A study of some polypyridylruthenium(II) complexes as DNA binders and photocleavage reagents.
The nature of the binding of several ruthenium polypyridyl complexes containing 2,2'-bipyridine (bipy), 4,4'-dimethyl-2,2'-bipyridine (DMB), 1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (DPP), 2,2',2"-terpyridine (terpy), 2,2'-biquinoline (biq), 1,4,5,8-tetraazaphenanthrene (TAP) and 1,4,5,8,9,12-hexaazatriphenylene (HAT), with calf thymus DNA, poly[d(A-T)] and poly[d(G-C)] were studied by absorption and emission spectroscopy, DNA melting techniques, and emission lifetime measurements. In low ionic strength phosphate buffer, spectroscopic changes and DNA stabilization depended on the polypyridyl ligands present, and indicated binding that varied from substantially electrostatic to intercalative. Ru(bipy)2(HAT)2+ and Ru(phen)3(2+), which bind by partial intercalation, also show a strong preference for poly[d(A-T)]. The emission quantum yields for most complexes were increased in the presence of DNA. An exception was Ru(TAP)3(2+) which has a markedly reduced emission quantum yield and lifetime in the presence of poly[d(G-C)] or CT-DNA, due to photoredox interaction with quanines. Emission decays of the complexes generally showed multiexponential behaviour. The ability of the ruthenium complexes to sensitise DNA cleavage was determined using pBR322 plasmid DNA. Ru(TAP)3(2+) is the most efficient sensitiser while uncharged complexes and complexes with very short-lived excited states do not cleave DNA.


Modification of alternan by dextranase.
Alternan is a unique glucan with a backbone structure of alternating alpha-(1 --> 6) and alpha-(1 --> 3) linkages. Previously, we isolated strains of Penicillium sp. that modify native, high molecular weight alternan in a novel bioconversion process to a lower molecular weight form with solution viscosity properties similar to those of commercial gum arabic. The mechanism of this modification was unknown. Here, we report that these Penicillium sp. strains secrete dextranase during germination on alternan. Furthermore, alternan is modified in vitro by commercial dextranases, and dextranase-modified alternan appears to be identical to bioconversion-modified alternan. This is surprising, since alternan has long been considered to be resistant to dextranase. Results suggest that native alternan may have localized regions of consecutive alpha-(1 --> 6) linkages that serve as substrates for dextranase. Dextranase treatment of native alternan, particularly with GRAS enzymes, may have practical advantages for the production of modified alternan as a gum arabic substitute.


Implications of iterative communication for biological system performance.
The performance of integrated biological systems can often be described by the behavior of component subunits: the proportion of subunits performing an activity, and the rate of recruitment to the activity, can be relevant to system performance. We develop a model for activation of subunits (receivers) to a task when activation requires repeated signals (iterative communication). The model predicts how system performance will be affected by the parameters of iterative communication. Receiver activation is influenced by the frequency of stimulation, by forgetting about past interactions, and by the number of stimuli needed to activate the receivers. These parameters, along with the probability of activated receivers returning to a de-activated state, modulate the system-wide time course of activation and the steady-state proportion of activated receivers. Parameters can interact to affect system-wide activation, and multiple parameter combinations can yield similar patterns of activation. Group performance is less variable at higher stimulation frequencies and in systems with greater numbers of receivers. Biological constraints on iterative communication, such as time and energy costs, may limit the parameter values that are feasible for a given system. Iterative communication parameters may be subject to natural selection at the system (group) level because they affect system performance.


Beliefs and attitudes of traditional healers regarding epilepsy in Cameroon.
People living with epilepsy suffer from stigmatization, overprotection, or exclusion, thus, part of these population in developing countries uses traditional medicine as a first resort. We prospectively conducted a study to determine the knowledge, attitudes, and practices (KAP) of traditional healers (THs) concerning epilepsy. Over a 9-month period, we included 208 THs practicing in the Littoral, Center and West regions of Cameroon who agreed to participate in the study. The THs were interviewed using a standardized questionnaire. Data were analyzed using Epi Info version 7.2 software. Two-hundred and eight THs were recruited, with a mean age ± standard deviation (SD) of 49.9 ± 11.4 years, and 169 (81.2%) were male. Primary 77(37.0%) and secondary 67(32.2%) levels of education were the most represented, and most of the THs had more than 10 years of professional experience. One hundred and forty-one TH (68,7%) had poor knowledge about epilepsy. The independent factors associated with poor knowledge were female sex, Muslim religion, and marital status of cohabitation. One hundred and eighty-four THs (88.4%) had a good attitude and practices toward people with seizures. Factors independently associated with poor practices and attitude were rural residence, Muslim religion, and education level. Our result confirmed that THs had poor knowledge about epilepsy but good attitudes and practices about epilepsy. THs were in favor of future collaboration with modern medicine in the care of people living with epilepsy.


Narratives to revert overconsumption: human-nature interdependence and Circular Economy.
Policy and practitioners' initiatives to stimulate sustainable consumption have so far failed to have notable impact on individuals' behaviors. The current commentary is a plea to social and sustainability scientists, particularly to economists dealing with sustainable agri-food systems, to dig deeper into the notion of narratives to trigger societal dynamics that stir consumers toward more sufficient lifestyles. As dominant cultural narratives have a critical role in shaping shared meanings and acceptable behaviors, in the future they could guide dramatic changes in individuals' conduct, triggering drastic modifications of current consumption patterns. Based on the power that concepts as the Circular Economy and the Anthropocene have had in the recent past, a future step to develop an ecological worldview across society, and nourish individual identities deeply committed with the preservation of natural ecosystems, is working on narratives based on the notion of human-nature interdependence.


Health-related quality of life, psychological well-being, and sexual function in patients with benign prostatic hyperplasia after prostatic surgery.
Patients with benign prostatic hyperplasia (BPH) may receive prostatic surgery due to severe lower urinary tract symptoms (LUTS). This study aimed to investigate the health-related quality of life (HRQoL), psychological well-being, and sexual function of patients with BPH after prostatic surgery and identify the predictors of HRQoL among this group of patients. This was a cross-sectional, descriptive, correlational study. A convenience sample of 94 participants was recruited from a urology center in a tertiary public hospital in Singapore. The 12-item Short Form Health Survey version 2 (SF-12v2), International Prostate Symptom Score (IPSS), Hospital Anxiety and Depression Scale (HADS), and 5-item International Index of Erectile Function (IIEF-5) were used to measure the study variables. Compared to the general population norms and the findings of similar studies conducted in western countries, this group of patients reported poorer physical health but better mental health as assessed by SF-12v2. Despite the prostatic surgery, over a quarter of the patients experienced moderate LUTS, and 13.8% experienced severe erectile dysfunction. Multiple linear regression analysis identified that LUTS (B=-0.51, p=0.02) and maximum flow rate (B=-0.23, p=0.02) predicted poor physical health, accounting for 45.9% of variance, while HADS-Anxiety (B=-1.07, p<0.01) and LUTS (B=-0.32, p=0.03) predicted poor mental health, accounting for 57.2% of variance. The physical health of BPH patients with prostatic surgery was poor, with many suffering moderate LUTS and sexual dysfunction. Special attention should be given to those patients with severe LUTS who have a low maximum flow rate or have anxiety symptoms.


99mTechnetium pyridoxylidene glutamate imaging in visceral heterotaxy (Ivemark's syndrome).
A two and one-half year old boy with complex congenital heart disease had Howell-Jolly bodies in his blood raising the possibility of the asplenia syndrome. A 99mTc-sulfur colloid liver-spleen scan was reported normal, but the right lobe of the abnormally reversed liver was mistaken for the spleen. The diagnosis of visceral heterotaxy (Ivemark's syndrome) was established after scanning the patient with a new radiopharmaceutical, 99mTechnetium pyridoxylidene glutamate. The agent clearly demonstrated a left-sided gall bladder, and on comparison with the sulfur colloid scan it was established that asplenia was present. Radionuclide imaging with the new generation of hepatobiliary agents is a reliable method to document asplenia and is useful in studying patients with visceral heterotaxy.


Work site access to fluoridated tap water and retail beverages: An assessment of the University of California, San Francisco campuses.
Employees with fluoridated drinking water access at work can reap oral health benefits. The purpose of this study was to assess the availability, appeal, and promotion of fluoridated tap water in publicly accessible spaces compared with retail beverages at the University of California, San Francisco. The authors collected information on beverages available in publicly accessible spaces at University of California, San Francisco hospitals and campuses in San Francisco, California, from December 2019 through February 2020 using a web-based survey tool. Data collected included fluoridated water and retail beverage locations; type of water or retail beverage source; number of water sources per station; cleanliness, flow, and any obstruction of water sources; proximity of water stations to retail beverage locations; signage near the beverage locations about water and beverage consumption; and type of retail beverages available. Fluoridated water stations were identified in 230 locations and had 377 water sources (for example, traditional drinking fountain and motion-sensor bottle-filling station). One water station was available for every 80 students and employees; however, 25% were obstructed, dirty, or had unsatisfactory flow. Approximately 1 in 5 watercoolers lacked disposable cups. Of 41 retail beverage locations identified, 29% had a water station within sight. Only 11% of beverage locations had signage encouraging healthier beverage choices. A systematic assessment of work site access to fluoridated water can provide actionable evidence to improve availability, appeal, and promotion. This study provides a model to assess work site availability of fluoridated drinking water that can be used for future evaluations.


Characterization of microsomal subfractions from porcine endometrium cells.
Crude microsomes from porcine endometrium and three subfractions obtained by a modification of Rothschild's technique were characterized by RNA/protein ratio, marker enzyme activities and morphological appearance. The microsomes were devoid of glucose-6-phosphatase activity. They contained approximately 10% of arylesterase-, approximately 30% of both NADPH-cytochrome reductase- and UDPgalactose-N-acetyl-glucosamine beta-D-galactosyltransferase- and approximately 60% of 5'-nucleotidase activities present in the homogenates. Subfraction I (smooth membranes) had twice the galactosyltransferase activity of Subfraction II (smooth and rough membranes + free ribosomes); both subfractions were rich in 5'-nucleotidase and cytochrome reductase activities. Subfraction III (rough membranes) had very low marker activities but exhibited the highest RNA/protein ratio, which was lowest in I.


Effect of exposure of human monocyte-derived macrophages to high, versus normal, glucose on subsequent lipid accumulation from glycated and acetylated low-density lipoproteins.
During atherosclerosis monocyte-derived macrophages accumulate cholesteryl esters from low-density lipoproteins (LDLs) via lectin-like oxidised LDL receptor-1 (LOX-1) and class AI and AII (SR-AI, SR-AII) and class B (SR-BI, CD36) scavenger receptors. Here we examined the hypothesis that hyperglycaemia may modulate receptor expression and hence lipid accumulation in macrophages. Human monocytes were matured into macrophages in 30 versus 5 mM glucose and receptor expression and lipid accumulation quantified. High glucose elevated LOX1 mRNA, but decreased SR-AI, SR-BI, LDLR, and CD36 mRNA. SR-BI and CD36 protein levels were decreased. Normo- and hyperglycaemic cells accumulated cholesteryl esters from modified LDL to a greater extent than control LDL, but total and individual cholesteryl ester accumulation was not affected by glucose levels. It is concluded that, whilst macrophage scavenger receptor mRNA and protein levels can be modulated by high glucose, these are not key factors in lipid accumulation by human macrophages under the conditions examined.


Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities.
In our present study, four new, designated as murrayakonine A-D (), along with 18 known carbazole alkaloids were isolated from CHCl3 : MeOH (1 : 1) crude extracts of the stems and leaves of Murraya koenigii (Linn.) Spreng. The structures of the all isolated compounds were characterized by analysis of HR-ESI-MS and NMR (1D and 2D spectroscopy) results, and comparison of their data with the literature data. For the first time, all the isolates were evaluated for their anti-inflammatory activities, using both in vitro and in vivo experiments, against the key inflammatory mediators TNF-α and IL-6. The new compound murrayakonine A (), O-methylmurrayamine A () and murrayanine () were proven to be the most active, efficiently inhibiting TNF-α and IL-6 release in a dose-dependent manner and showing decreased LPS induced TNF-α and IL-6 production in human PBMCs [corrected]. Furthermore, all the isolates were screened for their antimicrobial potential, and the compounds girinimbine () (IC50 3.4 μM) and 1-hydroxy-7-methoxy-8-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carbaldehyde () (IC50 10.9 μM) displayed potent inhibitory effects against Bacillus cereus. Furthermore, compounds murrayamine J () (IC50 11.7 μM) and koenimbine () (IC50 17.0 μM) were active against Staphylococcus aureus. However, none of the compounds were found to be active against Escherichia coli or Candida albicans.


Cytokine removal on extracorporeal life support for treatment of acute endotoxemia: a randomized controlled animal study.
We prospectively evaluated the effectiveness of resin adsorption incorporated in an extracorporeal life support (ELS) circuit in an animal model of sepsis for removal of cytokines and prevention of hemodynamic deterioration during the treatment of septic shock. Twelve female landrace pigs were randomly assigned to two groups, a study group(n=6), treated with high-flow resin adsorption (300 mL/min) and ELS, and a control group (n=6), treated only with ELS. Septic shock was induced by intravenous 0.02 μg/kg/min infusion was of Escherichia coli lipopolysaccharide (LPS). Measurements were carried out in the study group at baseline, at the end of LPS injection(t0) at 30(t1), 60(t2), 90(t3) and 120 min (t4) and 60 min after stopping resin-adsorption (t5). In the control group measurements were performed at baseline (t0), t1 and only t2, as no control animal survived beyond this latter experimental timepoint. The final population consisted of 9 animals, five in the study group and 4 in the control group. Plasma values of both tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were reduced during resin-adsorption (t1-t4) while these mediators increased in controls undergoing ELS only. With a clearance of TNF-α of 15,233 pg/min and IL-6 of 10,233 pg/min, 79.2% of TNF-α and 95.3% of IL-6 produced were adsorbed. Systemic vascular resistance decreased significantly in both groups at t0. While it further was reduced during the control experiments at t1 and t2, it returned to normal in the study animals. Cardiac output increased at t0, t1 and t2 in the control experiments. In contrast, in study animals after a peak at t0, it returned to the baseline value and did not vary thereafter. Combined resin-adsorption and ELS improved hemodynamics resulting from effective removal of inflammatory mediators in a pig model of septic shock.


Morphological alterations on Citrobacter freundii bacteria induced by erythrosine dye and laser light.
The effect of the laser irradiation (532 nm) on films prepared from Citrobacter freundii mixed with erythrosine dye was investigated by using atomic force microscopy. It was observed that morphological changes of bacterial surfaces after irradiations, which were attributed to cellular damage of the outer membranes, are a result of a photodynamic effect. The results suggested that the combination of erythrosine and laser light at 532 nm could be a candidate to a photodynamic therapy against C. freundii.


Nucleotide sequence of a region duplicated in Escherichia coli toc mutants.
We have sequenced about 5 kb of the Escherichia coli chromosome downstream from the tolC gene, looking for a topoisomerase gene. This region does not contain a topoisomerase gene.


Chlorinated aromatic hydrocarbons in fish from an area polluted by industrial effluents.
The content of chlorinated fat-soluble aromatic hydrocarbons was determined in fish from an area polluted by industrial effluents. The fish species investigated were selected among those used for human consumption. For some samples, both the fillet and liver were investigated. For others the whole fish was used. The following compounds were analysed and quantified: Trichlorobenzene, tetrachlorobenzene, pentachlorobenzene, hexachlorobenzene, heptachlorostyrene, octachlorostyrene and polychlorinated biphenyls. The results idicate an appreciable accumulation in fish of the higher chlorinated compounds as pentachlorobenzene, hexachlorobenzene, heptachlorostyrene and octachlorostyrene. Other chlorinated hydrocarbons as decachlorobiphenyl, pentachloronaphthalene, hexachloronaphthalene and hexachlorostyrene were identified, but not quantified. The total content of fat-soluble chlorine was determined in some samples before and after sulphuric acid treatment. The content of chlorine in the identified and quantified compounds accounted for between 40 and 100 per cent of the total amount of chlorine present in the samples as persistent (sulphuric acid resistant) compounds.


Treatment of electrographic seizures and status epilepticus in critically ill children: a single center experience.
Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in encephalopathic children in the pediatric intensive care unit (PICU) and associated with worse short-term outcome. Survey data indicate most physicians treat ES and ESE with antiepileptic drugs (AEDs), but few data are available regarding AED usage patterns. We aimed to describe AED usage for ES and ESE in critically ill children. We performed an observational study of patients who underwent continuous electroencephalographic (cEEG) monitoring in the PICU of a single quaternary care children's hospital. We collected data regarding age, clinical diagnoses, ES and ESE occurrence, and AEDs utilized. 200 subjects underwent cEEG. ES occurred in 21% (41/200) and ESE occurred in 22% (43/200). Of the 84 patients with ES or ESE, 80 received non-benzodiazepine AEDs including 48% (38 of 80) with ES and 52% (42 of 80) with ESE. The most commonly administered first AEDs were levetiracetam in 38% (30/80), phenobarbital in 31% (25/80), phenytoin-fosphenytoin in 28% (22/80), and valproate in 4% (3/80). Seizures terminated after administration of the first AED in 74% (28/38) with ES and 22% (9/41) with ESE. Levetiracetam, phenobarbital, and phenytoin-fosphenytoin are commonly used to manage ES and ESE at our center. Over half of subjects received multiple AEDs.


Serum tau and neurological outcome in cardiac arrest.
To test serum tau as a predictor of neurological outcome after cardiac arrest. We measured the neuronal protein tau in serum at 24, 48, and 72 hours after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Categories 3-5 at 6 months. Increased tau was associated with poor outcome at 6 months after cardiac arrest (median = 38.5, interquartile range [IQR] = 5.7-245ng/l in poor vs median = 1.5, IQR = 0.7-2.4ng/l in good outcome, for tau at 72 hours, p < 0.0001). Tau improved prediction of poor outcome compared to using clinical information (p < 0.0001). Tau cutoffs had low false-positive rates (FPRs) for good outcome while retaining high sensitivity for poor outcome. For example, tau at 72 hours had FPR = 2% (95% CI = 1-4%) with sensitivity = 66% (95% CI = 61-70%). Tau had higher accuracy than serum neuron-specific enolase (NSE; the area under the receiver operating characteristic curve was 0.91 for tau vs 0.86 for NSE at 72 hours, p = 0.00024). During follow-up (up to 956 days), tau was significantly associated with overall survival. The accuracy in predicting outcome by serum tau was equally high for patients randomized to 33 °C and 36 °C targeted temperature after cardiac arrest. Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice in several countries to predict outcome after cardiac arrest. Ann Neurol 2017;82:665-675.


Treatment for complete bilateral duplex kidneys with severe hydronephrosis and ureterectasis of the upper moiety in a child: A case report and literature review.
To explore the treatment experience of the duplex kidney. A case of the complete bilateral duplex kidney with severe hydronephrosis and ureterectasis in the upper moiety of the kidney diagnosed in the Department of Urology of Kunming Children's Hospital from 2021 to 2022 was retrospectively analyzed and relevant literature was reviewed. A 2-month-old baby girl was admitted to the hospital because of hydronephrosis of bilateral kidneys found by prenatal ultrasound for 3 months and fever for 3 days. After being given the relevant examinations, the girl was diagnosed with complete bilateral duplex kidneys with severe hydronephrosis and ureterectasis in the upper moiety, and urinary tract infection. The patient's urinary tract infection was poorly controlled after positive anti-infective therapy, so a bilateral ureterostomy was performed. After the surgery, urinary tract infection was soon cured. A bilateral ureteroureterostomy was performed 13 months later, and the patient recovered after 7 days. Cutaneous ureterostomy combined with late ureteroureterostomy for children with complete bilateral duplex kidneys with severe hydronephrosis in the upper moiety and ureter are not only beneficial to caregivers' nursing after the operation, but also have significance for salvaging renal function.


Disturbance of smooth muscle regulatory function by Eisenia foetida toxin lysenin: insight into the mechanism of smooth muscle contraction.
Lysenin, a toxin present in the coelomic fluid of the earthworm Eisenia foetida, is known to cause a long-lasting contraction of rat aorta smooth muscle strips. We addressed the mechanisms underlying its action on smooth muscle cells and present the first report demonstrating a completely new property of lysenin unrelated to its basic sphingomyelin-binding ability. Here we report lysenin enhancement effect on smooth muscle actomyosin ATPase activity and the ability of networking the actin filaments. The maximum enhancement of the ATPase activity of actomyosin at 120 mM KCl was observed at a molar ratio of lysenin to actin of about 1:10(5), while at 70 mM KCl at the ratio of about 1:10(6). The effect of lysenin became most pronounced only when both smooth muscle regulatory proteins, tropomyosin and caldesmon, were present. Co-sedimentation experiments indicated that lysenin did not displace neither tropomyosin nor caldesmon from the thin filament. Thus, the lysenin-dependent abolishment of the inhibitory effect of caldesmon on the ATPase activity was related rather to the modification of the filament structure. The ability of the toxin to exert its stimulatory effect at extremely low concentrations (as low as one molecule of lysenin per 10(6) actin molecules) may result from the long-range cooperative transitions in the entire thin filament with an involvement of smooth muscle tropomyosin, while the role of caldesmon may be limited exclusively to the inhibition of ATPase activity.


Proton pump inhibitor modifies inflammatory reaction in human gastric mucosa infected by Helicobacter pylori.
To examine whether proton pump inhibitors modify the production of oxygen-derived free radicals and related cytokines in the human gastric mucosa infected with H. pylori. Thirty-four H. pylori-positive peptic ulcer patients (23 gastric ulcer, 11 duodenal ulcer) were enrolled. Biopsy tissue samples were obtained endoscopically from the antrum and corpus. Tissue content of neutrophil myeloperoxidase (myeloperoxidase) and IL-8 was measured by ELISA. Mucosal production of oxygen-derived free radical was measured using luminol-dependent chemiluminescence (ChL). A proton pump inhibitor (either lansoprazole 30 mg, omeprazole 20 mg, or rabeprazole 10 mg) was administered daily by mouth to all patients for 8 weeks. Endoscopic examination was then repeated, and biochemical analysis was performed. Antral myeloperoxidase decreased significantly after proton pump inhibitor treatment (5.23 +/- 7.00-2.76 +/- 5.11 ng/mg, P < 0.02), but corpus myeloperoxidase was unchanged. IL-8 was also modified by proton pump inhibitors and these changes were parallel to those of myeloperoxidase. Corpus ChL was significantly increased from 88.5 +/- 69.8-159 +/- 172 counts/10 s/mg after proton pump inhibitor treatment, whereas antrum ChL was not altered. H. pylori infection rate was decreased in the antrum as well as the corpus. Proton pump inhibitor treatment stimulated oxygen-derived free radical production in the corpus mucosa.


Life in the allogeneic environment after lung transplantation.
Because infection and rejection are the principal complications of any transplant procedure and because the alveolar macrophage is crucial to the defense of the lung from infection and may play a role in lung allograft rejection, we have begun to assess functions of this cell that are thought to be important in lung defense from infection and in transplant immunity. Antimicrobial functions include chemotaxis, which is a mechanism for recruiting macrophages to sites of inflammation and phagocytosis, and intracellular killing of microorganisms. As an accessory cell, the alveolar macrophage is necessary for an effective immune response to develop against either microorganisms or transplantation antigens. Our results indicate that the chemotactic, phagocytic but not the killing capability of alveolar macrophages from lung recipients is impaired. Alveolar macrophages and blood monocytes from lung recipients are also significantly impaired in their support for mitogen and antigen presentation to lymphocytes. Thus, the generation of an effective immune response to a microorganism may be impaired. Alveolar macrophages from lung recipients, however, function as well as those from normal subjects in stimulating lymphocyte proliferation in response to donor antigens (primed lymphocyte test) or unrelated allogeneic antigens (mixed lymphocyte reaction), while their respective blood monocytes function poorly in this regard. Our conclusions are that the antimicrobial functions of the alveolar macrophages are impaired after lung transplantation and this may be one mechanism to explain the unusual susceptibility of the lung allograft to infection. Those functions related to transplant immunity, however, are preserved and indicate that the alveolar macrophage may play a role in allograft rejection.


Dual antisense oligonucleotide targeting miR-21/miR-155 synergize photodynamic therapy to treat triple-negative breast cancer and inhibit metastasis.
Triple negative breast cancer (TNBC) is a greatly aggressive subtype of breast cancer with high recurrence and mortality rates. Chemotherapy as a primary treatment for cancer is limited due to toxic side effects and drug resistance. Therefore, low toxicity and more effective breast cancer therapeutic approaches are greatly desired. In this study, a strategy which using ZIF-90 nanoparticles co-deliver Ce6-anti-miR-21 and Ce6-anti-miR-155 into the tumor cells was developed. Due to the pH responsive drug release of ZIF-90, antisense oligonucleotides (anti-miRNAs) and photosensitizers are able to be efficiently released inside tumor microenvironment. The nano delivery system captures overexpressed oncogenic miRNAs while the photosensitizer Ce6 generates ROS under light irradiation to effectively induce the apoptosis of tumor cell. This combinatorial effect was verified by results showing that the purposed therapic method could effectively inhibit tumor cell proliferation and metastasis. The concept of antisense oligonucleotide combined with photodynamic therapy has great potential in cancer treatment or adjuvant therapy.


Unique characteristics of patients who choose an intensive lifestyle medicine program to address chronic musculoskeletal pain.
Factors that motivate musculoskeletal patients to pursue an intensive, lifestyle medicine-based approach to care are poorly understood. To determine whether, compared to patients seeking musculoskeletal care through traditional pathways, patients who choose an intensive lifestyle medicine program for musculoskeletal pain endorse greater physical dysfunction, worse psychological health, and/or more biopsychosocial comorbidities. Cross-sectional analysis of existing medical records from 2018 to 2021. Orthopedic department of one academic medical center. Fifty consecutive patients who enrolled in an intensive lifestyle medicine program to address a musculoskeletal condition. Comparison groups were the following: (1) 100 patients who presented for standard nonoperative musculoskeletal care, and (2) 100 patients who presented for operative evaluation by an orthopedic surgeon and qualified for joint arthroplasty. Not applicable. Primary outcomes were age-adjusted, between-group differences in Patient-Reported Outcomes Measurement Information System (PROMIS) physical and psychological health measures. Secondary outcomes were between-group differences in sociodemographic and medical history characteristics. Patients who enrolled in the intensive lifestyle medicine program were more racially diverse (non-White race: lifestyle cohort 34% vs. comparison cohorts 16%-18%, p ≤ .029) and had a higher prevalence of obesity and diabetes than both comparison groups (mean body mass index: lifestyle cohort 37.6 kg/m2 vs. comparison cohorts 29.3-32.0, p < .001; diabetes prevalence: lifestyle cohort 32% vs. comparison cohorts 12%-16%, p ≤ .024). Compared to standard nonoperative patients, there were no clear between-group differences in PROMIS physical or psychological health scores. Compared to standard operative evaluation patients, patients in the lifestyle program reported worse anxiety but less pain interference (PROMIS Anxiety: B = 3.8 points [95% confidence interval, 0.1 to 7.4], p = .041; Pain interference: B = -3.6 [-6.0 to -1.2], p = .004). Compared to musculoskeletal patients who sought care through traditional pathways, patients who chose an intensive lifestyle medicine pathway had a higher prevalence of metabolic comorbidities, but there was substantial overlap in patients' physical, psychological, and sociodemographic characteristics.


[Development of neuroparalytic keratitis after retrobulbar administration of trimecaine].
The blood flow in the iris vessels slowed down and the vessel permeability increased early after a retrobulbar injection of trimecaine, a local anesthetic, this resulting in the development of tissue edema. Two days later neuroparalytic keratitis developed. The authors suppose that early vascular disorders resultant from blocking of the sensitive nerves are among the causes responsible for later changes in the corneal trophics.


Positive predictive value of the International Classification of Diseases, 10th revision, codes to identify osteonecrosis of the jaw in patients with cancer.
Osteonecrosis of the jaw (ONJ) is an important adverse event associated with therapies suppressing bone turnover, especially in patients with high-dose regimens of antiresorptive therapy, such as cancer patients. Danish health registries are an important resource for monitoring side effects of drugs. The International Classification of Diseases, 10th revision (ICD-10), currently used in Denmark, does not have a specific code for ONJ, making it difficult to monitor its occurrence. To estimate the positive predictive value (PPV) for ONJ of currently used ICD-10 codes, suggested by Danish oral and maxillofacial surgeons, in order to assess feasibility of identification of ONJ cases among cancer patients in the Danish National Registry of Patients (DNRP). This study was conducted in northern Denmark (1.8 million inhabitants) among patients with a history of cancer. In Denmark ONJ cases are referred to hospital-based departments of oral and maxillofacial surgery (DOMS). In the DNRP, we identified patients with potential ONJ diagnosed at DOMS (as suggested by a series of ICD-10 codes) from 1 January 2005 to 31 December 2009. To confirm or rule out ONJ, we reviewed hospital records of these patients originating from DOMS. A confirmed ONJ case was defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of previous craniofacial radiation therapy. The PPV was the proportion of confirmed cases among all potential cases. Among 85,910 eligible cancer patients, we identified 91 (0.11%) potential cases of ONJ, of which 18 were confirmed. The overall PPV was 20% (95% CI: 12-29%), ranging from 0% to50% for individual ICD-10 codes. A majority of cases identified by the suggested ICD-10 codes did not fulfill the criteria for ONJ, even though the potential cases were identified at DOMS. Therefore, reliance on ICD-10 codes, without hospital chart review, will lead to an overestimation of the occurrence of ONJ among cancer patients.


Contribution of immunohistochemistry toward the diagnosis of tumors of laboratory rats.
A polyclonal antibody detecting S-100 protein (S-100) and a monoclonal antibody demonstrating epithelial cell (Lu-5) were used in addition to routine, hematoxylin-eosin stain to improve the identification of tumors of neural or epithelial origin diagnosed in conventionally treated tissue from rat bioassays. Among 108 lesions tested for S-100, 51 reacted positively; they included benign and malignant schwannoma, endomyocardial disease, some cases of benign and malignant thymoma, and renal tubular adenoma. S-100 protein is considered particularly useful for discriminating of neoplasms of Schwann cell origin from mesenchymal tumors. 31 of 51 lesions tested for Lu-5 reacted positively: they comprised adenoma, carcinoma, benign and malignant thymoma and atriocaval node tumor of the heart. Lu-5 was especially useful to distinguish epithelial from mesenchymal neoplasms and was capable of identifying epithelial elements in lymphocyte-rich thymomas as well as in dedifferentiated or autolytic tumors. The binding of both antibodies in neoplastic tissue was compared with a complete set of anatomically normal rat tissues.


Familial and hereditary gastric cancer, an overview.
There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.


Cyclooxygenase-2 expression and clinical parameters in laryngeal squamous cell carcinoma, vocal fold nodule, and laryngeal atypical hyperplasia.
The diagnostic role of cyclooxygenase-2 (COX-2) expression in laryngeal atypical hyperplasia, vocal fold nodule, and laryngeal squamous cell carcinoma was examined. Specimens obtained from patients diagnosed with vocal fold nodule (n = 35), atypical hyperplasia (n = 35), laryngeal squamous cell carcinoma (n = 35), and clinical parameters were evaluated retrospectively. Although no staining was observed in patients with vocal fold nodules, staining was noted in laryngeal atypical hyperplasia and squamous cell carcinoma. The percentage of COX-2 staining was the highest in the carcinoma group. It was determined that COX-2 staining was significantly associated with laryngeal squamous cell carcinoma. It should be noted that overexpression of COX-2, a potentially important factor in the evolution of carcinogenesis in precancerous lesions, might be an indicator of the development of carcinoma.


Folk medicine used to heal malaria in Calabria (southern Italy).
In Italy, malaria was an endemic disease that was eradicated by the mid-20th century. This paper evaluates the prophylactic and therapeutic remedies used by folk medicine to cure malaria in Calabria (southern Italy).The data has been collected by analysing works of physicians, ethnographers, folklorists and specialists of the study of Calabrian history between the end of the 19th century and the 20th century. The data collected have allowed us to describe the most common cures used by the Calabrian people to treat malaria and the most evident symptoms of this disease, such as intermittent fever, hepato-spleenomegaly, asthenia and dropsy. This approach uncovered a heterogeneous corpus of empirical, magical and religious remedies, which the authors have investigated as evidences of past "expert medicine" and to verify their real effectiveness in the treatment of malaria.


Dystroglycanopathy muscles lacking functional glycosylation of alpha-dystroglycan retain regeneration capacity.
In dystroglycanopathies, lack of glycosylated alpha-dystroglycan (α-DG) alters membrane fragility leading to fiber damage and repetitive cycles of muscle degeneration and regeneration. However the effect of the glycosylation of α-DG on muscle regeneration is not clearly understood. In this study, we examined the regenerative capacity of dystrophic muscles in vivo in FKRP mutant and LARGE(myd) mice with little and complete lack of functionally glycosylated α-DG (F-α-DG) respectively. The number of regenerating fibers expressing embryonic myosin heavy chain (eMyHC) in the diseased muscles up to the age of 10 months is higher than or at similar levels to wild type muscle after notexin and polyethyleminine insults. The process of fiber maturation is not significantly affected by the lack of F-α-DG assessed by size distribution. The earlier appearance of a larger number of regenerating fibers after injury is consistent with the observation that the populations of myogenic satellite cells are increased and being readily activated in the dystroglycanopathy muscles. F-α-DG is expressed at trace amounts in undifferentiated myoblasts, but increases in differentiated myotubes in vitro. We therefore conclude that muscle regeneration is not impaired in the early stage of the dystroglycanopathies, and F-α-DG does not play a significant role in myogenic cell proliferation and fiber formation and maturation.


A comparison of three-dimensional finite element stress analysis with in vitro strain gauge measurements on dental implants.
The purpose of this study was to evaluate the compatibility of three-dimensional finite element stress analysis and in vitro strain gauge analysis in the measurement of strains on a dental implant. Two vertically placed implants embedded in a poly(methyl methacrylate) model were used. Strain gauges were bonded to the cervical parts of the implants, and seven cement-retained fixed partial dentures were fabricated. A three-dimensional model of the strain gauge analysis model was constructed, and an additional model in which human bone simulation was provided was also constructed. A static vertical load of 50 N was applied at certain locations to simulate centrally positioned axial and laterally positioned axial loading for strain gauge analysis and three-dimensional finite element stress analysis. Statistically significant increases in strain levels were recorded between loading types in the strain gauge analysis (P < .05). Strains obtained from strain gauge analysis were higher than for three-dimensional finite element stress analysis. There was a remarkable difference between the two finite element models under the conditions of laterally positioned axial loading. There are differences regarding the quantification of strains between strain gauge analysis and three-dimensional finite element stress analysis. However, there is a mutual agreement and compatibility between three-dimensional finite element stress analysis and in vitro strain gauge analysis on the determination of the quality of induced strains under applied load.


An approach to the interpretation of clinical data on the tumour control probability-dose relationship.
A conventional statistical model allows predicting the sterilisation rate as a function of dose. However, the computation requires data on biological parameters (proportion of clonogenic cells, survival per fraction, multiplication rate) which are inaccessible for human tumours. The curative dose 50% (TCD50) can be used as a synthesis of these parameters and its significance for the response-dose relationship of a population of tumours of uniform radiosensitivity is discussed. The slope of the dose-control curve provides vital information regarding the variation in radiocurability of the various individual tumours. The model allows the analysis of the clinical data and the separation of tumour subsets with different radiation responsiveness. It provides an evaluation of the benefit which could be obtained from the identification of the subsets and a guidance for the clinical, pathological and biological studies which relate to this identification. The change in the response-dose relationships with the tumour size cannot (usually) be explained by the cell number increase alone. Other possible factors of reduced radiocurability are discussed.


Salvage for intramedullary nailing breakage after operative treatment of trochanteric fractures.
Trochanteric fractures are one of the most common fractures in elderly people. The use of intramedullary nails is an option for their treatment, especially in unstable patterns. Nail breakage is a rarely reported complication. The aim of this study was to determine the prevalence of nail breakage in our center. Secondary objectives are to show the management of this complication in our institution as well as the technical problems, complications and final outcomes of these patients in our hands. In a retrospective case series review between 2010 and 2015, we analyzed 1481 patients with trochanteric and subtrochanteric fractures who had been treated by cephalomedullary nailing in our centre. 13 patients with nail breakage were identified. The percentage failure rate in our institution is 0.87%. 9 (69.2%) patients were women and 4 (3.8%) were men, with a mean age of 74.6 years (range 47-90). In all cases the mechanism of injury was a simple fall from standing height. Initial fracture types were: 1 case of AO/OTA 31A1, 6 cases of AO/OTA 31A2 and 6 cases of AO/OTA 31A3. Only 3 cases had a good overall reduction with a correct TAD, an optimal femoral neck-shaft angle and absence of fracture gaps >5 mm after surgery. The average time from the first surgery to the diagnosis of implant breakage was 333 days (range 70-1460), 11 months. Breakage occurred at the nail junction with the lag screw in 11 cases and in the distal nail aperture in 2 cases. An insufficient reduction with varus and fracture gaps >5 mm, the use of short nails in unstable patterns with subtrochanteric involvement and patients with certain comorbidities are facts observed that can contribute to the development of delayed or nonunion with subsequent nail breakage. Different salvage treatments, conversion to hip arthroplasty or revision osteosynthesis, may be considered but we think that prevention has to be the best treatment.


Genotoxic effects of potassium dichromate, sodium arsenite, cobalt chloride and lead nitrate in diploid yeast.
4 metal salts, potassium dichromate, sodium arsenite, cobalt chloride and lead nitrate were tested for their genotoxic effects in Saccharomyces cerevisiae. Potassium dichromate was the most potent agent for induction of gene conversion and reverse mutation. Sodium arsenite was virtually ineffective as a convertogen but gave a positive result for reversion. Cobalt chloride was the least toxic, exhibited a convertogenic activity but was only marginally active for reverse mutation. Lead nitrate was the most toxic salt but was genetically inactive.


A prospective randomized evaluation of biphasic versus monophasic waveform pulses on defibrillation efficacy in humans.
Biphasic waveforms have been suggested as a superior waveform for ventricular defibrillation. To test this premise, a prospective randomized intraoperative evaluation of defibrillation efficacy of monophasic and biphasic waveform pulses was performed in 22 survivors of out of hospital ventricular fibrillation who were undergoing cardiac surgery for implantation of an automatic defibrillator. The initial waveform used in a patient for defibrillation testing, either monophasic or biphasic, was randomly selected. Subsequently, each patient served as his or her own control for defibrillation testing of the other waveform. The defibrillation threshold was defined as the lowest pulse amplitude that would effectively terminate ventricular fibrillation with a single discharge delivered 10 s after initiation of an episode of ventricular fibrillation induced with alternating current. Each defibrillation pulse was recorded oscilloscopically, and defibrillation pulse voltage, current, resistance and stored energy were measured. Fifteen (68%) of the 22 patients had a lower defibrillation threshold with the biphasic pulse, 3 (14%) had a lower threshold with the monophasic pulse and 4 (18%) had equal defibrillation thresholds (within 1.0 J) regardless of waveform. The mean leading edge defibrillation threshold voltage was 317 +/- 105 V when the monophasic pulse was used and 267 +/- 102 V (16% less) when the biphasic pulse was used (p = 0.008). Mean leading edge defibrillation threshold current was 7.9 +/- 3.7 A when the monophasic pulse was used and 6.8 +/- 3.8 A (14% less) when the biphasic pulse was used (p = 0.051).(ABSTRACT TRUNCATED AT 250 WORDS)


Dexmedetomidine related cardiac arrest in a patient with permanent pacemaker; a cautionary tale.
Dexmedetomidine (Precedex), an alpha-2 adrenergic receptor agonist is frequently and safely used as sedative agent during surgical procedures. We report a case of a 76-year-old woman who developed cardiac arrest from the use of dexmedetomidine during pacemaker lead extraction procedure.


Fecal microbiota transplantation before hematopoietic stem cell transplantation in a pediatric case of chronic diarrhea with a FOXP3 mutation.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutation of the forkhead box protein 3 (FOXP3) gene, often leading to intractable and life-threatening diarrhea. Fecal microbiota transplantation (FMT), has been regarded in recent years as an available approach to reconstruct disrupted gut microbiome and successfully used to attenuates diarrhea induced by different underlying diseases. Therefore, FMT may have curative potential on the symptoms of enteropathy in patients with IPEX syndrome. Physical and laboratory examinations were performed, and clinical data were collected. FMT was administered via frozen fecal microbial solution, and the fecal microbiota composition was analyzed using 16S rDNA sequencing before and after FMT. The patient was diagnosed with IPEX syndrome with a mutation detected in the FOXP3 gene, which was identified as c.767T > C (p.M256T). He presented with recurrent watery diarrhea and respiratory infections after birth and developed a significant failure to thrive. Disturbances in the gut microbiota composition and marked decreased bacterial diversity were observed to be involved in the persistent and refractory diarrhea. After receiving FMT treatment, the patient responded with remission of the diarrhea without apparent side effects. His stool output significantly decreased, corresponding to increased microbial diversity and modification of his microbiota composition. The patient finally achieved full recovery after hematopoietic stem cell transplantation (HSCT). Our data suggest an association between the gut microbiota and clinical symptoms of patient with IPEX syndrome and demonstrate FMT as an alternative therapy for severe diarrhea unresponsive to routine therapy in these patients.


Glaucoma Drainage Device Erosions in Patients Receiving Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Retinopathy.
To determine if intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are associated with an increased risk of glaucoma drainage device (GDD) erosions. A retrospective chart review was conducted including patients with diabetic retinopathy and had a GDD implanted at a large academic institution. The rate of GDD erosions was compared between eyes that did or did not receive intravitreal anti-VEGF injections. A subanalysis was also performed the relationship between diabetic macular edema (DME) and intravitreal steroid injections and GDD erosions. A total of 677 eyes from 608 patients was included. A total of 447 eyes received at least one anti-VEGF injection; 230 eyes never received such therapy. Twenty eyes (4.5%) receiving anti-VEGF had at least one erosion event, compared to 7 eyes (3.0%) of patients not receiving anti-VEGF therapy (OR 1.49, p=0.37). Diabetic macular edema was associated with a significantly increased rate of erosion in eyes not receiving anti-VEGF (71.4% versus 31.4%, p=0.034), but not in eyes receiving anti-VEGF (30.0% versus 40.7%, p=0.34). Receiving more than one specific anti-VEGF agent, an increased frequency or total number of anti-VEGF injections, or receiving intravitreal steroids were not associated with an increased risk of erosion (p>0.05). In patients with diabetic retinopathy, the use of anti-VEGF does not result in an increased rate of GDD erosions or recurrent erosions. Further research is needed over a longer follow-up period to determine if longer or more frequent anti-VEGF treatment is a risk factor for recurrent erosions.


Nomograms for predicting prognostic value of inflammatory biomarkers in colorectal cancer patients after radical resection.
Increasing evidence indicates that inflammation plays a vital role in tumorigenesis and progression. However, the prognostic value of inflammatory biomarkers in colorectal cancer (CRC) has not been established. In this study, a retrospective analysis was conducted in patients with CRC in Fudan University Shanghai Cancer Center (FUSCC) between April 1, 2007 and April 30, 2014, and 5,336 patients were identified eligible. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) were analyzed. Kaplan-Meier analysis was used to calculate the 5-year overall survival (OS) and disease-free survival (DFS). Cox regression analysis was performed to assess the prognostic factors. Nomograms were established to predict OS and DFS, and Harrell's concordance index (c-index) was adopted to evaluate prediction accuracy. As results, the 5-year OS was 79.2% and the 5-year DFS was 56.0% in the cohort. Patients were stratified into 2 groups by NLR (≤2.72 and >2.72), PLR (≤219.00 and >219.00), LMR (≤2.83 and >2.83) and AGR (<1.50 and ≥1.50). Patients with NLR > 2.72, PLR > 219.00, LMR ≤ 2.83 and AGR < 1.50 were significantly associated with decreased OS and DFS (p < 0.001). Multivariate analysis indicated that NLR, LMR and AGR were independent factors of OS (p = 0.047, p = 0.008 and p < 0.001, respectively) and DFS (p = 0.009, p < 0.001 and p = 0.008, respectively). In addition, nomograms on OS and DFS were established according to all significant factors, and c-indexes were 0.765 (95% CI: 0.744-0.785) and 0.735 (95% CI: 0.721-0.749), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients.


In situ neutron diffraction for analysing complex coarse-grained functional materials.
Complex functional materials play a crucial role in a broad range of energy-related applications and in general for materials science. Revealing the structural mechanisms is challenging due to highly correlated coexisting phases and microstructures, especially for in situ or operando investigations. Since the grain sizes influence the properties, these microstructural features further complicate investigations at synchrotrons due to the limitations of illuminated sample volumes. In this study, it is demonstrated that such complex functional materials with highly correlated coexisting phases can be investigated under in situ conditions with neutron diffraction. For large grain sizes, these experiments are valuable methods to reveal the structural mechanisms. For an example of in situ experiments on barium titanate with an applied electric field, details of the electric-field-induced phase transformation depending on grain size and frequency are revealed. The results uncover the strain mechanisms in barium titanate and elucidate the complex interplay of stresses in relation to grain sizes as well as domain-wall densities and mobilities.


Comparison of the Adaptive Capacity in Old and Young Wistar Rats to Stress Exposure and Acute Hypoxic Hypoxia.
We compared behavioral and psychoemotional manifestations of young and old male Wistar rats in elevated plus-maze, the levels of corticosterone and testosterone, as well as the resistance to acute hypoxic hypoxia before and after stress exposure (10-min swimming sessions over 10 days). The behavioral characteristics, responses of the main stress hormone corticosterone, and resistance to acute hypoxic hypoxia were identical in both age groups before and after stress. A distinguishing feature was pronounced flattening of the psychoemotional manifestations in old animals. The main adaptive differences between young and old rats were revealed in the response of circulating testosterone to stress.


Cooperativity between platelet-activating factor and collagen in platelet aggregation.
Cell lysate obtained from cultured vascular endothelial cells contained a substance which induced platelet aggregation. This substance was identified as a phospholipid, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor; PAF), by thin-layer chromatography, phospholipase A2 digestion, inhibition by a specific antagonist, CV-3988, and agonist-specific refractory state. It was further found that PAF and collagen together induced extensive aggregation of platelets even with the concentrations by which each agonist alone could not induce aggregation of platelets at all.


Robust phase determination in complex solid solutions using diffuse multiple scattering.
A novel methodology is presented for identifying and distinguishing between structural phases in multi-phasic systems, such as piezoelectric materials like PMN-PT [Pb(Mg1/3Nb2/3)O3-PbTiO3], PIN-PMN-PT [Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3] and PZT [Pb(Zr,Ti)O3], using diffuse multiple scattering and Kossel line diffraction techniques. The method exploits the splitting of triple line intersections from special coplanar reflections combined with logical constraints to generate a splitting fingerprint for robust crystallographic phase determination and discrimination.


Treatment of depression in children and adolescents.
Depressive disorders during youth occur frequently, are chronic and recurrent, and are associated with significant functional impairment, morbidity, and mortality. Two psychotherapeutic approaches-cognitive behavioural therapy and interpersonal therapy-are each better than wait-list or treatment-as-usual approaches. Several antidepressants have proven efficacious compared with placebo; however, more than half the studies comparing antidepressant treatment with placebo in children and adolescents with depression have not shown any benefit of the active compounds. Suicide rates are decreasing overall in adolescents, and there seems to be a correlation between the use of selective serotonin reuptake inhibitors (SSRIs) and a decrease in completed suicide. However, there was a signal for increase in suicide attempts and suicidal ideation in patients on acute antidepressant treatment when all antidepressants were assessed as a single group. Thus, there is substantial debate about the best approach to treat this serious disorder. Here, we discuss the treatment options for depression in children and adolescents.


Estimates of the economic burden of rotavirus-associated and all-cause diarrhoea in Vellore, India.
To determine the cost of rotavirus and all-cause diarrhoea in Vellore, India. Parents of children <5 years of age accessing clinics, emergency rooms, or hospitals for acute diarrhoea completed a questionnaire detailing healthcare utilisation, medical and non-medical expenditures, and lost income. Faecal samples were screened for rotavirus and medical records were examined. Costs were estimated for inpatient and outpatient resource consumption, stratified by facility. Total societal costs of a hospitalised diarrhoeal episode were Rs 3278.50 (US$ 80.80) at a large referral hospital and Rs 1648.60 (US$ 40.60) at a smaller community hospital. Costs for rotavirus positive or negative gastroenteritis were similar. Median household expenditures per diarrhoeal episode at the referral and the community hospitals equalled 5.8% and 2.2% of the annual household income, respectively. Diarrhoeal disease in children constitutes a considerable economic burden. An appropriately priced and effective rotavirus vaccine may provide significant economic savings for the Indian household and healthcare system.


Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs.
Neuroendocrine neoplasms in hepatobiliary organs are very rare, but several cases of mixed adenoneuroendocrine carcinoma (MANEC) have been reported. In this study, we characterized the neuroendocrine component of biliary MANEC. A total of 274 cases of biliary cancer including 17 intrahepatic cholangiocarcinomas (CCs), 15 hepatic hilar CCs without preceding hepatobiliary disease, 55 hepatic hilar CCs with hepatolithiasis, 49 gallbladder cancers, 53 extrahepatic CCs, and 85 hepatocellular carcinomas were examined for a neuroendocrine component using immunohistochemistry with neuroendocrine markers (chromogranin A and synaptophysin). In the MANEC cases, in addition to a close histological examination, the proliferative activity and the expression of somatostatin receptor 2A were also evaluated. In addition to an ordinary adenocarcinoma, a neuroendocrine component occupying more than 30% of the entire tumor was also found in 4% (2/55 cases) of hepatic hilar cholangiocarcinomas with hepatolithiasis, 10% (5/49 cases) of gallbladder cancers, and 4% (2/53 cases) of extrahepatic cholangiocarcinomas, but not in the intrahepatic cholangiocarcinomas, hilar cholangiocarcinomas without preceding hepatobiliary disease, and hepatocellular carcinomas. Two cases were positive for somatostatin receptor 2A. The adenocarcinoma components were predominately located at the surface of the tumors, and the majority of stromal and vascular invasion and lymph node metastasis involved neuroendocrine components, showing the features of neuroendocrine tumor G2 or neuroendocrine carcinomas (NECs). NEC components showed higher proliferative activity on Ki67 immunostaining, compared to the adenocarcinoma components. Biliary MANECs are found in hepatic hilar cholangiocarcinomas with hepatolithiasis, gallbladder cancers, and extrahepatic cholangiocarcinomas and show a characteristic histology. Since the neuroendocrine component in biliary MANEC defines the prognosis, it is important to identify it and consider the indications for adjunctive therapy with somatostatin analogues.


Fusion protein of the hyaluronan binding domain from human TSG-6 with luciferase for assay of hyaluronan.
The gene expression plasmid, pET-Lmluc, for the fusion protein of the hyaluronan binding domain from human TSG-6 [product of tumor necrosis factor (TNF)-stimulated gene-6] and luciferase from Renilla reniformis was constructed. The fused gene was expressed in Escherichia coli and the resulted insoluble Lm-luc fusion protein was purified and refolded to recover both the hyaluronan binding capability and the luciferase activity. Hyaluronan as low as 1 ng ml(-1) was detected by using the indirect enzymatic immunological assay with the refolded Lm-luc fusion protein.


Biocompatibility analysis of high molecular weight chitosan obtained from Pleoticus muelleri shrimps. Evaluation in prokaryotic and eukaryotic cells.
The search for the exploitation and recycling of biomaterials is increasing for reducing the use of non-renewable resources and minimizing environmental pollution caused by synthetic materials. In this context, Chitosan (CS) being a naturally occurring biopolymer becomes relevant. The aim of the present work was to explore the effects of High Molecular Weight CS (H-CS) from Argentinean shrimp's wastes in prokaryotic and eukaryotic in vitro cell cultures. Ultrastructure of H-CS was analysed by SEM and TEM. In vitro studies were performed in prokaryotic (Lactobacillus casei BL23) and eukaryotic (Caco-2, ARPE-19, EA.hy926 and 3T3-L1) culture cells. High performance microscopic techniques were applied to examine culture cells. No changes in morphology were found in any of the cell types. In addition, fluorescent-dyed H-CS revealed that eukaryotic cells could internalize it optimally. Viability was maintained and proliferation rate even increased for Caco-2, ARPE-19 and 3T3-L1 cells under H-CS treatment. Besides, viability was neither altered in L. casei nor in EA.hy926 cells after H-CS exposure. In conclusion, H-CS could be a suitable biopolymer to be exploited for biomedical or food industry applications.


The concept of health promotion and the prevention of adolescent drug abuse.
A three-dimensional conceptual model for health promotion interventions to prevent adolescent drug abuse is elaborated. The model is based on an analysis of the concept of health into four domains--physical, psychological, social, and personal; an analysis of intervention approaches to change behavior into two major strategies--introducing/strengthening health-enhancing behavior, and weakening/eliminating health-compromising behavior; and an analysis of the foci of interventions into three levels--environmental, personality, and behavior. Components of a specific health promotion program, the Minnesota Heart Health Program, that are designed to prevent adolescent drug abuse are described. These include health behavior campaigns, educational interventions, and community organization. The theoretical content of the components is shown to be linked logically to the health promotion model.


An insight on the design of mercapto functionalized swelling brittle micas.
Surface modification of natural clay minerals with reagents containing metal chelating groups has great environmental value. The functionalization by adsorption or grafting guarantees a durable immobilization of the reactive organic groups, preventing their leaching when they are used in liquid media. The aim of this research was the designed mercapto functionalization of swelling brittle micas, Na-Mn, thorough both chemical and physical mechanisms. Na-Mn were functionalized with 2-mercaptoethylammonium (MEA), 2,3-dimercapto-1-propanol (BAL) and (3-mercaptopropyl)trimethoxysilane (MPTMS). The thiol concentration on swelling brittle micas is higher than the observed value for others adsorbents. The cation exchange reaction with MEA and one-step grafting with MPTMS in acid medium are the most efficient mercapto functionalization mechanism.


Sex differences in fear responses: Neural circuits.
Women have increased vulnerability to PTSD and anxiety disorders compared to men. Understanding the neurobiological underpinnings of these disorders is critical for identifying risk factors and developing appropriate sex-specific interventions. Despite the clear clinical relevance of an examination of sex differences in fear responses, the vast majority of pre-clinical research on fear learning and memory formation has exclusively used male animals. This review highlights sex differences in context and cued fear conditioning, fear extinction and fear generalization with a focus on the neural circuits underlying these behaviors in rodents. There are mixed reports of behavioral sex differences in context and cued fear conditioning paradigms, which can depend upon the behavioral indices of fear. However, there is greater evidence of differential activation of the hippocampus, amygdalar nuclei and the prefrontal cortical regions in male and female rodents during context and cued fear conditioning. The bed nucleus of the stria terminalis (BNST), a sexually dimorphic structure, is of particular interest as it differentially contributes to fear responses in males and females. In addition, while the influence of the estrous cycle on different phases of fear conditioning is delineated, the clearest modulatory effect of estrogen is on fear extinction processes. Examining the variability in neural responses and behavior in both sexes should increase our understanding of how that variability contributes to the neurobiology of affective disorders. This article is part of the Special Issue on 'Fear, anxiety and PTSD'.


Soil warming and trace gas fluxes: experimental design and preliminary flux results.
We conducted several experiments to determine a procedure for uniformly warming soil 5° C above ambient using a buried heating cable. These experiments produced a successful design that could: 1) maintain a temperature difference of 5° C over a wide range of environmental conditions; 2) reduce inter-cable temperture variability to ca. 1.5° C; 3) maintain a temperature difference of 5° C near the edges of the plot; and 4) respond rapidly to changes in the environment. In addition, this design required electrical power only 42% of the time. Preliminary measurements indicate that heating increased CO2 emission by a factor of ca. 1.6 and decreased the C concentration in the O soil horizon by as much as 36%. In addition, warming the soil accelerated the emergence and early growth of the wild lily of the valley (Maianthemum canadense Desf.). The relationship between CO2 flux and soil temperature derived from our soil warming experiment was consistent with data from other hardwood forests around the world. Since the other hardwood forests were warmed naturally, it appears that for soil respiration, warming the soil with buried heating cables differs little from natural, aboveground warming. By warming soil beyond the range of natural variability, a multi-site, long-term soil warming experiment may be valuable in helping us understand how ecosystems will respond to global warming.


RNA editing of interleukin-12 receptor beta2, 2451 C-to-U (Ala 604 Val) conversion, associated with atopy.
The production of IgE in B lymphocytes is down-regulated by IFN-gamma. IL-12 induces IFN-gamma production by T lymphocytes and natural killer cells by binding to its specific receptor. RNA editing is a post-transcriptional modification. Here we show that the RNA editing of IL-12 receptor (R) beta2 is associated with atopy. Atopic patients and non-atopic healthy controls were studied. Fragments of IL-12R beta2 cDNA and genomic DNA were amplified and sequenced. Furthermore, the function of the IL-12R beta2 chain was investigated. Sequence analysis of the cDNA clones representing IL-12R beta2 mRNA transcripts revealed a C-to-U conversion at nucleotide 2451 (Ala 604 Val) on exon 13 in some atopic patients. Surprisingly, sequence analysis of their genomic DNA showed no 2451 C-to-T (Ala 604 Val) mutation. We concluded that the observed C-to-U mismatch in the cDNA clone is due to a post-transcriptional modification, RNA editing. The C-to-U conversion was observed in 21 (20.6%) of 102 atopic patients, whereas this conversion was observed in only 4 (3.8%) of 104 non-atopic subjects (P<0.001). IFN-gamma production by peripheral blood mononuclear cells (PBMCs) stimulated with IL-12 in the subjects with the C-to-U conversion was significantly lower than that in the subjects without the C-to-U conversion. In atopic patients with the C-to-U conversion, PBMCs faintly showed the tyrosine phosphorylation of Stat4, and the IgE production by PBMCs was not suppressed by IL-12 whereas it was suppressed by IFN-gamma. The RNA editing of IL-12R beta2, 2451 C-to-U (Ala 604 Val) conversion causes impairment of the IL-12 signal cascade and the subsequent reduction in IFN-gamma production, resulting in the impaired down-regulation of IgE production. This is the first report indicating that atopy is associated with RNA editing.


Inhibition of E. coli Host RNA Polymerase Allows Efficient Extracellular Recombinant Protein Production by Enhancing Outer Membrane Leakiness.
With the growing interest in continuous cultivation of Escherichia coli, secretion of product to the medium is not only a benefit, but a necessity in future bioprocessing. In this study, it is shown that induced decoupling of growth and heterologous gene expression in the E. coli X-press strain (derived from BL21(DE3)) facilitates extracellular recombinant protein production. The effect of the process parameters temperature and specific glucose consumption rate (qS ) on growth, productivity, lysis and leakiness, is investigated, to find the parameter space allowing extracellular protein production. Two model proteins are used, Protein A (SpA) and a heavy-chain single-domain antibody (VHH), and performance is compared to the industrial standard strain BL21(DE3). It is shown that inducible growth repression in the X-press strain greatly mitigates the effect of metabolic burden under different process conditions. Furthermore, temperature and qS are used to control productivity and leakiness. In the X-press strain, extracellular SpA and VHH titer reach up to 349 and 19.6 mg g-1 , respectively, comprising up to 90% of the total soluble product, while keeping cell lysis at a minimum. The findings demonstrate that the X-press strain constitutes a valuable host for extracellular production of recombinant protein with E. coli.


A Longitudinal Study of Medical Practices' Treatment of Patients Who Use Tobacco.
Many patients who use tobacco have never been encouraged by their healthcare providers to quit. In recent years, incentives have been provided for medical practices to incorporate tobacco-cessation processes into routine care. This study examined growth in use of these processes as well as organizational and policy factors associated with their implementation. Data from three National Study of Physician Organizations surveys fielded in 2006-2013 were analyzed in 2014. The analyses estimated multivariate longitudinal and cross-sectional linear regression models to assess the relationship between implementation of cessation processes and change in practices' characteristics and external incentives, including state mandates for tobacco-cessation coverage. Systematic identification of patients who use tobacco increased in large (26% to 91%, p<0.0001) and small-medium practices (69% to 83%, p<0.0001). Neither routine advice to quit nor referral to counseling and guideline-based point-of-care reminders increased. Practice feedback to physicians on their use of cessation interventions increased (18% to 29%, p<0.0001) for small-medium practices. State-mandated coverage was associated with the use of cessation processes in small-medium practices (p<0.0001), as was pay for performance participation (p<0.0001); public reporting (p<0.0001); Medicaid revenue (p=0.02); and practice size (p<0.0001). Among large practices, predictors were practice size (p<0.0001); hospital ownership (p=0.004); public reporting (p=0.03); and primary care practice (p=0.04). The findings suggest that state-mandated coverage for tobacco-cessation treatment and increased use of external incentives such as pay for performance and public reporting programs may improve care for patients who use tobacco.


Multimorbidity, functional impairment, and mortality in older patients stable after prior acute myocardial infarction: Insights from the TIGRIS registry.
Data on the association of multimorbidity and functional impairment with cardiovascular (CV) and non-CV outcomes among older myocardial infarction (MI) patients are limited. Multimorbidity and functional impairment among older MI patients are associated with CV and non-CV mortality. Patients aged ≥65 years, 1-3 years post-MI, and enrolled between June 2013 and Novemeber 2014 from 349 sites in 25 countries in the global TIGRIS registry were categorized by age, number of comorbidities, and presence and degree of functional impairment. Functional impairment was calculated using five-dimension EuroQol based on three domains-mobility, self-care, and usual activities. The association between age, number of comorbid conditions, and degree of functional impairment with 2-year incidence of CV and non-CV death was evaluated using Poisson regression analysis. Older age was associated with higher number of comorbidities and functional impairment; after adjustment, increasing age was significantly associated with non-CV mortality (p = .03) but not CV mortality (p = .38). Greater functional impairment was associated with a higher rate and relatively equal magnitude risk of CV (rate ratios [RR] 1.52, 95% confidence intervals [CI]: 1.29-1.79, per one-step increase) and non-CV mortality (RR 1.42, 95% CI: 1.17-1.73). Multimorbidity was more strongly associated with CV mortality (RR 1.52, 95% CI: 1.38-1.67, per additional comorbidity) versus non-CV mortality (RR 1.29, 95% CI: 1.14-1.47, per additional comorbidity). Multimorbidity and functional impairment are prevalent among older post-MI patients and are associated with increased CV and non-CV mortality. These findings highlight the importance of considering comorbid conditions and functional impairment as predictors of risk for adverse outcomes and aspects of medical decision making. Clinical Trial Registration: NCT01866904.


Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas.
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.


Differential function of STAT5 isoforms in head and neck cancer growth control.
Up-regulation of the epidermal growth factor receptor (EGFR) is critical for the loss of growth control in a variety of human cancers, including squamous cell carcinoma of the head and neck (SCCHN). Stimulation of EGFR results in activation of mitogenic signaling pathways including Signal Transducers and Activators of Transcription (STATs). Stat5 activation has been primarily demonstrated in hematopoietic malignancies. Gene disruption studies suggest potentially distinct functions of the Stat5 isoforms, Stat5a and Stat5b, which are encoded by two genes closely linked on human chromosome 17. To determine the function of Stat5 in SCCHN growth control, we studied the expression and constitutive activation of Stat5a and Stat5b in normal and transformed human squamous epithelial cells. Increased constitutive activation of Stat5 was detected in transformed compared with normal squamous cells. Blockade of TGF-alpha or EGFR, abrogated Stat5 activation. Targeting of Stat5b using antisense oligonucleotides inhibited SCCHN growth. In addition, SCCHN cells stably transfected with dominant negative mutant Stat5b failed to proliferate in vitro. In contrast, targeting of Stat5a using either antisense or dominant negative strategies had no effect on cell growth. These results suggest that TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat5b but not Stat5a.


Effects of somatostatin and octreotide on portal-systemic collaterals in portal hypertensive rats.
Somatostatin and its long-acting analogue, octreotide, have been used to cease variceal bleeding with uncertain mechanisms. This study investigated whether somatostatin and octreotide have a direct vasoconstrictive effect on the portal-systemic collaterals of portal-hypertensive rats and potentiate the vasoconstriction induced by endothelin-1 in these vascular beds. The vascular responses of collateral vessels to graded concentrations of somatostatin (10(-9)-10(-5) mol/l), octreotide (10(-10)-10(-6) mol/l), norepinephrine (10(-9)-10(-5) mol/l) and vehicle (Krebs solution) were evaluated in perfused collateral vascular beds of rats with portal hypertension induced by partial portal vein ligation. In addition, the perfusion pressure changes of collateral vessels to endothelin-1 (10(-8) mol/l) in the presence of vehicle(control), somatostatin (10(-6) mol/l) and octreotide (10(-6) mol/l) were tested. Compared with the vehicle group, norepinephrine significantly increased the perfusion pressure of collateral vessels at concentrations between 10(-7) and 10(-5) mol/l. In contrast, neither somatostatin nor octreotide significantly changed the perfusion pressure. Somatostatin and octreotide significantly enhanced the endothelin-1-induced vasoconstrictive effect on the collaterals. Somatostatin and octreotide exert no direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats. In the presence of endothelin-1, somatostatin and octreotide exert a local vasoconstrictive effect on these vascular beds.


Lifetime Risk of Heart Failure and Trends in Incidence Rates Among Individuals With Type 2 Diabetes Between 1995 and 2018.
Background There are limited data on the lifetime risk of heart failure (HF) in people with type 2 diabetes and how incidence has changed over time. We estimated the cumulative incidence and incidence rates of HF among Danish adults with type 2 diabetes between 1995 and 2018 using nationwide data. Methods and Results In total, 398 422 patients (49% women) with type 2 diabetes were identified. During follow-up, 36 400 (9%) were diagnosed with HF and 121 459 (30%) were censored due to death. Using the Aalen-Johansen estimators, accounting for the risk of death, the estimated residual lifetime risk of HF at age 50 years was calculated as 24% (95% CI 22%-27%) in women and 27% (25%-28%) in men. During the observational period, the proportion of patients treated with statins, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and metformin increased from <30% to >60%. Similarly, the annual incidence rates of HF decreased significantly, with declines being greater in older versus younger individuals (5% versus 2% in age >50 versus ≤50 years, respectively; P<0.0001) and in women versus men (5% versus 4%, P=0.02), but similar in patients with and without IHD (4% versus 4%, P=0.53). Conclusions The current lifetime risk of HF in type 2 diabetes approximates 1 in 4 for men and women. Paralleled by an increase in use of evidence-based pharmacotherapy over the past decades, the risk of developing HF has declined across several subgroups and regardless of underlying IHD, suggesting that optimal diabetes treatment can mitigate HF risk.


Lysophosphatidylcholine potentiates vascular contractile responses in rat aorta via activation of tyrosine kinase.
We previously reported that while lysophosphatidylcholine (LPC) does not itself produce contraction, it significantly potentiates the contractile responses induced by high-K(+), UK14,304 (a selective alpha(2)-adrenoceptor agonist) and phorbol ester in the endothelium-denuded rat aorta. To further investigate this phenomenon, we examined the effects of genistein and tyrphostin B42 (both tyrosine kinase inhibitors) on the LPC-induced potentiation of the contractile responses to high-K(+) and UK14,304 in the endothelium-denuded rat aorta. Although genistein (3 x 10(-6) M, 10(-5) M) did not affect the high-K(+)-induced contractile response, it selectively inhibited the potentiating effect of LPC on the contraction and it strongly inhibited the LPC-induced augmentation of the associated increases in [Ca(2+)](i). Genistein also attenuated the LPC-induced augmentation effects on both the increase in [Ca(2+)](i) and contractile response induced by the UK14,304. In contrast, daidzein (10(-5) M) did not inhibit the potentiating effect of LPC. Tyrphostin B42 (3 x 10(-5) M) attenuated the potentiating effect of LPC on high K(+)-induced contractions. Western blot analysis showed that LPC increased the tyrosine phosphorylation of a number of proteins, including 42 and 44 kDa proteins and 53 - 64 kDa proteins. These protein phosphorylations were inhibited by genistein. Sodium orthovanadate (10(-4) M), a tyrosine phosphatase inhibitor, also markedly enhanced the high-K(+)-induced contractile responses. This enhancing effect was attenuated by genistein. These results suggest that the LPC-induced augmentation of contractile responses in the rat aorta is due to activation of tyrosine kinase, which in turn regulates Ca(2+) influx.


Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 4. Further investigation on the inner spacer.
Novel multi-target-directed ligands were designed by replacing the inner dipiperidino function of 3 with less flexible or completely rigid moieties to obtain compounds endowed with multiple biological properties that might be relevant to Alzheimer's disease. 15 was the most interesting, inhibiting AChE in the nanomolar range and inhibiting AChE-induced and self-promoted beta-amyloid aggregation in the micromolar range.


In vitro study on structural alteration of myoglobin by methylglyoxal.
Methylglyoxal (MG), a reactive α-oxoaldehyde, reacts with proteins to form irreversible advanced glycation end products (AGEs) following Maillard-like reaction. MG-induced AGE (MAGE) formation may be significant, particularly in diabetic condition with increased level of MG. Although myoglobin (Mb) is known to react with sugars to form AGEs, its interaction with MG is not known. Here we have studied interaction of Mb with MG. After in vitro reaction between Mb and MG at 25 °C for 7 days, the unchanged Mb and modified Mb (MG-Mb) were separated by ion exchange chromatography. Compared to Mb, MG-Mb exhibited higher electrophoretic mobility in native polyacrylamide gel electrophoresis, increased absorbance around 280 nm and more α-helical content, indicating structural changes of the modified protein. As shown by MALDI-mass spectrometry, MG converted Lys-16 and Lys-133 to carboxyethyllysine in MG-Mb. MAGE thus formed in MG-Mb may be associated with its enhanced mobility in native gel due to neutralization of positive charges and the observed structural changes in comparison with Mb.


DNA clones and RNA transcripts of four lampbrush loops from the Y chromosome of Drosophila hydei.
Drosophila hydei clones representing transcribed middle-repetitive sequences from four of six major lampbrush loops of the Y chromosome were isolated. Sequences homologous to each clone are clustered in a particular locus on the Y chromosome, but additional euchromatic sites were found for one of the transcribed clones. In situ hybridization to lampbrush-loops RNA permitted the identification of clones homologous with the two "nooses" loops on YS and with the "clubs" and "tubular ribbons" on the YL arm. Loop-specific nuclear RNA molecules range in size from 10S to 60S. Loop RNA is accumulated in the nucleus and remains attached to the loops during the course of primary spermatocyte growth. It disappears, however, along with the loop structures, during the first meiotic prophase. The structure and function of the Y chromosome and its lampbrush loops are briefly considered in the light of these findings.


Interpersonal-psychological theory and parental bonding predict suicidal ideation among soldiers in Taiwan.
Suicide is an important issue among military personnel, who have higher suicide rates compared with the general population. The interpersonal-psychological theory of suicide (IPTS) might provide an empirical explanation of this phenomenon, and parental bonding influences social adjustment and suicide. To investigate the relevance of IPTS and parental bonding for suicide among Taiwanese soldiers, a case-control study was conducted. Using a suicide-reporting system in a teaching general hospital in Southern Taiwan, 226 at-risk maladjusted soldiers and 229 well-adjusted controls were enrolled. We collected basic information, and participants answered four IPTS-based questions. Suicide risk was assessed using the Brief Symptom Rating Scale item 6. A four-factor model of the Parental Bonding Instrument assessed parental bonding. All participants were interviewed using the Mini International Neuropsychiatric Interview for primary screening and to recheck the accuracy of the Brief Symptom Rating Scale item 6 score. A parsimonious model obtained by regression analysis of risk factors indicated that poor academic performance, conduct-related issues in childhood, and exposure to life-threatening situations are risk factors for suicide intention. Maladjusted suicidal soldiers showed a sense of thwarted belongingness (β = 0.145; P < 0.001), higher perceived burdensomeness (β = 0.311; P < 0.001), less fear of death (β = 0.124; P < 0.05), lower paternal autonomy (β = -0.122; P < 0.05), and higher maternal indifference (β = 0.162; P < 0.0001). Interpersonal-psychological theory of suicide, accompanied by an assessment of parental bonding, could be used for assessing suicide risk and preventing suicide attempts.


YKL-40 protein is a marker of asthma.
Gaining asthma control is still a challenge in a large number of patients. It could be facilitated by using biomarkers indicating the grade of inflammation and correlating with clinical picture. Chitinases and chitinase-like proteins play a role in Th2-type inflammation. Thus, they may be useful in diagnosing and monitoring of asthma. The aim of the study was to investigate the relevance of YKL-40 as a good biomarker of asthma, its control, and severity. Level of YKL-40 was determined by means of immunoassay in sera of 59 asthmatics (39 women, 20 men, aged 23-76 years) and 29 healthy controls (18 women, 11 men, aged 20-80 years). Asthma severity and control were assessed according to GINA guidelines. Differences between groups were compared with the use of Mann-Whitney's U-test. Correlations between variables were assessed with Pearson's test. Symptoms of asthma were found to be controlled in 12 (20%), partly controlled in 17 (29%), and uncontrolled in 30 (51%) patients. YKL-40 levels were significantly higher, on average, in asthmatics compared to control group (median levels: 125.3 U and 84.1 U, respectively, p < .001). YKL-40 correlated with the number of blood eosinophils (r = 0.376, p = 0.05). However, no relations have been found between YKL-40 level and asthma severity, control, or total serum IgE (r = -0.05, p = .05). YKL-40 seems to be a good marker of asthma. However, its level may not correlate with clinical outcome.


Evaluation of a point-of-care electrochemical meter to detect subclinical ketosis and hypoglycaemia in lactating dairy cows.
To evaluate and validate a hand-held electrochemical meter (Precision Xtra®) as a screening test for subclinical ketosis and hypoglycaemia in lactating dairy cattle. Method comparison study using a convenience sample. Blood samples were collected into plain tubes from the coccygeal vessels of 181 Holstein cows at 2-4 weeks of lactation during summer in Iran. Blood β-hydroxybutyrate concentration (BHB) and glucose concentration were immediately measured by the electrochemical meter after applying 20 μL of blood to the reagent strip. Passing-Bablok regression and Bland-Altman plots were used to determine the accuracy of the meter against laboratory reference methods (BHB dehydrogenase and glucose oxidase). Serum BHB ranged from 0.1 to 7.3 mmol/L and serum glucose ranged from 0.9 to 5.1 mmol/L. Passing-Bablok regression analysis indicated that the electrochemical meter and reference methods were linearly related for BHB and glucose, with a slope estimate that was not significantly different from 1.00. Clinically minor, but statistically significant, differences were present for the intercept value for Passing-Bablok regression analysis for BHB and glucose, and bias estimates in the Bland-Altman plots for BHB and glucose. The electrochemical meter provided a clinically useful method to detect subclinical ketosis and hypoglycaemia in lactating dairy cows. Compared with other method validation studies using the meter, we attributed the improved performance of the electrochemical meter to application of a fixed volume of blood (20 μL) to the reagent strip, use of the meter in hot ambient conditions and use of glucose oxidase as the reference method for glucose analysis.


Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies.
Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.Genet Med 18 6, 554-562.


Comprehension of iconic gestures by chimpanzees and human children.
Iconic gestures-communicative acts using hand or body movements that resemble their referent-figure prominently in theories of language evolution and development. This study contrasted the abilities of chimpanzees (N=11) and 4-year-old human children (N=24) to comprehend novel iconic gestures. Participants learned to retrieve rewards from apparatuses in two distinct locations, each requiring a different action. In the test, a human adult informed the participant where to go by miming the action needed to obtain the reward. Children used the iconic gestures (more than arbitrary gestures) to locate the reward, whereas chimpanzees did not. Some children also used arbitrary gestures in the same way, but only after they had previously shown comprehension for iconic gestures. Over time, chimpanzees learned to associate iconic gestures with the appropriate location faster than arbitrary gestures, suggesting at least some recognition of the iconicity involved. These results demonstrate the importance of iconicity in referential communication.


Bilateral neurovascular cheek flaps for one stage lower lip reconstruction.
Bilateral neurovascular cheek flaps, using a modification of McHugh's unilateral cheek flap, have been used to reconstruct large lower lip defects as one stage procedures in 31 patients. The simple surgical techniques are described. The results are quite satisfactory, both functionally and cosmetically.


A rare presentation of zygomycosis (mucormycosis) and review of the literature.
Zygomycosis (mucormycosis) is a rare fungal infection seen most often in association with prolonged neutropenia. Intestinal zygomycosis is extremely rare and difficult to diagnose, but it is important not to miss, because early medical and surgical treatment can improve survival. This report describes a 56 year old woman who developed this infection while receiving chemotherapy for acute lymphoblastic leukaemia. Medical and surgical measures proved unsuccessful because there was a delay in diagnosis and institution of appropriate treatment.


Pharmacokinetic analysis of vilobelimab, anaphylatoxin C5a and antidrug antibodies in PANAMO: a phase 3 study in critically ill, invasively mechanically ventilated COVID-19 patients.
Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed. From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2-168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5-156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5-21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9-152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25. This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trial registration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420.


The origins of human gene mapping. With particular reference to the contributions of J. B. S. Haldane.
Methods in human gene mapping, including those developed by Bell and Haldane, Morton, and the more recent ones using somatic cell fusion, restriction fragment length polymorphism (RFLP), and multipoint linkage, are briefly reviewed.


[Changes in the cytochemical activity of the lymphocytes to antigenic action. I. Lymphocyte dehyrogenases on the administration of bovine serum albumin and ram erythrocytes].
A study of the changes in dehydrogenase level in lymphocytes after injection of different antigens--bovine serum albumin (BSA) and sheep red blood cells (SRBC) was made. The activity of succinate and alpha-glycerophosphate dehydrogenases altered during the first days after the antigens administration, but before the appearance of antibodies in the peripheral circulation. These changes were specific of BSA and SRBC, respectively.