gene. We compared the pattern using nuclear extracts from human brain and lymphocytes. Interestingly, a correlation was observed between monoamine oxidase B enzyme activity in blood cells (platelets) and the binding pattern of two uncharacterized transcription factors. These data are well in line with the long-standing notion that interindividual differences in platelet monoamine oxidase may represent differences in expression of the enzyme rather than genotypic variation.


The rewarming benefit of anterior torso heat pad application in mildly hypothermic conscious adult trauma patients remains inconclusive.
The rewarming benefit of anterior torso heat pad application in mildly hypothermic conscious adult trauma patients remains inconclusive in this randomized comparative clinical trial. There was no between-group rewarming gain in ear canal temperature when an anterior torso chemical heat pad was compared with blankets. Patient awareness, and favorable perception of, being administered the active intervention (heat pad) could explain the significant improvement in patient-rated cold discomfort discerned with the heat pad. In the context of marginal demonstrated benefit, it would have been informative to ascertain adverse effects related to the heat pad, including burn injury to the chest wall.


Normal paediatric bone marrow: magnetic resonance imaging appearances from birth to 5 years.
Bone marrow (BM) assessment is an important aspect of paediatric MRI, with the marrow cavity visible on almost every clinical MR examination. In practice, however, assessment for marrow infiltration in paediatric patients can be challenging. Our aim was to review the MRI appearance of normal BM from 0 to 5 years. Consecutive body MR examinations over 7 years were retrospectively reviewed in patients aged 0-5 years. Patients with anticipated BM abnormality were excluded. All patients had imaging of the spine and/or pelvis with T1-weighted (T1) ± T2 with fat saturation, post-contrast T1-weighted, diffusion-weighted or out-of-phase sequences. Nineteen patients were included: nine (47%) infants, 11 (58%) boys, mean age 18.2 months (range 1 day to 3 years and 10 months). On T1 imaging, 69% infant marrow sites and 24% in children >1 year were isointense, the remainder were hyperintense. One hundred per cent BM was T2 fat saturation hyperintense. Enhancement following contrast was seen in 16% of BM sites. Restricted diffusion was seen in 100% infant BM and 50% BM in children >1 year. On out-of-phase imaging, no signal loss was seen in infants, and 21% BM in children >1 year showed signal loss. Due to normal age-related differences in BM histology, MRI for marrow assessment in infants and young children can be misleading and may mimic marrow infiltration.


Effects of transforming growth factor-beta 2, interleukin 6 and fibronectin on corneal epithelial wound healing.
The aim of this study was to compare the effects of topically applied transforming growth factor-beta 2 (TGF-beta 2) and interleukin 6 (IL-6), alone and combined with fibronectin, on the rate of corneal wound healing in rabbits. Twenty-eight rabbits were used for the experiment. After the right eye of each rabbit was debrided with n-heptyl alcohol, the animals were divided into four treatment groups (six rabbits per group) and one control group (four rabbits). The debrided eyes were treated, beginning immediately after wounding and continuing every 2 hours from 8 a.m. to 8 p.m. for 48 hours. Group 1 received TGF-beta 2; group 2 IL-6; group 3, TFR-beta 2 and purified fibronectin; group 4, IL-6 and fibronectin; control group, balanced salt solution. At set intervals each eye was stained with fluorescein and photographed; epithelial defects were measured with a computer-assisted digitizer. The healing rate was calculated by linear regression analysis. The mean healing rates in groups 1, 2, 3, 4, and controls were respectively 1.65 +/- 0.16, 1.68 +/- 0.11, 1.99 +/- 0.12, 2.23 +/- 0.09, and 0.93 +/- 0.18 mm2/h. Mean epithelial healing rates for all drug-treatment groups were significantly faster than controls. The healing rates of groups 3 and 4 were significantly faster than groups 1 and 2. We conclude that cytokines, in combination with extracellular matrix proteins, facilitate corneal epithelial wound healing in vivo, possibly by making corneal epithelial cells more sensitive to fibronectin receptors.


Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy.
B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting.


A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus.
The pyramidal neurons in the CA1 area of hippocampal slices from 17- to 19-day-old rats have been investigated by means of patch clamp. Excitatory postsynaptic currents (EPSCs) were elicited by stimulating the Schaffer collateral at a frequency below 0.2 Hz. It was found that inhibition of glutamatergic transmission by 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 100 microM 2-amino-5-phosphonovaleric acid (D-APV) left a small component of the EPSC uninhibited. The amplitude of this residual EPSC (rEPSC) comprised 25 +/- 11% of the total EPSC when measured at a holding potential of -50 mV. The rEPSC was blocked by selective P2 blocker pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS) 10 microM and bath incubation with non-hydrolysable ATP analogues, ATP-gamma-S and alpha, beta-methylene-ATP at 50 and 20 microM, respectively. The rEPSC was dramatically potentiated by external Zn2+ (10 microM). In another series of experiments exogenous ATP was applied to the CA1 neurons in situ. An inward current evoked by ATP was inhibited by PPADS to the same extent as the rEPSC. It is concluded that, depending on membrane voltage, about one-fifth to one-quarter of the EPSC generated by the excitatory synaptic input to the hippocampal CA1 neurons of rat is due to the activity of P2X receptors.


Overuse and abuse of Swan-Ganz catheters.
The widespread use of the Swan-Ganz catheter is a result of a general misconception. It is widely accepted that the collection of data is a way of practicing scientific medicine. That is simply not true. The data must on balance contribute to a better outcome for patients as established by a scientific trial. The present widescale use of the catheter provides a striking example of the misuse or even mindless use of technology. Because of a tenuous risk-benefit balance, it is not at all certain that the general use of the Swan-Ganz catheter is justifiable and its use at best is semi-scientific. A reasonable approach would be to suspend its use pending an appropriate clinical trial which established safety and efficacy. Although the prospects for a clinical trial are bright, the prospects for a moratorium are not at all bright. While awaiting the results of an appropriate trial, individual physicians should only use the catheter when the probability is high that the data obtained by its use will provide more effective decision making. Such an approach by itself should result in a near-moratorium. Its present use is not a form of scientific medicine but at best a form of semi-scientific clinical practice.


Adult lifetime body mass index trajectories and endometrial cancer risk.
To identify body mass index (BMI) trajectories in adult life and to examine their association with endometrial cancer (EC) risk, also exploring whether relations differ by hormonal replacement therapy use. Pooled analysis of two case-control studies. Italy and Switzerland. A total of 458 EC cases and 782 controls. We performed a latent class growth model to identify homogeneous BMI trajectories over six decades of age, with a polynomial function of age. Odds ratios (ORs) and the corresponding 95% CI for EC risk were derived through a multiple logistic regression model, correcting for classification error. The relation of BMI trajectories with endometrial cancer. We identified five BMI trajectories. Compared with women in the 'Normal weight-stable' trajectory, a reduction by about 50% in the risk of EC emerged for those in the 'Underweight increasing to normal weight' (95% CI 0.28-0.99). The 'Normal weight increasing to overweight' and the 'Overweight-stable' trajectories were associated with, respectively, an excess of 3% (95% CI 0.66-1.60) and of 71% (95% CI 1.12-2.59) in cancer risk. The OR associated to the trajectory 'Overweight increasing to obese' was 2.03 (95% CI 1.31-3.13). Stronger effects emerged among hormonal replacement therapy never users (OR 2.19 for the 'Overweight-stable' trajectory and OR 2.49 for the 'Overweight increasing to obese' trajectory). Our study suggests that longer exposure to overweight and obesity across a lifetime is associated with an increased risk of endometrial cancer. Weight during adulthood also appears to play an important role. Longer exposure to overweight and obesity across a lifetime is associated with an increased risk of endometrial cancer.


Acute liver failure and severe hemophagocytosis secondary to parvovirus B19 infection.
Parvovirus infection presenting as severe hemophagocytosis is extremely rare. We report a 13-year-old girl with acute parvovirus infection who had severe hemophagocytosis resulting in severe pancytopenia and hepatic failure.


Thermodynamics of an aminoglycoside modifying enzyme with low substrate promiscuity: The aminoglycoside N3 acetyltransferase-VIa.
Kinetic, thermodynamic, and structural properties of the aminoglycoside N3-acetyltransferase-VIa (AAC-VIa) are determined. Among the aminoglycoside N3-acetyltransferases, AAC-VIa has one of the most limited substrate profiles. Kinetic studies showed that only five aminoglycosides are substrates for this enzyme with a range of fourfold difference in kcat values. Larger differences in KM (∼40-fold) resulted in ∼30-fold variation in kcat /KM . Binding of aminoglycosides to AAC-VIa was enthalpically favored and entropically disfavored with a net result of favorable Gibbs energy (ΔG < 0). A net deprotonation of the enzyme, ligand, or both accompanied the formation of binary and ternary complexes. This is opposite of what was observed with several other aminoglycoside N3-acetyltransferases, where ligand binding causes more protonation. The change in heat capacity (ΔCp) was different in H2 O and D2 O for the binary enzyme-sisomicin complex but remained the same in both solvents for the ternary enzyme-CoASH-sisomicin complex. Unlike, most other aminoglycoside-modifying enzymes, the values of ΔCp were within the expected range of protein-carbohydrate interactions. Solution behavior of AAC-VIa was also different from the more promiscuous aminoglycoside N3-acetyltransferases and showed a monomer-dimer equilibrium as detected by analytical ultracentrifugation (AUC). Binding of ligands shifted the enzyme to monomeric state. Data also showed that polar interactions were the most dominant factor in dimer formation. Overall, thermodynamics of ligand-protein interactions and differences in protein behavior in solution provide few clues on the limited substrate profile of this enzyme despite its >55% sequence similarity to the highly promiscuous aminoglycoside N3-acetyltransferase. Proteins 2017; 85:1258-1265. © 2017 Wiley Periodicals, Inc.


Clustered base substitutions in CTP synthetase conferring drug resistance in Chinese hamster ovary cells.
Dominantly acting mutations that eliminate the allosteric regulation of CTP synthetase confer a form of multidrug resistance and a mutator phenotype to cultured Chinese hamster ovary cells. Mutations responsible for this phenotype have been identified in 23 independent strains selected for resistance to arabinosyl cytosine and 5-fluorouracil. All these mutations were due to base substitutions at seven sites within a highly conserved region of the ctps gene. This clustering should make it feasible to assess the role of such mutations in the development of drug resistance encountered in the treatment of malignant disease.


Religiosity, depression, and quality of life in Korean patients with breast cancer: a 1-year prospective longitudinal study.
To investigate the association among religiosity and depression, anxiety, and quality of life in women with breast cancer. The sample consisted of 284 patients with breast cancer who were undergoing surgery. They were assessed with the following instruments at baseline and at 1 year after surgery: the Duke Religious Index (DRI), the Montgomery-Asberg Depression Rating Scale, the Hospital Anxiety Depression Scale, and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Depression was diagnosed with the Mini International Neuropsychiatric Interview. The prevalence of depression at baseline and at 1 year was 22.5% and 16.5%, respectively. The religious groups did not differ significantly with respect to the prevalence of depression or scores on psychiatric measures at either baseline or at 1 year. The prevalence of depression significantly decreased only in the Protestant group, from 30.1% to 15.7%. Scores on the DRI were significantly negatively correlated with scores on all of the anxiety and depression scales at 1 year after surgery in this group. In contrast, scores on the religious activity subscale of the DRI were significantly positively correlated with scores on the Hospital Anxiety Depression Scale at baseline or at 1 year among Catholic participants. The DRI scores of Protestant respondents were significantly positively correlated with scores on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 at 1 year after surgery. Religiosity plays an important role in the emotional state and quality of life of Korean women with breast cancer. However, its clinical meaning may differ according to the type of religious affiliation and the stage of illness.


Effects of dynamic cardiomyoplasty on left ventricular systolic and diastolic performance in an acute canine model.
Although dynamic cardiomyoplasty (DCMP) is currently being evaluated as an alternative to end-stage congestive heart failure, the overall results of DCMP are variable and inconclusive. We evaluated the effect of classic DCMP on systolic and diastolic cardiac function in normal heart using reliable indicators which minimize the influences of load conditions. Six experimental dogs were evaluated with the acute nonpreconditioning model. The slope of the linear preload recruitable stroke work relationship (Mw) showed a significant increase with latissimus dorsi muscle (LDM) stimulation (postwrap non-stimulation 59.1+/-6.3, postwrap stimulation 98.6+/-9.7 erg cm(-3) x 10(3); P < 0.01), and the x-intercept (V0) was unchanged; these were utilized as the indicators of left ventricular systolic function. The constant of pressure decay (tau) increased after LDM wrap (prewrap 45.8+/-6.0, postwrap nonstimulation 69.3+/-10.3, postwrap stimulation 72.3+/-13.9 ms; P < 0.05), and the peak filling rate was unchanged after LDM wrap, which were utilized as the indicators of diastolic function. We concluded that classic dynamic cardiomyoplasty is effective in assisting systolic cardiac function, but may to some degree have a detrimental effect on the diastolic cardiac function.


Preclinical atherosclerosis and cardiovascular events: Do we have a consensus about the role of preclinical atherosclerosis in the prediction of cardiovascular events?
Atherosclerosis has a long preclinical phase, and the risk of cardiovascular (CV) events may be high in asymptomatic subjects. Conventional risk factors provide information for the statistical probability of developing CV events, but they lack precision in asymptomatic subjects. This review aims to summarize the role of some widely publicized indicators of early atherosclerosis in predicting CV events. The earliest measurable indicator of the atherosclerotic process is endothelial dysfunction, measured by flow-mediated dilation (FMD) of the brachial artery. However, reduced FMD is a stronger predictor of future CV events in patients with existing CV disease than in apparently healthy persons. Alternatively, measurement of carotid artery intima-media thickness does not improve the predictive value of risk factor scores, while detection of asymptomatic atherosclerotic plaques in carotid or common femoral arteries by ultrasound indicates high CV risk. Coronary calcium is a robust and validated help in the estimation of vascular changes and risk, which may improve risk stratification beyond traditional risk factors with relatively low radiation exposure. Arterial stiffness of the aorta, measured as the carotid-femoral pulse wave velocity is an independent marker of CV risk at the population level, but it is not recommended as a routine procedure because of measurement difficulties. Low ankle-brachial index (ABI) indicates flow-limiting atherosclerosis in the lower limbs and indicates high CV risk, while normal ABI does not rule out advanced asymptomatic atherosclerosis. Novel circulating biomarkers are associated with the atherosclerotic process. However, because of limited specificity, their ability to improve risk classification at present remains low.


Human Cooperation When Acting Through Autonomous Machines.
Recent times have seen an emergence of intelligent machines that act autonomously on our behalf, such as autonomous vehicles. Despite promises of increased efficiency, it is not clear whether this paradigm shift will change how we decide when our self-interest (e.g., comfort) is pitted against the collective interest (e.g., environment). Here we show that acting through machines changes the way people solve these social dilemmas and we present experimental evidence showing that participants program their autonomous vehicles to act more cooperatively than if they were driving themselves. We show that this happens because programming causes selfish short-term rewards to become less salient, leading to considerations of broader societal goals. We also show that the programmed behavior is influenced by past experience. Finally, we report evidence that the effect generalizes beyond the domain of autonomous vehicles. We discuss implications for designing autonomous machines that contribute to a more cooperative society.


Multitasking and the technical quality of the electrocardiogram.
The electrocardiogram (ECG) is a powerful clinical tool for diagnosing cardiac abnormalities. Proper ECG data acquisition is essential because it allows physicians to interpret ECG results accurately and efficiently. This is especially important for patients with acute myocardial infarction, so that they can receive early treatment. As a result of multitasking, ECGs are acquired by two groups of personnel at the University of Alberta Hospital, Edmonton - ECG technologists and non-ECG technologists. To evaluate the effectiveness and quality of ECG acquisition at the University of Alberta Hospital site. All adult ECGs acquired at the University of Alberta Hospital site from January 1 to June 30, 2000 were assessed. An ECG was classified as unacceptable if it lacked demographics identifying the patient, and/or it was of such poor technical quality that the interpretation was compromised. Of 25,509 ECGs acquired during this period, 13,849 (54%) and 11,660 (46%) ECGs were acquired by ECG technologists and non-ECG technologists, respectively. Eleven ECGs (0.08%) acquired by the ECG technologists and 3683 ECGs (32%) acquired by the non-ECG technologists were of unacceptable quality. The technical cost spent on these unacceptable ECGs is approximately $100,000 a year at this institution. Multitasking has resulted in a high rate of unacceptable ECGs. There is a significant difference in the effectiveness and quality of ECG acquisition performed by ECG technologists and non-ECG technologists. Poorly acquired ECGs impede proper diagnosis for patients, subject the institution to potential medical legal consequences and add an unnecessary burden to the health care budget.


Physicochemical properties and release characteristics of starches from seeds of Indian Shahi Litchi.
Many conventional sources of starches are from staple foods. Non-conventional and cheap sources of starch are being explored. Starch was isolated from Shahi Litchi seeds using two extraction media; acidic (citric acid 0.3%, w/w; LC) and alkaline (NaOH 0.5%, w/w; LN). Each starch was investigated for various properties such as structural, morphological and functional. The percentage yield of LN and LC was 11% and 12.6%, respectively. Morphological properties of both starches show same structural makeup, but compound granules were in LN starch. Moisture content, amylose content was found to be higher LC starch than in LN starch, which indicates that extraction media affects the properties of starch. FTIR confirmed the carbohydrate nature of the both isolated starches. TGA data of both starches reveal slight difference in stability with temperature. In vitro release of both starches shows the release up to 58.95±0.04% and 67.184±0.07% in 5h for LN and LC, respectively, that indicates that these starches can be used in delayed drug delivery and targeting drugs to the colon.


Influence of infection with non-filarial helminths on the specificity of serological assays for antifilarial immunoglobulin G4.
Serological assays based on the detection of immunoglobulin (Ig) G4 antibodies to crude filarial extracts are widely used for epidemiological and diagnostic purposes. We tested 195 samples collected in 1998 from an area of Brazil where filariasis is not endemic and 13 (6.7%) had levels of antifilarial IgG4 antibodies that were defined as positive. Both Strongyloides infection and the presence of Strongyloides antibody responses were associated with higher antifilarial antibody responses. None of the specimens had a positive response to the Brugia malayi recombinant antigen (Bm14). These data suggest that serodiagnostic assays based on the use of crude filarial antigens should be interpreted with caution because of the potential for cross-reactivity with Strongyloides.


Enrollment of Neonates in More Than One Clinical Trial.
Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks' gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.


Post-traumatic stress disorder: review of the Comprehensive Soldier Fitness program.
Since the start of the wars in Afghanistan and Iraq, the U.S. military has implemented several population-based initiatives to enhance psychological resilience and prevent psychological morbidity in troops. The largest of these initiatives is the Army's Comprehensive Soldier Fitness (CSF) program, which has been disseminated to more than 1 million soldiers. However, to date, CSF has not been independently and objectively reviewed, and the degree to which it successfully promotes adaptive outcomes and prevents the development of deployment-related mental health disorders such as post-traumatic stress disorder (PTSD) is uncertain. This paper critically evaluates the theoretic foundation for and evidence supporting the use of CSF.


The role of the adjacency between background cues and objects in visual localization during ocular pursuit.
Subjects used eye movements to pursue a light target that moved from left to right with a velocity of 15 deg s-1. The stimulus was a sudden five-fold decrease in target intensity during the movement. The subject's task was to localize the stimulus relative to either a single stationary background point or the midpoint between two points (28 deg apart) placed 0.5 deg above the target path. The stimulus was usually mislocated in the direction of eye movement; the mislocation was affected by the spatial adjacency between background and stimulus. When an auditory, rather than a visual, stimulus was presented during tracking, target position at the time of stimulus presentation was visually mislocated in the direction opposite to that of eye movement. The effect of adjacency between background and target remained the same. The involvement of processes of subject-relative and object-relative visual perception is discussed.


A vibrotactile wristband to help older pedestrians make safer street-crossing decisions.
Older pedestrians are overrepresented in fatal accidents. Studies consistently show gap-acceptance difficulties, especially in complex traffic situations such as two-way streets and when vehicles approached rapidly. In this context, the present research was aimed at assessing the effectiveness of a vibrotactile device and study older pedestrian's behavior when wearing the wristband designed to help them make safer street-crossing decisions. Twenty younger-old participants (age 60-69), 20 older-old participants (age 70-80) and 17 younger adults (age 20-45) carried out a street-crossing task in a simulated two-way traffic environment with and without a vibrotactile wristband delivering warning messages. The percentage of decisions that led to collisions with approaching cars decreased significantly when participants wore the wristband. Benefits tended to be greater particularly among very old women, with fewer collisions in the far lane and when vehicles approached rapidly when they wore the wristband. But collisions did not fall to zero, and responses that were in accordance with the wristband advice went up to only 51.6% on average, for all participants. The wristband was nevertheless considered useful and easy to use by all participants. Moreover, behavioral intentions to buy and use such a device in the future were greater in both groups of older participants, but not among the younger adults. This haptic device was able to partly compensate for some age-related gap-acceptance difficulties and reduce street-crossing risks for all users. These findings could be fruitfully applied to the design of devices allowing communication between vehicles, infrastructures, and pedestrians.


Liquid Biopsy Holds Its Own in Tumor Profiling.
Results from the largest liquid biopsy study to date indicate that the genetic changes detected by analyzing circulating tumor DNA in blood samples largely recapitulate those identified through conventional tissue biopsy. Sequencing circulating tumor DNA in plasma could be a useful option for monitoring the development of resistance to targeted therapy.


The precise timing of tachycardia entrainment is determined by the postpacing interval, the tachycardia cycle length, and the pacing rate: Theoretical insights and practical applications.
Previous observations have reported that the number of pacing stimuli required to entrain a tachycardia varies on the basis of arrhythmia type and location, but a quantitative formulation of the number needed to entrain (NNE) that unifies these observations has not been characterized. We sought to investigate the relationship between the number of pacing stimulations, the tachycardia cycle length (TCL), the overdrive pacing cycle length (PCL), and the postpacing interval (PPI) to accurately estimate the timing of tachycardia entrainment. First, we detailed a mathematical derivation unifying electrophysiological parameters with empirical confirmation in 2 patients undergoing catheter ablation of typical atrial flutter. Second, we validated our formula in 44 patients who underwent various catheter ablation procedures. For accuracy, we corrected for rate-related changes in conduction velocity. We derived the equations NNE = |(PPI - TCL)/(TCL - PCL)| + 1 and Tachycardia advancement = (NNE - 1) × (TCL - PCL) - (PPI - TCL), which state that the NNE and the amount of tachycardia advancement on the first resetting stimulation are determined using regularly measured intracardiac parameters. In the retrospective cohort, the observed PPI - TCL highly correlated with the predicted PPI - TCL (mean difference 5.8 ms; r = 0.97; P < .001), calculated as PPI - TCL = (NNE - 1) × (TCL - PCL) - tachycardia advancement. The number of pacing stimulations required to entrain a reentrant tachycardia is predictable at any PCL after correcting for cycle length-dependent changes in conduction velocity. This relationship unifies established empirically derived diagnostic and mapping criteria for supraventricular tachycardia and ventricular tachycardia. This relationship may help elucidate when antitachycardia pacing episodes are ineffective or proarrhythmic and could potentially serve as a theoretical basis to customize antitachycardia pacing settings for improved safety and effectiveness.


Multioside, an active ingredient from adonis amurensis, displays anti-cancer activity through autophagosome formation.
Adonis amurensis Regel & Radde, commonly found in East Asia, has been traditionally used to treat cardiac insufficiency and edema. Although this plant extract has been shown to regulate cell growth and neovascularization, the anti-cancer mechanism of A. amurensis has not been fully investigated. In this study, we aimed to examine the anti-cancer activity of A. amurensis and identify its underlying mechanism. The growth of cancer cells was evaluated by MTT and hollow fiber assays. A cancer xenograft nude mouse model was used to assess the anti-cancer activities in vivo. Autophagic activity was measured by the detection of autophagosome formation and by performing a monodansylcadaverine (MDC) assay. A. amurensis extract showed potent anti-cancer activity both in vitro and in vivo. Importantly, the treatment of cancer cells with A. amurensis extract dramatically increased the formation of autophagosomes and was involved in the activation of multiple signaling components including AKT, ERK, and MAPK. Furthermore, we isolated an active ingredient, Multioside, which exhibited strong anti-cancer activity through autophagy. A. amurensis displays anti-cancer activity that is mediated by the activation of autophagy, suggesting that A. amurensis could be a useful therapeutic anti-cancer agent.


Serum amino acid analysis with pre-column derivatization: comparison of the o-phthaldialdehyde and N,N-diethyl-2,4-dinitro-5-fluoroaniline methods.
We compared two pre-column derivatization methods, o-phthaldialdehyde (OPA) and N,N-diethyl-2,4-dinitro-5-fluoroaniline (FDNDEA), for analysis of serum amino acids by reversed-phase high-performance liquid chromatography. Separations took 102 and 106 min for FDNDEA and OPA (reconditioning included), respectively, allowing a very good resolution of 30 amino acids by the former process and 38 by the latter. Linearity, within- and between-day variability and advantages in terms of accuracy and speed were studied for both methods. Twenty serum samples from healthy volunteers were assayed with OPA, FDNDEA and with the reference method of ion-exchange and post-column ninhydrin reaction (amino acid analyser), which took 170 min. The correlation between OPA and ninhydrin was good for all the amino acids (r = 0.959) except for the last-eluting lysine. Good agreement was found for FDNDEA (r = 0.987), which appeared in general to be a highly reproducible technique. Both pre-column methods were more sensitive than the post-column ninhydrin method.


Pulse pressure during the initial resuscitative period in patients with septic shock treated with a protocol-driven resuscitation bundle therapy.
Maintaining a mean arterial pressure (MAP) ≥ 65 mmHg during septic shock should be based on individual circumstances, but specific target is poorly understood. We investigated associations between time-weighted average (TWA) hemodynamic parameters during the initial resuscitative period and 28-day mortality. Prospectively collected data were obtained from a septic shock patient registry, according to the Sepsis-3 definition, between 2016 and 2018. The TWA systolic blood pressure, diastolic blood pressure, MAP, shock index, and pulse pressure (PP) during the first 6 hours after shock recognition were compared. Multivariable regression analysis was performed to assess associations between these parameters and 28-day mortality. Of 340 patients with septic shock, 92 died. Only the median TWA PP differed between the survivors and non-survivors (39.2 mmHg vs. 43.0 mmHg, p = 0.020), whereas the other indexes did not. When PP was divided into quartiles (< 34, 34 to 40, 40 to 48, and > 48 mmHg), the mortality rate was higher in the highest quartile (41.2%). Multivariable logistic analysis revealed that PP (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.012 to 1.622; p = 0.039) and PP of > 48 mmHg (OR, 2.25; 95% CI, 1.272 to 3.981; p = 0.005) were independently associated with 28-day mortality. PP was significantly associated with 28-day mortality in patients with septic shock and MAP maintained at > 65 mmHg during the first 6 hours. Further studies are warranted to optimize strategies for maintaining PP and MAP at > 65 mmHg during the early resuscitative period.


The association between hypoparathyroidism and cognitive impairment: a systematic review.
Hypocalcemia and low parathyroid hormone levels have been commonly suggested as factors able to induce central nervous system disturbances. However, evidences on the occurrence of cognitive impairment are limited or underestimated. The aim of this review is, therefore, to systematically summarize the available evidence concerning the occurrence of cognitive impairment among subjects suffering from idiopathic or secondary hypoparathyroidism. A systematic selection of the available literature was performed by searching the online databases PubMed, Scopus and Web of Knowledge. The present systematic review included sixteen case report articles and one cross-sectional controlled study. Case reports were the most representative literature sources and involved ten women and seven men. The presence of cognitive impairment was mostly discussed in association with idiopathic hypoparathyroidism (HPT); five articles described the occurrence of cognitive impairment following postsurgical HPT. The case-controlled study reported a significant presence of peculiar cognitive deficits (e.g. reduced inhibitory control, impairment in visuo-spatial functioning among, and psychomotor retardation) among HPT subjects compared to healthy controls, with serum total calcium and its product with phosphorus as independent predictors of neuropsychological dysfunctions. Even though mostly based on single case reports, the presence of neuropsychological dysfunctions in the context of HPT appears to be a consistent core finding.


Alleviating mechanical constraints to ventilation with heliox improves exercise endurance in adult survivors of very preterm birth.
Adult survivors of very preterm birth (PRET) have significantly lower aerobic exercise capacities than their counterparts born at term (CONT), but the underlying cause is unknown. To test whether expiratory flow limitation (EFL) during exercise negatively affects exercise endurance in PRET, we had PRET and CONT exercise to exhaustion breathing air and again breathing heliox. In PRET, EFL decreased and time-to-exhaustion increased significantly while breathing heliox. Heliox had a minimal effect on EFL and had no effect on time-to-exhaustion in CONT. We conclude that aerobic exercise endurance in PRET is limited, in part, by mechanical ventilatory constraints, specifically EFL.


Chondroitin Sulfate Is Required for Onset and Offset of Critical Period Plasticity in Visual Cortex.
Ocular dominance plasticity is easily observed during the critical period in early postnatal life. Chondroitin sulfate (CS) is the most abundant component in extracellular structures called perineuronal nets (PNNs), which surround parvalbumin-expressing interneurons (PV-cells). CS accumulates in PNNs at the critical period, but its function in earlier life is unclear. Here, we show that initiation of ocular dominance plasticity was impaired with reduced CS, using mice lacking a key CS-synthesizing enzyme, CSGalNAcT1. Two-photon in vivo imaging showed a weaker visual response of PV-cells with reduced CS compared to wild-type mice. Plasticity onset was restored by a homeoprotein Otx2, which binds the major CS-proteoglycan aggrecan and promotes its further expression. Continuous CS accumulation together with Otx2 contributed bidirectionally to both onset and offset of plasticity, and was substituted by diazepam, which enhances GABA function. Therefore, CS and Otx2 may act as common inducers of both onset and offset of the critical period by promoting PV-cell function throughout the lifetime.


PTPN22 splice forms: a new role in rheumatoid arthritis.
Genetic variation in the protein tyrosine phosphatase non-receptor type gene 22 (PTPN22, encoding lymphoid tyrosine phosphatase, LYP) influences the risk of developing multiple autoimmune diseases, but the underlying mechanisms are not completely understood. In a recent study published in Genome Medicine, Ronninger et al. showed that there are differences in the expression of PTPN22 isoforms between peripheral blood mononuclear cells from rheumatoid arthritis patients and those of healthy controls. This study provides new insights into the role of PTPN22 in autoimmune diseases.


Microplastics contamination in sediments from Portuguese inland waters: Physical-chemical characterisation and distribution.
Plastics are the major constituent of waste accumulated in inland waters and subsequently transferred to the ocean. The smaller plastic particles, typically obtained from the fragmentation of larger pieces, are vehicles for food chain accumulation of plastic components and contaminants sorbed to these particles through their ingestion by small organisms. The monitoring of the level and trends of the contamination by microplastics is essential to determine the relevance and potential sources of this contamination necessary to define strategies to reduce this threat. This work presents microplastic contamination levels and trends of sediments of four Portuguese inland waters, namely Ria de Aveiro, Ria Formosa, Mira river, and Mondego river, between 02/2019 and 09/2020. The contamination is classified considering the type of polymer and size, shape, and colour of particles. Polymers are identified by micro-ATR-FTIR with true and false identification rates larger and lower than 95% and 5%, respectively. Duplicate analysis results are used to quantify contamination heterogeneity subsequently applied to assess if a specific contamination trend is not meaningful for a 99% confidence level. The analytical procedure is described in detail to clarify the scope of the analysis. Tests' quality is controlled by following strict quality control measures. Results from sixty-three sediment samples proved the ubiquitous presence of microplastic (MP) in these inland waters with contamination levels ranging between 20 MP kg-1 and 1090 MP kg-1, excluding six samples not contaminated with these particles. Overall, more than 86% of the microplastics were fragments lower than 1000 μm, and 33% were identified as polyethylene or polypropylene. A large diversity of microplastic colours was observed. For the Mondego River and Ria de Aveiro locations monitored for consecutive years, no significant variations of microplastic contamination were observed for a 99% confidence level.


N-Phenyl and N-phenylalkyl-maleimides acting against Candida spp.: time-to-kill, stability, interaction with maleamic acids.
N-Phenyl and N-phenylalkyl maleimides (alkyl chain=(CH(2))n; n=0-4) and their respective open derivatives (maleamic acids) were evaluated against Candida spp. with the microbroth dilution method following the guidelines of CLSI (formely NCCLS). MIC values of maleimides without pre-incubation and submitted to different pre-incubation times into the growth media, time-to-kill studies as well as a time-dependent UV-spectroscopy study of the maleimides in water, led to determine that maleimides display antifungal activities with their intact maleimide ring, being in addition their activities not dependent on the length of the alkyl chain. They are not only fungistatic but fungicidal with very low MICs and MFCs, displaying strong fungicide activities not only against standardized but also clinical isolates of Candida albicans and non-albicans Candida spp.


The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells.
We show here that the antidiabetic agents metformin and phenformin and the AMPK activator AICAR exert strong anti-tumoural effects on tPTEN-/- lymphoma cells and on human T-ALL cell lines and primary samples. The compounds act by inhibiting tumour metabolism and proliferation and by inducing apoptosis in parallel with an activation of AMPK and an inhibition of constitutive mTOR. In tPTEN-/- cells, the drugs potentiated the anti-leukaemic effects of dexamethasone, and metformin and phenformin synergised with 2-deoxyglucose (2DG) to impair tumour cell survival. In vivo, metformin and AICAR strongly decreased the growth of luciferase-expressing tPTEN-/- cells xenografted in Nude mice, demonstrating that metabolism targeting could be a potent adjuvant strategy for lymphoma/leukaemia treatment.


Subclinical myocardial dysfunction in patients with reverse-remodeled dilated cardiomyopathy.
The aim of this study was to test the hypothesis that patients with reverse-remodeled dilated cardiomyopathy (DCM), whose ejection fractions (EFs) were normalized after optimal pharmacologic therapy, had subclinical myocardial dysfunction. Thirty-two patients with reverse-remodeled DCM, defined as having an initial EF ≤ 35%, which then recovered to ≥50% after optimal pharmacologic therapy, and 11 normal controls with preserved EFs were retrospectively studied. Averaged peak systolic and early diastolic radial, circumferential, and longitudinal speckle-tracking strain rates were assessed from an 18-segment left ventricular model. Similarly, averaged peak systolic radial, circumferential, and longitudinal speckle-tracking strain was obtained. Peak systolic and early diastolic longitudinal strain rates, peak systolic and early diastolic circumferential strain rates, and peak circumferential and longitudinal strain in patients with reverse-remodeled DCM were significantly lower than those in normal controls, but peak systolic and early diastolic radial strain rates and peak radial strain in patients with reverse-remodeled DCM were similar to those in normal controls. Isometric handgrip stress testing showed a significant decrease in EF from 56 ± 5% to 51 ± 5% (P < .001). Of note, the increase of afterload resulting from isometric handgrip stress testing was associated with a decrease in peak systolic circumferential and longitudinal strain rates and peak circumferential strain in patients with reverse-remodeled DCM. The circumferential and longitudinal myocardial function of patients with reverse-remodeled DCM is lower compared with that of normal controls with preserved EFs. Furthermore, the increase in afterload was associated with the decrease in circumferential and longitudinal myocardial systolic function. These findings suggest that in treated patients with DCM with reverse remodeling, left ventricular mechanics may not be normal, even when EFs are normal.