Ultrasound-guided dexmedetomidine combination with modified high fascia iliaca compartment block for arthroscopic knee surgery: what is the optimal dose of dexmedetomidine?
Total knee arthroplasty (TKA) is a common orthopedic procedure for end-stage knee osteoarthritis. Although effective in relieving pain and improving function, postoperative pain is still a common and distressing problem for many patients. This study aims to investigate efficacy of combined administration of dexmedetomidine and modified high fascia iliaca compartment block (H-FICB) in managing acute and chronic pain after TKA, as well as to identify the optimal dosage of dexmedetomidine. A double-blind, randomized controlled trial was conducted to evaluate the effects of dexmedetomidine in patients undergoing TKA. A total of 96 patients undergoing TKA were randomly assigned to one of three groups, were treated with different doses of dexmedetomidine All groups received H-FIB. Pain scores, opioid consumption, side effects, and quality of life were recorded 48 h postoperatively. The intraoperative consumption of remifentanil and propofol in Group Db was significantly reduced compared with that in Group D0 and Da (P < 0.05). Compared with D0 and Da group, Db group had the lowest number of rescue analgesia, analgesia time and morphine accumulative dosage 48 h after operation (P < 0.05). The Db group had the lowest scores on the numerical rating scale at rest (P < 0.05) and during movement (P < 0.01), followed by the Da group and then the D0 group. Additionally, the incidence of nausea and vomiting was significantly reduced in the Db group (P < 0.05). Furthermore, the Db group had the lowest incidence of chronic pain (P < 0.05). In comparison to the other two groups, the administration of combined dexmedetomidine and H-FIB resulted in a significant reduction in pain scores, opioid consumption, and side effects. The optimal dosage of dexmedetomidine was determined to be 1 μg/kg, which provided the most favorable pain relief with minimal adverse effects.


Fast preparation of free-standing nanohydroxyapatite-vertically aligned carbon nanotube scaffolds.
We present a simple, low cost, and fast method to produce free-standing nanohydroxyapatite/carbon-based scaffolds. We electrodeposited nanohydroxyapatite onto vertically aligned carbon nanotube flakes and reticulated vitreous carbon bars. We prepared a highly crystalline and homogeneous thin film without any post-thermal treatment, and our results evidence that we can control the nanohydroxyapatite crystal formation according to the substrate employed. Immersion tests using simulated body fluid showed that these new nanobiomaterials had in vitro bioactivity. The free-standing nanohydroxyapatite/carbon-based scaffolds have been shown to be a suitable surface for mesenchymal stem cell adhesion with active formation of membrane projections and cell monolayer formation.


Integrating partonomic hierarchies in anatomy ontologies.
Anatomy ontologies play an increasingly important role in developing integrated bioinformatics applications. One of the primary relationships between anatomical tissues represented in such ontologies is part-of. As there are a number of ways to divide up the anatomical structure of an organism, each may be represented by more than one valid partonomic (part-of) hierarchy. This raises the issue of how to represent and integrate multiple such hierarchies. In this paper we describe a solution that is based on our work on an anatomy ontology for mouse embryo development, which is part of the Edinburgh Mouse Atlas Project (EMAP). The paper describes the basic conceptual aspects of our approach and discusses strengths and limitations of the proposed solution. A prototype was implemented in Prolog for evaluation purposes. With the proposed name set approach, rather than having to standardise hierarchies, it is sufficient to agree on a suitable set of basic tissue terms and their meaning in order to facilitate the integration of multiple partonomic hierarchies.


The core role of macrophages in hepatocellular carcinoma: the definition of molecular subtypes and the prognostic risk system.
Background: In patients with hepatocellular carcinoma (HCC), the tumor microenvironment (TME) is resistant to immunotherapy because of its specificity. It is meaningful to explore the role of macrophage, which is one of the most abundant immune cells in the TME, in cellular communication and its effect on the prognosis and immunotherapy of HCC. Methods: Dimensionality reduction and clustering of the single-cell RNA-seq data from the GSE149614 dataset were carried out to identify the cellular composition of HCC. CellChat was used to analyze the communication between different cells. The specifically highly expressed genes of macrophages were extracted for univariate Cox regression analysis to obtain prognostic genes for HCC cluster analysis, and the risk system of macrophage-specifically highly expressed genes was developed by random forest analysis and multivariate Cox regression analysis. Prognosis, TME infiltration, potential responses to immunotherapy, and antineoplastic drugs were compared among molecular subtypes and between risk groups. Results: We found that HCC included nine identifiable cell types, of which macrophages had the highest communication intensity with each of the other eight cell types. Of the 179 specifically highly expressed genes of macrophage, 56 were significantly correlated with the prognosis of HCC, which classified HCC into three subtypes, which were reproducible and produced different survival outcomes, TME infiltration, and immunotherapy responses among the subtypes. In the integration of four macrophage-specifically highly expressed genes for the development of a risk system, the risk score was significantly involved in higher immune cell infiltration, poor prognosis, immunotherapy response rate, and sensitivity of six drugs. Conclusion: In this study, through single-cell RNA-seq data, we identified nine cell types, among which macrophage had the highest communication intensity with the rest of the cell types. Based on specifically highly expressed genes of macrophage, we successfully divided HCC patients into three clusters with distinct prognosis, TME, and therapeutic response. Additionally, a risk system was constructed, which provided a potential reference index for the prognostic target and preclinical individualized treatment of HCC.


Conservation and over-representation of G-quadruplex sequences in regulatory regions of mitochondrial DNA across distinct taxonomic sub-groups.
G-quadruplexes have important regulatory roles in the nuclear genome but their distribution and potential roles in mitochondrial DNA (mtDNA) are poorly understood. We analysed 11883 mtDNA sequences from 18 taxonomic sub-groups and identified their frequency and location within mtDNA. Large differences in both the frequency and number of putative quadruplex-forming sequences (PQS) were observed amongst all the organisms and PQS frequency was negatively correlated with an increase in evolutionary age. PQS were over-represented in the 3'UTRs, D-loops, replication origins, and stem loops, indicating regulatory roles for quadruplexes in mtDNA. Variations of the G-quadruplex-forming sequence in the conserved sequence block II (CSBII) region of the human D-loop were conserved amongst other mammals, amphibians, birds, reptiles, and fishes. This D-loop PQS was conserved in the duplicated control regions of some birds and reptiles, indicating its importance to mitochondrial function. The guanine tracts in these PQS also displayed significant length heterogeneity and the length of these guanine tracts were generally longest in bird mtDNA. This information provides further insights into how G4s may contribute to the regulation and function of mtDNA and acts as a database of information for future studies investigating mitochondrial G4s in organisms other than humans.


[Early reactive changes of the astrocytes in the midbrain paranigral nucleus after forebrain ischemia and cerebroprotector Ropren administration in rats].
The aim of this study was to detect morphological equivalents of cerebroprotective effect of polyprenol drug Ropren on the astrocytes of the midbrain paranigral nucleus (PNN) which are located outside the focus of forebrain ischemia in rats. In mature rats (n = 8) the cerebral ischemia was reproduced under the narcosis by bilateral occlusion of both carotid arteries. Four rats received daily intraperitoneal injections of 11.6 mg/kg of cerebroprotector Ropren. Sham-operated animals served as a control. The animals were decapitated at experimental day 7. Astrocytes of anterior ventral portion of midbrain PNN were studied using an immunocytochemical method demonstrating glial fibrillary acidic protein. The number of astrocytes, their cell body profile area, the length of their major processes and the distance between their cell bodies and capillary wall were measured. It was found that Ropren suppressed astrocyte hypertrophic reaction, their migration towards the vascular wall and presumably stimulated the proliferation of these cells.


Predictive assessment of a non-linear random effects model for multivariate time series of infectious disease counts.
Infectious disease counts from surveillance systems are typically observed in several administrative geographical areas. In this paper, a non-linear model for the analysis of such multiple time series of counts is discussed. To account for heterogeneous incidence levels or varying transmission of a pathogen across regions, region-specific and possibly spatially correlated random effects are introduced. Inference is based on penalized likelihood methodology for mixed models. Since the use of classical model choice criteria such as AIC or BIC can be problematic in the presence of random effects, models are compared by means of one-step-ahead predictions and proper scoring rules. In a case study, the model is applied to monthly counts of meningococcal disease cases in 94 departments of France (excluding Corsica) and weekly counts of influenza cases in 140 administrative districts of Southern Germany. The predictive performance improves if existing heterogeneity is accounted for by random effects.


The Development of Parenting Efficacy Among New Mothers and Fathers.
Predictors of prenatal and postnatal parenting efficacy were examined in a sample of 115 primiparous mothers and 73 fathers in an effort to examine the association between preexisting parental characteristics and prenatal efficacy and the association between prenatal characteristics and postnatal efficacy when aspects of the current parenting context are taken into account. The most robust predictors of maternal postnatal efficacy included both prenatal efficacy, which significantly predicted postnatal efficacy independent of all other predictors including the current parenting context, and perceived infant temperamental reactivity as both a main effect and as buffered by social support. This was not the case for fathers, whose postnatal efficacy was primarily a function of their amount of involvement in parenting tasks and social support. The differential predictors of mother and father efficacy as well as their implications for future research are discussed.


Gender differences in self-reported anxiety, depression, and somatization among ecstasy/MDMA polydrug users, alcohol/tobacco users, and nondrug users.
Previous research has found gender differences in both psychological and physiological responses to drugs. The present investigation explores gender variability in patterns of drug use in relation to self-reported depression, anxiety, and somatization. The current study confirms that heavy illegal drug users are represented by a preponderance of males than females. However, within each drug group category, females generally reported higher psychopathology scores than males. This was significant for all three subscales in the alcohol/tobacco group, for depression scores in the alcohol/tobacco, cannabis/alcohol, and light Ecstasy users group, and for depression scores for the alcohol group. Interestingly, in the male sample, drug users reported higher symptom ratings than nondrug users, whereas women's scores remained constant across drug groups.


[A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder].
Several cases of Parkinsonian syndrome, cognitive impairment or hyperammonemia induced by sodium valproate have been described in the literature. We report the first case presenting an association of the three adverse effects occurring with divalproate sodium prescribed for bipolar disorder: a 58-year-old man with a history of bipolar type I disorder presented with Parkinsonian syndrome and cognitive impairment of insidious onset. This patient had been treated for several years with lithium carbonate, with a successful effect on mood swings, but with distressing adverse effects such as hand tremor and diarrhoea. Lithium therapy was progressively withdrawn while sodium divalproate was initiated. Associated medications, unchanged for several years, were amisulpride (daily dose: 100 mg), liothyronine, ciprofibrate and benfluorex. The patient was treated with sodium divalproate for seven months (daily dose: 1,000 mg), and with trihexyphenidyle for one month for extrapyramidal symptoms. At hospital admission, he presented with temporal disorientation, slowed thinking, severe anterograde memory deficits, and Parkinsonian syndrome. The minimal mental state (MMS) score was 16 (maximum: 30). The patient was anxious but did no present with mood symptoms. He also developed hyperammonemia (124 micromol/liter, normal range: 15 to 60 micromol/liter) without signs or biochemical evidence of hepatic failure. Valproate concentrations were within the therapeutic ranges (79 mg/l, normal range: 50 to 100 mg/l). The CT-scan showed cerebral and cerebellar atrophy with enlarged ventricles. The electroencephalogram showed generalized slowing waves. All the symptoms resolved within one month after the withdrawal of divalproate: the extrapyramidal hypertonia resolved, the MMS score was 29. The CT-scan and the electroencephalogram returned to normal. The divalproate was replaced by lithium. After a one-year follow-up, the cognitive and neurological symptomatology did not reappear at the exception of the pre-existing hand tremor. The pathophysiology of valproate induced hyperammonemic encephalopathy remains unclear. A possible mechanism is neuronal toxicity induced by increased intracellular concentrations of glutamate and ammonium in astrocytes. Indeed, these abnormal intracellular concentrations increase the intracellular osmolarity and thus induce rise in intracranial pressure and cerebral oedema. Reversible dementia could be due to a direct toxic effect of valproate on the central nervous system or to an indirect effect mediated through valproate-induced hyperammonemia. It has been suggested that the occurrence of extrapyramidal syndrome could be explained by a disturbance in the GABAergic pathways inducing reversible dopamine inhibition. A drug adverse reaction should always be considered when a patient treated with valproate presents with extrapyramidal symptoms and cognitive disorders even when valproate concentrations are within standard therapeutic ranges.


Delta-aminolevulinate dehydratase activity in mice with hereditary anemia.
Homozygous (f/f) but not heterozygous (f/+) mice of the highly congenic strain, FL/ Re, manifest a severe transitory siderocytic fetal anemia. Adults of both f/f and f/+ genotype manifest decreased hepatic, splenic, and renal levels of triangle up-amino-levulinate dehydratase (ALD) activity compared to homozygous (+/+) mice of the same strain. The degree of augmentation in splenic ALD activity following phenylhydrazine administration is high in +/+, intermediate in f/+, and low in f/f mice. These findings suggest that perhaps a deficiency in the fetal level of ALD may be responsible for the transitory fetal anemia.


Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies.
Many anti-SARS-CoV-2 neutralizing antibodies target the ACE2-binding site on viral spike receptor-binding domains (RBDs). The most potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly-emergent zoonotic sarbecoviruses and variants, but usually show only weak neutralization potencies. We characterized two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibited broad recognition and potent neutralization of zoonotic coronavirus and SARS-CoV-2 variants. C118-RBD and C022-RBD structures revealed CDRH3 mainchain H-bond interactions that extended an RBD β-sheet, thus reducing sensitivity to RBD sidechain changes, and epitopes that extended from the cryptic epitope to occlude ACE2 binding. A C118-spike trimer structure revealed rotated RBDs to allow cryptic epitope access and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.


Vasopressin modulation of medullary blood flow and pressure-natriuresis-diuresis in the decerebrated rat.
Studies in our laboratory and others have demonstrated that arginine vasopressin (AVP) exerts potent vasoconstrictor actions on the vessels supplying the renal medulla. The physiological importance of these vascular effects of AVP has been difficult to assess because of high endogenous levels of AVP in anesthetized, surgically prepared animals. We have developed a decerebrated, hypophysectomized, renal-denervated rat model that enables us to study the effects of low levels of AVP on the pressure-diuresis, relationship under acute conditions. These rats maintain normal mean arterial pressure (MAP) and plasma AVP (2.5 pg/ml). Cortical and medullary blood flow (CBF and MBF, respectively) were measured by laser-Doppler flowmetry and total renal blood flow (RBF) by transit time flowmetry. Renal interstitial fluid pressure (RIFP) and urinary sodium excretion (UNaV) responses were determined during controlled increases of MAP produced by aortic occlusion below the renal arteries. From a baseline of 97 +/- 2 mmHg, 30% increases in MAP resulted in a 63% increase in MBF, 35% increase in RIFP, and sixfold increase in UNaV, whereas CBF and RBF remained unchanged. Infusion of AVP (0.50 ng.kg-1.min-1, which increased plasma AVP from normal control levels of 3 pg/ml to 11 pg/ml) produced no change in baseline MAP, RBF, or CBF but lowered MBF by 24%, RIFP by 26%, and UNaV by 71%. The slope of the relationship of AP and UNaV, MBF, and RIP was reduced to nearly zero by these small increases of plasma AVP. We conclude that an increase of plasma AVP in the range that occurs with water restriction decreases MBF selectively and greatly attenuates the arterial pressure-MBF and pressure-natriuretic relationship.


Isolation and identification of new bacterial stains producing equol from Pueraria lobata extract fermentation.
Equol is a nonsteroidal estrogen that is produced by intestinal bacterial metabolism. Equol and equol-producing bacteria have been extensively investigated with soybean-based materials under anaerobic condition. In this study, an under-appreciated plant material, Pueraria lobata, was used to find new bacterial strains that produce equol under aerobic conditions. Three new intestinal bacteria, CS1, CS2, and CS3, were isolated, and internal transcribed spacer analysis revealed that belonging to genus Pediococcus and Lactobacillus. HPLC analysis showed that these strains produced equol or its related intermediates when fermenting P. lobata extract. In comparison to fermentation of P. lobata extract, soybean germ extract was also fermented. While the isolated strains did not produce equol in this extract, they produced other equol-related precursors. To test the modularity effect of these fermentation mixtures with the newly isolated bacteria, MCF-7 cell proliferation assay was performed, which showed that all extracts fermented with those strains has a modularity effect. Fermenting P. lobata extract with strain CS1 demonstrated the best modularity effect.


Review article: Nutritional therapy in alcoholic liver disease.
Chronic alcohol consumption may lead to primary and secondary malnutrition. In particular, protein energy malnutrition not only aggravates alcoholic liver disease but also correlates with impaired liver function and increased mortality. Therefore, in these patients, adequate nutritional support should be implemented in order to improve their prognosis. Clinical trials addressing this issue have shown that nutritional therapy either enterally or parenterally improves various aspects of malnutrition, and there is increasing evidence that it may also improve survival. Therefore, malnourished alcoholics should be administered a diet rich in carbohydrate- and protein-derived calories preferentially via the oral or enteral route. Micronutrient deficiencies typically encountered in alcoholics, such as for thiamine and folate, require specific supplementation. Patients with hepatic encephalopathy may be treated with branched-chain amino acids in order to achieve a positive nitrogen balance. Fatty liver represents the early stage of alcoholic liver disease, which is usually reversible with abstinence. Metadoxine appears to improve fatty liver but confirmatory studies are necessary. S-adenosyl-L-methionine may be helpful for patients with severe alcoholic liver damage, since various mechanisms of alcohol-related hepatotoxicity are counteracted with this essential methyl group donor, while a recent large trial showed that the use of polyenylphosphatidylcholine is of limited efficacy.


Volatile oil of Artemisia santolina decreased morphine withdrawal jumping in mice.
Flowered aerial parts of Artemisia santolina Schrenk (Asteraceae), which is found in the central and western regions of Iran were collected from Khorasan province and the volatile oil extracted by hydro distillation. The oil (0.5% v/w) was analyzed by GC and GC/MS using DB-5 column. The effect of this oil on the withdrawal syndrome was determined in mice. After induction of dependency by morphine, mice were intraperitoneally administered different concentrations of the oil. Morphine-withdrawal inducing by naloxone was assessed by recording the incidence of escape jumps for 60 min. The results indicated that a significant difference between the essential oil received group (at dose of 3.6 mg/kg) and control group was shown but the lower doses were not effective. Essential oil analysis showed that there were forty-six components, representing 95.4% of the oil. The oil of A. santolina which is rich in oxygenated monoterpenes with the major components, trans-verbenol (34.6%) and p-mentha3-en-8-ol (13.1%), can decreased the number of withdrawal jumping in addicted mice.


Association between unintentional injuries and self-harm among adolescent emergency department patients.
Unintentional injury, a leading cause of morbidity among adolescents, may also be a risk factor for deliberate self-harm. To inform clinical and public health prevention efforts in adolescent populations, we examined whether distinct subtypes of unintentional injury were differentially associated with deliberate self-harm. Statewide, all-payer, individually linkable administrative data on adolescent patients presenting to any California emergency department (ED) in 2010 (n = 490,071) were used to investigate longitudinal associations between subtypes of unintentional injury and deliberate self-harm. Adolescents aged 10-19 years presenting with unintentional drug poisoning, other poisoning, fall, suffocation, or cutting/piercing injuries formed the exposure groups; adolescents presenting with unintentional strike injuries formed the primary referent group. Study patients were followed back in time (2006-2009) to compare the groups' odds of a prior ED visit for deliberate self-harm, as well as forwards in time (2010-2015) to compare their risks of subsequent self-harm. Unintentional drug-poisoning injury was strongly associated with increased likelihood of ED visits for deliberate self-harm, assessed both retrospectively (adjusted OR = 4.52; 95% confidence interval [CI] = 3.08, 6.64) and prospectively (adjusted RR = 3.74; 95% CI = 3.03, 4.60). Positive associations with odds of prior self-harm and/or risk of subsequent self-harm were also observed for patients with unintentional non-drug poisoning, suffocation, and cutting/piercing injuries. Certain subtypes of unintentional injury, particularly drug poisoning, are strongly associated with risk for deliberate self-harm among adolescents, a finding with implications for targeting clinical assessment and intervention in emergency department settings. More research is needed to understand the mechanisms underlying these associations.


An Epidemic Outbreak of Cutaneous Leishmaniasis Presenting as Suppurative Folliculitis: A Study of 6 Cases.
Folliculitis is defined as the inflammation of the follicles. The most common cause of folliculitis is infection. Here, we report an unusual cause of suppurative infundibulitis-which had not yet been described in the literature-due to Leishmania infection, and exemplified by 6 cases that occurred in the setting of an epidemic outbreak. The 6 individuals were immigrants from Morocco. Most of them were men (4 men and 2 women), and most of them were less than 30 years old (apart from one 40-year-old woman). In all cases, a cutaneous biopsy was performed. There was a granulomatous folliculitis with suppurative granulomas in all the cases. All cases showed prominence of plasma cells in the inflammatory infiltrate, and leishmanias were found in all cases. They were mainly seen in the abscessified central areas. The amount of organisms varied from a few to a moderate amount. They were stained by the anti-CD1a antibody (Novocastra) and by a polyclonal homemade anti-leishmania antibody. In addition, in 1 case, microbiological culture was performed, and Leishmania major was demonstrated as the causative agent of the infection.


Complete restoration of fertility in a patient treated for androgen-secreting granulosa cell tumor - Case report.
A 35-yr-old patient suffering from secondary amenorrhea for two years before she was diagnosed. Secondary amenorrhea occurred after the first normal vaginal delivery, and it was initially associated with breastfeeding and a formerly diagnosed thyroid disease. Transvaginal ultrasound confirmed a tumorous mass of the right ovary. Blood hormone tests detected high serum inhibin B and Anti-Müllerian hormone levels and high androgen level with no signs of virilization. Surgical treatment was indicated for a definitive diagnosis of suspected sex cord-stromal tumor. Right-sided laparoscopic salpingo-oophorectomy was performed, and the histopathological analysis confirmed the diagnosis of granulosa cell tumor adult type. The oncological team recommended adjuvant chemotherapy after the operation, but the patient did not give an informed consent. One month after surgical treatment, spontaneous menstrual bleeding occurred with normalization of sex hormone levels and the menstrual cycle. Nine months after surgical treatment, the patient was examined again due to secondary amenorrhea. Ultrasound confirmed a vital intrauterine pregnancy. The pregnancy course was normal, and the patient had a full-term spontaneous vaginal delivery of her second child. Restoration of fertility after a temporary loss due to hormone-secreting granulosa cell tumor is possible after sparing surgical treatment. The role of adjuvant chemotherapy is controversial, particularly in patients with stage I-II disease because of the rarity of this tumor and the absence of prospective randomized studies.


Decisional answer tree analysis of exudative age-related macular degeneration treatment outcomes.
The use of intravitreal ranibizumab in exudative age-related macular degeneration (eAMD) has become commonplace. We aim to investigate the early predictors of this treatment outcome. Seventy-one treatment-naive eyes of 71 patients with eAMD of all lesion subtypes who received intravitreal ranibizumab treatment and completed 12 months of follow-up were included. All patients were loaded with three injections of ranibizumab at monthly intervals. Further injections were given if clinically indicated based on logMAR best-corrected visual acuity (BCVA) and optical coherence tomography findings. Casenotes of eligible patients were reviewed retrospectively. The main outcome measure was logMAR BCVA change at month 12. The mean number of injections given over 12 months was 5.4 ± 1.9. A total of 88.7 % of the patients achieved visual stabilisation (loss of <15 letters) and 15.0 % achieved visual improvement (gain of ≥15 letters). The mean letter change at 12 months was +0.3 letters. Regression analysis showed that baseline BCVA and letter change at month 3 predicted visual acuity outcome at month 12 (baseline BCVA: t = 6.97, p < 0.001; letter change: t = 5.84, p < 0.01) but age, gender and eAMD in the fellow eye were not predictive. Finally, a decisional answer tree model demonstrated that letter change at month 3 was a strong predictor of visual outcome at month 12 with an overall accuracy of 69 %. We found that letter change from baseline at month 3 was strongly predictive of visual outcome at month 12.


Effects of six anaesthetic agents on UDP-glucuronic acid and other nucleotides in rat liver.
Anaesthesia affects the liver nucleotide pool. It was the aim of the present study to examine how anaesthesia for 60 min with pentobarbital, ketamin + diazepam, halothane, enflurane and isoflurane may influence the nucleotide pool in the rat liver, studied with isotachophoresis. It was found that none of the agents gave both safe and reproducible anaesthesia without affecting the nucleotide pools or affecting the experiments in some other way. Halothane and isoflurane were the two best alternatives with respect to both efficiency and safety. Isoflurane may be preferable since it gives a higher energy charge.


Concurrent administration of albumin with total parenteral nutrition in sick newborn infants.
The effects of concurrent administration of albumin with total parenteral nutrition were studied in 12 premature newborns (birth weight 1.26 +/- 0.1 kg [mean +/- SEM] and gestational age 30 +/- 0.8 weeks [mean +/- SEM]) compared with a control group of 12 premature newborns (birth weight 1.17 +/- 0.2 kg and gestational age 29 +/- 0.1 weeks) who received total parenteral nutrition. All newborns had a plasma albumin level below 3 g/dL and were in cardiorespiratory distress requiring assisted ventilation. Albumin supplementation of total parenteral nutrition resulted in a sustained increase in serum albumin concentration as well as increased mean arterial blood pressures in the study group. Slow albumin infusion had no observed effect on the severity of respiratory distress. Study group infants regained birth weight earlier than control group infants. These data suggest that the concurrent administration of albumin may be clinically beneficial in critically ill newborn infants.


Matrix metalloproteinase-1 is the major collagenolytic enzyme responsible for collagen damage in UV-irradiated human skin.
Punch biopsies of human skin were obtained 1 day after irradiation with two minimal-erythema doses (MED) from either a UVB light source or a Solar Simulator and incubated in organ culture for 72 h. Organ culture fluids obtained at 24, 48 and 72 h were analyzed for collagenolytic activity and for reactivity with antibodies to matrix metalloproteinase-1 (MMP-1; interstitial collagenase) and MMP-13 (collagenase-3). High levels of collagenolytic activity were seen in organ culture fluid from skin exposed to either light source. MMP-1 was strongly induced in parallel, increasing from less than 100 ng/ml in organ culture fluid from control skin to approximately 1.1 microg/ml in culture fluid from UV-treated skin. Whereas most of the detectable MMP-1 in control culture fluid was represented by the latent form of the enzyme, approximately 50% of the enzyme was present as the active form in organ culture fluid of UV-exposed skin. In contrast, there was no detectable MMP-13 in control organ culture fluid and very little change after UV exposure (less than 100 ng/ml in both cases). Finally, neutralization studies with a blocking antibody to MMP-1 removed 95 +/- 4% of the collagenolytic activity in the organ culture fluid from UV-treated skin. These findings strongly implicate MMP-1 rather than MMP-13 as the major collagenolytic enzyme responsible for collagen damage in photoaging.


Effects of extrusion cooking on functional properties of mixtures of full-fat soy and sweet potato.
Full-fat soy and sweet potato were extruded at 0:100, 25:75, 50:50, 75:25 and 100:0 ratios in an Insta-Pro 600 single screw extruder operated at 180, 200, 220 rpm respectively. Functional properties: bulk density, expansion ratio, water absorption and solubility indices and trypsin inhibitor were assayed. Results showed that addition of soybeans to sweet potatoes considerably increased the protein, fat, ash and trypsin inhibitor levels of the raw material mixtures. It also led to decreases in viscosities of raw mixtures, with corresponding increases in pasting temperatures. Addition of soybean significantly (p <0.05) affected expansion ratio, water absorption and solubility indices and trypsin inhibitor but not bulk density. Variation in screw rotation speed (rpm) significantly (p <0.05) affected only water solubility index at increasing speed. Extrudates generally received severe heat treatment, rendering them applicable only in soup bases, flour mixes and breakfast foods.


Increases in levels of schistosome-specific immunoglobulin E and CD23(+) B cells in a cohort of Kenyan children undergoing repeated treatment and reinfection with Schistosoma mansoni.
Age prevalence curves for areas in which schistosomiasis is endemic suggest that humans develop partial immunity to reinfection beginning in early adolescence. We conducted a 2-year longitudinal study to determine whether children infected with Schistosoma mansoni develop protection-related immune responses after treatment with praziquantel and whether the development of these immune responses is accelerated by frequent treatment after reinfection. Children (8-10 years old) were tested for S. mansoni every 4 months and treated with praziquantel when positive (arm A; n=68) or were tested and treated at the end of the 2-year follow-up period (arm B; n=49). Children in arm A who remained free of infection during follow-up had significantly higher baseline levels of schistosome-specific immunoglobulin E (IgE) than did children with > or =2 repeat diagnoses of S. mansoni infection. Children with > or =2 repeat diagnoses of S. mansoni infection had significantly increased levels of anti-schistosome IgE and CD23(+) B cells after receiving > or =3 praziquantel treatments over the course of follow-up. No increase in either parameter was seen in children who received only the baseline praziquantel treatment. B cell activation and anti-schistosome IgE are associated with resistance to S. mansoni in children, and these immunological parameters can be increased by multiple rounds of infections and praziquantel-induced cures.


Cobalt Oxide 2D Nanosheets Formed at a Polarized Liquid|Liquid Interface toward High-Performance Li-Ion and Na-Ion Battery Anodes.
Cobalt oxide (Co3O4)-based nanostructures have the potential as low-cost materials for lithium-ion (Li-ion) and sodium-ion (Na-ion) battery anodes with a theoretical capacity of 890 mAh/g. Here, we demonstrate a novel method for the production of Co3O4 nanoplatelets. This involves the growth of flower-like cobalt oxyhydroxide (CoOOH) nanostructures at a polarized liquid|liquid interface, followed by conversion to flower-like Co3O4 via calcination. Finally, sonication is used to break up the flower-like Co3O4 nanostructures into two-dimensional (2D) nanoplatelets with lateral sizes of 20-100 nm. Nanoplatelets of Co3O4 can be easily mixed with carbon nanotubes to create nanocomposite anodes, which can be used for Li-ion and Na-ion battery anodes without any additional binder or conductive additive. The resultant electrodes display impressive low-rate capacities (at 125 mA/g) of 1108 and 1083 mAh/g, for Li-ion and Na-ion anodes, respectively, and stable cycling ability over >200 cycles. Detailed quantitative rate analysis clearly shows that Li-ion-storing anodes charge roughly five times faster than Na-ion-storing anodes.


Possibilities of Integrated Fabrication of Insulation Systems in Electric Drives by Injection Molding of Thermosets.
Due to the increasing demand for electro mobility and specifically for electrified vehicles, the demand for electric drive technology is expanding significantly with changing requirements in terms of the process and the application. The electrical insulation system of the stator is an essential part of the fabrication process with a high impact on the application properties. Due to limitations-for example, in terms of suitable materials for the stator insulation-a new technology of integrated fabrication by injection molding of thermosets has been founded. In this study, two epoxy (EP) types with different fillers were investigated to prove their suitability in terms of the material properties in the fabrication process and the application. A general realization of the integrated fabrication of insulation systems in electrical engineering by injection molding was proved. Further, the differences regarding the suitability of the two materials are portrayed. It was demonstrated that mainly the filler material influences the fabrication process and the properties in the application, leading to differing suitability in terms of the EP 3162 EMG within the fabrication process and in terms of XW 6640-1 within the application properties of the thermal conductivity and the thermal linear expansion. It was further shown that the filler within the material system is required to increase the thermal conductivity needed for the application. The inclusion of the filler influences the reaction kinetics and the viscosity behavior. A fabrication of the material with fillers is however still possible.


Effect of high-altitude exposure in the elderly: the Tenth Mountain Division study.
More than 5 million people/year over age 60 visit high altitude, which may exacerbate underlying cardiac or pulmonary disease. We hypothesized that the elderly would exhibit an impaired functional capacity at altitude, with increased myocardial ischemia compared with sea level (SL). Twenty veterans (68+/-3 years) were studied at (1) SL, (2) acute simulated altitude to 2500 m, and (3) after 5 days of acclimatization to 2500 m. With acute altitude, PaO2 and oxyhemoglobin saturation decreased and pulmonary artery pressure increased 43%, associated with sympathetic activation. VO2peak decreased 12% acutely but normalized after acclimatization. The best predictor of VO2peak with acute altitude was VO2peak at SL (r=.94). The double product that induced 1-mm ST depression during exercise with acute altitude was 5% less than SL but normalized after acclimatization. One patient with severe coronary disease sustained a myocardial infarction after an exercise test. Moderate altitude exposure in the elderly is associated with hypoxemia, sympathetic activation, and pulmonary hypertension resulting in a reduced exercise capacity that is predictable based on exercise performance at SL. Patients with coronary artery disease who are well compensated at SL do well at moderate altitude, although acutely ischemia may be provoked at modestly lower myocardial and systemic work rates. The elderly acclimatize well with normalization of SL performance after 5 days. A prudent policy would be for elderly individuals, particularly those with coronary artery disease, to limit their activity during the first few days at altitude to allow this acclimatization process to occur.


Assessment of the image quality of virtual monochromatic spectral computed tomography images: a phantom study considering object contrast, radiation dose, and frequency characteristics.
Fast kilovoltage (kVp)-switching technology cannot obtain conventional 120 kVp images; thus, 70 keV virtual monochromatic spectral computed tomography (CT) images (VMSI) are generally used. The contrast-to-noise ratio (CNR) is used to evaluate the image quality of VMSI; however, CNR does not include frequency characteristics. The present study aimed to investigate the evaluation methods of VMSI considering frequency characteristics by comparing the image quality of 70 keV VMSI with that of conventional 120 kVp images. The evaluated object contrasts were 70 and 300 Hounsfield units (HU). Scans used two radiation dose levels: low (LD) and standard (SD). The volume CT dose index of LD and SD was 4.8- and 12 mGy, respectively. Images were reconstructed by filtered back projection, evaluating CNR, noise power spectrum (NPS), task transfer function (TTF), and system performance (SP) function calculated as TTF2/ NPS. The total NPS values (spatial frequency range: 0.2 ~ 0.4 mm-1) of 70 keV VMSI were higher than those of 120 kVp images. The spatial frequency TTF values that reached 10% (f10%) of the 70 keV VMSI changed based on object contrast. For the low-contrast condition, a lower f10% was observed with 70 keV VMSI. The CNR of 70 keV VMSI was comparable to that of 120 kVp images in low- and high-contrast conditions. However, for 70 keV VMSI, SP of low-contrast was low, and SP of high-contrast was high, compared with those of 120 kVp images. This study suggested that only CNR was not sufficient to evaluate the image quality of VMSI; thus, evaluation methods considering frequency characteristics should be used.


Development of medical pressure and temperature sensors employing optical spectrum modulation.
Fiber optic Fabry-Perot sensors have been developed whose optical reflectance varies with optical cavity depth (pressure) or with change in a material's refractive index (temperature). These sensors employ a unique combination of features: they are interrogated by an LED; they are designed to operate within a single reflectance cycle; and their returned light is analyzed by a dichroic ratio technique. The sensors use a step index glass fiber and are relatively insensitive to absolute light levels and fiber bending. They have an expanded linear operating range and can be built for low cost disposable applications. Sensor performance meets or exceeds established medical requirements.


Binding modes of two scorpion toxins to the voltage-gated potassium channel kv1.3 revealed from molecular dynamics.
Molecular dynamics (MD) simulations are used to examine the binding modes of two scorpion toxins, margatoxin (MgTx) and hongotoxin (HgTx), to the voltage gated K+ channel, Kv1.3. Using steered MD simulations, we insert either Lys28 or Lys35 of the toxins into the selectivity filter of the channel. The MgTx-Kv1.3 complex is stable when the side chain of Lys35 from the toxin occludes the channel filter, suggesting that Lys35 is the pore-blocking residue for Kv1.3. In this complex, Lys28 of the toxin forms one additional salt bridge with Asp449 just outside the filter of the channel. On the other hand, HgTx forms a stable complex with Kv1.3 when the side chain of Lys28 but not Lys35 protrudes into the filter of the channel. A survey of all the possible favorable binding modes of HgTx-Kv1.3 is carried out by rotating the toxin at 3° intervals around the channel axis while the position of HgTx-Lys28 relative to the filter is maintained. We identify two possible favorable binding modes: HgTx-Arg24 can interact with either Asp433 or Glu420 on the vestibular wall of the channel. The dissociation constants calculated from the two binding modes of HgTx-Kv1.3 differ by approximately 20 fold, suggesting that the two modes are of similar energetics.


Focal parietal cell differentiation in a well-differentiated (intestinal-type) early gastric cancer.
A well-differentiated (intestinal-type) early gastric cancer characterized by multifocal areas containing adenocarcinoma cells with eosinophilic cytoplasm is presented. The electron microscopy revealed that cytoplasmic eosinophilia was mainly due to the presence of numerous mitochondria. In addition, individual cells showed features of preparietal cell differentiation such as numerous mitochondria, tubulovesicles, intracellular canaliculi and rare mucin granules. There were also adenocarcinoma cells with a pyloric gland (mucopeptic) differentiation as revealed by the presence of granules with a dense protein core eccentrically located in the mucus matrix. These ultrastructural data suggested a gastric epithelial cell differentiation. The implications with regard to the classification and histogenesis of this tumor are discussed.


Selective binding of tumor suppressor p53 protein to topologically constrained DNA: Modulation by intercalative drugs.
Selective binding of the wild type tumor suppressor protein p53 to negatively and positively supercoiled (sc) DNA was studied using intercalative drugs chloroquine (CQ), ethidium bromide, acridine derivatives and doxorubicin as a modulators of the level of DNA supercoiling. The p53 was found to lose gradually its preferential binding to negatively scDNA with increasing concentrations of intercalators until the DNA negative superhelix turns were relaxed. Formation of positive superhelices (due to further increasing intercalator concentrations) rendered the circular duplex DNA to be preferentially bound by the p53 again. CQ at concentrations modulating the closed circular DNA topology did not prevent the p53 from recognizing a specific target sequence within topologically unconstrained linear DNA. Experiments with DNA topoisomer distributions differing in their superhelix densities revealed the p53 to bind selectively DNA molecules possessing higher number of negative or positive superturns. Possible modes of the p53 binding to the negatively or positively supercoiled DNA and tentative biological consequences are discussed.


Properties of L-type calcium channel gating current in isolated guinea pig ventricular myocytes.
Nonlinear capacitative current (charge movement) was compared to the Ca current (ICa) in single guinea pig ventricular myocytes. It was concluded that the charge movement seen with depolarizing test steps from -50 mV is dominated by L-type Ca channel gating current, because of the following observations. (a) Ca channel inactivation and the immobilization of the gating current had similar voltage and time dependencies. The degree of channel inactivation was directly proportional to the amount of charge immobilization, unlike what has been reported for Na channels. (b) The degree of Ca channel activation was closely correlated with the amount of charge moved at all test potentials between -40 and +60 mV. (c) D600 was found to reduce the gating current in a voltage- and use-dependent manner. D600 was also found to induce "extra" charge movement at negative potentials. (d) Nitrendipine reduced the gating current in a voltage-dependent manner (KD = 200 nM at -40 mV). However, nitrendipine did not increase charge movement at negative test potentials. Although contamination of the Ca channel gating current from other sources cannot be fully excluded, it was not evident in the data and would appear to be small. However, it was noted that the amount of Ca channel gating charge was quite large compared with the magnitude of the Ca current. Indeed, the gating current was found to be a significant contaminant (19 +/- 7%) of the Ca tail currents in these cells. In addition, it was found that Ca channel rundown did not diminish the gating current. These results suggest that Ca channels can be "inactivated" by means that do not affect the voltage sensor.


Fundamental Mechanisms of Immune Checkpoint Blockade Therapy.
Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069-86. ©2018 AACR.


Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays.
The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oligonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD.


Analysis of the long-term beneficial effects of menopausal hormone therapy on sleep quality and menopausal symptoms.
A large number of menopausal women report sleep disturbances along with psychological, somatic and urogenital menopausal symptoms. The aim of this study was to evaluate the efficacy of menopausal hormonal therapy (MHT) in improving subjective sleep quality and the severity of menopausal symptoms. An institutional ethics committee approved this retrospective chart review of 342 women treated with MHT for menopausal symptoms. Standard 28-day MHT consisted of the oral administration of 2 mg estradiol daily for 14 days, followed by 2 mg estradiol and 10 mg dydrogesterone daily for the remaining 14 days. A subgroup of 14 participants with a family history of cancer and mammography scores of 3 and above, received only tibolone 2.5 mg daily. Perceived sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI), while the assessment of menopausal symptoms was performed using the Kupperman Menopause Index (KMI) and menopause rating scale (MRS). Of the 342 patients, 79 were followed-up for 3 years. Compared to the baseline scores, the mean decrease in PSQI scores was 1.53±0.29 points (P<0.0001) at 1 month, 2.21±0.187 points (P<0.0001) at 2 months and 2.26±0.6 points (P<0.0001) after 3 years of MHT. The KMI scores also decreased by a mean of 6.37±1.59 points (P<0.0001) at 1 month and by 8.73±1.92 points after 3 years (P<0.0001). The MRS scores decreased by a mean of 3.56±1.05 points (P<0.0001) at 1 month and by 4.28±2.01 points (P<0.0001) after 3 years, as compared to the baseline scores. Patients receiving tibolone MHT did not report any improvement in sleep quality (P=0.956). On the whole, the findings of this study indicate that conventional MHT has a rapid and prolonged beneficial effect on self-reported sleep quality and menopausal symptoms in women. However, further clinical studies are warranted to compare the effects of different MHT regimens.


A multicenter pragmatic study of an evidence-based intervention to improve adenoma detection: the Quality Improvement in Colonoscopy (QIC) study.
Low adenoma detection rates (ADRs) at colonoscopy are linked to significantly higher interval cancer rates, and vary between colonoscopists. Studies demonstrate that lesion detection is improved by: withdrawal time of ≥ 6 minutes; use of hyoscine butylbromide; position change; and rectal retroflexion. We evaluated the feasibility of implementing the above "bundle" of interventions into colonoscopy practice, and the effect on ADR. A longitudinal cohort design was used. Implementation combined central training, local promotion, and feedback. The uptake marker was change in hyoscine butylbromide use. Comparisons were between the 3 months before and the 9 months after the implementation phase, globally, by endoscopy unit and by quartile when colonoscopists were ranked according to baseline ADR. Chi-squared or Fisher's tests were used to evaluate significance. 12 units participated. Global and quartile analyses included data from 118 and 68 colonoscopists and 17 508 and 14 193 procedures respectively. A significant increase in hyoscine butylbromide use was observed globally (54.4 % vs. 15.8 %, P < 0.001), in all endoscopy units (P < 0.001) and quartiles (P < 0.001). A significant increase in ADR was observed globally (18.1 % vs. 16.0 %, P = 0.002) and in the lower two colonoscopist quartiles (P < 0.001), with a nonsignificant increase in the upper middle quartile and a significant fall to 21.5 %. in the upper quartile. The significant variations in ADR among the upper three quartiles disappeared. In routine clinical practice, introduction of a simple, inexpensive, evidence-based "bundle" of measures is feasible and is associated with higher global ADR, driven by improvements amongst the poorest performing colonoscopists.


GH, but not GHRH, plays a role in the development of experimental autoimmune encephalomyelitis.
GH has been suggested to influence the function of the immune system in several species. Experimental autoimmune encephalomyelitis (EAE) (an animal model for multiple sclerosis) has been reported not to occur in GH-deficient (GHD) mice. The aim of this study was to elucidate the effects of GH and GHRH replacement on development of EAE in a mouse model of isolated GHD due to removal of the GHRH gene [GHRH knockout (GHRHKO)]. We studied two groups of adult female mice: 12 GH-sufficient animals (control) and 36 GHRHKO animals. All mice were immunized with myelin oligodendrocyte glycoprotein peptide, a peptide known to induce EAE. GHRHKO mice were left untreated or were treated for 4 wk with daily sc injections of recombinant GH or of a GHRH super agonist JI-38 (JI38-GHD). Evaluation of EAE symptoms was carried out daily, and T-proliferative assay and histopathological analysis of the spinal cord were performed. GHRHKO mice were less prone to develop EAE when compared with control mice. GH (but not JI-38) restored the original susceptibility of mice to the disease, despite lack of complete serum IGF-I normalization. GH treatment was also associated with a markedly increase in spleen size and T-cell proliferation specific to myelin oligodendrocyte glycoprotein peptide. GH (but not GHRH) plays an important role in the development of EAE.


Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications.
Mesenchymal stem cells (MSCs) have regenerative, immunoregulatory properties and can be easily isolated and expanded in vitro. Despite being a powerful tool for clinical applications, they present limitations in terms of delivery, safety, and variability of therapeutic response. Interestingly, the MSC secretome composed by cytokines, chemokines, growth factors, proteins, and extracellular vesicles, could represent a valid alternative to their use. It is noteworthy that MSC-derived extracellular vesicles (MSC-EVs) have the same effect and could be advantageous compared to the parental cells because of their specific miRNAs load. MiRNAs could be useful both in diagnostic procedures such as "liquid biopsy" to identify early pathologies and in the therapeutic field. Not only are MSC-EVs' preservation, transfer, and production easier, but their administration is also safer, hence some clinical trials are ongoing. However, much effort is required to improve the characterization of EVs to avoid artifacts and guarantee reproducibility of the studies.


Sharing Data With Shared Benefits: Artificial Intelligence Perspective.
Artificial intelligence (AI) and data sharing go hand in hand. In order to develop powerful AI models for medical and health applications, data need to be collected and brought together over multiple centers. However, due to various reasons, including data privacy, not all data can be made publicly available or shared with other parties. Federated and swarm learning can help in these scenarios. However, in the private sector, such as between companies, the incentive is limited, as the resulting AI models would be available for all partners irrespective of their individual contribution, including the amount of data provided by each party. Here, we explore a potential solution to this challenge as a viewpoint, aiming to establish a fairer approach that encourages companies to engage in collaborative data analysis and AI modeling. Within the proposed approach, each individual participant could gain a model commensurate with their respective data contribution, ultimately leading to better diagnostic tools for all participants in a fair manner.


Effectiveness of aquatic exercise for musculoskeletal conditions: a meta-analysis.
To investigate the effectiveness of aquatic exercise in the management of musculoskeletal conditions. A systematic review was conducted using Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, and The Cochrane Central Register of Controlled Trials from earliest record to May 2013. We searched for randomized controlled trials (RCTs) and quasi-RCTs evaluating aquatic exercise for adults with musculoskeletal conditions compared with no exercise or land-based exercise. Outcomes of interest were pain, physical function, and quality of life. The electronic search identified 1199 potential studies. Of these, 1136 studies were excluded based on title and abstract. A further 36 studies were excluded after full text review, and the remaining 26 studies were included in this review. Two reviewers independently extracted demographic data and intervention characteristics from included trials. Outcome data, including mean scores and SDs, were also extracted. The Physiotherapy Evidence Database (PEDro) Scale identified 20 studies with high methodologic quality (PEDro score ≥6). Compared with no exercise, aquatic exercise achieved moderate improvements in pain (standardized mean difference [SMD]=-.37; 95% confidence interval [CI], -.56 to -.18), physical function (SMD=.32; 95% CI, .13-.51), and quality of life (SMD=.39; 95% CI, .06-.73). No significant differences were observed between the effects of aquatic and land-based exercise on pain (SMD=-.11; 95% CI, -.27 to .04), physical function (SMD=-.03; 95% CI, -.19 to .12), or quality of life (SMD=-.10; 95% CI, -.29 to .09). The evidence suggests that aquatic exercise has moderate beneficial effects on pain, physical function, and quality of life in adults with musculoskeletal conditions. These benefits appear comparable across conditions and with those achieved with land-based exercise. Further research is needed to understand the characteristics of aquatic exercise programs that provide the most benefit.


Linitis plastica of the cecum.
Linitis plastica of the cecum is rare. The authors describe a case of this condition in a 16-year-old man. The commonest presenting symptom is a change in bowel habit. Histologically there are three recurring features--diffuse infiltration of the bowel wall by small darkly staining tumour cells, the presence of multiple "signet-ring" cells indicating mucin production and, third, an attempt at gland formation. The prognosis is poor; no patient has survived longer than 27 months.


Assessment of risk factors for postdural puncture headache in women undergoing cesarean delivery in Jordan: a retrospective analytical study.
Postdural puncture headache (PDPH) is one of the most recognized complications after spinal anesthesia in women undergoing cesarean delivery. This study aimed to investigate the incidence of PDPH and its associated risk factors in women undergoing cesarean delivery in Jordan. This study included all women who underwent cesarean delivery at King Abdullah University Hospital in Jordan during 2015. Patient characteristics including age, weight, occurrence of PDPH, needle type, repeated puncture attempt, history of spinal anesthesia and PDPH, presence of tension headache, preeclampsia, migraine, sinusitis, and caffeine withdrawal were collated from hospital records. Statistical analyses were performed to assess the association of these characteristics with PDPH. The study cohort consisted of 680 women. Among these, only 43 (6.3%) had developed PDPH. The only factors that showed significant association (P<0.01) with PDPH were repeated puncture attempt and presence of tension headache. The repeated puncture attempt increased the risk of PDPH 2.55-fold, while presence of tension headache increased the risk 4.60-fold. Furthermore, the use of the traumatic 27 G Spinostar needle increased the risk of repeated puncture attempt 28.45-fold (P<0.01) compared with the use of the pencil-point 25 G Whitacre needle. The major risk factors associated with the incidence of PDPH in women undergoing cesarean delivery in Jordan are repeated puncture attempt and presence of tension headache. The use of the pencil-point 25 G Whitacre needle is recommended since this was associated with a substantially reduced risk of repeated spinal puncture than the traumatic 27 G Spinostar needle.


Tunneling ultramicroelectrode: nanoelectrodes and nanoparticle collisions.
We describe the fabrication of a nanometer-size electrode based on an insulating TiO2 film and a metal nanoparticle (NP). The TiO2 film is deposited on the conducting Pt surface of an ultramicroelectrode (UME) to block electron transfer (ET) to solution species. The film thickness is, however, thin enough to enable tunneling to Pt NPs; thus, the subsequent contact of metal NP to the TiO2 film restores the ET to solution species solely on the NP surface via facile electron tunneling. Consequently, the composite of UME/metal oxide film/NP offers nm-scale active area. The TiO2 film is electrochemically deposited on the Pt UME (Pt UME/TiO2), monitoring the cyclic voltammetry (CV) of ferrocenemethanol until the oxidation wave just disappears. A single Pt NP is captured in a collision experiment by observing the current increase upon contact of the Pt NP with the Pt UME/TiO2 by means of Pt NP-mediated electrochemical reduction of Fe(CN)6(3-). The resultant Pt UME/TiO2/Pt NP (or tunneling UME, T-UME) showed long-term stability and robustness with well-defined electrochemical response, suggesting applicability as a novel nm-size electrode for CV and steady-state measurements such as those with scanning electrochemical microscopy (SECM). Here, we employed the T-UME to measure SECM approach curves and showed remarkable approach capability for a nm-size SECM probe.


Use of Ultrasonography to Discriminate Psoriatic Arthritis from Fibromyalgia: A Post-Hoc Analysis of the ULISSE Study.
In psoriatic arthritis (PsA) patients with concomitant chronic widespread pain, the differential diagnosis with fibromyalgia syndrome (FMS) can be challenging. We evaluated whether ultrasound (US) examination of entheseal sites can distinguish pain from (PsA) enthesitis versus FMS. PsA and FMS patients underwent clinical evaluation and gray-scale (GS; B-mode) and power Doppler (PD) US examination of the entheses. At least one enthesis with GS- and PD-mode changes was found in 90% and 59.3% of PsA patients (n = 140) and 62.7% and 35.3% of FMS patients (n = 51), respectively. GS and PD identified changes in 49.5% and 19.2% of the 840 PsA entheses and 22.5% and 7.9% of the 306 FMS entheses, respectively. Receiver operating characteristic curve analysis showed an area under the curve of 0.77 and 0.66 for B- and PD-mode, respectively, 3.5 being the best cut-off GS-score to discriminate the two conditions. Multivariate regression showed that Achilles and proximal patellar tendon enthesitis (B-mode) were strongly associated with PsA (odds ratio, ~2). Principal component analysis (B-mode) confirmed that PsA patients have a higher number of involved entheses and patterns of entheseal involvement than FMS patients. US evaluation of the entheses may help differentiate chronic widespread pain from PsA versus FMS.


Computational Study on the Water Corrosion Process at Schreibersite (Fe2NiP) Surfaces: from Phosphide to Phosphates.
Phosphorus (P) is a fundamental element for whatever form of life, in the same way as the other biogenic macroelements (SONCH). The prebiotic origin of P is still a matter of debate, as the phosphates present on earth are trapped in almost insoluble solid matrixes (apatites) and, therefore, hardly available for inclusion in living systems in the prebiotic era. The most accepted theories regard a possible exogenous origin during the Archean Era, through the meteoritic bombardment, when tons of reactive P in the form of phosphide ((Fe,Ni)3P, schreibersite mineral) reached the primordial earth, reacting with water and providing oxygenated phosphorus compounds (including phosphates). In the last 20 years, laboratory experiments demonstrated that the corrosion process of schreibersite by water indeed leads to reactive phosphates that, in turn, react with other biological building blocks (nucleosides and simple sugars) to form more complex molecules (nucleotides and complex sugars). In the present paper, we study the water corrosion of different crystalline surfaces of schreibersite by means of periodic DFT (density functional theory) simulations. Our results show that water adsorbs molecularly on the most stable (110) surface but dissociates on the less stable (001) one, giving rise to further reactivity. Indeed, subsequent water adsorptions, up to the water monolayer coverage, show that, on the (001) surface, iron and nickel atoms are the first species undergoing the corrosion process and, in a second stage, the phosphorus atoms also get involved. When adsorbing up to three and four water molecules per unit cell, the most stable structures found are the phosphite and phosphate forms of phosphorus, respectively. Simulation of the vibrational spectra of the considered reaction products revealed that the experimental band at 2423 cm-1 attributed to the P-H stretching frequency is indeed predicted for a phosphite moiety attached to the schreibersite (001) surface upon chemisorption of up to three water molecules.


Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance.
Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.


Functional behaviour from controlled self-assembly: challenges and prospects.
Many naturally occurring systems show us how multi-component supramolecular assemblies can generate useful functional behaviour. In this article the problems and limitations associated with achieving such behaviour in artificial multi-component assemblies is discussed, together with two examples of functions in artificial supramolecular assemblies based on (i) host-guest chemistry in cavities of cages, and (ii) light-harvesting in multi-chromophore arrays. Important challenges for the future are summarised.


Transcutaneous electrical retinal stimulation therapy for age-related macular degeneration.
This reports the preliminary outcome of a transpalpebral electrical retinal stimulation therapy for age-related macular degeneration (ARMD).Twenty-one patients consisting of 16 with wet-type (Group-W) and 5 with dry-type (Group-D) ARMD with a mean age of 73.9 ± 9.5 years (range 51 to 85 years) were recruited for this study. Transpalpebral electrical retinal stimulation (20 minutes, 800 muA) was applied on the patients 4 times per day for up to 1 month. The mean best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS] score) changed from 29.5±5.1 to 31.8±5.0 in Group-W and from 39.8±4.7 to 42.9±4.9 in Group-D. Neither ocular nor systemic adverse effects were observed with the exception of one patient who developed contact dermatitis. Due to several limitations such as lack of control, patients' learning effect, etc, the efficacy of the therapy could not be drawn. This preliminary study, however, showed that the transpalpebral electrical retinal stimulation therapy can be non-invasively applied on wet-type ARMD patients.


A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction.
Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD(+)-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes.


[Mental health, work and retirement: a focus on mental allienation].
It is an exploratory-descriptive study that aimed to analyze the disability retirement of employees of the UFRN for mental and behavioral disorders in the period 2000-2005. The sample was obtained from records of the DAS/PRH/UFRN. Of 43 retirees, 58% were men, 41% retire between 41-50 years and 35% between 51-60 years, 44% occupied position/function for the high school level and 28% for the elementary level. The mood disorders lead to 61% of the retirements by mental alienation, followed by thought disorders (19%), organic mental disorders and personality disorder (4%). We found that they lived with intense psychological distress creating an indirect burden on their lives and on their family's life facing lost opportunities of life and to the adjusted years of disability affecting their work.


Light-scattering detection below the level of single fluorescent molecules for high-resolution characterization of functional nanoparticles.
Ultrasensitive detection and characterization of single nanoparticles (<100 nm) is important in nanotechnology and life sciences. Direct measurement of the elastically scattered light from individual nanoparticles represents the simplest and the most direct method for particle detection. However, the sixth-power dependence of scattering intensity on particle size renders very small particles indistinguishable from the background. Adopting strategies for single-molecule fluorescence detection in a sheathed flow, here we report the development of high sensitivity flow cytometry (HSFCM) that achieves real-time light-scattering detection of single silica and gold nanoparticles as small as 24 and 7 nm in diameter, respectively. This unprecedented sensitivity enables high-resolution sizing of single nanoparticles directly based on their scattered intensity. With a resolution comparable to that of TEM and the ease and speed of flow cytometric analysis, HSFCM is particularly suitable for nanoparticle size distribution analysis of polydisperse/heterogeneous/mixed samples. Through concurrent fluorescence detection, simultaneous insights into the size and payload variations of engineered nanoparticles are demonstrated with two forms of clinical nanomedicine. By offering quantitative multiparameter analysis of single nanoparticles in liquid suspensions at a throughput of up to 10 000 particles per minute, HSFCM represents a major advance both in light-scattering detection technology and in nanoparticle characterization.


Long-term survival after the Fontan operation: Twenty years of experience at a single center.
Existing studies of patients palliated with the Fontan operation are limited by heterogeneous patient populations and incomplete follow-up. This study aimed to describe long-term post-Fontan survival in a modern patient cohort. All 773 patients who underwent a first Fontan operation at our institution between 1992 and 2009 were reviewed. The primary outcome was the composite endpoint of Fontan takedown, heart transplantation, or death before 2013. Follow-up rate was 99.2%. Survival with intact Fontan circulation was 94% at 1 year (95% confidence interval [95% CI], 92%-95%), 90% at 10 years (95% CI, 88%-92%), 85% at 15 years (95% CI, 82%-88%), and 74% at 20 years (95% CI, 67%-80%). Distinct risk factors were identified for early (≤1 year) and late composite outcomes. Independent risk factors for early outcome included prolonged pleural drainage (hazard ratio [HR], 4.4; P < .001), intensive care unit stay >1 week (HR, 2.4; P < .001), Fontan before 1997 (HR, 3.3; P < .001), preoperative atrioventricular valve regurgitation (HR, 2.0; P < .001), and longer crossclamp time (HR, 1.3 per 10 minutes; P < .001). Late outcome was predicted by atrioventricular valve regurgitation prior to Fontan (HR, 2.0; P ≤ .001), and post-Fontan ICU stay >1 week (HR, 2.4; P < .001). Long-term mortality after Fontan operation remains substantial. Risk factors for death or loss of Fontan circulation differ between the early and late postoperative periods. Long-term survival has not improved appreciably over the last decade, suggesting that alternatives to the Fontan are warranted.


Characterizing the morphology of protein binding patches.
Let the patch of a partner in a protein complex be the collection of atoms accounting for the interaction. To improve our understanding of the structure-function relationship, we present a patch model decoupling the topological and geometric properties. While the geometry is classically encoded by the atomic positions, the topology is recorded in a graph encoding the relative position of concentric shells partitioning the interface atoms. The topological-geometric duality provides the basis of a generic dynamic programming-based algorithm comparing patches at the shell level, which may favor topological or geometric features. On the biological side, we address four questions, using 249 cocrystallized heterodimers organized in biological families. First, we dissect the morphology of binding patches and show that Nature enjoyed the topological and geometric degrees of freedom independently while retaining a finite set of qualitatively distinct topological signatures. Second, we argue that our shell-based comparison is effective to perform atomic-level comparisons and show that topological similarity is a less stringent than geometric similarity. We also use the topological versus geometric duality to exhibit topo-rigid patches, whose topology (but not geometry) remains stable upon docking. Third, we use our comparison algorithms to infer specificity-related information amidst a database of complexes. Finally, we exhibit a descriptor outperforming its contenders to predict the binding affinities of the affinity benchmark. The softwares developed with this article are availablefrom http://team.inria.fr/abs/vorpatch_compatch/.


High intramuscular adipose tissue content associated with prognosis and postoperative complications of cancers.
Sarcopenia has been considered an adverse prognostic factor in cancer patients. Intramuscular adipose tissue content, as a new marker of sarcopenia, can effectively reflect skeletal muscle quality. The aim of this study was performed to evaluate the association between high intramuscular adipose tissue content (IMAC) and survival outcomes and postoperative complications in cancer patients. Specific databases, including the Web of Science, Embase and Web of Science, were systematically searched to identify relevant articles evaluating the prognostic value of IMAC in cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were utilized for comprehensive analysis. All data analyses were performed using STATA 12.0 software. A total of 25 studies from 24 articles including 5663 patients were enrolled in the study. Meta-analysis showed that high IMAC was associated with unfavourable overall survival (OS) (HR: 2.21, 95% CI: 1.70-2.86, P < 0.001), relapse-free survival (RFS) (HR: 1.51, 95% CI: 1.30-1.75, P < 0.001) and disease-specific survival (DSS) (HR: 1.64, 95% CI: 1.19-2.28, P = 0.003). Subgroup analysis revealed that high IMAC remained an adverse prognostic factor when stratified by different country, treatment methods, cancer type or analysis type. High IMAC had better predictive value for gallbladder carcinoma (GBC) (HR: 3.50, 95% CI: 1.98-6.17, P < 0.001), hepatocellular carcinoma (HCC) (HR: 1.84, 95% CI: 1.45-2.33, P < 0.001), pancreatic cancer (PC) (HR: 2.11, 95% CI: 1.67-2.66, P < 0.001) and colorectal cancer (CRC) (HR: 2.54, 95% CI: 1.27-5.10, P = 0.009). High IMAC was also identified as a significant risk factor for postoperative complications (OR: 2.05, 95% CI: 1.22-3.46, P = 0.007). High IMAC was associated with an adverse prognosis and an increased risk of postoperative complications in cancer patients. IMAC may be a good indicator of sarcopenia.


A neural measure of the degree of face familiarity.
Recognizing a face as familiar is essential in our everyday life. However, 'familiarity' covers a wide range - from people we see every day to those we barely know. Although face recognition is studied extensively, little is known about how the degree of familiarity affects neural face processing, despite the critical social importance of this dimension. Here we report the results of a multivariate cross-classification EEG experiment, where we study the temporal representational dynamics of the degree of familiarity. Participants viewed highly variable face images of 20 identities. Importantly, we measured face familiarity using subjective familiarity ratings in addition to testing explicit knowledge and reaction times in a face matching task. A machine learning algorithm, trained to discriminate familiar and unfamiliar faces from a separate study, was used to predict the degree of face familiarity from the pattern of the EEG data. We found that the neural representations of the degree of familiarity emerge between 400 - 600 msec post-stimulus onset for famous persons. The correlation between decoding performance and behavioral familiarity was more reliable, occurred earlier and lasted longer when personally familiar and viewers' own faces were included in the analysis. Our findings provide new insights into how the brain represents faces with various degrees of familiarity and show that the degree of familiarity can be decoded reliably from the EEG at a relatively late time window. These results support the idea that representations of familiar faces form part of a general neural signature of the familiarity component of recognition memory processes.


Individually randomized group treatment trials: a critical appraisal of frequently used design and analytic approaches.
We reviewed published individually randomized group treatment (IRGT) trials to assess researchers' awareness of within-group correlation and determine whether appropriate design and analytic methods were used to test for treatment effectiveness. We assessed sample size and analytic methods in IRGT trials published in 6 public health and behavioral health journals between 2002 and 2006. Our review included 34 articles; in 32 (94.1%) of these articles, inappropriate analytic methods were used. In only 1 article did the researchers claim that expected intraclass correlations (ICCs) were taken into account in sample size estimation; in most articles, sample size was not mentioned or ICCs were ignored in the reported calculations. Trials in which individuals are randomly assigned to study conditions and treatments administered in groups may induce within-group correlation, violating the assumption of independence underlying commonly used statistical methods. Methods that take expected ICCs into account should be used in reexamining past studies and planning future studies to ensure that interventions are not judged effective solely on the basis of statistical artifacts. We strongly encourage investigators to report ICCs from IRGT trials and describe study characteristics clearly to aid these efforts.


Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors.
3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3 nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24 h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist.


Abscess penetration of cefpirome: concentrations and simulated pharmacokinetic profiles in pus.
Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown. Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2 g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied. At abscess incision performed 158 ± 112 min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from ≤0.1 (limit of quantification) to 47 (mean 8.4 ± 14.1 ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183 ± 106 mg/L in plasma and 12 ± 16 mg/L in the abscess. A cefpirome concentration of 2 mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics. Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates.


Sedative antidepressants and insomnia.
The present review addresses the relationship between sleep and depression and how serotonergic transmission is implicated in both conditions. Literature searches were performed in the PubMed and MedLine databases up to March 2010. The terms searched were "insomnia", "depression", "sedative antidepressants" and "serotonin". In order to pinpoint the sedative antidepressants most used to treat insomnia, 34 ISI articles, mainly reviews and placebo-controlled clinical trials, were selected from 317 articles found in our primary search. Sleep problems may appear months before the diagnosis of clinical depression and persist after the resolution of depression. Treatment of insomnia symptoms may improve this comorbid disease. Some antidepressant drugs can also result in insomnia or daytime sleepiness. Serotonin (5-HT) demonstrates a complex pattern with respect to sleep and wakefulness that is related to the array of 5-HT receptor subtypes involved in different physiological functions. It is now believed that 5HT2 receptor stimulation is subjacent to insomnia and changes in sleep organization related to the use of some antidepressants. Some drugs commonly prescribed for the treatment of depression may worsen insomnia and impair full recovery from depression. 5-HT2 receptor antagonists are promising drugs for treatment strategies since they can improve comorbid insomnia and depression.


History of antibiotics. From salvarsan to cephalosporins.
Infections have represented for a long time the leading cause of death in humans. During the 19th century, pneumonia, tuberculosis, diarrhea and diphtheria were considered the main causes of death in children and adults. Only in the late 19th century did it become possible to correlate the existence of microscopic pathogens with the development of various diseases. Within a few years the introduction of antiseptic procedures had begun to reduce mortality due to postsurgical infections. Sanitation and hygiene played a significant role in the reduction of the mortality due to several infectious diseases. The introduction of the first compounds with antimicrobial activity succeeded in conquering many diseases. In this review we analyzed, from a historical perspective, the development of antibiotics and the circumstances that led to their discovery. The first compound with antimicrobial activity was introduced in 1911 by Erlich. He focused his research activity on the discovery of a "magic bullet" to treat syphilis. Afterwards, Foley and colleagues brought penicillin to the forefront. Streptomycin represents the first drug discovered for the treatment of tuberculosis, and its development included the first use of clinical trials. Finally, with the development of cephalosporins, the introduction of new antimicrobial compounds with broad activity against gram-positive and also some gram-negative bacteria began.


Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma.
Thirty-one patients were diagnosed by morphologic and immunophenotypic features as having primary Ki-1 anaplastic large-cell lymphoma (Ki-1 ALCL). the median age was 35 years (range, 4 months to 78 years); the male:female ratio was 18:13. B symptoms were observed in 13 patients. Peripheral adenopathy was present in 26 patients, while mediastinal adenopathy occurred in five. There was extranodal disease in 13 patients; the most common extranodal site was skin with seven affected. Seventeen patients had stage III/IV disease. Immunophenotypes were T cell in 24 patients and B cell in four patients; immunophenotype could not be determined in three patients. Cytogenetic abnormalities in chromosomes 2, 5, and 7 were detected in three patients. Although therapy was heterogeneous, the actuarial 2-year survival was 73%. Two-year disease-free survival was 39% for all patients; for stages I and II, it was 62% compared with 20% for stages III and IV (P = .001). Complete remission (CR) occurred in 21 of 23 patients receiving combination chemotherapy; however, nine relapses, including six of seven stage IV patients, occurred within 21 months of diagnosis. Preliminary observations suggest that Ki-1 ALCL may have a quiescent phase in the rare patient with only localized skin disease. However, the disease generally behaves as an intermediate- to high-grade lymphoma, and patients with Ki-1 ALCL should receive curative-intent combination chemotherapy.


Results from a pre-post, uncontrolled pilot study of a mindfulness-based program for early elementary school teachers.
Mindfulness-based programs are a novel and promising approach for supporting teachers' occupational health and well-being. Although rationales for mindfulness programs for teachers have been offered, the empirical research base evaluating approaches for educating teachers in mindfulness is still developing. This study reports the findings of a pilot study of a mindfulness-based program. This study is unique in that it is one of the only studies of the Mindfulness-Based Emotional Balance (MBEB) program to focus on early elementary teachers, to be implemented by a new instructor, and to recruit teachers via extrinsic motivators. A pre-post, uncontrolled pilot study of a 27.5-h mindfulness-based program for teachers was conducted with 21 pre-kindergarten-third-grade teachers from the Pacific Northwest of the USA. Program acceptability was assessed based on attendance and teacher reports of program benefits. Effect sizes for within-person changes (from pre- to post-program) in teachers' skills and mindsets, well-being, occupational health, and teaching practices were calculated. Teachers also suggested improvements to the program. With regard to program attendance and acceptability, teachers attended 87% of sessions, with 58% of teachers reporting a personal benefit and 58% of teachers reporting a professional benefit of the program. Effect sizes for changes in teachers' skills and mindsets ranged from small to large, |d| = 0.30 to 0.83, and ranged from small to medium for changes in teachers' well-being |d| = 0.07 to 0.48, occupational health |d| = 0.14 to 0.39, and teaching practices |d| = 0.15 to 0.48. Teachers suggested shortening the program and linking it more closely to their work in the classroom. This study suggests that the MBEB program may be beneficial to early elementary teachers, even when implemented by someone other than the program developer, and when provided with extrinsic motivation to participate (more closely mapping to a larger-scale trial of the program). Teachers' suggestions regarding program length and structure are considered, along with useful avenues for future research on mindfulness-based programs for teachers.


Collaborative and partnership research for improvement of health and social services: researcher's experiences from 20 projects.
Getting research into policy and practice in healthcare is a recognised, world-wide concern. As an attempt to bridge the gap between research and practice, research funders are requesting more interdisciplinary and collaborative research, while actual experiences of such processes have been less studied. Accordingly, the purpose of this study was to gain more knowledge on the interdisciplinary, collaborative and partnership research process by investigating researchers' experiences of and approaches to the process, based on their participation in an inventive national research programme. The programme aimed to boost collaborative and partnership research and build learning structures, while improving ways to lead, manage and develop practices in Swedish health and social services. Interviews conducted with project leaders and/or lead researchers and documentation from 20 projects were analysed using directed and conventional content analysis. Collaborative approaches were achieved by design, e.g. action research, or by involving practitioners from several levels of the healthcare system in various parts of the research process. The use of dual roles as researcher/clinician or practitioner/PhD student or the use of education designed especially for practitioners or 'student researchers' were other approaches. The collaborative process constituted the area for the main lessons learned as well as the main problems. Difficulties concerned handling complexity and conflicts between different expectations and demands in the practitioner's and researcher's contexts, and dealing with human resource issues and group interactions when forming collaborative and interdisciplinary research teams. The handling of such challenges required time, resources, knowledge, interactive learning and skilled project management. Collaborative approaches are important in the study of complex phenomena. Results from this study show that allocated time, arenas for interactions and skills in project management and communication are needed during research collaboration to ensure support and build trust and understanding with involved practitioners at several levels in the healthcare system. For researchers, dealing with this complexity takes time and energy from the scientific process. For practitioners, this puts demands on understanding a research process and how it fits with on-going organisational agendas and activities and allocating time. Some of the identified factors may be overlooked by funders and involved stakeholders when designing, performing and evaluating interdisciplinary, collaborative and partnership research.


Inactivation of mitogen-activated protein kinase signaling pathway reduces caspase-14 expression in impaired keratinocytes.
Several investigations have revealed that caspase-14 is responsible for the epidermal differentiation and cornification, as well as the regulation of moisturizing effect. However, the precise regulation mechanism is still not clear. This study was aimed to investigate the expression of caspase-14 in filaggrin-deficient normal human epidermal keratinocytes (NHEKs) and to explore the possible mechanism that contributes to the regulation of caspase-14. The filaggrin-deficient NHEKs were induced by transfection with lentivirus (LV) vector encoding small hairpin RNAs (shRNA). The inhibitors SB203580, PD98059 and SP600125 were used for suppressing the expression of p38 mitogen-activated protein kinase (MAPK), p44/42 MAPK and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). The expression of filaggrin, p38 MAPK, p44/42 MAPK and SAPK/JNK, caspase-14, keratin1and keratin2 were detected by western blot. In filaggrin-deficient NHEKs, the expression of p38, p44/42 MAPK and SAPK/JNK and caspase-14 were significantly decreased. The inhibition of p38 and SAPK/JNK reduced the expression of caspase-14, while the p44/42 MAPK showed no consistent effects. Moreover, the filaggrin knockdown decreased the expression of keratin2, but had no effects on the level of keratin1. The decreased expression of caspase-14 in filaggrin-deficient NHEKs may be induced by the inactivation of MAPK signaling pathway. These provide a novel perspective to understand the mechanism for the protective effects of filaggrin and caspase-14 on skin barrier function.


Feasibility Assessment of a School Nurse-Led Approach Using Chronic Absenteeism to Establish the School-Based Active Surveillance Process.
This article shares what was learned from the feasibility assessment of a nurse-led school-based active surveillance (SBAS) pilot to track chronic absenteeism using myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as an exemplar. This pilot encompassed a 3-year period with training and feedback from school nurses (SNs) on data collection and ME/CFS. SNs found that the SBAS process helped them effectively identifying undiagnosed conditions. The assessment revealed the importance of focusing outreach efforts and establishing relationships with the school leadership in developing health policies and programs in the school setting. The pilot data were used to develop a manual to guide SNs for the SBAS process. This can be viewed as a model for SNs in establishing a surveillance to identify and track conditions like ME/CFS. With overlapping symptoms of Long COVID to ME/CFS, this assessment may provide insights for additional efforts to understand the impact of Long COVID on students' education.