Cyclic peroxides and the thiobarbituric assay.
Several monocyclic peroxide compounds and two acyclic hydroperoxides have been tested for activity in the thiobarbituric acid test. All cyclic peroxides tested which have beta dioxygen functionality on non-tertiary carbons gave positive thiobarbituric acid tests at 532 nm. (epsilon = 10(3) --10(4)) Two acyclic unsaturated hydroperoxides which were derived from gamma-linolenic acid also gave positive thiobarbituric acid tests. In addition to the 532-nm-absorbing species, all peroxidic compounds tested showed a transient absorption at 450 nm during the thiobarbituric acid test. The species responsible for this 450 nm absorption appears to be an intermediate in a series reaction sequence. This intermediate is converted, in time, to the 532-nm-absorbing species. Thiobarbituric acid assay of the crude autoxidation product mixture of gamma-linolenic acid also shows this transient 450-nm-absorbing species. Added ferric ion enhances the 532 nm abosrbance of the thiobarbituric acid assay of cyclic peroxides.


[Association of Indoor Air Pollution, Single Nucleotide Polymorphism of HIF-1α Gene with Susceptibility to Lung Cancer in Han Population in Fujian Province].
Hypoxia inducible factor-1α (HIF-1α) is associated with the progression and metastasis of lung cancer. There are, however, few studies on the relationship between the single nucleotide polymorphisms of HIF-1α and susceptibility to lung cancer. Therefore, we aimed to investigate the relationship between indoor air pollution, HIF-1α rs2057482, and the susceptibility to primary lung cancer of the Fujian Han population. The present study is a hospital-based case-control study. We recruited 1,096 lung cancer and 1,110 controls that were admitted to the Department of Thoracic Surgery of the First Affiliated Hospital and Union Hospital of Fujian Medical University and Fuzhou General Hospital of Nanjing Military Region from January 2006 to December 2012. The primary lung cancer cases were identified via pathological methods. Both case and control groups received questionnaires. Genotyping of HIF-1α gene rs2057482 locus polymorphism in all subjects were analyzed by MALDI-TOF-MS technique. Individuals who carried the T-genotype of HIF-1α rs2057482 were more susceptible to small cell carcinoma (odds ratio of 1.725, 95%CI: 1.047-2.842). After adjusting for general and lung cancer-related factors, we found that in the co-dominant genetic model, rs2057482 TT carriers were 2.195 times more likely to develop lung cancer than CC carriers (95%CI: 1.038-4.463) in the population that were exposed to passive smoking. In the dominant genetic model, the risk of lung cancer was 1.911 times (95%CI: 1.121-3.258) that in the carriers of the rs2057482 T allele with a family history of cancer. In the recessive genetic model, rs2057482 TT carriers had a 0.159-fold increased risk of lung cancer (95%CI: 0.028-0.920) than TC+CC carriers in people with a history of lung disease. In the additive genetic model, the risk of lung cancer in rs2057482 TC+TT carriers was 1.542 times (95%CI: 1.107-2.340) that in the CC family of people with a family history of cancer. HIF-1α rs2057482 may be associated with lung cancer susceptibility. .


Increased diagnosis of enlarged vestibular aqueduct by multiplex PCR enrichment and next-generation sequencing of the SLC26A4 gene.
The enlarged vestibular aqueduct (EVA) is the commonest malformation of inner ear accompanied by sensorineural hearing loss in children. Three genes SLC26A4, FOXI1, and KCNJ10 have been associated with EVA, among them SLC26A4 being the most common. Yet, hotspot mutation screening can only diagnose a small number of patients. Thus, in this study, we designed a new molecular diagnosis panel for EVA based on multiplex PCR enrichment and next-generation sequencing of the exon and flanking regions of SLC26A4. A total of 112 hearing loss families with EVA were enrolled and the pathogenicity of the rare variants detected was interpreted according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Our results showed that 107/112 (95.54%) families carried SLC26A4 biallelic mutations, 4/112 (3.57%) carried monoallelic variants, and 1/112 (0.89%) had none variant, resulting in a diagnostic rate of 95.54%. A total of 49 different variants were detected in those patients and we classified 30 rare variants as pathogenic/likely pathogenic, of which 13 were not included in the Clinvar database. Our diagnostic panel has an increased diagnostic yield with less cost, and the curated list of pathogenic variants in the SLC26A4 gene can be directly used to aid the genetic counseling to patients.


Along with cyclic electron flow and non-photochemical quenching, water-to-water cycle is involved uniquely in alleviating Zn stress-caused photodamage in Melia azedarach.
Zinc (Zn) is a widespread industrial pollutant that has detrimental effects on plant growth and development. Photoprotective properties ensure plant survival during stress by protecting the photosynthetic apparatus. This occurs via numerous mechanisms, including non-photochemical quenching (NPQ), cyclic electron flow (CEF) and the water-to-water cycle (WWC). However, whether and how Zn stress affects the photoprotective properties of plants to enhance the tolerance of Zn toxicity remains unknown. In this study, we treated Melia azedarach plants with different Zn concentrations ranging from 200 to 1000 mg kg-1. We then analyzed the activities of two leaf photosynthetic pigment components-photosystems I and II (PSI and PSII)-and the relative expression levels of their subunit genes. As expected, we found that Zn treatment decreases photosynthesis and increases photodamage in M. azedarach leaves. The Zn treatments exacerbated a variety of photodamage phenotypes in photosystem activities and altered the expression levels of key photosystem complex genes and proteins. Furthermore, our results demonstrated that PSI was more seriously damaged than PSII under Zn stress. Subsequently, we compared differences in photodamage in the NPQ, CEF and WWC photoprotection pathways under Zn stress and found that each exerted a protective function again photodamage under 200 mg kg-1 Zn stress. The NPQ and CEF may also play major protective roles in the avoidance of irreversible photodamage and helping to ensure survival under higher (i.e., 500 and 1000 mg kg-1) levels of Zn stress. Thus, our study revealed that NPQ- and CEF-based photoprotection mechanisms are more effective than WWC in M. azedarach upon Zn stress.


Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteins during mitophagy.
PGAM5 is a protein phosphatase located in the inner mitochondrial membrane through its transmembrane (TM) domain and is cleaved within the TM domain upon mitochondrial dysfunction. We found previously that cleaved PGAM5 is released from mitochondria, following proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy, a selective form of autophagy specific to mitochondria. Here, we examined the role of cleaved PGAM5 outside mitochondria. Deletion mutants that mimic cleaved PGAM5 existed not only in the cytosol but also in the nucleus, and a fraction of cleaved PGAM5 translocated to the nucleus during mitophagy induced by the uncoupler CCCP. We identified serine/arginine-related nuclear matrix protein of 160 kDa (SRm160)/SRRM1, which contains a highly phosphorylated domain rich in arginine/serine dipeptides, called the RS domain, as a nuclear protein that interacts with PGAM5. PGAM5 dephosphorylated SRm160, and incubation of lysates from WT cells, but not of those from PGAM5-deficient cells, induced dephosphorylation of SRm160 and another RS domain-containing protein SRSF1, one of the most characterized serine/arginine-rich (SR) proteins. Moreover, phosphorylation of these proteins and other SR proteins, which are commonly reactive toward the 1H4 monoclonal antibody that detects phosphorylated SR proteins, decreased during mitophagy, largely because of PGAM5 activity. These results suggest that PGAM5 regulates phosphorylation of these nuclear proteins during mitophagy. Because SRm160 and SR proteins play critical roles in mRNA metabolism, PGAM5 may coordinate cellular responses to mitochondrial stress at least in part through post-transcriptional and pre-translational events.


Emergence of consistent intra-individual locomotor patterns during zebrafish development.
The analysis of larval zebrafish locomotor behavior has emerged as a powerful indicator of perturbations in the nervous system and is used in many fields of research, including neuroscience, toxicology and drug discovery. The behavior of larval zebrafish however, is highly variable, resulting in the use of large numbers of animals and the inability to detect small effects. In this study, we analyzed whether individual locomotor behavior is stable over development and whether behavioral parameters correlate with physiological and morphological features, with the aim of better understanding the variability and predictability of larval locomotor behavior. Our results reveal that locomotor activity of an individual larva remains consistent throughout a given day and is predictable throughout larval development, especially during dark phases, under which larvae demonstrate light-searching behaviors and increased activity. The larvae's response to startle-stimuli was found to be unpredictable, with no correlation found between response strength and locomotor activity. Furthermore, locomotor activity was not associated with physiological or morphological features of a larva (resting heart rate, body length, size of the swim bladder). Overall, our findings highlight the areas of intra-individual consistency, which could be used to improve the sensitivity of assays using zebrafish locomotor activity as an endpoint.


Self-care of the feet in people with type 2 diabetes. A qualitative study.
To understand the experiences of adults over 65 years of age with type 2 diabetes mellitus, regarding foot self-care. Qualitative phenomenological study with a descriptive approach. It is carried out in the facilities of the Primary Care Center of Les Planes de Sant Joan Despí, Barcelona, belonging to the Catalan Institute of Health. For the data collection, a semi-structured and individual interview was used, with a script of basic aspects to be explored, not closed and focused on the objectives of the research. The interviews were carried out between June 2019 and December 2020. A thematic analysis was carried out concomitantly with the collection of these. A final sample of 13 persons (4 men and 9 women) participated in the study. Adherence to diabetic foot self-care recommendations is irregular. Participants explain risky behaviours despite knowing that they can cause injury to feet previously considered high risk. The evaluation of the podiatrist supposes an economic cost that some people cannot afford. The nurse has to do an exhaustive follow-up of how persons with diabetes take care of her feet, insisting on preventive recommendations not only in the annual review but every time the person attends the diabetes follow-up consultation. Effective nurse-podiatrist communication is needed to improve prevention and follow-up of people at risk of diabetic foot disease.


STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts.
In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.


Crystal structure of potassium tri-ethyl-hydridoborate ('superhydride').
In the title compound, formally K+·C6H16B-, the contact sphere of potassium consists of eleven hydrogen atoms from three different anions, assuming an arbitrary cut-off of 3 Å. The shortest inter-action, 2.53 (2) Å, involves the hydridic hydrogen H01, which fulfils a bridging function in the formation of chains of KHBEt3 units parallel to the a axis [K1-H01i 2.71 (2) Å, K1-H01-K1ii 126.7 (9)°, operators x∓1/2, -y + , -z + 1].


Development of children born to mothers with cancer during pregnancy: comparing in utero chemotherapy-exposed children with nonexposed controls.
Cancer is diagnosed in approximately 1 per 1000 pregnant women. Lifesaving cancer therapy given to the mother during pregnancy appears in conflict with the interest of the developing fetus. Often, termination of pregnancy is suggested but has not been proven in any type of cancer to improve maternal prognosis, while very few studies have documented the long-term effects of in utero chemotherapy exposure on child outcome. To counsel patients about the risk of continuing a pregnancy while undergoing cancer treatment, we performed developmental testing to provide more detailed follow-up on children exposed in utero to chemotherapy. Mother-infant pairs, enrolled in the Cancer and Pregnancy Registry, were offered developmental testing for children who were ≥18 months of age. Based on age, the Bayley Scales of Infant Development-Third Edition, the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Wechsler Intelligence Scale for Children, Third Edition, or the Wechsler Individual Achievement Test was administered. All parents or primary caregivers completed the Child Behavior Checklist, a parent questionnaire to assess behavior and emotional issues. Results of children exposed to chemotherapy before delivery were compared with children whose mothers were also diagnosed with cancer during pregnancy but did not receive chemotherapy before delivery. No significant differences were noted in cognitive skills, academic achievement, or behavioral competence between the chemotherapy-exposed group and the unexposed children. Of children, 95% scored within normal limits on cognitive assessments; 71% and 79% of children demonstrated at or above age equivalency in mathematics and reading scores, respectively; and 79% of children scored within normal limits on measures of behavior. Older children had significantly higher rates of internalizing behavior problems. We could not demonstrate a significant difference in cognitive ability, school performance, or behavioral competence for children exposed to chemotherapy in utero compared with nonexposed controls. The majority of these children scored within normal limits on all developmental measures. Premature birth was more prevalent in the chemotherapy-exposed group yet did not predict developmental outcome. Older children in the sample demonstrated higher rates of internalizing behavior problems.


Molecular cloning in Escherichia coli, expression, and nucleotide sequence of the gene for the ethylene-forming enzyme of Pseudomonas syringae pv. phaseolicola PK2.
The gene for the ethylene-forming enzyme of Pseudomonas syringae pv. phaseolicola PK2 was found to be encoded by an indigenous plasmid, designated pPSP1. The gene for the ethylene-forming enzyme was cloned and expressed in Escherichia coli JM109. Nucleotide sequence analysis of the clone revealed an open reading frame that encodes 350 amino acids (mol. wt. 39,444). In a comparison with other proteins, the homology score for the entire amino-acid sequence of the ethylene-forming enzyme of Pseudomonas syringae versus ethylene-forming enzymes from plants and 2-oxoglutarate-dependent dioxygenases was low. However, functionally significant regions are conserved.


The role of autonomic pathways in peripheral apelin-induced gastrointestinal dysmotility: involvement of the circumventricular organs.
What is the central question of this study? Are central autonomic pathways and circumventricular organs involved in apelin-induced inhibition of gut motility? What is the main finding and its importance? Peripherally administered apelin-13 inhibits gastric and colonic motor functions through sympathetic and parasympathetic autonomic pathways, which seems to be partly mediated by the apelin receptor in circumventricular organs. Peripheral administration of apelin-13 has been shown to inhibit gastrointestinal (GI) motility, but the relevant mechanisms are incompletely understood. This study aimed to investigate (i) whether the apelin receptor (APJ) is expressed in circumventricular structures involved in autonomic functions, (ii) whether they are activated by peripherally administered apelin, (iii) the role of autonomic pathways in peripheral exogenous apelin-induced GI dysmotility, and (iv) the changes in apelin levels in the extracellular environment of the brain following its peripheral application. Ninety minutes after apelin-13 administration (300 μg kg-1 , i.p.), gastric emptying (GE) and colon transit (CT) were measured in rats that underwent parasympathectomy and/or sympathectomy. Plasma and cerebrospinal fluid (CSF) samples were also collected from another group of rats that received apelin-13 or vehicle injection. The immunoreactivities for APJ and c-Fos in circumventricular organs (CVOs) were evaluated by immunohistochemistry. Compared with vehicle-treated rats, GE and CT were inhibited significantly by apelin-13 treatment, and were completely restored in animals that underwent the combination of parasympathectomy and sympathectomy and sympathectomy alone, respectively. Apelin concentrations were elevated in both plasma and CSF following peripheral administration of apelin-13. APJ expression was detected in area postrema (AP), subfornical organ and organum vasculosum of lamina terminalis, and c-Fos expression was observed in response to apelin injection. Apelin-induced c-Fos expression in AP was partially attenuated by pretreatment with the cholecystokinin-1 receptor antagonist lorglumide, whereas it was completely abolished in vagotomized rats. The present data suggest that APJ in CVOs could indirectly contribute to the inhibitory action of peripheral apelin on GI motor functions.


Optogenetics 3.0.
Optogenetic methods use light to modulate the activities of target cells in vivo. By improving inter- and intracellular trafficking of light-sensitive switch proteins called opsins, Gradinaru et al. (2010) have developed a new generation of optogenetic tools capable of regulating the activity of targeted neurons with exquisite precision and efficiency.


The essence of linkage-based imprinting detection: comparing power, type 1 error, and the effects of confounders in two different analysis approaches.
Imprinting is critical to understanding disease expression. It can be detected using linkage information, but the effects of potential confounders (heterogeneity, sex-specific penetrance, and sex-biased ascertainment) have not been explored. We examine power and confounders in two imprinting detection approaches, and we explore imprinting-linkage interaction. One method (PP) models imprinting by maximising lod scores w.r.t. parent-specific penetrances. The second (DRF) approximates imprinting by maximising lods over differential male-female recombination fractions. We compared power, type 1 error, and confounder effects in these two methods, using computer-simulated data. We varied heterogeneity, penetrance, family and dataset size, and confounders that might mimic imprinting. Without heterogeneity, PP had more imprinting-detecting power than DRF. PP's power increased when parental affectedness status was ignored, but decreased with heterogeneity. With heterogeneity, type 1 error increased dramatically for both methods. However, DRF's power also increased under heterogeneity, more than was attributable to inflated type 1 error. Sex-specific penetrance could increase false positives for PP but not for DRF. False positives did not increase on ascertainment through an affected "mother". For PP, non-penetrant individuals increased information, arguing against using affected-only methods. The high type 1 error levels under some circumstances means these methods must be used cautiously.


Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis.
This extension study provided continued treatment to subjects with active rheumatoid arthritis who had participated for ≥16 weeks in a pharmacokinetic similarity study of PF-05280586 (potential rituximab biosimilar). Objectives were to evaluate overall pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of PF-05280586 after transition from rituximab reference products to PF-05280586, and follow-up of biomarker and efficacy assessments. Subjects were offered ≤3 additional courses of treatment of PF-05280586, with or without a single transition from rituximab in Europe (rituximab-EU; MabThera) or the US (rituximab-US; Rituxan) to PF-05280586. Each course comprised 2 intravenous infusions (1,000 mg on days 1 and 15, separated by 24 weeks [± 8 weeks]). Of 220 subjects in the parent study, 185 were randomized and included in this study. There were no notable differences in drug concentrations between groups or across courses, with little variation in depletion of CD19+ B cells between groups, and no apparent relationship between infusion-related reactions and antidrug antibodies with or without single transition from rituximab reference products to PF-05280586. Long-term safety and tolerability of PF-05280586 was acceptable in all groups for up to 96 weeks, with a low incidence of treatment-emergent adverse events independent of single drug transition. The percentage of subjects with a low disease activity score and disease activity score remission was similar across groups for all time points, and responses were sustained until end of study. This study demonstrated acceptable safety, tolerability, and immunogenicity, with or without single transition from rituximab reference products to PF-05280586, without increased immunogenicity on single transition.


COVID-19's Effect on Pregnancy Care for Incarcerated People.
Prisons and jails are high risk environments for COVID-19. Little is known about COVID-19's impact on pregnancy care for the tens of thousands of pregnant people who pass through these institutions each year. This study aimed to describe how COVID-19 has influenced prisons' and jails' pregnancy care services. We conducted a cross-sectional survey of a convenience sample of U.S. prisons and jails and report descriptive statistics. We received 17 responses. Sites reported changes in prenatal care delivery, support programming, housing, and visitation. Most sites implemented changes in housing arrangements to quarantine individuals at-risk for COVID-19. Many sites increased their use of virtual technology to supplement for suspended in-person appointments, programming, and visitation. The impact of COVID-19 on pregnancy care delivery and support services for incarcerated pregnant people is variable. As the pandemic continues, research and policy should ensure that incarcerated pregnant people have access to full scope pregnancy care.


Earth history events shaped the evolution of uneven biodiversity across tropical moist forests.
Far from a uniform band, the biodiversity found across Earth's tropical moist forests varies widely between the high diversity of the Neotropics and Indomalaya and the relatively lower diversity of the Afrotropics. Explanations for this variation across different regions, the "pantropical diversity disparity" (PDD), remain contentious, due to difficulty teasing apart the effects of contemporary climate and paleoenvironmental history. Here, we assess the ubiquity of the PDD in over 150,000 species of terrestrial plants and vertebrates and investigate the relationship between the present-day climate and patterns of species richness. We then investigate the consequences of paleoenvironmental dynamics on the emergence of biodiversity gradients using a spatially explicit model of diversification coupled with paleoenvironmental and plate tectonic reconstructions. Contemporary climate is insufficient in explaining the PDD; instead, a simple model of diversification and temperature niche evolution coupled with paleoaridity constraints is successful in reproducing the variation in species richness and phylogenetic diversity seen repeatedly among plant and animal taxa, suggesting a prevalent role of paleoenvironmental dynamics in combination with niche conservatism. The model indicates that high biodiversity in Neotropical and Indomalayan moist forests is driven by complex macroevolutionary dynamics associated with mountain uplift. In contrast, lower diversity in Afrotropical forests is associated with lower speciation rates and higher extinction rates driven by sustained aridification over the Cenozoic. Our analyses provide a mechanistic understanding of the emergence of uneven diversity in tropical moist forests across 110 Ma of Earth's history, highlighting the importance of deep-time paleoenvironmental legacies in determining biodiversity patterns.


tRNA-mRNA mimicry drives translation initiation from a viral IRES.
Internal ribosome entry site (IRES) RNAs initiate protein synthesis in eukaryotic cells by a noncanonical cap-independent mechanism. IRESes are critical for many pathogenic viruses, but efforts to understand their function are complicated by the diversity of IRES sequences as well as by limited high-resolution structural information. The intergenic region (IGR) IRESes of the Dicistroviridae viruses are powerful model systems to begin to understand IRES function. Here we present the crystal structure of a Dicistroviridae IGR IRES domain that interacts with the ribosome's decoding groove. We find that this RNA domain precisely mimics the transfer RNA anticodon-messenger RNA codon interaction, and its modeled orientation on the ribosome helps explain translocation without peptide bond formation. When combined with a previous structure, this work completes the first high-resolution description of an IRES RNA and provides insight into how RNAs can manipulate complex biological machines.


Essential oil from Lavandula angustifolia elicits expression of three SbWRKY transcription factors and defense-related genes against sorghum damping-off.
Sorghum damping-off, caused by Fusarium solani (Mart.) Sacc., is a serious disease which causes economic loss in sorghum production. In this study, antagonistic activity of lavender essential oil (EO) at 0.5, 0.75, 1.0, 1.25, 1.5, and 1.6% against F. solani was studied in vitro. Their effects on regulation of three SbWRKY transcription factors, the response factor JERF3 and eight defense-related genes, which mediate different signaling pathways, in sorghum were investigated. Effects of application under greenhouse conditions were also evaluated. The results showed that lavender EO possesses potent antifungal activity against F. solani. A complete inhibition in the fungal growth was recorded for lavender EO at 1.6%. Gas chromatography-mass spectrometric analysis revealed that EO antifungal activity is most likely attributed to linalyl anthranilate, α-terpineol, eucalyptol, α-Pinene, and limonene. Observations using transmission electron microscopy revealed many abnormalities in the ultrastructures of the fungal mycelium as a response to treating with lavender EO, indicating that multi-mechanisms contributed to their antagonistic behavior. Results obtained from Real-time PCR investigations demonstrated that the genes studied were overexpressed, to varying extents in response to lavender EO. However, SbWRKY1 was the highest differentially expressed gene followed by JERF3, which suggest they play primary role(s) in synchronously organizing the transcription-regulatory-networks enhancing the plant resistance. Under greenhouse conditions, treating of sorghum grains with lavender EO at 1.5% prior to infection significantly reduced disease severity. Moreover, the growth parameters evaluated, the activities of antioxidant enzymes, and total phenolic and flavonoid contents were all enhanced. In contrast, lipid peroxidation was highly reduced. Results obtained from this study support the possibility of using lavender EO for control of sorghum damping-off. However, field evaluation is highly needed prior to any usage recommendation.


[Musculoskeletal rehabilitation and bone. Development of Simulator (Jouba) for horse riding therapy and utility for the aged].
Horseback riding therapy is popularly used as one of the physiotherapy in Europe. Dr. Kimura hit upon Horseback Riding Robot, which can precisely simulate horseback motion ; as a result, he has developed and completed the Horseback Riding Robot, which can be worked by six motors. The Horseback Riding Robot, however, is very expensive. For that reason we have decided to turn over a new leaf and have developed a home machine by realizing one motor type. We proved the muscle strength trainings by use of Horse Riding Robot and a home machine, unlike a existing monotonous and boring muscle training, to be worthwhile and effective.


Double-blind randomized phase III study comparing a mixture of natural agents versus placebo in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer.
There is no widely accepted intervention in the prevention of acute mucositis during chemoradiotherapy for head and neck carcinoma. In the present double-blind study, we tested 4 natural agents, propolis, aloe vera, calendula, and chamomile versus placebo. Patients undergoing concomitant chemo-intensity-modulated radiotherapy (IMRT) were given natural agent or matched placebo; grade 3 mucositis on physical examination according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was the primary endpoint. Various covariates were tested at logistic regression, including the individual amount of mucosa receiving at least 9.5 Gy per week (V9.5w). One hundred seven patients were randomized from January 2011 to July 2014, and 104 were assessable (51%-49% were assigned to the placebo group and 53%-51% were assigned to the natural agent). Overall, 61 patients developed peak grade 3 mucositis with no difference between arms (P = .65). Conversely, V9.5w (P = .007) and primary site (P = .037) were independent predictors. The selected natural agents do not prevent mucositis, whereas the role of V9.5w is confirmed.


Successful treatment of patients with refractory idiopathic membranous nephropathy with low-dose Rituximab: A single-center experience.
The recognition of idiopathic membranous nephropathy (IMN) as an autoimmune disease has paved the way for the use of B-cell-depleting agents, such as Rituximab (RTX), which is now a first-line drug for treating IMN with proven safety and efficacy. Nevertheless, the usage of RTX for the treatment of refractory IMN remains controversial and challenging. To evaluate the efficacy and safety of a new low-dose RTX regimen for the treatment of patients with refractory IMN. A retrospective study was performed on refractory IMN patients that accepted a low-dose RTX regimen (RTX, 200 mg, once a month for five months) in the Xiyuan Hospital of Chinese Academy of Chinese Medical Sciences' Department of Nephrology from October 2019 to December 2021. To assess the clinical and immune remission data, we performed a 24 h urinary protein quantification (UTP) test and measured the serum albumin (ALB) and serum creatinine (SCr) levels, phospholipase A2 receptor (PLA2R) antibody titer, and CD19+ B-cell count every three months. A total of nine refractory IMN patients were analyzed. During follow-up conducted twelve months later, the results from the 24 h UTP decreased from baseline [8.14 ± 6.05 g/d to 1.24 ± 1.34 g/d (P < 0.05)] and the ALB levels increased from baseline [28.06 ± 8.42 g/L to 40.93 ± 5.85 g/L (P < 0.01)]. Notably, after administering RTX for six months, the SCr decreased from 78.13 ± 16.49 μmol/L to 109.67 ± 40.87 μmol/L (P < 0.05). All of the nine patients were positive for serum anti-PLA2R at the beginning, and four patients had normal anti-PLA2R titer levels at six months. The level of CD19+ B-cells decreased to 0 at three months, and CD19+ B-cell count remained at 0 up until six months of follow-up. Our low-dose RTX regimen appears to be a promising treatment strategy for refractory IMN.


The use of MSSV pyrolysis to assist the molecular characterisation of aquatic natural organic matter.
Microscale sealed vessel pyrolysis (MSSVpy) with online gas chromatography mass spectrometry (GC-MS) was used with several other established and complementary analytical methods to robustly characterize the structure of aquatic natural organic matter (NOM) and to practically assess the analytical value of MSSVpy. The NOM used in the study was from North Pine (NP) reservoir, which is one of the major source waters supplying Brisbane, the capital city of the Australian state of Queensland. The reservoir has moderate dissolved organic carbon (DOC; 5mgL(-1)) levels and is impacted by algae which periodically occur in bloom proportions. The hydrophobic (HPO; 65% initial DOC) and transphilic (TPI; 12%) fractions showed H/C values >1, low UV(abs) and low aryl-C measured by NMR which are all indicative of low aromaticity. MSSVpy produced distinctly higher product concentrations than traditional flash pyrolysis and the molecular profile of the HPO and TPI fractions revealed by MSSVpy was correlated with the other analytical data to help establish their structural relevance. Prolific distributions of alkyl substituted aromatic (e.g., benzenes, naphthalenes) and hydroaromatic (e.g., tetralins) products detected in the HPO fraction were attributed to the aromatisation of terpanes and other aliphatic compounds from algal, and possibly also plant sources. Alkyl phenols also detected in HPO in high abundance, are probably from algal biopolymers, but may also reflect a contribution from non-methoxylated lignin units of catchment grasses. There was no analytical evidence of the dihydroxy or methoxy aromatic structures typical of wood lignin or tannin. N-organic pyrolysates (e.g., alkyl pyrroles, pyridines, indoles) of diagenetically altered proteins were concentrated in the TPI fraction. The quantitative importance of the N-organic moiety of the TPI fraction was corroborated by a low C/N ratio and distinctive amide and amine signals detected by (13)C NMR and FTIR. This integrated study demonstrates that the qualitative speciation provided by MSSVpy can make a significant contribution to the structural characterisation and source recognition of aquatic NOM.


Block training periodization in alpine skiing: effects of 11-day HIT on VO2max and performance.
Attempting to achieve the high diversity of training goals in modern competitive alpine skiing simultaneously can be difficult and may lead to compromised overall adaptation. Therefore, we investigated the effect of block training periodization on maximal oxygen consumption (VO2max) and parameters of exercise performance in elite junior alpine skiers. Six female and 15 male athletes were assigned to high-intensity interval (IT, N = 13) or control training groups (CT, N = 8). IT performed 15 high-intensity aerobic interval (HIT) sessions in 11 days. Sessions were 4 x 4 min at 90-95% of maximal heart rate separated by 3-min recovery periods. CT continued their conventionally mixed training, containing endurance and strength sessions. Before and 7 days after training, subjects performed a ramp incremental test followed by a high-intensity time-to-exhaustion (tlim) test both on a cycle ergometer, a 90-s high-box jump test as well as countermovement (CMJ) and squat jumps (SJ) on a force plate. IT significantly improved relative VO2max by 6.0% (P < 0.01; male +7.5%, female +2.1%), relative peak power output by 5.5% (P < 0.01) and power output at ventilatory threshold 2 by 9.6% (P < 0.01). No changes occurred for these measures in CT. tlim remained unchanged in both groups. High-box jump performance was significantly improved in males of IT only (4.9%, P < 0.05). Jump peak power (CMJ -4.8%, SJ -4.1%; P < 0.01), but not height decreased in IT only. For competitive alpine skiers, block periodization of HIT offers a promising way to efficiently improve VO2max and performance. Compromised explosive jump performance might be associated with persisting muscle fatigue.


[Histotopochemical investigations on elastic membranes of blood vessels with special regard of diabetes mellitus. iv. Heavy metals (author's transl)].
Both of the methods for the histochemical detection of heavy metals have given corresponding results. In normal animals and also in non-diabetic men was a visible strong fluorescence after application of 2-methyl-8-hydroxychinoline and a strong sulfide-silver-reaction. This results are also in animals with diabetes mellitus clear. In asymptomatical and clinical manifest diabetes mellitus is established in contrast a weak exhibition of the elastic membranes of vessels with both of the methods.


Identifying crash contributory factors at urban roundabouts and using association rules to explore their relationships to different crash types.
The use of roundabouts improves intersection safety by eliminating or altering conflict types, reducing crash severity, and causing drivers to reduce speeds. However, roundabout performances can degrade if precautions are not taken during either the design or the operation phase. Therefore, additional information on the safety of the roundabouts is extremely helpful for planners and designers in identifying existing deficiencies and in refining the design criteria currently being used. The aim of the paper was to investigate the crash contributory factors in 15 urban roundabouts located in Italy and to study the interdependences between these factors. The crash data refer to the period 2003-2008. The identification of the crash contributory factors was based on site inspections and rigorous analyses performed by a team of specialists with a relevant road safety engineering background. Each roundabout was inspected once every year from 2004 to 2009, both in daytime and in nighttime. Overall, 62 different contributory factors and 2156 total contributory factors were identified. In 51 crashes, a single contributory factor was found, whereas in the other 223 crashes, a combination of contributory factors was identified. Given the large amount of data, the interdependences between the contributory factors and between the contributory factors and the different crash types were explored by an association discovery. Association discovery is the identification of sets of items (i.e., crash contributory factors and crash types in our study) that occur together in a given event (i.e., a crash in our study). The rules were filtered by support, confidence, and lift. As a result, 112 association rules were discovered. Overall, numerous contributory factors related to the road and environment deficiencies but not related to the road user or to the vehicle were identified. The most important factors related to geometric design were the radius of deflection and the deviation angle. In existing roundabouts, the improvement of these factors might be quite expensive, but the crucial role of a moderate radius of deflection and a large deviation angle in the design of new roundabouts was stressed. Many of the contributory factors were related to markings and signs, and these factors could be easily removed with low-cost safety measures. Furthermore, because of the association between the markings, signs, and geometric design contributory factors, the study results suggest that the improvement in markings and signs might also have a significant effect in the sites where geometric design deficiencies were identified as contributory factors.


Early corticosteroids requirement after the diagnosis of ulcerative colitis diagnosis can predict a more severe long-term course of the disease - a nationwide study of 1035 patients.
There are limited data regarding clinical outcomes in ulcerative colitis (UC) patients who require early corticosteroids (CS) use. To evaluate the rate of early CS utilisation (within 30 days of diagnosis) as a predictive marker for long-term outcomes, colectomy and CS dependency, in a population-based cohort of incident UC cases. Nationwide data were obtained from the Veterans Affairs (VA) health care system for the period 2001-2011. Incident UC cases were identified. A retrospective cohort design and time-to-event survival analysis were used to track outcomes of interest. Cox regression multivariate analysis was employed. One thousand and thirty-five newly diagnosed patients with UC were identified and included in the analysis; 236 (23%) of those patients required early CS therapy. Patients were followed-up over a median time of 4.7 years (IQR 2.8-6.8) after UC diagnosis. The 5-year cumulative probability of requiring colectomy varied significantly by early CS use status (13% among early CS users compared to 4% among those who did not require early CS treatment, P < 0.001). Similar variation in the 5-year cumulative probability of CS dependency by early CS status was observed. Early CS users were more likely to require colectomy 2.9 (CI 1.7-5.0, P < 0.001) and to become CS dependent 4.5 (95% CI 3.6-5.7, P < 0.001) than non-users. Early CS use can help identify those patients who have a more active disease course of UC. Recognising this can be among the indicators that can help physicians identify patients who may require early initiation of more aggressive therapy.


Twelve tips for medical students to make the best use of ward-based learning.
With a multitude of healthcare professionals willing to teach, a placement on a ward is an invaluable learning opportunity; yet as students, we often struggle to maximize this placements' potential. This article provides 12 tips for medical students to optimize their learning in a ward-based environment. Current literature and personal experiences of the authors were used to develop the tips. The 12 tips are (1) prepare yourself, (2) identify knowledge, skills, and attributes, (3) engage in peer-to-peer learning, (4) get to know the interprofessional team, (5) talk to the patient first, (6) present findings and gain feedback, (7) tap into seniors' experience, (8) immerse yourself and be proactive, (9) check patient notes, (10) manage the clock, (11) enhance your CV, and (12) embrace the spirit of lifelong learning. These tips will enable us to effectively improve our learning and positively shape us into outstanding future doctors.


An animal model of iron overload and its application to study hepatic ferritin iron mobilization by chelators.
Administration of 3,5,5-trimethylhexanoyl ferrocene in the diet of male Wistar rats results in a substantial increase in hepatic ferritin protein (greater than 2-fold) and of ferritin iron (4-8-fold). The iron-loading in liver, under the conditions used, appears to be essentially in parenchymal cells rather than in reticulo-endothelial cells. It is suggested that the model represents a useful system for the study of the potential efficacy of new iron chelators for the mobilization of hepatic storage iron. The ability of desferal (DFO) and of a new siderophore, desferrithiocin (DFT), to mobilize hepatic ferritin iron is observed in this model of iron overload. Desferrithiocin stimulates ferritin iron mobilization, when administered either by gavage or by intraperitoneal injection, whereas desferal is active intraperitoneally but inactive orally. Our studies lead to the conclusion that DFT merits further examinations, for its activity as an orally active iron chelator.


Ultrasound Doppler vector tomography measurements of directional blood flow.
An experimental system has been developed to verify the possibility of detecting flow activity using a technique called ultrasound Doppler vector tomography. A tomography algorithm is used to reconstruct blood flow vector fields using data from computer-controlled ultrasound continuous-wave Doppler scanning equipment. The result is a picture in which the brightness variations represent the reconstructed values of the curl of the velocity field (inverted delta x v). Continuous ultrasound is transmitted into a region with flow activity and the Doppler-shifted signals are received. To obtain measurement data suited for fan beam tomography, the scanning is performed in a plane from points encircling the region. Reconstructions have been achieved using measurement data from two different flow phantoms. A comparison between the experimental results and simulations shows good conformity.


VP22-mediated intercellular transport correlates with enhanced biological activity of MybEngrailed but not (HSV-I) thymidine kinase fusion proteins in primary vascular cells following non-viral transfection.
The intercellular transport properties of the herpes simplex virus (HSV) protein VP22 have been harnessed to enhance the effectiveness of viral gene transfer. We investigated the intercellular transport and biological effects of VP22 fused with the dominant negative c-Myb chimera, MybEngrailed (MybEn) and HSV-I thymidine kinase (TK), in primary vascular smooth muscle cells (VSMC) following non-viral transfection. Porcine VSMC transfected with plasmids encoding MybEn, TK and their respective N- and C-terminal VP22 fusion proteins were assayed for the extent and distribution of transgene expression (by immunohistochemistry), culture growth and apoptosis. The N-terminal MybEn fusion with VP22 (MybEnVP22) and both TK fusions, but not VP22MybEn, exhibited intercellular spread from primary transfected to up to 200 surrounding cells. pMybEnVP22-transfected cultures exhibited growth inhibition and apoptosis rates that were 10.6 +/- 3.6 and 3.2 +/- 1.0 fold higher than in pMybEn-transfected cultures; pVP22MybEn-transfected cultures showed no difference in these parameters. pTK-transfected cultures underwent 60-70% cell death in the presence of ganciclovir despite <2% primary transfection, which was not increased in cultures transfected with plasmids encoding VP22-TK fusions. The close correlation between immunocytochemical and biological assays suggests that intercellular transport is crucial to the enhanced biological activity of the MybEnVP22 fusion. The "intrinsic" bystander activity of TK was 4-fold greater than was "engineered" by VP22 fusion, probably reflecting the abundance of gap junctions between VSMC. VP22 fusion may enhance the efficiency of non-viral gene delivery when combined with the appropriate therapeutic transgene, target tissue and transfection method.


The Spanish version of the Psychiatric/Mental health clinical placement survey and an assessment of Spanish student attitudes towards mental health.
WHAT IS KNOWN ON THE SUBJECT?: The Psychiatric/Mental Health Clinical Placement Survey preplacement, validated in English and widely used, assesses nursing student attitudes towards the mental health field. There are no validated scales in Spanish to assess students' attitudes towards mental health, nor is there evidence of attitudes in Spanish students. WHAT DOES THIS ARTICLE ADD TO EXISTING KNOWLEDGE?: The present study was the first to address the validity of a scale which evaluates nursing student attitudes towards mental health issues, in Spanish. Until now, no knowledge was available on nursing student attitudes towards mental health issues in the Spanish context. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The results provide faculty professors with a validated tool to use to assess attitudinal changes in students, following theoretical and practical training in mental health. To have an up-to-date perspective on student attitudes towards both the field of mental health and people with severe mental illness, thereby providing the opportunity to focus on those aspects requiring improvement. Abstract Introduction The encouragement of positive attitudes towards mental health is necessary in order to improve the quality of healthcare assistance. The attitudes of nursing students towards mental health are unknown, and there are no validated scales for their assessment. Aims To adapt the Psychiatric/Mental Health Clinical Placement Survey (PMHCPS) to Spanish and examine its psychometric properties; to describe the attitudes of nursing students towards the mental health field. Method Confirmatory factorial analysis (CFA), internal consistency and construct validity were performed. An assessment of the students' attitudes was also conducted. Results The CFA showed appropriate fit, and total internal consistency was adequate. With regard to construct validity, knowledge was associated with practicum mark. The students achieved above mid-range scores for all subscales, except negative stereotypes. Gender differences were observed. Discussion The PMHCPS, translated to Spanish, enables the students' attitude towards the mental health field to be assessed, thus identifying those areas of student attitudes and competencies requiring improvement. Implications for practice To provide Spanish nursing faculties with access to a scale, with which to assess changes in student attitudes. The assessment results may then be utilized to formulate teaching methods in order to improve the quality of health care the students might provide as future nursing professionals.


Impaired inhibitory Fcgamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy.
The inhibitory Fc-gamma receptor FcgammaRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcgammaRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcgammaRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcgammaRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare -386C/-120A FcgammaRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcgammaRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcgammaRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcgammaRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.


Oxidation kinetics of ethanol by human cytochrome P450 2E1. Rate-limiting product release accounts for effects of isotopic hydrogen substitution and cytochrome b5 on steady-state kinetics.
A number of cytochrome P450 (P450) 2E1 substrates are known to show kinetic deuterium isotope effects of approximately 5 on Km (DK = DKm/HKm), but not on kcat, in rat liver microsomes (e.g. N-nitrosodimethylamine, ethanol, and CH2Cl2). We observed DKm values of 3-5 for recombinant human P450 2E1-catalyzed ethanol oxidation. Replacing NADPH and O2 with the oxygen surrogate cumene hydroperoxide yielded similar results. Ferric P450 2E1 reduction was fast (k >1000 min-1) even in the absence of substrate. These results indicate that the basis for the increase in Km is in the latter portion of the catalytic cycle. The intrinsic isotope effect (Dk) for ethanol oxidation was determined (competitively) to be 3.8, indicating that C-H bond cleavage is isotopically sensitive. Pre-steady-state studies showed a burst of product formation (k = 410 min-1), with the burst amplitude corresponding to the P450 concentration. Deuteration of ethanol resulted in an isotope effect of 3.2 on the rate of the burst. We conclude that product release is rate-limiting in the oxidation of ethanol to acetaldehyde by P450 2E1. The steady-state kinetics can be described by a paradigm in which the kcat approximates the rate of product release, and Km is an expression in which the denominator is dominated by the rate of C-H bond breaking.


3-Nitrotyrosine as a biomarker for vascular involvement in Fabry disease.
Enzyme replacement therapy in Fabry disease was initiated in 2001. In a significant proportion of patients, the apparent removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease. Shu et al. show a link between accumulation of globotriaosylceramide in the endothelial cells and 3-nitrotyrosine formation, indicating endothelial nitric oxide synthase uncoupling. 3-Nitrotyrosine will be useful to better understand Fabry vasculopathy, and to evaluate additional therapeutic interventions targeting oxidative stress.


Limits of cryofixation as seen by Fourier transform infrared spectra of metmyoglobin azide and carbonyl hemoglobin in vitrified and freeze-concentrated aqueous solution.
The limits of cryofixation were probed by investigating metmyoglobin azide and carbonyl hemoglobin in approximately 5 wt% aqueous solution by Fourier transform infrared spectroscopy. Spectra of solutions cooled slowly and recorded in steps between 295 K and 190 K are compared with those obtained by "hyperquenching" either into their glassy states at 80 K, or into freeze-concentrated solution at 170 K. For metmyoglobin azide we conclude from an analysis of its covalently and ionically bound azide that it is impossible to freeze-in its high-spin/low-spin equilibrium even by hyperquenching, and that its vitrified state must correspond to a temperature T < 226 K for the Fe(II) site of the protein. In the amide I spectral region of carbonyl hemoglobin (HbCO), a band at approximately 1654 cm-1 due to alpha-helical structures is the dominant band in spectra recorded at ambient temperature and in the vitrified state, but in the spectrum of HbCO quenched at similar rates into a freeze-concentrated state, a band at approximately 1650 cm-1, tentatively assigned to unordered structures, becomes the dominant feature. This band is absent in the spectra of freeze-concentrated samples obtained by heating a vitrified sample to 170 K. We surmise that HbCO is dehydrated by freeze-concentration to a larger extent in solution quenched rapidly at 170 K than in a vitrified solution heated to 170 K, and that this dehydration is the primary cause for HbCO's perturbation. We conclude that freeze-concentration induced by heating a vitrified solution can cause less perturbations of a protein than does quenching into a freeze-concentrated state. Therefore it can be advantageous for the practice of freeze-etching to vitrify first a solution by "hyperquenching" and thereafter freeze-etch at e.g. approximately 170 K.


Enhancing effect of 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran on diethylnitrosamine hepatocarcinogenesis in rats.
Enhancement of diethylnitrosamine(DENA)-induced hepatic tumor production in rats was observed by sequential exposure to 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) or 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF). This effect was more evident in the group of rats treated with 2,3,4,7,8-PenCDF (80 micrograms/rat), in which approximately 43% of this compound administered was accumulated in the liver at 8 weeks after the last treatment.


Application of direct PCR in a forensic case of yew poisoning.
Intoxications with yew (Taxus spp.) pose a challenge to forensic toxicology because a variety of Taxus ingredients have been associated with its toxic effects. To provide preliminary evidence in cases where plant material is available, we introduce a novel direct PCR assay for the detection of DNA traces from Taxus spp. This assay has been successfully applied to a forensic case of suicidal poisoning via ingestion of Taxus leaves. PCR primers were designed to target a sequence located in the internal transcribed spacer 1 (ITS1) of nuclear ribosomal DNA, which is well conserved among species of the genus Taxus and can, therefore, be exploited to discriminate between Taxus and other conifers. Because ITS1 exists as a multicopy sequence within the plant genome, the assay provides enough sensitivity to work with trace amounts that are below the DNA content of a single cell. Specificity of the assay was tested with DNA extracts from Taxaceae and selected representatives from other related plant families (Cephalotaxaceae, Cupressaceae and Pinaceae). When combined with the commercial Phire® Plant Direct PCR Kit (Finnzymes), the primers allowed application of a two-step cycling protocol (without the annealing step), and because direct PCR requires only little sample pre-treatment, results from PCR could be obtained within 1.5 h after analysis had begun. Direct PCR was performed with diluted gastric content from the forensic case. Amplification products of the expected size were purified and sequenced. Sequence data were subjected to Basic Local Alignment Search Tool analysis and affiliated with ITS1 from Taxus spp.


Influence of lid position on astigmatism.
The influence of 3 different lid positions on the astigmatism of 50 young healthy eyes was investigated with an autorefractor. The results showed that a significant amount of astigmatism may be induced when the palpebral aperture is voluntarily narrowed.


Identification of biotransformation products of macrolide and fluoroquinolone antimicrobials in membrane bioreactor treatment by ultrahigh-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.
Ultrahigh-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry was applied for the identification of transformation products (TPs) of fluoroquinolone (norfloxacin and ciprofloxacin) and macrolide (azithromycin, erythromycin, and roxitromycin) antimicrobials in wastewater effluents from a Zenon hollow-fiber membrane bioreactor (MBR). The detected TPs were thoroughly characterized using the accurate mass feature for the determination of the tentative molecular formulae and MS-MS experiments for the structural elucidation of unknowns. Several novel TPs, which have not been previously reported in the literature, were identified. The TPs of azithromycin and roxithromycin, identified in MBR effluent, were conjugate compounds, which were formed by phosphorylation of desosamine moiety. Transformation of fluoroquinolones yielded two types of products: conjugates, formed by succinylation of the piperazine ring, and smaller metabolites, formed by an oxidative break-up of piperazine moiety to form the 7-[(2-carboxymethyl)amino] group. A semi-quantitative assessment of these TPs suggested that they might have contributed significantly to the overall balance of antimicrobial residues in MBR effluents and thus to the overall removal efficiency. Determination of TPs during a period of 2 months indicated a conspicuous dynamics, which warrants further research to identify microorganisms involved and treatment conditions leading to their formation.


Segmental zoster paresis of limbs: report of three cases and review of literature.
Segmental zoster paresis is a relatively rare complication characterized by focal motor weakness, which may occur in limbs affected by herpes zoster. We demonstrate the clinical characteristics of segmental zoster paresis by reviewing the cases of 138 patients, including 3 of our patients. We report 3 patients with zoster paresis of the limbs. Patients 1 and 3 showed motor weakness in the left shoulder and arm after developing a herpetic rash in the left C5-C6 dermatomes. Patient 2 showed weakness in the right thigh and groin after a right L2-L3 herpetic eruption. The electromyograms of all 3 patients showed abnormal spontaneous activity in the affected muscles. Intravenous acyclovir and corticosteroid pulse therapy were added to oral antiviral drugs for patients 1 and 2. All 3 patients recovered favorably. Our review of the literature revealed that antiviral treatment may prevent the occurrence of zoster paresis; however, there is insufficient evidence to show what treatment hastens recovery from zoster paresis. Segmental zoster paresis is still underrecognized by neurologists. Awareness of this disorder is important because it may eliminate unnecessary invasive investigations and lead to appropriate treatment. Further studies on the treatment are necessary.


Periprocedural anemia management in severe aortic stenosis patients undergoing transcatheter aortic valve implantation.
Preoperative anemia is a common finding in patients with severe aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI), and it has been shown to be associated with high mortality. The present review provides an overview of current management strategies of perioperative anemia in TAVI patients, including red blood cell transfusion, blood conservative protocol, iron supplementation, and erythropoietin administration. The goal is to recognize the treatable causes of anemia and treat them, in order to reduce transfusions and improve the outcome.


State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.
To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.


Assessment of the genetic contribution to brain magnetic resonance imaging lesion load and atrophy measures in multiple sclerosis patients.
Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing-remitting MS (RRMS) patients. Ninety-nine PMS and 214 RRMS patients underwent a 3-T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis. Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p = 0.002), whereas inflammatory-related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p = 0.004 and p = 0.008, respectively). As for SNPs, the rs7104613T mapping to SPON1 gene was associated with reduced deep grey matter volume (β = -0.731, p = 3.2*10-7 ) in PMS, whereas we found evidence of association between white matter volume and rs740948A mapping to SEMA3A gene (β = 22.04, p = 5.5*10-6 ) in RRMS. Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.


Experimentally Validated QSAR Model for Surface pK a Prediction of Heterolipids Having Potential as Delivery Materials for Nucleic Acid Therapeutics.
The application of lipid-based drug delivery technologies for bioavailability enhancement of drugs has led to many successful products in the market for clinical use. Recent studies on amine-containing heterolipid-based synthetic vectors for delivery of siRNA have witnessed the United States Food and Drug Administration (USFDA) approval of the first siRNA drug in the year 2018. The studies on various synthetic lipids investigated for delivery of such nucleic acid therapeutics have revealed that the surface pK a of the constructed nanoparticles plays an important role. The nanoparticles showing pK a values within the range of 6-7 have performed very well. The development of high-performing lipid vectors with structural diversity and falling within the desired surface pK a is by no means trivial and requires tedious trial and error efforts; therefore, a practical solution is called for. Herein, an attempt to is made provide a solution by predicting the statistically significant pK a through a predictive quantitative structure-activity relationship (QSAR) model. The QSAR model has been constructed using a series of 56 amine-containing heterolipids having measured pK a values as a data set and employing a partial least-squares regression coupled with stepwise (SW-PLSR) forward algorithm technique. The model was tested using statistical parameters such as r 2, q 2, and pred_r 2, and the model equation explains 97.2% (r 2 = 0.972) of the total variance in the training set and it has an internal (q 2) and an external (pred_r 2) predictive ability of ∼83 and ∼63%, respectively. The model was validated by synthesizing a series of designed heterolipids and comparing measured surface pK a values of their nanoparticle assembly using a 2-(p-toluidino)-6-napthalenesulfonic acid (TNS) assay. Predicted and measured surface pK a values of the synthesized heterolipids were in good agreement with a correlation coefficient of 93.3%, demonstrating the effectiveness of this QSAR model. Therefore, we foresee that our developed model would be useful as a tool to cut short tedious trial and error processes in designing new amine-containing heterolipid vectors for delivery of nucleic acid therapeutics, especially siRNA.


Sexual neurosteroids and synaptic plasticity in the hippocampus.
Sexual neurosteroids (SN), namely 17β-estradiol (E2) and 5α-dehydrotestosterone (DHT), are synthesized in the hippocampus, where they induce circuit modifications by changing the number of excitatory spine synapses in a paracrine and sex-specific manner. The mechanisms of this sex-specific synapse turnover, which are likely to affect cognitive functions, are poorly understood. We found that hippocampal neurons synthesize estradiol, which maintains LTP and synapses in females but not in males. In females, inhibition of estradiol synthesis results in impairment of LTP and synapse loss. These effects were not seen in males. The essential role of local estrogen on the stability and maintenance of connectivity in the hippocampus is consistent with age-related cognitive decline in women after menopause. In male animals the regulation of synaptic stability and plasticity by locally synthesized sexual steroids remains to be clarified. This article is part of a Special Issue entitled SI: Brain and Memory.


Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies.
Several studies have used neuroimaging techniques to investigate brain correlates of the attentional modulation of pain. Although these studies have advanced the knowledge in the field, important confounding factors such as imprecise theoretical definitions of attention, incomplete operationalization of the construct under exam, and limitations of techniques relying on measuring regional changes in cerebral blood flow have hampered the potential relevance of the conclusions. Here, we first provide an overview of the major theories of attention and of attention in the study of pain to bridge theory and experimental results. We conclude that load and motivational/affective theories are particularly relevant to study the attentional modulation of pain and should be carefully integrated in functional neuroimaging studies. Then, we summarize previous findings and discuss the possible neural correlates of the attentional modulation of pain. We discuss whether classical functional neuroimaging techniques are suitable to measure the effect of a fluctuating process like attention, and in which circumstances functional neuroimaging can be reliably used to measure the attentional modulation of pain. Finally, we argue that the analysis of brain networks and spontaneous oscillations may be a crucial future development in the study of attentional modulation of pain, and why the interplay between attention and pain, as examined so far, may rely on neural mechanisms shared with other sensory modalities.


Sexual dysfunction in treated breast cancer patients.
This study examined the impact of breast cancer therapy on women's sexuality. A questionnaire concerning various sexual problems experienced before and after treatment was anonymously completed by 50 women in the outpatient clinic of our hospital's Division of Radiation Oncology. To be eligible, subjects had to be disease-free and sexually active. They also had to have undergone surgery at least one year previously and have completed CT and or RT. Fifty-eight percent of the women involved had undergone mastectomy and 42% had undergone quadrantectomy followed by RT. Ninety percent of the subjects continued sexual activity after treatment, but there was an increase in the incidence of sexual problems which resulted in a slight reduction in the quality of their sex lives. Sixty-four percent of the women experienced an absence of sexual desire and 48% low sexual desire, while 38% had dyspareunia, 44% frigidity and 42% lubrication problems. Vaginismus, brief intercourse and female orgasmic disorder were reported by 30% of the subjects. Thirty-six percent suffered from sexual dysfunction before treatment, which worsened in about 27%, while in 49% of women sexual problems arose mainly after chemotherapy (26%) or surgery (12%). About one-half experienced changes in the relationship with their partner. Breast cancer patients experienced sexual dysfunction: ours found it easier to discuss the problems with their partner during their illness (62%) than with doctors and psychologists (15%).


Low conduction in cardiac muscle. Biophysical model.
Mechanisms of slow conduction in cardiac muscle are categorized and the most likely identified. Propagating action potentials were obtained experimentally from a synthetically grown strand of cardiac muscle (around 50 mum by 30 mm) and theoretically from a one-dimensional cable model that incorporated varying axial resistance and membrane properties along its length. Action potentials propagated at about 0.3 m/s, but in some synthetic strands there were regions (approximately 100 mum in length) where the velocity decreased to 0.002 m/s. The electrophysiological behavior associated with this slow conduction was similar to that associated with slow conduction in naturally occurring cardiac muscle (notches, Wenckebach phenomena, and block). Theoretically, reasonable changes in specific membrane capacitance, membrane activity, and various changes in geometry were insufficient to account for the observed slow conduction velocities. Conduction velocities as low as 0.009 m/s, however, could be obtained by increasing the resistance (r(i)) of connections between the cells in the cable; velocities as low as 0.0005 m/s could be obtained by a further increase in r(i) made possible by a reduction in membrane activity by one-fourth, which in itself decreased conduction velocity by only a factor of 1/1.4. As a result of these findings, several of the mechanisms that have been postulated, previously, are shown to be incapable of accounting for delays such as those which occur in the synthetic strand as well as in the atrioventricular (VA) node.


LDL-receptor mutations in Europe.
Familial hypercholesterolemia (FH) is a clinical definition for a remarkable increase of cholesterol serum concentration, presence of xanthomas, and an autosomal dominant trait of either increased serum cholesterol or premature coronary artery disease (CAD). The identification of the low-density lipoprotein (LDL)-receptor (LDLR) as the underlying cause and its genetic characterization in FH patients revealed more insights in the trafficking of LDL, which primarily transports cholesterol to hepatic and peripheral cells. Mutations within LDLR result in hypercholesterolemia and, subsequently, cholesterol deposition in humans to a variable degree. This confirms the pathogenetic role of LDLR and also highlights the existence of additional factors in determining the phenotype. Autosomal dominant FH is caused by LDLR deficiency and defective apolipoprotein B-100 (APOB), respectively. Heterozygosity of the LDLR is relatively common (1:500). Clinical diagnosis is highly important and genetic diagnosis may be helpful, since treatment is usually effective for this otherwise fatal disease. Very recently, mutations in PCSK9 have been also shown to cause autosomal dominant hypercholesterolemia. For autosomal recessive hypercholesterolemia, mutations within the so-called ARH gene encoding a cellular adaptor protein required for LDL transport have been identified. These insights emphasize the crucial importance of LDL metabolism intra- and extracellularly in determining LDL-cholesterol serum concentration. Herein, we focus on the published European LDLR mutation data that reflect its heterogeneity and phenotypic penetrance.


Defective monocyte chemotaxis in patients with epidermoid tumors of the head and neck.
Monocyte chemotactic activity was assayed by a modified Boyden-Chamber method using the chemoattractant casein and was found to be impaired in 13 patients with epidermoid tumors of the head and neck. Using 7 healthy subjects as controls, the depression in both monocyte chemotactic activity and monocyte random migration in the patients with tumors was found to be statistically significant by the "leading front" technique (P < 0.05).


Adolescents with suicidal ideation: health care use and functioning.
To improve our understanding of the clinical needs among youth with suicidal ideation (SI), we examined health care utilization patterns, functional impairment, and comorbidity among youth who endorsed SI, compared with a control group of youth without SI. This study included 99 youth with SI in the past year and 99 matched controls. Participants were 13- to 17-year-old youth who were enrolled in a large integrated care delivery system who had seen a provider at least one time in the past year. The 2 groups were compared with regard to health care utilization, functional impairment, and comorbid mental health symptoms, while adjusting for depression severity, lifetime diagnosis of depression or anxiety, and medical comorbidity. Youth with SI had a significantly higher mean functional impairment compared with youth without SI, both at baseline (84% vs 60% "definitely impaired") and 6-month follow-up (57% vs 39% "definitely impaired"). Less than 15% in either group attended a mental health specialty visit in the 12 months before or after baseline, and under 10% received antidepressant or anxiolytic medication. Family-report data suggested that a higher proportion of youth with SI received mental health care from sources outside their health care system compared with youth without SI. The presence of SI is associated with more severe functional impairment, comorbidity, and depression severity. Yet, only a minority of adolescents with SI receive mental health services, and clinical detection is low. This study suggests that better screening, recognition, and treatment of SI is needed to address the clinical impairment of youth with SI.


Evaluation of S201086/GLPG1972, an ADAMTS-5 inhibitor, for the treatment of knee osteoarthritis in ROCCELLA: a phase 2 randomized clinical trial.
To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis. ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis.


Social safeness and disordered eating: Exploring underlying mechanisms of body appreciation and inflexible eating.
Feelings of social safeness and connectedness have been associated with adaptive emotion regulation processes and well-being indicators. Further, literature has demonstrated that interpersonal experiences play an important role in the etiology and maintenance of body and eating psychopathology. However, the study of the role of social variables and emotion regulation processes in the engagement in inflexible eating rules and eating psychopathology is still in its early stages. The current study aims to fill some gaps within the literature and explore the mediator role of body appreciation and inflexible eating rules in the link between social safeness and disordered eating. Participants were 253 women, aged between 18 and 50 years old, who completed a series of online self-report measures. Results from the tested path analysis model showed that social safeness holds a significant effect on eating psychopathology, through the mechanisms of body appreciation and inflexible eating rules. Also, results suggested that women who present higher levels of social safeness tend to present a more positive and respectful attitude towards their body and decreased adoption of inflexible eating rules, which seem to explain lower levels of disordered eating behaviours. These findings seem to present empirical support for the development of intervention programs that promote a positive, affectionate and healthy relationship with one's body image, in order to prevent the inflexible adherence to eating rules and disordered eating behaviours.


Human tumor necrosis factor alpha (TNF alpha) mutants with exclusive specificity for the 55-kDa or 75-kDa TNF receptors.
To probe the ligand receptor interface, a number of point mutations were introduced in selected regions of human tumor necrosis factor (TNF) alpha by site-directed mutagenesis. The mutated proteins were expressed in Escherichia coli and analyzed for selective binding to recombinant 55- and 75-kDa TNF receptors in competition with radiolabeled wild-type TNF alpha. Generally, mutations in the loop from position 29 to 34 and at positions 86 and 146 preferentially impaired binding to the 75-kDa TNF receptor, whereas mutations in the region from 143 to 145 mainly affected binding to the 55-kDa TNF receptor. Mutation of the conserved Tyr87 resulted in a dramatic loss of binding activity to both receptors. The selectivity for one or the other receptor type was found to be enhanced by combining two or three point mutations, the effects of the single mutations with respect to receptor selectivity being at least additive. A combination of the mutations Arg32-->Trp and Ser86-->Thr yielded a double mutant (R32W-S86T) with wild-type binding to the 55 kDa, but no measurable binding to the 75-kDa TNF receptor. In contrast, combining the Asp143-->Asn and Ala145-->Arg mutations (D143N-A145R) resulted in a complete loss of binding to the 55-kDa TNF receptor, whereas binding to the 75-kDa TNF receptor was impaired by only 5-10-fold. In functional assays, selective activation of the 55-kDa TNF receptor by the R32W-S86T mutant elicited a full cytotoxic response in human KYM-1 cells and secretion of interleukin 6 and granulocyte-macrophate colony-stimulating factor in human umbilical vein endothelial cells. In contrast, stimulation of the 75-kDa TNF receptor with the D143N-A145R mutant as well as with agonistic antibodies failed to induce these responses.


Manubrium Reconstruction.
To date, there is no standard approach for manubrial reconstruction. We had previously utilized mesh; however, this resulted in breakage, infection, and poor cosmesis. In this case series, we describe our transition to iliac wing autograft reconstruction. We examined 7 patients who underwent manubrial resection and reconstruction: 2 with mesh and methyl methacrylate and 5 with an iliac wing autograft. The outcomes of the autograft patients were overall favorable with no short-term complications or instances of breakage. We conclude that an iliac wing autograft for manubrial reconstruction is feasible and effective alternative to methyl methacrylate mesh.


Type of endothelial cells affects HepaRG cell acetaminophen metabolism in both 2D and 3D porous scaffold cultures.
Recent advances in developing in vitro tissue models show that function of hepatocytes is altered in when cultured in 3D configuration and co-culturing with various non-parenchymal cells. However, tissue source for such non-parenchymal cells on viability and metabolic products of hepatocytes have not been explored. In this study, we evaluated the effect of 2D and 3D cultures either with HepaRG cells alone or in combination with liver sinusoidal endothelial cells (LSECs) and human umbilical vein ECs (HUVECs). For 3D cultures, we used chitosan-gelatin porous structures formed by freeze-drying. We cultured cells for 8 days before challenging with 1 mm acetaminophen (APAP) and assessed APAP, APAP-sulfate and APAP-glucuronide for 24 hours at 6-hour time intervals using high-performance liquid chromatography. We used multiple methods (phase contrast, confocal and scanning electron microscopy and histology via hematoxylin and eosin staining) to ensure cell distribution. We also measured total protein content and albumin secretion and viability. HUVEC 3D co-cultures showed the lowest HepaRG cell viability, while both 2D and 3D LSEC co-cultures had highest HepaRG cell viability. In addition, 3D cultures had significantly higher EC viability relative to 2D cultures. Further, HUVEC co-cultures showed reduced total protein content and albumin expression as early as day 4. However, urea production on a total protein content basis did not change. In addition, LSEC 3D co-cultures had the highest APAP conversion with reduced APAP-sulfate and APAP-glucuronide formation. CYP3A4 was higher in co-culture with HUVEC for 2D and 3D cultures. In conclusion, HepaRG cells with EC co-cultures demonstrated sensitivity to the EC line used.


Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis.
We generated four transgenic mice with a 34 kb genomic fragment including the complete human neurofilament heavy (NF-H) gene. This human NF-H fragment contained all regulatory elements for tissue-specific expression, and in two transgenic lines, human NF-H proteins were produced at levels up to 2-fold the levels of endogenous mouse NF-H protein. By 3-4 months of age, these NF-H transgenics progressively develop neurological defects and abnormal neurofilamentous swellings that are highly reminiscent of those found in amyotrophic lateral sclerosis (ALS). We propose that a modest up-regulation of NF-H cross-linkers can result in an impairment of neurofilament transport, causing neuronal swellings with ensuing axonopathy and muscle atrophy, a mechanism of pathogenesis pertinent to the possible etiology of ALS.


Cytokine signaling: cytokine-inducible signaling inhibitors.
Seven members of a family of cytokine-inducible proteins have been identified, a number of which have been shown to act as negative regulators of cytokine action. All of these proteins contain a central Src homology 2 domain, as well as conserved motifs in their carboxy-terminal regions.


[Diagnostic indicators of comorbid alcohol and mood disorders].
To identify mood disorders (depression and anxiety) concomitant with alcoholism. The study involved 305 patients treated in the Ivanovo oblast addiction dispensary during July 2014 - August 2015. Along with clinical/psychopathological examination, the 20-item Zung's self-rating depression scale, the Beck questionnaire for depression, the Hospital Anxiety And Depression Scale, the Hamilton Depression Scale, Spilberger-Khanin State/trait anxiety test and the Dembo-Rubinstein method of self-esteem measurement were used. The real level of depressive disorders in patients was much higher compared to depressive complaints that patients expressed spontaneously. The combination of depression and anxiety, family history of mental illness and alcoholism, positive effect of antidepressants on the dynamics of affective states were shown as well.


Corneal in vivo confocal microscopy to detect belantamab mafodotin-induced ocular toxicity early and adjust the dose accordingly: a case report.
New targeted antibody-drug conjugates (ADCs) against multiple myeloma are known to induce adverse effects that may lead to treatment discontinuation. Preclinical studies reported early severe ocular damage related to the use of belantamab mafodotin (belamaf), including ocular surface inflammation, severe dry eye, and a specific toxicity to the cornea, namely microcystic keratopathy. While belamaf-induced ocular changes have not been prospectively studied, a better understanding of mechanisms involved as well as kinetics may aid in anticipating dose adjustment rather than stopping the treatment once clinical ocular damage is too severe. A 61-year-old woman scheduled for belamaf as a fifth-line treatment against multiple myeloma was prospectively included. Clinical examinations were performed before and every 3 weeks afterward, together with in vivo confocal microscopy (IVCM) of the cornea. Visual acuity, symptoms, slit-lamp examination, and ultrastructural changes of the cornea were recorded according to the received dose of belamaf. More precisely, kinetics, shape, density, and location of the toxic corneal lesions have been followed and analyzed using IVCM. Also, specific lesions at the sub-basal nerve plexus layer were detected and characterized for the first time. This advanced approach allowed a better understanding of the belamaf-induced toxicity, further balancing the dose to maintain good vision and eye health while continuing the treatment. Systematic ultrastructural analysis and follow-up of the corneal state during ADCs treatment for multiple myeloma may open new avenues in the therapeutic approach. Early preclinical detection of ocular damage may accurately contribute to finding the correct dose for each patient and not stopping the treatment due to severe ocular adverse effects.


Inhibition of sarco-endoplasmic reticulum calcium ATPases (SERCA) by polycyclic aromatic hydrocarbons: lack of evidence for direct effects on cloned rat enzymes.
Previous studies have demonstrated that immunosuppressive polycyclic aromatic hydrocarbons (PAHs) disrupt Ca2+ homeostasis leading to inhibition of the Ca(2+)-dependent pathways of T cell and B cell activation. The sustained Ca(2+)-elevation produced by immunosuppressive PAHs may result from the inhibition of Ca(2+)-ATPases in the endoplasmic reticulum (SERCA). The purpose of the present study was to determine whether PAHs directly inhibit cloned SERCA enzymes, and whether there is any selectivity for certain isoforms. PAHs were examined for their effects on purified cloned rat SERCA enzymes, including SERCA1, SERCA2a and SERCA3, transiently expressed in human embryonic kidney (HEK) cells. Results showed that known SERCA inhibitors, thapsigargin (100 nM) and 2,5-di(t-butyl)-1,4-benzohydroquinone (10 mumol), completely inhibited all rat SERCA isoforms, whereas 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, benzo(e)pyrene, anthracene, 3-methyl-cholanthrene, 9,10-dimethylanthracene and benz(a)anthracene at concentrations as high as 10 mumol appeared to have little inhibitory effect on any of the SERCA. The results demonstrating that PAHs do not inhibit cloned SERCA enzymes suggest that metabolism may be required for PAH-induced inhibition, or that other cellular elements, not present in the HEK transfection model, may be required for activity.


Discrimination and anxiety: Using multiple polygenic scores to control for genetic liability.
An established body of research indicates that discrimination is associated with increased symptoms of anxiety and negative affect. However, the association cannot be interpreted unambiguously as an exposure effect because a common set of genetic factors can simultaneously contribute to increased liability for symptoms of anxiety, negative affect, and the perception of discrimination. The present study elucidates the association between discrimination and anxiety/negative affect by implementing strict genetic controls in a large sample of adults. We used data from the biomarker project of the Study of Midlife Development in the United States (MIDUS), a national probability sample of noninstitutionalized, English-speaking respondents aged 25 to 74 y. Participants who consented to provide genetic data were biologically unrelated and of European ancestry as determined by genotype principal components analysis (n = 1,146). A single structural regression model was fit to the data with three measures of discrimination specified to load onto a latent factor and six measures of anxiety and negative affect specified to load onto a second latent factor. After accounting for potential genetic confounds-polygenic scores for anxiety, depression, and neuroticism and the first five genetic principal components-greater discrimination was associated with greater anxiety/negative affect (β = 0.53, SE = 0.04, P < 0.001). Findings suggest that measures of perceived discrimination should be considered environmental risk factors for anxiety/negative affect rather than indices of genetic liability for anxiety, depression, or neuroticism. Clinical interventions and prevention measures should focus on ways to mitigate the impact of discrimination to improve mental health at the population level.


Self-limited acute hepatotoxicity caused by pegvisomant.
We present a case of acute severe hepatitis in a patient with acromegaly receiving combination therapy with somatostatin analogs and pegvisomant. Hepatitis resolved completely 18 weeks after diagnosis of hypertransaminasemia without discontinuation of therapy and with a close clinical and biochemical follow-up. In this case, despite the severity of the hepatitis, therapy could be continued as hypertransaminasemia was gradually decreasing after the maximum peak. We also review the literature on toxic hepatitis associated to pegvisomant therapy analyzing the etiology, clinical predisposing factors and natural evolution.


Current Status and Future Perspectives on the Internet of Things in Oncology.
The Internet of Things (IoT) has penetrated many aspects of everyday human life. The use of IoT in healthcare has been expanding over the past few years. In this review, we highlighted the current applications of IoT in the medical literature, along with the challenges and opportunities. IoT use mainly involves sensors and wearables, with potential applications in improving the quality of life, personal health monitoring, and diagnosis of diseases. Our literature review highlights that the current main application studied in the literature is physical activity tracking. In addition, we discuss the current technologies that would help IoT-enabled devices achieve safe, quick, and meaningful data transfer. These technologies include machine learning/artificial intelligence, 5G, and blockchain. Data on current IoT-enabled devices are still limited, and future research should address these devices' effect on patients' outcomes and the methods by which their integration in healthcare will avoid increasing costs.


Conceptual knowledge modulates memory recognition of common items: The selective role of item-typicality.
This work examines the influence of stored conceptual knowledge (i.e., schema and item-typicality) on conscious memory processes. Specifically, we tested whether item-typicality selectively modulates recollection and familiarity-based memories as a function of the availability of a categorical schema during encoding. Experiment 1 manipulated both encoding type (categorical vs. perceptual) and item-typicality (typical vs. atypical) in a single Remember-Know paradigm. Experiment 2 replicated and extended the previous study with a complementary source-memory task. In both experiments, we observed that typical items led to more Guess responses, while atypical items led to more Remember responses. These findings support the idea that the activation of a congruent categorical schema selectively enhances familiarity-based memories, likely due to the bypassing of the activated mechanisms for novel information. In contrast, atypical items improved recollective-based memories only, suggesting that their lesser fit with the stored prototype might have triggered those novelty processing mechanisms. Moreover, atypical items enhanced memory in the categorical condition for both item recognition and recollection memories only, suggesting an episodic gain due to inconsistency/novelty. The source memory results gave further credence to the argument that "Remember" judgments were based on truly recollective experiences and presented the same interaction between encoding type and item-typicality observed in recollective-based memories. Overall, the results suggest that the supposedly opposite conceptual knowledge effects actually coexist and interact, albeit selectively, in the modulation of recollection and familiarity processes.