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Background: Many people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone., Methods: Patients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4-8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3-6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience., Results: Over a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients., Conclusions: Ketamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings., (© 2024. The Author(s).)

Objectives: As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label., Methods: This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit., Results: Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited., Conclusions: In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

Children exposed to prenatal maternal psychological distress are at elevated risk for a range of adverse outcomes; however, it remains poorly understood whether postnatal influences can ameliorate impairments related to prenatal distress. The current study evaluated if sensitivematernal care during the first postnatal year could mitigate child cognitive and emotional impairments associated with prenatal psychological distress. Prenatal maternal psychological distress was assessed via self-reports of anxiety, depression, and perceived stress for 136 mothers at five prenatal and four postpartum time points. Quality of maternal care (sensitivity to nondistress, positive regard, and intrusiveness reverse-scored) were assessed during a mother-child play interaction at 6 and 12 months. Child cognitive function and negative emotionality were assessed at 2 years, using The Bayley Scales and the Early Childhood Behavior Questionnaire. Elevated prenatal distress was associated with poorer child cognitive function and elevated negative emotionality. Children exposed to elevated prenatal maternal distress did not, however, display these outcomes if they received high-quality caregiving. Specifically, maternal care moderated the relation between prenatal psychological distress and child cognitive function and negative emotionality. This association remained after consideration of postnatal maternal psychological distress and relevant covariates. Sensitive maternal care was associated with altered offspring developmental trajectories, supporting child resilience following prenatal distress exposure.

During the postpartum period, new mothers experience drastic changes in their body, brain, and life circumstances. Stress from the emotional and physical demands of caring for an infant is associated with negative mood and parenting outcomes. The use of active coping strategies can increase mothers' resilience during the postpartum period. However, little is known about the association between coping styles and maternal brain responses to infant cues. In the current study, we examined the associations among trait coping style, maternal brain responses, and behavioral sensitivity in a socioeconomically diverse sample of first-time mothers (N = 59). The use of more active trait coping strategies compared to passive coping strategies was associated with increased brain responses to infant cry sounds in brain regions that are critically involved in motivation and emotion regulation-substantia nigra, anterior cingulate gyrus, and inferior frontal gyrus. Increased brain activations in the midbrain and anterior cingulate gyrus were further associated with higher levels of maternal sensitivity observed during interactions with the infant. Thus, the findings provide support for mothers' use of more active coping styles to promote neural and behavioral resilience for a positive transition to parenthood., (© 2022. The Author(s).)

Objectives: To characterize child, parent, and family adjustment for patients followed in a multidisciplinary spina bifida (SB) clinic., Methods: Participants were drawn from clinical cases seen through a multidisciplinary outpatient SB clinic at a children's hospital between 2017 and 2019. Participants included 209 youth under 19 years old who were diagnosed with SB and their parents. Self-reported internalizing symptoms were measured in youth in grade 3 through 12 using the 25-item Revised Children's Anxiety and Depression Scale-25 (RCADS-25). Self- and parent-reported quality of life and family functioning were obtained using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and Family Impact Modules., Results: A total of 45.7% of children and adolescents reported at-risk psychosocial functioning on the PedsQL. In contrast, only 5% of patients reported clinically elevated internalizing symptoms on the RCADS. Parents' quality of life and family functioning in the study were higher than in most studies of parents of children with other chronic health conditions, children with attention deficit-hyperactivity disorder, and healthy control samples., Conclusion: Our findings indicate that children and adolescents with SB are at risk for poor health-related quality of life (HRQOL); however, poorer HRQOL may not necessarily be associated with more severe psychiatric symptoms in this population. Examining resilience factors that may help to buffer against challenges to HRQOL will be important in informing future interventions., Competing Interests: Conflicts of Interest The authors report no conflicts of interest., (© 2022 American Spinal Injury Association.)

The transition to becoming a mother involves numerous emotional challenges, and the ability to effectively keep negative emotions in check is critical for parenting. Evidence suggests that experiencing socioeconomic disadvantage interferes with parenting adaptations and alters neural processes related to emotion regulation. The present study examined whether socioeconomic disadvantage is associated with diminished neural activation while mothers engaged in volitional (i.e., purposeful) emotion regulation. 59 mothers, at an average of 4 months postpartum, underwent fMRI scanning and completed the Emotion Regulation Task (ERT). When asked to regulate emotions using reappraisal (i.e., Reappraise condition; reframing stimuli in order to decrease negative emotion), mothers with lower income-to-needs ratio exhibited dampened neural activation in the dorsolateral and ventrolateral PFC, middle frontal and middle temporal gyrus, and caudate. Without explicit instructions to down-regulate (i.e., Maintain condition), mothers experiencing lower income also exhibited dampened response in regulatory areas, including the middle frontal and middle temporal gyrus and caudate. Blunted middle frontal gyrus activation across both Reappraise and Maintain conditions was associated with reduced maternal sensitivity during a mother-child interaction task. Results of the present study demonstrate the influence of socioeconomic disadvantage on prefrontal engagement during emotion regulation, which may have downstream consequences for maternal behaviors.

The path to sustainable small-scale fisheries (SSF) is based on multiple learning processes that must transcend generational changes. To understand young leaders from communities with sustainable SSF management practices in Mexico, we used in-depth interviews to identify their shared motivations and perceptions for accepting their fishing heritage. These possible future decision-makers act as agents of change due to their organizational and technological abilities. However, young people are currently at a crossroads. Many inherited a passion for the sea and want to improve and diversify the fishing sector, yet young leaders do not want to accept a legacy of complicated socioenvironmental conditions that can limit their futures. These future leaders are especially concerned by the uncertainty caused by climate change. If fishing and generational change are not valued in planning processes, the continuity of fisheries, the success of conservation actions, and the lifestyles of young fishers will remain uncertain., (© 2021. The Author(s).)

Introduction. Acquired resistance against the antibiotics that are active against Ureaplasma species has been described. Hypothesis/Gap Statement. Diagnostics combined with antimicrobial sensitivity testing are required for therapeutic guidance. Aim. To report the prevalence of antimicrobial resistance among Cuban Ureaplasma isolates and the related molecular mechanisms of resistance. Methodology. Traditional broth microdilution assays were used for antimicrobial sensitivity testing in 262 clinical Ureaplasma species isolates from Cuban patients between 2013 and 2018, and a subset of samples were investigated in parallel with the commercial MYCO WELL D-ONE rapid culture diagnostic assay. The underlying molecular mechanisms for resistance were determined by PCR and sequencing for all resistant isolates. Results. Among the tested isolates, the tetracycline and erythromycin resistance rates were 1.9 and 1.5%, respectively, while fluoroquinolone resistance was not found. The tet (M) gene was found in all tetracycline-resistant isolates, but also in two tetracycline-susceptible Ureaplasma c linical isolates. We were unable to determine the underlying mechanism of erythromycin resistance. The MYCO WELL D-ONE kit overestimated tetracycline and erythromycin resistance in Ureaplasma spp. isolates. Conclusions. Although low levels of antibiotic resistance were detected in Cuban patients over a 5-year period, continued surveillance of the antibiotic susceptibility of Ureaplasma is necessary to monitor possible changes in resistance patterns.

Small organic molecules have been extensively applied to achieve enzymatic inhibition. Although numerous efforts have been made to deliver efficient inhibitors, small inhibitors applications are hindered by many drawbacks. Moreover, reporters comprising nanoparticle inhibitory activity against enzymes are very scarce in the literature. In this scenario, carbon nanodots (CDs) emerge as promising candidates for efficient enzyme inhibition due to their unique properties. Here, CDs specific molecular characteristics (core composition and chemical surface groups) have been investigated to produce a more potent enzyme inhibition. Mushroom tyrosinase (mTyr) has been adopted as an enzymatic prototype. The CDs revealed a high affinity to mTyr (Ka ≈ 10 6  M -1 ), mainly through hydrophobic forces and followed by slight mTyr structural alteration. CDs competitively inhibit mTyr, with low inhibition constant (K I  = 517.7 ± 17.0 nM), which is up 70 fold smaller then the commercial inhibitor (kojic acid) and the starch nanoparticles previously reported. The results expose that the CDs act as a hydrophobic agglomerate with carboxyl groups on its surface, mimicking characteristics found on small molecule inhibitors (but with superior performance). All these results highlight the CD excellent potential as an efficient low toxic Tyr inhibitor, opening the prospect of using these nanoparticles in the cosmetic and food industries., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Patients with differences in sex development represent a complex pediatric population with varying psychosocial and medical needs. Due to the complexity of care, families likely benefit from multidisciplinary care allowing for coordination of psychosocial and health services. Unfortunately, there are few data on the experiences of families of patients with differences of sex development in a multidisciplinary setting, such as their satisfaction with health care or their level of shared decision making., Methods: Patients and guardians seen in a multidisciplinary, differences in sex development clinic were asked to participate in an anonymous online survey of their satisfaction with health care delivery (Patient Satisfaction Questionnaire Short Form) and involvement in shared decision making (Shared Decision Making Questionnaire). Welch's t-test was used to compare mean survey scores to historical and contemporary control populations., Results: In all, 22 guardians and 1 young adult patient completed surveys. Median patient age was 36 months. Patient diagnoses were diverse, with the most common diagnosis beings 46, XY DSD (34.8%). At the time of their clinic visit, 7 patients had undergone surgery. Mean satisfaction scores were higher than a primary care population and comparable to patients and patients' caregivers with chronic medical conditions. The mean shared decision making score was well above adult populations and similar to caregiver reports in pediatric outpatient clinics., Conclusions: Despite the complex treatment associated with differences of sex development, families are very satisfied with the quality of care they receive in a multidisciplinary setting and appear to feel personally invested in the decision making process.

Early parenting relies on emotion regulation capabilities, as mothers are responsible for regulating both their own emotional state and that of their infant during a time of new parenting-related neural plasticity and potentially increased stress. Previous research highlights the importance of frontal cortical regions in facilitating effective emotion regulation, but few studies have investigated the neural regulation of emotion among postpartum women. The current study employed a functional neuroimaging (fMRI) approach to explore the association between perceived stress, depressive symptoms, and the neural regulation of emotion in first-time mothers. Among 59 postpartum mothers, higher perceived stress during the postpartum period was associated with less self-reported use of cognitive reappraisal in everyday life, and greater use of emotion suppression. While viewing standardized aversive images during the Emotion Regulation Task (ERT), mothers were instructed to experience their natural emotional state (Maintain) or to decrease the intensity of their negative emotion by using cognitive reappraisal (Reappraise). Whole-brain analysis revealed a two-way interaction of perceived stress x condition in the right dorsolateral prefrontal cortex (DLPFC) at p < .05 cluster-wise corrected, controlling for postpartum months and scanner type. Higher levels of perceived stress were associated with heightened right DLPFC activity while engaging in cognitive reappraisal versus naturally responding to negative stimuli. Higher right DLPFC activity during Reappraise versus Maintain was further associated with elevated parenting stress. Findings suggest that stress and everyday reappraisal use is reflected in mothers' neural regulation of emotion and may have important implications for their adaptation to parenthood., (© 2021. The Psychonomic Society, Inc.)

Rhipicephalus microplus (Canestrini, 1888) is one of the species with medical and economic relevance that has been reported in the list of Cuban tick species. Some morphological characterizations about the R. microplus species in Cuba have been published; however, molecular studies are lacking. Molecular phylogenetic analyses have grouped R. annulatus, R. australis and three clades of R. microplus in a complex named R. microplus. The present study aimed to characterize two R. microplus tick isolates, established as colonies at the Cuban National Laboratory of Parasitology. Morphological characterization of adult specimens was carried out by using Scanning Electron Microscopy. The sequences of mitochondrial genes: 12S rRNA, 16S rRNA and the subunit I of cytochrome c oxidase (coxI) and one nuclear sequence: internal transcribed spacer 2 (its2) were used for phylogenetic analyses. The life cycle under laboratory conditions for both isolates was also characterized. Tick specimens of both colonies showed morphological characteristics comparable with those distinctive for the R. microplus species. Phylogenies based on mitochondrial gene sequences identified congruently the Cuban tick colonies within the clade A of R. microplus. The life cycle of both isolates under laboratory conditions lasted 65 ± 5 days and the reproductive performance of female ticks of each colony also were similar with approximately 2500 larvae obtained from fully engorged female ticks. This study constitutes the first molecular characterization of ticks from the R. microplus species in Cuba., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We investigated a spray drying process for preparing water-soluble salts of high molecular weight chitosan (CH) intended for pharmaceutical excipient applications. CH was derived from chitin of marine lobster origin ( Panulirus argus ). The effects of organic acid (acetic or lactic acid) and the ratio (difference) of inlet/outlet air temperature (140/90 °C or 160/100 °C) on spray drying were studied. The yield of spray-dried CH salt powders ranged from 50% to 99% in laboratory and industrial-scale processes. The spray-dried dry powder of CH salts consisted of spherical agglomerated particles with an average diameter of 36.2 ± 7.0 µm (CH acetate) and 108.6 ± 11.5 µm (CH lactate). After dispersing the spray-dried CH salt powder samples in purified water, the mean particle sizes obtained for the CH acetate salts were 31.4 nm (batch A001), 33.0 nm (A002) and 44.2 nm (A003), and for the CH lactate salts 100.8 nm (batch L001), 103.2 nm (L002) and 121.8 nm (L003). The optimum process conditions for spray drying were found: an inlet air temperature of 160 ± 5 °C, an outlet temperature of 100 ± 5 °C and an atomizer disk rotational speed of 18,200 min -1 . The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) results confirmed the amorphous state of the CH salts. The 1 H nuclear magnetic resonance (NMR) and Fourier transform infrared (FT-IR) spectra of CH acetate and lactate salts verified that the spray drying process does not affect the polymer backbone. In conclusion, both laboratory and industrial-scale spray drying methods for preparing water-soluble acid salts of CH are reproducible, and the physicochemical properties of the corresponding CH acid salts are uniform.

ZnO particles were synthetized by the sol-gel method and subsequent heat treatment of 400, 500 and 600 °C was applied. The nano ZnO particles were incorporated to the unsaturated polyester resin by solution blending at 0.05 wt % concentration. X-ray diffraction detected the formation of a wurtzite-like structure. Viscoelastic behavior of neat polyester and nanocomposites revealed the nano ZnO particles does not promote better mechanical properties because of a weak interaction and the glass transition temperature of the polyester was favored by the presence of a higher quantity of nano-size ZnO particles. Thermogravimetric analysis at 5, 10 and 20 °C/min allowed determining the degradation kinetic parameters based on the Friedman and Kissinger models for neat polyester and nanocomposites. Heating rates promoted an increase in the temperature degradation and the addition of ZnO particles promoted a catalyst effect that reduce the amount of thermal energy needed to start the thermal degradation.

Background: Integrative research summarizing promotive and protective factors that reduce the effects of childhood abuse and neglect on pregnant women and their babies' healthy functioning is needed., Objective: This narrative systematic review synthesized the quantitative literature on protective and promotive factors that support maternal mental health and maternal-infant bonding among women exposed to childhood adversity, including childhood abuse and neglect., Methods: Using a comprehensive list of key terms related to the perinatal period, childhood adversity, and protective/promotive factors, 8423 non-duplicated articles were identified through database searches in PsychInfo and Web of Science, and references in retrieved articles. Thirty-seven full text articles were inspected; of those 18 were included., Results: Protective and promotive factors fell into three categories: a) women's internal capacities (e.g., self-esteem, coping ability), b) external early resources (e.g., positive childhood experiences) and c) external contemporaneous resources (e.g., social support). Although all three categories were associated with more resilient outcomes, external contemporaneous factors, and specifically, social support, were the most commonly-studied protective and/or promotive factor. Social support from family and romantic partners during the perinatal period was particularly protective for women with histories of childhood abuse and neglect and was examined across several dimensions of support and contexts., Conclusions: The presence of women's internal capacities, and external early and contemporaneous resources help to foster more positive outcomes during the perinatal period for women with histories of childhood adversity. Future research should study co-occurring multilevel promotive and protective factors to inform how they integratively deter the intergenerational transmission of risk., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Context: Antenatal corticosteroids are commonly administered to pregnant women at risk for delivering between 23 and 34 gestational weeks; they provide crucial benefits to fetal lung maturation and reduce risk for neonatal morbidity and mortality. Corticosteroids are maximally efficacious for lung maturation when administered within 2 to 7 days of delivery. Accurately identifying the timing of preterm delivery is thus critical to ensure that antenatal corticosteroids are administered within a week of delivery and to avoid unnecessary administration to women who will deliver at term. A plausible biomarker for predicting time of delivery is placental corticotropin-releasing hormone (pCRH)., Objective: To assess whether pCRH concentrations predict time to delivery and specifically which women will deliver within a week of treatment., Design: pCRH concentrations were evaluated before administration of the corticosteroid betamethasone, and timing of delivery was recorded., Participants: A total of 121 women with singleton pregnancies who were prescribed betamethasone., Results: Elevated pCRH concentrations were associated with a shorter time from treatment to delivery. Receiver-operating characteristic curves revealed that pCRH may improve the precision of predicting preterm delivery., Conclusions: In the current sample, pCRH concentrations predicted the likelihood of delivering within 1 week of corticosteroid treatment. Current findings suggest that pCRH may be a diagnostic indicator of impending preterm delivery. Increasing the precision in predicting time to delivery could inform when to administer antenatal corticosteroids, thus maximizing benefits and reducing the likelihood of exposing fetuses who will be delivered at term.

The volume of a protein can be estimated from its molecular weight. This approach has also been applied in force microscopy experiments. Two factors contribute to the determination of the volume from a force microscope image, the applied force and the tip radius. Those factors act in opposite directions. Here, we demonstrate that in the optimum conditions to image a protein, the apparent volume deduced from an AFM image overestimates the real protein volume. The lateral broadening due to the tip finite size, makes the simulated volume to exceed the real protein volume value, while the force applied by the tip tends to decrease the measured volume. The measured volume could coincide with the real volume for either a point-size tip at zero force or when the compression exerted by the tip compensates its dilation effects. The interplay between the above factors make unsuitable to apply the molecular weight method to determine the volume of a protein from AFM data., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Problem drug-related behavior (PDB) among patients on chronic opioid therapy may reflect an opioid use disorder. This study assessed PDB prevalence and the relationship between PDB and ongoing prescription of opioids at a primary care clinic that implemented a multifaceted opioid management program., Methods: A chart review of patients in a chronic opioid registry assessed prevalence of different types of PDB over 2 years, and whether opioids were prescribed during the last 3 months of the 2-year study period among patients with different levels of PDB., Results: Among 233 registry patients, 84.1% exhibited PDB; 45.5% exhibited ≥3 types of PDB. At the end of 2 years, most registry patients were still prescribed opioids, though patients with ≥3 types of PDB were less likely than those without PDB to be prescribed opioids (62.3% vs. 78.4%, P = 0.016)., Conclusions: PDB was pervasive in this population of patients on chronic opioid therapy. Those with the most PDB, and thus with the greatest likelihood of opioid use disorder and its social and medical consequences, were the least likely to be prescribed opioids by the clinic after 2 years. Given the rising rates of illicit opioid use in the U.S., it is important that clinics work closely with their patients who display PDB, systematically assess them for opioid use disorder, and offer evidence-based treatment., (© Copyright 2016 by the American Board of Family Medicine.)

Background: Manufacturers and laboratories might benefit from using a modern integrated tool for quality management/assurance. The tool should not be confounded by commutability issues and focus on the intrinsic analytical quality and comparability of assays as performed in routine laboratories. In addition, it should enable monitoring of long-term stability of performance, with the possibility to quasi "real-time" remedial action. Therefore, we developed the "Empower" project., Methods: The project comprises four pillars: (i) master comparisons with panels of frozen single-donation samples, (ii) monitoring of patient percentiles and (iii) internal quality control data, and (iv) conceptual and statistical education about analytical quality. In the pillars described here (i and ii), state-of-the-art as well as biologically derived specifications are used., Results: In the 2014 master comparisons survey, 125 laboratories forming 8 peer groups participated. It showed not only good intrinsic analytical quality of assays but also assay biases/non-comparability. Although laboratory performance was mostly satisfactory, sometimes huge between-laboratory differences were observed. In patient percentile monitoring, currently, 100 laboratories participate with 182 devices. Particularly, laboratories with a high daily throughput and low patient population variation show a stable moving median in time with good between-instrument concordance. Shifts/drifts due to lot changes are sometimes revealed. There is evidence that outpatient medians mirror the calibration set-points shown in the master comparisons., Conclusions: The Empower project gives manufacturers and laboratories a realistic view on assay quality/comparability as well as stability of performance and/or the reasons for increased variation. Therefore, it is a modern tool for quality management/assurance toward improved patient care.

We have found that four taxanes with chemical modifications at positions C10 and C13 were active against all types of taxane resistant cell lines, resistant by P-gp overexpression, by mutations in the β-tubulin binding site or by overexpression of the highly dynamic βIII-tubulin isotype. We have characterized the interaction of taxanes with high activity on chemotherapy resistant tumoural cells with microtubules, and also studied their cellular effects. The biochemical property enhanced in comparison with other taxanes is their potency at inducing tubulin assembly, despite the fact that their interactions with the microtubule binding sites (pore and luminal) are similar as studied by NMR and SAXS. A differential interaction with the S7-S9 loop (M-loop) is responsible for their enhanced assembly induction properties. The chemical changes in the structure also induce changes in the thermodynamic properties of the interaction, indicating a higher hydrophilicity and also explaining their properties on P-gp and βIII overexpressing cells and on mutant cells. The effect of the compounds on the microtubular network is different from those observed with the classical (docetaxel and paclitaxel) taxanes, inducing different bundling in cells with microtubules being very short, indicating a very fast nucleation effect and reflecting their high assembly induction power., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

According to the measurement paradigm, assays claiming the same measurand should give equivalent results within clinically relevant constraints. The key to accomplish this paradigm is standardization of assays to an SI-traceable reference measurement system. However, measurement results for complex analytes often are not expressed in SI-, but in arbitrary units, defined, for example, by an international conventional measurement standard. Traceability to such a standard mostly does not lead to among assay equivalence. To achieve this, the concept of harmonization has been proposed. We describe here the practical aspects involved with the "Step-Up" design. It essentially comprises a sequence of method comparisons with selected sets of commutable samples. The outcome of each phase allows to decide whether the step-up to the next phase can be set. The harmonization process itself uses a statistically valid location measure as surrogate reference measurement procedure. The design also foresees a protocol for sustaining the first-established harmonization status. For the design to be successful, it is essential that as many assays as possible are involved in the method comparison leading to the harmonization target, and that it can be shown that they sufficiently correlate to that target with consistency of performance over the covered measurement range., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Various studies have demonstrated that alterations in the deformability of cancerous cells are strongly linked to the actin cytoskeleton. By using atomic force microscopy (AFM), it is possible to determine such changes in a quantitative way in order to distinguish cancerous from non-malignant cells. In the work presented here, the elastic properties of human bladder cells were determined by means of AFM. The measurements show that non-malignant bladder HCV29 cells are stiffer (higher Young's modulus) than cancerous cells (HTB-9, HT1376, and T24 cell lines). However, independently of the histological grade of the studied bladder cancer cells, all cancerous cells possess a similar level of the deformability of about a few kilopascals, significantly lower than non-malignant cells. This underlines the diagnostic character of stiffness that can be used as a biomarker of bladder cancer. Similar stiffness levels, observed for cancerous cells, cannot be fully explained by the organization of the actin cytoskeleton since it is different in all malignant cells. Our results underline that it is neither the spatial organization of the actin filaments nor the presence of stress fibers, but the overall density and their 3D-organization in a probing volume play the dominant role in controlling the elastic response of the cancerous cell to an external force.

Patients taking high-dose opioids chronically for tumor-related or neuropathic pain may develop pain that is refractory to opioids. One option for control of such pain is the use of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. We describe a case of opioid-refractory pain that responded to a low-dose IV infusion of ketamine in the inpatient setting. The patient was then successfully transitioned to oral memantine for long-term outpatient management, in a novel use of this oral NMDA receptor antagonist. We present recent findings from basic research on pain mechanisms to explain why opioid tolerance, as in this patient, may contribute to the analgesic benefit of NMDA receptor antagonists.

A middle-aged woman began experiencing spells of profound anterograde amnesia several months after beginning intrathecal baclofen treatment for generalized dystonia. Her spells met criteria for transient global amnesia, but were unusual because of their frequent recurrence and because their frequency was somewhat dose-dependent on baclofen. Fludrocortisone decreased the frequency of these episodes, and sublingual nitroglycerin both prevented and terminated them. Baclofen-induced amnesia in rodents is a reliable model of memory impairment. In contrast, baclofen-induced memory impairment in humans is uncommon. Baclofen- associated transient global amnesia has not previously been reported.

Objective: Members of "Asociación de Ecografía Digestiva" decided to carry out a multicenter retrospective study on fine-needle aspiration biopsy for pancreatic space-occupying lesions under ultrasonographic guidance and via the percutaneous route in order to assess this technique s performance versus endoscopic ultrasound-guided biopsy., Subjects: 10 hospitals for a total of 222 patients with suspiciously malignant, 8-120-mm pancreatic lesions were included in the study., Results: The analysis of results shows a sensitivity of 89%, a specificity of 98%, a positive predictive value of 99%, and a negative predictive value of 74%, for an overall diagnostic accuracy of 91%. No major complications occurred., Conclusion: Percutaneous fine-needle aspiration for pancreatic lesions is highly cost-effective and has few and mild complications.

A depressing synapse transforms a time interval into a voltage amplitude. The effect of that transformation on the output of the neuron and network depends on the kinetics of synaptic depression and properties of the postsynaptic neuron and network. Using as examples neural circuits that incorporate depressing synapses, we show how short-term depression can contribute to a surprising variety of time-dependent computational and behavioral tasks.

A man in his 50's with a prior traumatic brain injury and multiple psychiatric disorders developed acute pain and swelling in his left leg distal to the mid shin. These symptoms arose during an exacerbation of his post-traumatic stress disorder (PTSD). Among his traumatic memories, he reported having witnessed the combat injury and death of a friend who had lost his left leg distal to the mid shin. A diagnosis of conversion disorder was technically excluded because the findings met criteria for Complex Regional Pain Syndrome (CRPS) type I. Based on recent research into the neurobiology of CRPS, PTSD and conversion disorder, we propose a supraspinal mechanism which could explain how emotional stress can produce both symptoms and signs.

The firing rate of neocortical pyramidal neurons is believed to represent primarily the average arrival rate of synaptic inputs; however, it has also been found to vary somewhat depending on the degree of synchrony among synaptic inputs. We investigated the ability of pyramidal neurons to perform coincidence detection, that is, to represent input timing in their firing rate, and explored some factors that influence that representation. We injected computer-generated simulated synaptic inputs into pyramidal neurons during whole-cell recordings, systematically altering the phase delay between two groups of periodic simulated input events. We explored how input intensity, the synaptic time course, inhibitory synaptic conductance, and input jitter influenced the firing rate representation of input timing. In agreement with computer modeling studies, we found that input synchronization increases firing rate when intensity is low but reduces firing rate when intensity is high. At high intensity, the effect of synchrony on firing rate could be switched from reducing to increasing firing rate by shortening the simulated excitatory synaptic time course, adding inhibition (using the dynamic clamp technique), or introducing a small input jitter. These opposite effects of synchrony may serve different computational functions: as a means of increasing firing rate it may be useful for efficient recruitment or for computing a continuous parameter, whereas as a means of decreasing firing rate it may provide gain control, which would allow redundant or excessive input to be ignored. Modulation of dynamic input properties may allow neurons to perform different operations depending on the task at hand.

Liver biopsy is frequently necessary for candidate evaluation or histologic follow-up of transplanted livers. Although generally considered to be safe, it carries a risk of complications in up to 0.5% of cases; hemorrhage being the most important. It can present as an asymptomatic intra- or perihepatic hematoma or result in overt hemorrhage of variable intensity. Patients with deranged hemostasis or on antiaggregant therapy are at high-risk for hemorrhagic complications. Percutaneous liver biopsy may be contraindicated if hemostasis is profoundly disordered. Safety values are not well defined: arbitrary limits are 60% prothrombin activity and 60,000 platelets per mm3. Patients with more altered values are candidates for alternative techniques, such as transjugular biopsy. Another option is the so-called plugged percutaneous liver biopsy, which uses direct injection of a plugging material into the biopsy tract. Different materials have been used: Tissucol, absorbable gelatin sponge, or hemostasis coils. We communicate our experience with Tissucol (fibrin glue) plugging in 30 percutaneous liver biopsies on 16 patients after liver transplantation with prothrombin activity <60%, platelet count <60,000 per mm3, or both. Only two complications were observed. Plugged liver biopsy is an efficient and relatively safe procedure in patients with impaired hemostasis; it can be performed even when transjugular biopsy is not available.

Short-term synaptic plasticity, which is common in the central nervous system, may contribute to the signal processing functions of both temporal integration and coincidence detection. For temporal integrators, whose output firng rate depends on a running average of recent synaptic inputs, plasticity modulates input synaptic strength and thus may directly control signalling gain and the function of neural networks. But the firing probability of an ideal coincidence detector would depend on the temporal coincidence of events rather than on the average frequency of synaptic events. Here we have examined a specific case of how synaptic plasticity can affect temporal coincidence detection, by experimentally characterizing synaptic depression at the synapse between neurons in the nucleus magnocellularis and coincidence detection neurons in the nucleus laminaris in the chick auditory brainstem. We combine an empirical description of this depression with a biophysical model of signalling in the nucleus laminaris. The resulting model predicts that synaptic depression provides an adaptive mechanism for preserving interaural time-delay information (a proxy for the location of sound in space) despite the confounding effects of sound-intensity-related information. This mechanism may help nucleus laminaris neurons to pass specific sound localization information to higher processing centres.

Collagenous colitis is a disorder which has been diagnosed with increasing frequency in the last few years, probably due to the routine obtention of colon biopsy specimens in the study of patients with chronic diarrhoea. Good responses have been reported with a number of therapies, although only a scarce number of clinical trials have been performed, partly because of the small number of patients studied. Two cases of collagenous colitis with different therapeutic approaches are here reported. All medical therapy options for this interesting disorder are reviewed.

To assess behavioral experience effects on synaptic plasticity after brain damage, the present study examined the effects of complex motor skills training (the acrobatic task) on synaptic changes in layer V of the motor cortex opposite unilateral damage to the forelimb sensorimotor cortex (FLsmc). Adult male rats were given lesions or sham operations followed by 28 d of training on the acrobatic task [acrobat condition (AC)]. As a motor activity control [motor control (MC)], lesion and sham animals were given simple repetitive exercise. Previously, FLsmc lesions and acrobatic training have independently been found to result in increases in synapse to neuron ratios in the intact motor cortex relative to controls, and both of these effects were replicated in the present study. In addition, acrobat training after lesions significantly increased layer V synapses per neuron relative to sham-AC and lesion-MC rats. Thus, the combination of acrobatic training and lesions resulted in an enhanced synaptogenic response. Synapse subtypes were also differentially affected by the conditions. Lesion-MC and sham-AC primarily had increases in the number of synapses per neuron formed by multiple synaptic boutons in comparison to sham-MC. In contrast, lesion-AC had increases in both multiple and single synapses. Multiple synaptic spines and perforated synapses were also differentially affected by training versus lesions. On tests of coordinated forelimb use, lesion-AC rats performed better than lesion-MC rats. In addition to supporting a link between behavioral experience and structural plasticity after brain damage, these findings suggest that adaptive neural plasticity may be enhanced using behavioral manipulations as "therapy."

Background: To describe the prevalence of Helicobacter pylori infection in patients with reflux esophagitis, and compare it with that in patients with normal endoscopy., Methods: Fifty-five patients with endoscopic peptic esophagitis and 55 symptomatic patients with normal endoscopy were studied. Age and sex distribution were similar in both groups. At endoscopy biopsy specimens were taken from gastric antrum and body (H & E, Gram stain and culture)., Results: H. pylori was found in 74.5% (95% CI = 62-84%) of patients with reflux esophagitis, and in 76.4% (CI = 64-86%) of cases with normal endoscopy (a non-significant difference). In patients with esophagitis and H. pylori infection normal histologic antral mucosa was observed in 7.3% of cases (CI = 2.5-19.4%). In patients with normal endoscopy the corresponding figure was 4.8% (CI = 1.3-15.8%) (a non-significant difference). At gastric body from infected patients the percentages of patients with normal histologic mucosa was 29.3% (n = 12) and 23.8% (n = 10), in both groups respectively., Conclusions: The prevalence of H. pylori infection in patients with reflux esophagitis was 74.5%, and no difference was observed when comparing with infection rate in patients with normal endoscopy (76.4%). Therefore, a non-significant association was found between this esophageal disorder and H. pylori infection.

We report the case of a 51-years-old female who was prophylactically treated with diphenylhydantoin after surgery of an intracranial aneurysm. Twenty-four days after beginning the treatment, a general syndrome appeared, in addition to a diffuse cutaneous exanthema. Four days later, a cholestatic syndrome, compatible with "toxic cholestatic acute hepatitis", was developed. The suppression of the drug, was followed by rapid clinical improvement and gradual normalization of transaminases values, although biochemical cholestasis persisted for months.

Objectives: To study some aspects of the immunological abnormalities of C and non-A non-B non-C posttransfusional chronic hepatitis through the spontaneous and mitogen-stimulated "in vitro" production of immunoglobulins by peripheral blood lymphocytes., Experimental Design: Peripheral blood lymphocytes from non-A non-B posttransfusional chronic hepatitis patients and from healthy volunteers were cultured in presence and absence of Pokeweed mitogen and the secreted immunoglobulins (IgG, IgA and IgM) were measured by ELISA in the supernatants. The results in both groups were compared., Patients: 23 posttransfusional chronic hepatitis patients, 11 males and 12 females with an average age of 46.73 +/- 11.2 yrs (range: 24-69 yrs), have been studied. The histological diagnosis was chronic active hepatitis (CAH) in 13 cases, CAH with bridge necrosis in 6 patients and CAH with associated cirrhosis in 4 cases. The control group was composed by 11 healthy volunteers, 5 male and 6 female, with an average age of 38.45 +/- 12.77 yrs (range: 26-65 yrs). No one of the control group was positive for anti-HCV antibodies while in the posttransfusional chronic hepatitis patients group, 19 were positive and 4 negative., Results: No significant differences in the spontaneous production of immunoglobulins between both groups has been found, however, when peripheral blood lymphocytes were stimulated with Pokeweed mitogen, a statistically significant lower production of immunoglobulins was observed in chronic hepatitis patients when compared with the control group. In non-A non-B posttransfusional chronic hepatitis patients, no relation has been found between the immunoglobulins production and histological findings or anti-HCV antibody titles., Conclusions: In the chronic phase of C and non-A non-B non-C posttransfusional chronic hepatitis, stimulated immunoglobulin production is significantly decreased for each immunoglobulin compared with the control group. These results suggest a failure in T-B lymphocyte cooperation in these infections since 82.6% of our patients were positive for HCV serological markers.

We studied the frequency and time of appearance of antibodies to the hepatitis C virus (HCV) retrospectively in the sera of 127 patients who underwent heart surgery between 1983 and 1986. They received blood from volunteer donors hepatitis B surface antigen (HBsAg) negative with normal serum alanine-aminotransferase levels. A prospective follow-up was carried out every 15 days for at least 6 months from the moment of the transfusion. Of the ten patients who developed biochemical criteria of post-transfusional non-A non-B hepatitis, six seroconverted to anti-HCV (60%). Of the other 117, two were already positive before transfusion (1.51%), one patient showed antibodies only in the first post-transfusional serum (passive transfer), and another two patients with no evidence of post-transfusional hepatitis developed HCV antibodies on the 90th day, remaining indefinitely (afterwards seroconversion without hepatitis); both patients' earlier sera were anti-HCV negative. Four (40%) of the ten patients with post-transfusional hepatitis did not develop any serum markers to known hepatotropic agents. Although these findings do not exclude a viral infection by these viruses, they are consistent with the involvement of an unidentified non-A, non-B, non-C agent.

Aim: To communicate the results of two different schedules (cyclic and continuous) of mebendazole therapy for hepatic and intraabdominal hydatid disease., Design: Prospective and randomized., Patients: 26 cases of abdominal hydatid disease., Results: No significant differences were registered between both groups., Conclusion: Cyclic mebendazole therapy does not improve the results of continuous treatment in abdominal hydatid disease.