Productive Chlamydia trachomatis lymphogranuloma venereum 434 infection in cells with augmented or inactivated autophagic activities.
Autophagy, a eukaryotic cellular activity leading to the degradation of cellular components, serves as a defense mechanism against facultative intracellular bacteria as well as a growth niche for the obligate intracellular bacterium Coxiella burnetii. We here demonstrate that the obligate intracellular bacterial pathogen Chlamydia trachomatis lymphogranuloma venereum strongly induced autophagy in the middle of the chlamydial developmental cycle (24 h after infection), a time point with maximal level of chlamydial replication, but not during the early stages with low overall chlamydial metabolism (before 8 h). No autophagy induction was evident in cells exposed to heat- and UV-inactivated elementary bodies (EBs, the infectious form of Chlamydia) or to inocula from which EBs had been removed before inoculation. Blocking chlamydial development with chloramphenicol also prevented autophagy induction in cells infected with infectious EBs. It appears that autophagy is activated primarily in response to the metabolic stress consequent to chlamydial replication. However, autophagy-defective ATG5(-/-) cells supported chlamydial development as efficiently as autophagy-proficient ATG5(+/+) cells.


24-hydroxyursolic acid from the leaves of the Diospyros kaki (Persimmon) induces apoptosis by activation of AMP-activated protein kinase.
There are multiple lines of evidence that persimmon extract and its constituents have potent antitumor activity against human cancer cells. However, the molecular mechanisms of 24-hydroxyursolic acid, a triterpenoid found in persimmon, on antitumor activities are not yet understood. Here, we demonstrate that 24-hydroxyursolic acid inhibited cell proliferation, strongly activated AMP-activated protein kinase (AMPK) and mediated critical anticancer effects by inhibition of cyclooxygenase (COX-2) expression in HT-29 cells. In addition, 24-hydroxyursolic acid induced cellular apoptosis by activation of poly(ADP-ribose) polymerase (PARP), caspase-3, and phosphorylation of p53 at Ser15. It also strongly induced DNA fragmentation in HT-29 cells and thereby significantly inhibited colony formation of HT-29 cells in soft agar. In addition, 24-hydroxyursolic acid blocked the EGF-induced ERKs phosphorylation and led to the inhibition of AP-1 activity and cell transformation in JB6 CL41 cells. Collectively, these findings are the first to reveal a molecular basis for the anticarcinogenic action of 24-hydroxyursolic acid and might account for the reported chemopreventive and chemotherapic effects of persimmon extracts.


Chromatin regulation and gene centrality are essential for controlling fitness pleiotropy in yeast.
There are a wide range of phenotypes that are due to loss-of-function or null mutations. Previously, the functions of gene products that distinguish essential from nonessential genes were characterized. However, the functions of products of non-essential genes that contribute to fitness remain minimally understood. Using data from Saccharomyces cerevisiae, we investigated several gene characteristics, which we are able to measure, that are significantly associated with a gene's fitness pleiotropy. Fitness pleiotropy is a measurement of the gene's importance to fitness. These characteristics include: 1) whether the gene's product functions in chromatin regulation, 2) whether the regulation of the gene is influenced by chromatin state, measured by chromatin regulation effect (CRE), 3) whether the gene's product functions as a transcription factor (TF) and the number of genes a TF regulates, 4) whether the gene contains TATA-box, and 5) whether the gene's product is central in a protein interaction network. Partial correlation analysis was used to study how these characteristics interact to influence fitness pleiotropy. We show that all five characteristics that were measured are statistically significantly associated with fitness pleiotropy. However, fitness pleiotropy is not associated with the presence of TATA-box when CRE is controlled. In particular, two characteristics: 1) whether the regulation of a gene is more likely to be influenced by chromatin state, and 2) whether the gene product is central in a protein interaction network measured by the number of protein interactions were found to play the most important roles affecting a gene's fitness pleiotropy. These findings highlight the significance of both epigenetic gene regulation and protein interaction networks in influencing the fitness pleiotropy.


Can ultrasound of the major salivary glands differentiate Sjögren's disease from its major mimics?
Ultrasound of the major salivary glands (SGUS) is widely used to assess the major salivary glands in Sjögren's disease (SjD). Little is known, however, regarding the diagnostic accuracy of SGUS to differentiate SjD from its mimics. This study aims to investigate the diagnostic accuracy of SGUS in differentiating SjD from other diseases with salivary gland involvement. SGUS was performed in 20 consecutive patients with SjD and 20 consecutive patients with well-established systemic disease, i.e., with either sarcoidosis, amyloidosis, HIV infection or chronic HCV infection. Images were scored independently by two blinded observers using the Hocevar scoring system. Diagnostic accuracy to discriminate between the patient (sub-)groups was explored. The accuracy of SGUS to differentiate SjD from other systemic diseases was excellent (area under ROC curve of 0.91). The optimal cut-off value to define positive or negative ultrasound for SS was 15. Sensitivity, specificity, positive predictive value and negative predictive value were high, varying from 85-90%, and diagnostic odds ratio was 51. SGUS was positive in the vast majority of SjD patients (n=18), but also in 2 patients with HIV infection and one patient with sarcoidosis. SGUS score differed significantly between patients with SjD and other systemic diseases (median 27 vs. 10, p<0.001) as well as between SjD patients and patients with either sarcoidosis, amyloidosis, HIV or HCV infection (all p<0.05). This study indicates that SGUS has a potentially high diagnostic accuracy to discriminate SjD from systemic diseases which can also cause salivary gland involvement.


Has mortality related to alcohol decreased in Sweden?
In Sweden sales of alcohol dropped 17% from 1976 to 1982. Similarly, comparison of data from 1979 and 1982 shows that the mortality from cirrhosis of the liver declined appreciably, by 28% in men and 29% in women. During 1979-82 mortality from pancreatitis also declined noticeably, by 30% in men and 36% in women. By contrast, no decrease occurred in mortality from alcoholic psychosis, alcoholism, or alcohol intoxication. The decrease in mortality from cirrhosis of the liver and pancreatitis is probably explained by a decrease in the consumption of alcohol among an important subgroup of high consumers of alcohol. The lack of a decrease in mortality from alcoholic psychosis, alcoholism, and alcohol intoxication may be because such diagnoses are often made in socially deteriorated, more dependent alcoholic subjects who have not been able to reduce their consumption.


Oleic acid levels regulated by glycerolipid metabolism modulate defense gene expression in Arabidopsis.
Stearoyl-acyl-carrier-protein-desaturase-mediated conversion of stearic acid (18:0) to oleic acid (18:1) is a key step, which regulates levels of unsaturated fatty acids in cells. We previously showed that stearoyl-acyl-carrier-protein-desaturase mutants ssi2/fab2 carrying a loss-of-function mutation in the plastidial glycerol-3-phosphate (G3P) acyltransferase (act1) have elevated 18:1 levels and are restored in their altered defense signaling. Because G3P is required for the acylation of 18:1 by G3P acyltransferase, it was predicted that reduction of G3P levels should increase 18:1 levels and thereby revert ssi2-triggered phenotypes. Here we show that a mutation in G3P dehydrogenase restores both salicylic acid- and jasmonic acid-mediated phenotypes of ssi2 plants. The G3P dehydrogenase gene was identified by map-based cloning of the ssi2 suppressor mutant rdc8 (gly1-3) and confirmed by epistatic analysis of ssi2 with gly1-1. Restoration of ssi2-triggered phenotypes by the gly1-3 mutation was age-dependent and correlated with the levels of 18:1. Regeneration of G3P pools by glycerol application in ssi2 and ssi2 gly1-3 plants caused a marked reduction in the 18:1 levels, which rendered these plants hypersensitive to glycerol. This hypersensitivity in ssi2 was rescued by the act1 mutation. Furthermore, overexpression of the ACT1 gene resulted in enhanced sensitivity to glycerol. Glycerol application also lowered the 18:1 content in SSI2 plants and converted these into ssi2-mimics. Our results show that 18:1 levels in plastids are regulated by means of acylation with G3P, and a balance between G3P and 18:1 is critical for the regulation of salicylic acid- and jasmonic acid-mediated signaling pathways.


Phase-Tuned Entangled State Generation between Distant Spin Qubits.
Quantum entanglement between distant qubits is an important feature of quantum networks. Distribution of entanglement over long distances can be enabled through coherently interfacing qubit pairs via photonic channels. Here, we report the realization of optically generated quantum entanglement between electron spin qubits confined in two distant semiconductor quantum dots. The protocol relies on spin-photon entanglement in the trionic Λ system and quantum erasure of the Raman-photon path information. The measurement of a single Raman photon is used to project the spin qubits into a joint quantum state with an interferometrically stabilized and tunable relative phase. We report an average Bell-state fidelity for |ψ^{(+)}⟩ and |ψ^{(-)}⟩ states of 61.6±2.3% and a record-high entanglement generation rate of 7.3 kHz between distant qubits.


Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment.
Patients with subclinical and treated overt hyperthyroidism have an excess vascular mortality rate. Several symptoms and signs in overt hyperthyroidism suggest abnormality of cardiac autonomic function that may account in part for this excess mortality rate, but few studies have examined cardiac autonomic function in untreated and treated hyperthyroidism. We assessed heart rate turbulence (HRT) and time-domain parameters of heart rate variability in a large, unselected cohort of patients with overt hyperthyroidism referred to our thyroid clinic (n = 259) and compared findings with a group of normal subjects with euthyroidism (n = 440). These measures were also evaluated during antithyroid therapy (when serum-free thyroxine and triiodothyronine concentrations returned to normal but thyrotropin remained suppressed (i.e., subclinical hyperthyroidism, n = 110) and when subjects were rendered clinically and biochemically euthyroid (normal serum thyrotropin, free thyroxine and triiodothyronine concentrations, n = 219). We found that overall measures of heart rate variability and those specific for cardiac vagal modulation were attenuated in patients with overt hyperthyroidism compared with normal subjects; measurements of overall heart rate variability remained low in those with low levels of serum thyrotropin but returned to normal in patients with biochemical euthyroidism. Measurements of HRT (onset and slope) were also decreased in patients with overt hyperthyroidism, but HRT slope returned to normal values with antithyroid treatment. This study is the first to evaluate HRT in overt and treated hyperthyroidism.


Histone deacetylase inhibitors merged with protein tyrosine kinase inhibitors.
Histone deacetylases (HDACs) are a family of metal enzymes which mainly regulates the acetylation level of histone, together with histone acetyl transferases (HATs). Recently, because many HDAC inhibitors (HDACis) have entered clinical trials for both solid and liquid tumors, HDACs are recognized as one of the promising targets for cancer treatment. The current trend is that more and more HDAC inhibitors are used in combination with other antitumor agents in order to optimize their effect and toxicity. Protein tyrosine kinases (PTKs) which play important roles in cellular signal transduction pathways and regulate series of physiological and biochemical processes, are another family of hot antitumor targets. This brief review will mainly talk about several reported chimeric HDACs-PTKs inhibitors.


Factors Associated With High Frequency of Suicidal Ideation in Medically Ill Veterans.
Suicide is a leading cause of death, and rates are especially high among medically ill, older individuals. Health-related psychosocial correlates of suicidal ideation (SI) may be particularly important for medically ill older adults as they may clarify who may benefit from interventions to reduce SI. This study examined whether demographic, physical health, and/or health-related psychosocial factors were associated with high frequency of SI in older, medically ill Veterans experiencing elevated anxiety or depression. This cross-sectional study included 302 Veterans with (1) a cardiopulmonary condition and functional impairment and (2) elevated symptoms of depression and/or anxiety. Participants were classified as having either no, low, or high SI, based on self-reported ideation, from the Patient Health Questionnaire-9. SI was reported in 26.8% of the full sample and high SI was reported by 12.6% of participants. Logistic regression analyses predicting high versus no SI found the odds of high SI increased 4.7 times (95% confidence interval, 2.6-8.3) for each 1-unit increase in maladaptive coping and 4.1 times (95% confidence interval, 1.2-14.3) for each 1-unit increase in physical health severity/functional limitations. Older, medically ill Veterans with comorbid depression and/or anxiety frequently reported SI and were at greater risk of experiencing a high frequency of SI if they engaged in maladaptive coping strategies and/or had high levels of functional impairment. Effective interventions to reduce SI for this population should focus on reducing maladaptive coping and minimizing negative behavioral, cognitive, and emotional reactions to functional limitations.


Predictors of immunity after hepatitis A vaccination in HIV-infected persons.
Hepatitis A virus (HAV) infection remains a health risk for human immunodeficiency virus (HIV)-infected persons. While the inactivated HAV vaccine affords protection to immunocompetent persons >95% of the time, rates of developing protective antibody (anti-HAV) in HIV+ persons are considerably lower. Although low CD4+ T-cell counts have previously been reported to be correlated with this poor response, the effect of HIV viraemia on HAV vaccine response has not previously been reported. The medical records of HIV-infected patients who had received at least one dose of HAV vaccine (Havrix, 1440 EIU) were reviewed for factors associated with the development of a protective anti-HAV response. Serological data with regard to anti-HAV status after vaccination were available in 238 patients with 133 individuals (49.6%) developing immunity after vaccination. In a logistic regression model, the only factors associated with a protective antibody response were an HIV plasma RNA level <1000 copies/mL at the time of vaccination (P = 0.011) and male gender (P = 0.016). Neither nadir CD4+ T cell count nor CD4+ T-cell count at time of vaccination were predictive of the development of anti-HAV. Suppression of HIV replication at time of vaccination is associated with a protective antibody response to HAV vaccination in HIV-infected adults. The low rate of response warrants further research in alternative strategies for HAV vaccination among HIV-infected persons.


Prevalence of Chronic Hepatitis B Virus Infection in the United States.
Chronic hepatitis B virus (HBV) infection represents a major global health problem, affecting an estimated 257-291 million persons worldwide and is associated with substantial morbidity and mortality because of clinical complications, such as liver cirrhosis and hepatocellular carcinoma. Despite existing resources for vaccination, screening, and treatment, the burden of chronic HBV remains significant within the United States (US). Both the World Health Organization (WHO) and US Department of Health and Human Services (DHHS) have articulated formal hepatitis elimination plans, although an updated assessment of the epidemiology and prevalence of chronic HBV is needed to inform these initiatives. The Chronic Liver Disease Foundation (CLDF), a nonprofit 501(c)(3) educational organization dedicated to raising awareness of liver disease, partnered with a panel of leading US hepatologists to conduct an updated literature review to develop a contemporary HBV prevalence range estimate. Panel members researched and evaluated the peer-reviewed literature on HBV prevalence and, in May 2019, discussed their findings during a live HBV epidemiology workshop. The panel proposed an overall estimated prevalence for chronic HBV infection in the US of 1.59 million persons (range 1.25-2.49 million). This review provides a summary of the workshop findings and conclusions, which may serve to inform future initiatives focused on HBV screening and prevention in the US.


[Efforts to prevent static foot diseases in Hungary during the last 40 years].
The necessity of fighting against the harms causing static foot diseases has arisen before about 40 years. On the basis of large-scale foot measurements shoes, correctly constructed from the viewpoint of health, for children and workers were produced. We have switched over to metric system of direct character. The modern development of the industrial technology and commercial network is necessary.


Tumor angiogenesis, vascularization, and contrast-enhanced magnetic resonance imaging.
Angiogenesis, the process by which new blood vessels are generated, occurs during wound healing, in the female reproductive system during ovulation and gestation, and during embryonic development. The process is carefully controlled with positive and negative regulators, because several vital physiological functions require angiogenesis. The consequences of abnormal angiogenesis are either excessive or insufficient blood vessel growth. Ulcers, strokes, and heart attacks can result from the absence of angiogenesis normally required for natural healing, whereas excessive blood vessel proliferation may favor tumor growth and dissemination, blindness, and arthritis. In this review, the process of angiogenesis and the characteristics of the resulting tumor vasculature are outlined. Contrast-enhanced magnetic resonance imaging techniques that currently are available for basic research and clinical applications to study various aspects of tumor angiogenesis and neovascularization are discussed.


The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer.
Progression through the cell cycle is governed by cyclin-dependent kinases (cdks), whose activity is inhibited by the cdk inhibitors. Cyclins, cdks, and cdk inhibitors are frequently deregulated in cancers. This chapter reviews the prognostic significance of alterations in cdk inhibitors. Loss of p27 protein provides independent prognostic information in breast, prostate, colon, and gastric carcinomas, and immunohistochemical (IHC) staining for p27 may eventually become part of routine histopathologic processing of cancers. Loss of IHC staining for p21 may be prognostic in certain cancers but conflicting results are reported in breast cancer. Reports on homozygous deletion of p16 and p15 genes suggest the value of larger, prospective studies with standardized treatment protocols to definitively establish the prognostic utility of p15/p16 deletions in acute leukemias. Larger trials and the development of a consensus on methods for deletion analysis, IHC staining, and tumor scoring will be needed to move these molecular assays from bench to bedside.


Potential surgical targets for deep brain stimulation in treatment-resistant depression.
The goal of this study was to evaluate the definition of treatment-resistant depression (TRD), review the literature regarding deep brain stimulation (DBS) for TRD, and identify potential anatomical and functional targets for future widespread clinical application. A comprehensive literature review was performed to determine the current status of DBS for TRD, with an emphasis on the scientific support for various implantation sites. The definition of TRD is presented, as is its management scheme. The rationale behind using DBS for depression is reviewed. Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral habenula. Deep brain stimulation electrodes thus far have been implanted and activated in only the first 3 of these structures in humans. These targets have proven to be safe and effective, albeit in a small number of cases. Surgical intervention for TRD in the form of DBS is emerging as a viable treatment alternative to existing modalities. Although the studies reported thus far have small sample sizes, the results appear to be promising. Various surgical targets, such as the subgenual cingulate cortex, inferior thalamic peduncle, and nucleus accumbens, have been shown to be safe and to lead to beneficial effects with various stimulation parameters. Further studies with larger patient groups are required to adequately assess the safety and efficacy of these targets, as well as the optimal stimulation parameters and long-term effects.


Novel KLK4 and MMP20 mutations discovered by whole-exome sequencing.
Non-syndromic amelogenesis imperfecta (AI) is a collection of isolated inherited enamel malformations that follow X-linked, autosomal-dominant, or autosomal-recessive patterns of inheritance. The AI phenotype is also found in syndromes. We hypothesized that whole-exome sequencing of AI probands showing simplex or recessive patterns of inheritance would identify causative mutations among the known candidate genes for AI. DNA samples obtained from 12 unrelated probands with AI were analyzed. Disease-causing mutations were identified in three of the probands: a novel single-nucleotide deletion in both KLK4 alleles (g.6930delG; c.245delG; p.Gly82Alafs*87) that shifted the reading frame, a novel missense transition mutation in both MMP20 alleles (g.15390A>G; c.611A>G; p.His204Arg) that substituted arginine for an invariant histidine known to coordinate a structural zinc ion, and a previously described nonsense transition mutation in a single allele of FAM83H (c.1379G>A; g.5663G>A; p.W460*). Erupted molars and cross-sections from unerupted parts of the mandibular incisors of Mmp20 null mice were characterized by scanning electron microscopy. Their enamel malformations closely correlated with the enamel defects displayed by the proband with the MMP20 mutation. We conclude that whole-exome sequencing is an effective means of identifying disease-causing mutations in kindreds with AI, and this technique should prove clinically useful for this purpose.


Reconfigurable microfluidic photonic crystal slab cavities.
We demonstrate the spectral and spatial reconfigurability of photonic crystal double-heterostructure cavities in silicon by microfluidic infiltration of selected air holes. The lengths of the microfluidic cavities are changed by adjusting the region of infiltrated holes in steps of several microns. We systematically investigate the spectral signature of these cavities, showing high Q-factor resonances for a broad range of cavity lengths. The fluid can be removed by immersing the device in toluene, offering complete reconfigurability. Our cavity writing technique allows for tolerances in the infiltration process and provides flexibility as it can be employed at any time after photonic crystal fabrication.


A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD. Parkinson Study Group.
Preclinical evidence suggests that manipulation of the glutamatergic system may provide an alternative strategy for therapeutic intervention in PD. Remacemide hydrochloride is a low affinity NMDA channel blocker that might improve parkinsonian symptoms by modulating glutamatergic overactivity in the basal ganglia or slow worsening by decreasing excitotoxicity. The authors performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of remacemide in patients with early PD who were not yet receiving levodopa or dopamine agonists. The primary objective was to assess the short-term tolerability and safety of three dosage levels of remacemide. Two hundred patients were randomized to receive either remacemide 150 mg, 300 mg, or 600 mg, or matching placebo daily for 5 weeks. Significantly fewer patients receiving remacemide 600 mg daily were able to tolerate 5 weeks of their assigned treatment on a BID schedule compared with patients receiving placebo (64% versus 94%, p = 0.0002). Most patients who experienced intolerable side effects on the BID schedule, however, could tolerate the same daily dosage on a QID schedule. The most common adverse events were dizziness and nausea. There were no serious adverse events or clinically significant treatment-related changes in vital signs, laboratory values, or electrocardiograms. There was no evidence of improvement in PD signs or symptoms associated with remacemide monotherapy. Remacemide was generally well tolerated and safe in this 5-week trial. There was no evidence for a symptomatic effect of remacemide monotherapy in patients with early PD. Based on its favorable safety profile and several animal studies, further studies of remacemide are warranted as symptomatic therapy in levodopa-treated patients and as a neuroprotective agent.


On-line detection of nonspecific protein adsorption at artificial surfaces.
A detailed understanding of the interaction of proteins with artificial surfaces is essential for many applications in medicine and biochemistry. The affinity of surfaces toward proteins may, for instance, remove pharmacological proteins from media or control the adherence of pathogenic bacteria to protheses. Only a few analytical techniques now exist that can be used to study the binding process in real time, using unlabeled proteins. By investigating the adsorption kinetics of fibrinogen at differently terminated self-assembled monolayers (SAMs) of alkanethiols on thin gold films, it is demonstrated that acoustic plate-mode sensors are a promising analytical tool for studying the adsorption of proteins. In agreement with previous studies for fibrinogen, it is shown in situ that hexa(ethylene glycol)-terminated SAMs (HS(CH2)11 (OCH2CH2)6OH) exhibit very low protein adsorption and that methyl-terminated SAMs (HS(CH2)11CH3) tend to absorb large amounts of protein nonspecifically. The observed adsorption kinetics deviate from classical Langmuir behavior; these kinetics are compatible with a mechanism that involves an unfolding of fibrinogen after adsorption. Film quality is controlled by IR, XPS, and contact angle measurements.


Extracellular microRNAs in blood differentiate between ischaemic and haemorrhagic stroke subtypes.
Rapid identification of patients suffering from cerebral ischaemia, while excluding intracerebral haemorrhage, can assist with patient triage and expand patient access to chemical and mechanical revascularization. We sought to identify blood-based, extracellular microRNAs 15 (ex-miRNAs) derived from extracellular vesicles associated with major stroke subtypes using clinical samples from subjects with spontaneous intraparenchymal haemorrhage (IPH), aneurysmal subarachnoid haemorrhage (SAH) and ischaemic stroke due to cerebral vessel occlusion. We collected blood from patients presenting with IPH (n = 19), SAH (n = 17) and ischaemic stroke (n = 21). We isolated extracellular vesicles from plasma, extracted RNA cargo, 20 sequenced the small RNAs and performed bioinformatic analyses to identify ex-miRNA biomarkers predictive of the stroke subtypes. Sixty-seven miRNAs were significantly variant across the stroke subtypes. A subset of exmiRNAs differed between haemorrhagic and ischaemic strokes, and LASSO analysis could distinguish SAH from the other subtypes with an accuracy of 0.972 ± 0.002. Further analyses predicted 25 miRNA classifiers that stratify IPH from ischaemic stroke with an accuracy of 0.811 ± 0.004 and distinguish haemorrhagic from ischaemic stroke with an accuracy of 0.813 ± 0.003. Blood-based, ex-miRNAs have predictive value, and could be capable of distinguishing between major stroke subtypes with refinement and validation. Such a biomarker could one day aid in the triage of patients to expand the pool eligible for effective treatment.


Ceramic liner fracture and impingement in total hip arthroplasty.
Ceramic-on-ceramic bearing surfaces were developed to provide an alternate to metal-on-polyethylene to decrease wear-induced osteolysis in total hip arthroplasty patients. In an effort to decrease the risk of ceramic acetabular component fracture or damage during implantation, a raised metal rim was added. How many fractures or impingements have occurred in our population of patients with ceramic liners with raised rims? With IRB-approved consent, a case series was reviewed from a single center registry and 4 of 169 patients were identified who had revision hip surgery with the ceramic liner with a raised metal rim: one for ceramic liner fracture and three for metallosis, pain, and squeaking. Implant alignment and operative findings were reviewed. One ceramic liner fracture and three cases of metallosis from impingement of the femoral neck on the posterior elevated metal rim of the acetabular liner were observed at revision. The femoral neck in each patient had a divot that corresponded to a divot in the posterosuperior liner rim. Three of the four patients had audible squeaking or clicking prior to revision. A total of 3% of patients in this series had clinically significant impingement with this implant type. Acoustic phenomenon in a ceramic on ceramic bearing surface should be investigated with a cross-table lateral radiograph to evaluate component position. If symptomatic impingement is demonstrated, revision should be considered to avoid failure from metallosis or fracture.


Renal cystic disease proteins play critical roles in the organization of the olfactory epithelium.
It was reported that some proteins known to cause renal cystic disease (NPHP6; BBS1, and BBS4) also localize to the olfactory epithelium (OE), and that mutations in these proteins can cause anosmia in addition to renal cystic disease. We demonstrate here that a number of other proteins associated with renal cystic diseases - polycystin 1 and 2 (PC1, PC2), and Meckel-Gruber syndrome 1 and 3 (MKS1, MKS3) - localize to the murine OE. PC1, PC2, MKS1 and MKS3 are all detected in the OE by RT-PCR. We find that MKS3 localizes specifically to dendritic knobs of olfactory sensory neurons (OSNs), while PC1 localizes to both dendritic knobs and cilia of mature OSNs. In mice carrying mutations in MKS1, the expression of the olfactory adenylate cyclase (AC3) is substantially reduced. Moreover, in rats with renal cystic disease caused by a mutation in MKS3, the laminar organization of the OE is perturbed and there is a reduced expression of components of the odor transduction cascade (G(olf), AC3) and α-acetylated tubulin. Furthermore, we show with electron microscopy that cilia in MKS3 mutant animals do not manifest the proper microtubule architecture. Both MKS1 and MKS3 mutant animals show no obvious alterations in odor receptor expression. These data show that multiple renal cystic proteins localize to the OE, where we speculate that they work together to regulate aspects of the development, maintenance or physiological activities of cilia.


Hemodynamic changes during laparoscopic radiofrequency ablation of normal adrenal tissue in dogs.
To determine the hemodynamic response to radiofrequency ablation (RFA) of normal adrenal tissue in dogs. Experimental study. Healthy adult mixed-breed dogs (n=6). During general anesthesia a Swan-Ganz thermodilution catheter was flow directed into the pulmonary artery and used to quantify cardiac output. An arterial catheter was used for direct blood pressure measurements. An RFA device was introduced into the left adrenal gland under observation through laparoscopic instrumentation. Blood samples were collected and hemodynamic variables studied after a stable surgical anesthetic depth was achieved (time 1), during CO(2) insufflation of the abdomen (time 2), during adrenal RFA (time 3), and after completed RFA (time 4). Catecholamine determinations were performed with a human enzyme immunoassay. Histopathology was performed to verify medullary necrosis. Arterial, pulmonary arterial and central venous pressure, and plasma norepinephrine increased more during RFA than during abdominal insufflation. Heart rate and cardiac index did not differ between time points. High baseline epinephrine was present and significant differences between time points were not detected. Systemic vascular resistance had very high individual variation and differences were not detected. RFA of normal adrenal tissues is associated with severe hemodynamic alterations. Further studies of the optimal blockage of catecholamine-induced hypertension in dogs are warranted. Clinicians should prepare for potential hypertensive crisis during RFA of adrenal masses, especially if treating a margin of normal tissue.


Development of a Cartilage Shear-Damage Model to Investigate the Impact of Surface Injury on Chondrocytes and Extracellular Matrix Wear.
Background Many i n vitro damage models investigate progression of cartilage degradation after a supraphysiologic, compressive impact at the surface and do not model shear-induced damage processes. Models also neglect the response to uninterrupted tribological stress after damage. It was hypothesized that shear-induced removal of the superficial zone would accelerate matrix degradation when damage was followed by continued load and articulation. Methods Bovine cartilage underwent a 5-day test. Shear-damaged samples experienced 2 days of damage induction with articulation against polyethylene and then continued articulation against cartilage (CoC), articulation against metal (MoC), or rest as free-swelling control (FSC). Surface-intact samples were randomized to CoC, MoC, or FSC for the entire 5-day test. Samples were evaluated for chondrocyte viability, GAG (glycosaminoglycan) release (matrix wear surrogate), and histological integrity. Results Shear induction wore away the superficial zone. Damaged samples began continued articulation with collagen matrix disruption and increased cell death compared to intact samples. In spite of the damaged surface, these samples did not exhibit higher GAG release than intact samples articulating against the same counterface ( P = 0.782), contrary to our hypothesis. Differences in GAG release were found to be due to tribological testing against metal ( P = 0.003). Conclusion Shear-induced damage lowers chondrocyte viability and affects extracellular matrix integrity. Continued motion of either cartilage or metal against damaged surfaces did not increase wear compared with intact samples. We conjecture that favorable reorganization of the surface collagen fibers during articulation protected the underlying matrix. This finding suggests a potential window for clinical interventions to slow matrix degradation after traumatic incidents.


The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.
The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."


Nonablative radiofrequency for active acne vulgaris: the use of deep dermal heat in the treatment of moderate to severe active acne vulgaris (thermotherapy): a report of 22 patients.
Acne vulgaris is an exceedingly common condition in adolescence and may extend into adult life in some individuals. Even though this condition is at times minimized, it has been found to have a profound impact in the quality of life of many affected individuals. Acne scarring can be even more of a source of psychological and social problems than active acne is, and when inadequately treated, the latter can lead to the former. Moderate and severe acne vulgaris usually require a regimen of systemic and/or topical medications, which are given for several months or even years and frequently require multiple visits to the physician office, the laboratory, etc. This results in loss of time at school and considerable expense. Side effects from medications and the frequent need to use alternative drugs when there is no response to medical treatment are possible. To evaluate the role of a novel medical device that uses radiofrequency as a source of energy to produce volumetric tissue heating, while sparing the epidermis, allowing for a procedure with no down time and no postoperative care required. Twenty-two patients, 10 women and 12 men, ranging in age from 16 to 28, with moderate to severe, scarring, cystic, active, acne vulgaris participated. Only nine of these patients were on concomitant medical treatment such as oral antibiotics or topical agents. All 22 patients were treated with a new nonablative radiofrequency unit, which delivers a concomitant spray of cryogen for epidermal sparing. One session was done in 20 patients and two sessions in 2 patients. The average fluence per energy delivery was 72 J/cm2. Follow-up ranged from 1 to 8 months. Patient questionnaires and active acne lesion counts were used to evaluate the response to treatment. Excellent response was seen in 82% (n=18). Modest response was seen in 9% (n=2), and no response was seen in 9% (n=2); t-test on active lesion counts before treatment and after treatment was less than 0.009004. No side effects were identified on any of these patients. No down time from the procedure was seen. Only topical anesthesia, ELA-Max 5% (Ferndale Labs, Ferndale, MI) was used; 59% of patients were on no acne medication before, during, or after the procedure. Nonablative radiofrequency appears to be a new safe and effective treatment alternative for moderate to severe acne vulgaris. Further research is in progress to evaluate this treatment modality in a larger number of patients.


The infected diabetes-related foot: Comparison of erythrocyte sedementation rate/albumin and C-reactive protein/albumin ratios with erythrocyte sedimentation rate and C-reactive protein to differentiate bone and soft tissue infections.
The objective of this study was to evaluate the effectiveness of C-reactive protein (CRP)/albumin, erythrocyte sedimentation rate (ESR)/albumin ratio, ESR, CRP and albumin to differentiate bone and soft tissue infection in persons with diabetes. We retrospectively evaluated 242 individuals admitted to hospital with diabetes-related foot infections (DFI). We categorised DFI cases as either bone (OM) or soft tissue infection based on bone culture and/or histology. We evaluated the diagnostic accuracy of CRP, ESR, albumin, CRP/albumin and ESR/albumin as biomarkers to diagnose OM in persons with diabetes. The median age was 53 years (74% male). There were 224 diabetes-related patients of which 125 had been diagnosed with osteomyelitis. The ESR/albumin and CRP/albumin ratios cut-points were >17.84 and >1.83, respectively. ESR/albumin and CRP/albumin ratios had similar diagnostic parameters: AUC (0.71, 0.71), sensitivity (70.0%, 57.0%), specificity (62.0%, 75.0%), positive predictive value (67.0%, 71.0%) and negative predictive value (66.0% and 71.0%). In contrast diagnostic efficiency of CRP and ESR were AUC 0.71 and 0.71, sensitivity (45.6%, 71.2%), specificity (85.5%, 60.7%), positive predictive value (70.0%, 65.9%) and negative predictive value (59.5%, 66.4%), respectively. When comparing area under the curves, the results showed that ESR/albumin was not significantly different to ESR alone (Delong test pvs ESR >0.1). Similarly, CRP/albumin was not significantly different to CRP alone (Delong test pvs CRP >0.1). In conclusion, ESR/albumin and CRP/albumin ratios provided comparable results as using ESR and CRP alone.


Personal identification of cold case remains through combined contribution from anthropological, mtDNA, and bomb-pulse dating analyses.
In 1968, a child's cranium was recovered from the banks of a northern Canadian river and held in a trust until the "cold case" was reopened in 2005. The cranium underwent reanalysis at the Centre for Forensic Research, Simon Fraser University, using recently developed anthropological analysis, "bomb-pulse" radiocarbon analysis, and forensic DNA techniques. Craniometrics, skeletal ossification, and dental formation indicated an age-at-death of 4.4 ± 1 year. Radiocarbon analysis of enamel from two teeth indicated a year of birth between 1958 and 1962. Forensic DNA analysis indicated the child was a male, and the obtained mitochondrial profile matched a living maternal relative to the presumed missing child. These multidisciplinary analyses resulted in a legal identification 41 years after the discovery of the remains, highlighting the enormous potential of combining radiocarbon analysis with anthropological and mtDNA analyses in producing confident personal identifications for forensic cold cases dating to within the last 60 years.


Retrospective study of rFVIIa, 4-factor PCC, and a rFVIIa and 3-factor PCC combination in improving bleeding outcomes in the warfarin and non-warfarin patient.
In case of severe bleeding, the physician must rapidly and effectively halt bleeding without the risk of thromboembolic complications. Despite widespread use, no study has directly compared recombinant activated factor VII (rFVIIa), the rFVIIa and 3-factor prothrombin complex concentrate (PCC) combination ("combination"), and 4-factor PCC on their effectiveness in improving patient outcomes. This study examined the medical records of 299 patients, 65.2% on warfarin prior to admission, who received these hemostatic agents and were admitted to an ICU or through the emergency department at Oregon Health & Science University. Mortality, length of stay, change in international normalized ratio (INR), plasma use, and number of thromboembolic complications were used to assess effectiveness. In patients receiving warfarin, the combination group had the greatest decrease in INR as well as lowest overall INR, but experienced a higher number of clotting complications, while the rFVIIa group used the most plasma. Non-warfarin patients in the combination group had the shortest length of stay among survivors, but the rFVIIa group had the lowest mortality. Based on this data, it may be prudent to further study the use of rFVIIa in treating extreme bleeding in the non-warfarin patient, while this study supports other data that 4-factor PCC may be the most prudent for the warfarin patient. Am. J. Hematol. 91:705-708, 2016. © 2016 Wiley Periodicals, Inc.


Code of Professional Conduct for Clinical Embryologists.
The Association of Clinical Embryologists (ACE) is the professional body of and for clinical embryologists practising in the UK. ACE was founded in 1993 to promote high standards of practice in clinical embryology and to support the professional interests of embryologists. ACE presently has in excess of 400 members.


Fast computing of color matching by means of matrix representation. Part 1: transmission-type colorant.
Color matching today is based upon the metamerism principle which necessitates agreement of only a trichromatic specification. The amounts of a set of three dyes (e.g., cyan, magenta, and yellow) to reach a certain chromaticity and lightness (u,v,Y) is decided uniquely when the spectral density distributions of the dyes are known. The problem of calculating the amount of dye is reduced to solving simultaneous integral equations, which is not always easy. The calculation was executed conventionally by changing the dye amount systematically and selecting the combination of dye amount that gave the least color difference. This systematic sweeping method is not efficient, so that it takes more than 10 min to calculate a set of dye amount within 0.001 C.I.E. (1964) color difference, even with a computer. The author investigated the computer program of fast color matching for routine work by means of matrix representation between dye amount and trichromatic specification.


PSPC1 Inhibition Synergizes with Poly(ADP-ribose) Polymerase Inhibitors in a Preclinical Model of BRCA-Mutated Breast/Ovarian Cancer.
Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining PSPC1 siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of γH2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that PSPC1 inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and PSPC1 inhibition merits further clinical investigation to enhance PARP inhibitor efficacy.


Age-related nuclear cataract and indoleamine 2,3-dioxygenase-initiated tryptophan metabolism in the human lens.
Tryptophan-derived UV filters (kynurenine and 3-hydroxylkynurenine glucoside) have recently been shown to bind to human lens proteins. These UV filter adducts increase in amount with age and appear to be mainly responsible for the yellowing of the lens in man. On the basis of research performed in other tissues, it has been assumed that indoleamine 2,3-dioxygenase (IDO) may be the first and probably rate-limiting enzyme in UV filter biosynthesis. In this study, 25 human lenses were examined by a reliable and sensitive assay method with a monoclonal antibody specific for IDO. IDO activity was detected in all lenses ranging from 26 to 80 years, and there was no clear relationship of IDO activity with age. The mean activity was 0.85 + 0.49 nmol of kynurenine/h/lens. The level in the iris/ciliary body was negligible (<0.05 nmol of kynurenine/h). The lens IDO activity is consistent with UV filter turnover values obtained previously. These findings indicate that IDO is the first enzyme in the UV filter pathway and that UV filter biosynthesis is active even in aged lenses. Yellowing of the aged lens may therefore be preventable by drug-induced suppression of IDO activity.


Factors associated with physical activity in Canadian adults with diabetes.
The purpose of this study was to identify key demographic and health factors associated with physical activity (PA) participation in adults with type 1 or type 2 diabetes. Participants were adults > or = 18 yr of age living in the province of Alberta, Canada who were previously diagnosed with type 1 (N = 697) or type 2 (N = 1614) diabetes. Individuals were recruited from the Canadian Diabetes Association (Alberta) registry and through a random digit-dialing protocol. Multiple and logistic regression models were employed to identify demographic and health factors related to PA levels, of which many to date have not been examined in this population. Analyses were conducted separately for type 1 and type 2 groups. Of those with type 1 and type 2 diabetes, 63.7 and 71.9%, respectively, were not achieving recommended PA levels. For those with type 1, higher PA levels were associated with a younger age, being single, higher income, lower level of perceived disability, and not smoking. For the type 2 group, a younger age, male gender, higher education, higher income, lower body mass index, and lower level of perceived disability were associated with higher PA levels. Many of our results for both diabetes types are consistent with findings from other limited research in this domain. Contrary to previous research, however, a significant negative relationship was reported between body mass index and PA for the type 2 group. In addition, perceived disability was negatively associated with PA, which, to date, has not been reported in the literature with type 2 individuals. Research and practice related to physical activity promotion for this population should take into account specific demographic and health factors associated with PA.


The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus.
Despite the numerous studies on the relation of albuminuria with increased risk of all-cause mortality in type 2 diabetes mellitus, it remains uncertain whether microalbuminuria and/or gross proteinuria are independent risk factors for cardiovascular mortality. Moreover, the association of albuminuria with cardiovascular mortality in people with type 2 diabetes mellitus has not been well described in US populations. To estimate the relative risks (RRs) for the associations of microalbuminuria and gross proteinuria with cardiovascular disease mortality among persons with older-onset diabetes mellitus. We conducted a prospective cohort study of 840 people with older-onset diabetes mellitus who provided urine samples in the 1984-1986 examination of a population-based study of diabetic persons. The presence of microalbuminuria was determined by an agglutination inhibition assay and gross proteinuria by a reagent strip. The main outcome was time to mortality from cardiovascular disease, as determined from death certificates. Of the 840 older-onset diabetic persons, 54.8% had normoalbuminuria, while 24.8% had microalbuminuria and 20.5% had gross proteinuria. During the 12-year follow-up (6127 person-years), we identified 364 deaths from cardiovascular disease. Compared with persons with normoalbuminuria, those with microalbuminuria and gross proteinuria had significantly higher risks of cardiovascular mortality. The RR as controlled for age, sex, glycemic control, insulin use, alcohol intake, physical activity, cardiovascular disease history, antihypertensive use, and retinopathy severity, was 1.84 (95% confidence interval [CI], 1.42-2.40) for those with microalbuminuria and 2.61 (95% CI, 1.99-3.43) for those with gross proteinuria. Further adjustment for other factors did not change the relations we found. When the end point used was mortality from coronary heart disease, stroke, or all causes, the increased risks were significant for both microalbuminuria (adjusted RRs [95% CIs], 1.96 [1.42-2.72], 2.20 [1.29-3.75], and 1.68 [1.35-2.09], respectively) and gross proteinuria (adjusted RRs [95% CIs], 2.73 [1.95-3.81], 2.33 [1.28-4.24], and 2.47 [1.97-3.10], respectively). Results from our population-based study strongly suggest that both microalbuminuria and gross proteinuria were significantly associated with subsequent mortality from all causes and from cardiovascular, cerebrovascular, and coronary heart diseases. These associations were independent of known cardiovascular risk factors and diabetes-related variables.


Optical patterning of features with spacing below the far-field diffraction limit using absorbance modulation.
Absorbance modulation is an approach that enables the localization of light to deep sub-wavelength dimensions by the use of photochromic materials. In this article, we demonstrate the application of absorbance modulation on a transparent (quartz) substrate, which enables patterning of isolated lines of width 60 nm for an exposure wavelength of 325 nm. Furthermore, by moving the optical pattern relative to the sample, we demonstrate patterning of closely spaced lines, whose spacing is as small as 119 nm.


Sexual function after treatment for rectal cancer: a review.
Sexual function is one element of QOL that may be significantly altered following treatment for rectal cancer, but the incidence and contributing risk factors are generally poorly understood. Nevertheless, the impact of rectal cancer therapy on sexual function should be conveyed to patients preoperatively. In addition to helping patients evolve realistic expectations, it will help clinicians identify those for whom interventions may be appropriate. In the past 10 years, there has been an increase in the number of studies reporting sexual dysfunction following rectal cancer treatment. However, these studies are difficult to interpret collectively for a variety of reasons. Most importantly, sexual dysfunction lacks a standardized definition, which leads to poor comparability between studies. The best inclusive definitions describe sexual dysfunction as a collection of distinct symptoms, which differ for men and women. The absence of sexual activity is sometimes used as a surrogate for sexual dysfunction, but this is confounded by an individual's desire and opportunity for sexual activity, and may not be an accurate reflection of physiologic functionality. Additional factors complicating assimilation of studies include the absence of baseline data, missing data, small sample sizes, and heterogeneity in use of validated and nonvalidated instruments. The purpose of this article is to systematically review the contemporary literature reporting sexual function after rectal surgery to determine the overall risk of sexual dysfunction, evaluate possible contributing factors, and identify questions that should be addressed in future studies.


Synthesis of mevalonate pathway lipids in fibroblasts from Zellweger and X-linked ALD patients.
Fibroblasts were cultured to determine the involvement of peroxisomes in cholesterol and dolichol synthesis. For this purpose, the behavior of cells from patients with Zellweger syndrome, with X-linked adrenoleukodystrophy, and from nondiseased control subjects was studied. Cells both after pretreatment with mevinolin and without pretreatment were incubated in a medium containing [3H]-mevalonate. In fibroblasts from patients with peroxisomal defects, the cholesterol content and mevalonate incorporation into cholesterol were decreased by 10-20% in comparison with control cells. Mevinolin pretreatment decreased the incorporation rate of [3H]-mevalonate into cholesterol but increased the labeling of ubiquinone and dolichol both in diseased and control cells. Squalene synthase activity was unchanged, whereas the activity of farnesyl-pyrophosphate synthase was increased in the diseased states. The results show that in patients with peroxisomal deficiency neither the amount nor the rate of synthesis of cholesterol and dolichol is reduced to any greater extent.


Categorical implicit learning in real-world scenes: evidence from contextual cueing.
The present study examined the extent to which learning mechanisms are deployed on semantic-categorical regularities during a visual searching within real-world scenes. The contextual cueing paradigm was used with photographs of indoor scenes in which the semantic category did or did not predict the target position on the screen. No evidence of a facilitation effect was observed in the predictive condition compared to the nonpredictive condition when participants were merely instructed to search for a target T or L (Experiment 1). However, a rapid contextual cueing effect occurred when each display containing the search target was preceded by a preview of the scene on which participants had to make a decision regarding the scene's category (Experiment 2). A follow-up explicit memory task indicated that this benefit resulted from implicit learning. Similar implicit contextual cueing effects were also obtained when the scene to categorize was different from the subsequent search scene (Experiment 3) and when a mere preview of the search scene preceded the visual searching (Experiment 4). These results suggested that if enhancing the processing of the scene was required with the present material, such implicit semantic learning can nevertheless take place when the category is task irrelevant.


[Routine outcome monitoring (ROM) early in treatment and disorder specific. Observational study into generic and specific questionnaires to measure the early change in depression treatment].
Mental health care institutions use routine outcome monitoring (ROM) to determine whether a patient responds well to treatment. However, it has been still unanswered whether disorder specific or generic measurement instruments can best be used for this purpose. In addition, little is known about when a first indication can be given for the outcome of the treatment.
 AIM: To provide insight into the sensitivity to change of two questionnaires: a generic and a specific one, which were both used for clients with a depressive disorder. An additional objective is to provide insight into when a first indication can be given for the outcome of the treatment.
 METHOD: An observational cohort study with data from 518 patients with a depressive disorder. The Outcome Questionnaire (OQ-45.2) and the Inventory of Depressive Symptomatology (IDS-SR) were used to measure the course of treatment.
 RESULTS: The depression specific IDS-SR appeared to be more sensitive to change than the generic OQ-45.2, especially at the beginning of treatment. With a measurement frequency of once every four weeks, the best time to get a first indication on the outcome of the treatment was between week 4 and week 8.
 CONCLUSION: For clients and practitioners whose treatment focus is reducing depressive symptoms, a disorder specific questionnaire is preferable to monitor this. The measurement between 4 and 8 weeks is important for, if necessary, adjusting the treatment, and to improve the treatment outcome.


Parathyroid hormone receptor in intact embryonic chicken bone: characterization and cellular localization.
The specific localization and the characterization of the parathyroid hormone (PTH) receptor in bone have been studied using 18-d embryonic chick calvariae and biologically active, electrolytically labeled [125I] bovine PTH(1-34). Binding was initiated by adding [125I]-bPTH(1-34) to bisected calvariae at 30 degrees C. Steady state binding was achieved at 90 min at which time 10 mg drg wt of calvaria specifically bound 17% of the added [125I]bPTH(1-34). Nonspecific binding in the presence of 244 nM unlabeled bPTH(1-34) was less than 2%. Insulin, glucagon, and calcitonin (1 microgram/ml) did not compete for PTH binding sites. Half-maximal inhibition of binding was achieved at concentrations of unlabeled bPTH(1-34) or bPTH(1-84) of about 10 nM. The range of concentration (2-100 nM) over which bPTH(1-34) and bPTH(1-84) stimulated cyclic 3'5'adenosine monophosphate (cAMP) production was similar to that which inhibited the binding of [125I]bPTH(1-34). Light microscope autoradiograms showed that grains were concentrated over cells (osteoblasts and progenitor cells) at the external surface of the calvariae and in trabeculae. In the presence of excess unlabeled PTH, labeling of control autoradiograms was reduced to near background levels. No labeling of osteocytes or osteoclasts was observed. At the electron microscopic level, grains were localized primarily over cell membranes. A quantitative analysis of grain distribution suggested that cellular internalization of PTH occurred.


Effects of dietary onion (Allium cepa L.) in a high-fat diet streptozotocin-induced diabetes rodent model.
The present study was conducted to investigate the effects of two dietary doses of freeze-dried onion powder on diabetes-related symptoms in a high-fat (HF) diet streptozotocin (STZ)-induced diabetes rat model. Five-week-old male Sprague-Dawley rats were fed a HF diet for 2 weeks and then randomly divided into 4 groups as follows: HF control (HFC), diabetic control (DBC), onion low (ONL; 0.5%) and onion high (ONH; 2.0%). Diabetes was induced by an intraperitoneal injection of STZ (40 mg/kg body weight) in all groups except the HFC group. After 4 weeks on the experimental diets, fasting blood glucose levels for both onion-fed groups were higher than in the DBC and HFC groups, albeit only significantly so (p < 0.05) in the ONL group. Serum insulin concentrations and insulin resistance were dose-dependently increased (however, not significantly so) in the onion-fed groups compared to the DBC group. Pancreatic beta-cell function and liver glycogen concentrations were nonsignificantly higher in the DBC and ONH groups compared to the ONL group. Additionally, the ONH group had significantly higher lipid concentrations (except for high-density lipoprotein cholesterol) compared to all other groups. The ONL group showed a similar hyperlipidemic trend, however to a lesser extent, with only triglycerides significantly differing from those of the DBC and HFC groups. The results suggest that the HF onion diet may increase insulin secretion and consequently insulin resistance in a dose-dependent manner, resulting in a worsened hyperglycemic and hyperlipidemic diabetic state. We conclude that higher dietary fat may impair the antidiabetic effects of dietary onion intake as has been previously reported.


Study of ethmoidal mucosa in a population at occupational high risk of sinonasal adenocarcinoma.
The occurrence of nasal adenocarcinomas was first described in 1965. Since 1988 these tumors have been accepted as an occupational disease for woodworkers in Italy. There are several underlying reasons why there is interest in studying the ways in which sinonasal adenocarcinomas occur. Often diagnosed at advanced stages of development because their symptoms are non-specific, these tumors are associated with a high mortality rate. A multidisciplinary study protocol was developed in this investigation. The aim was to identify the factors and conditions that promote sinonasal tumor growth in a population at risk due to occupational exposure to wood dust. Sixty-eight carpenters with a minimum of 10 years exposure to wood dust were studied. The control group comprised 81 volunteers. The patients underwent the following protocol: completion of a case report form, physical examination, evaluation of nasal cavity patency, clinical laboratory tests and histological study of the nasal mucosa. Our study provides significant evidence of the elevated incidence of pavimentous metaplasia in workers occupationally exposed to wood dust. In addition, it underscores a significant deficit of immunoglobulin A in such workers compared to the controls. However, we did not find, as reported elsewhere in the literature, a statistically significant difference between cases and controls as regards nasal symptoms and hyperemia of the nasal mucosa. Our study showed that, even in the absence of evident sinonasal lesions, it is still possible to determine an increased incidence of morphofunctional changes in subjects occupationally exposed to wood dust. Our findings may lead to the identification of occupational groups prone to elevated risk of the disease.


Evaluating a comprehensive strategy to improve engagement to group-based behavioral parent training for high-risk families of children with ADHD.
Behavioral parent training (BPT) is an evidence-based intervention for the treatment of attention-deficit/hyperactivity disorder (ADHD) and related disruptive behavioral disorders of childhood. Despite convincing data on effectiveness, engagement to BPT, particularly for high-risk families, has been a long standing, yet understudied, issue. Data from a clinical trial of a comprehensive BPT approach to enhance engagement and outcomes (the Strategies to Enhance Positive Parenting [STEPP] program) are presented herein. The STEPP program was compared to a traditional group-based BPT program on propensity to attend treatment, propensity to complete homework over the course of treatment, and dropout from BPT. Additionally, factors empirically related to engagement to treatment and targeted by the STEPP program were analyzed to determine whether these factors were enhanced by participation in the STEPP program. In a randomized cohort of 80 single-mothers of school-age children with ADHD, analyses demonstrated that the STEPP program lead to greater propensity to attend treatment over time and a greater propensity to complete homework over the course of treatment. Furthermore, participation in the STEPP Program was associated with a lower rate of dropout. Finally, data suggested that parents assigned to the STEPP program reported significant improvements in factors empirically related to engagement that were targeted within the STEPP program (i.e., amount and quality of social support from their group members, expectations for treatment, and perceived barriers to treatment participation). Results of the study have implications for targeting engagement throughout the process of BPT, particularly for high-risk families.


Cardiovascular risk factor distribution and subjective risk estimation in urban women--the BEFRI study: a randomized cross-sectional study.
Awareness represents a major modulator for the uptake of preventive measures and healthy life-style choices. Women underestimate the role of cardiovascular diseases as causes of mortality, yet little information is available about their subjective risk awareness. The Berlin Female Risk Evaluation (BEFRI) study included a randomized urban female sample aged 25-74 years, in which 1,066 women completed standardized questionnaires and attended an extensive clinical examination. Subjective estimation was measured by a 3-point Likert scale question asking about subjective perception of absolute cardiovascular risk with a 10 year outlook to be matched to the cardiovascular risk estimate according to the Framingham score for women. An expected linear increase with age was observed for hypertension, hyperlipidemia, obesity, and vascular compliance measured by pulse pressure. Knowledge about optimal values of selected cardiovascular risk factor indicators increased with age, but not the perception of the importance of age itself. Only 41.35% of all the participants correctly classified their own cardiovascular risk, while 48.65% underestimated it, and age resulted as the most significant predictor for this subjective underestimation (OR = 3.5 for age >50 years compared to <50, 95% CI = 2.6-4.8, P <0.0001). Therefore, although socioeconomic factors such as joblessness (OR = 1.9, 95% CI = 1.4-2.6, P <0.0001) and combinations of other social risk factors (low income, limited education, simple job, living alone, having children, statutory health coverage only; OR = 1.5, 95% CI = 1.1-2.1, P = 0.009) also significantly influenced self-awareness, age appeared as the strongest predictor of risk underestimation and at the same time the least perceived cardiovascular risk factor. Less than half of the women in our study population correctly estimated their cardiovascular risk. The study identifies age as the strongest predictor of risk underestimation in urban women and at the same time as the least subjectively perceived cardiovascular risk factor. Although age itself cannot be modified, our data highlights the need for more explicit risk counseling and information campaigns about the cardiovascular relevance of aging while focusing on measures to control coexisting modifiable risk factors.


ZnO-nanorods Promoted Synthesis of α-amino Nitrile Benzofuran Derivatives using One-pot Multicomponent Reaction of Isocyanides.
In this work ZnO-nanorod (ZnO-NR) as reusable catalyst promoted Strecker-type reaction of 2,4-dihydroxyacetophenone, isopropenylacetylene, trimethylsilyl cyanide (TMSCN), primary amines and isocyanides at ambient temperature under solvent-free conditions and produced α-amino nitriles benzofuran derivatives in high yields. These synthesized compounds may have antioxidant ability. ZnO-NRs in these reactions were prepared according to reported article. 2,4-dihydroxyacetophenone 1 (2 mmol) and isopropenylacetylene 2 (2 mmol) were mixed and stirred for 30 min in the presence of ZnO-NR (10 mol%) under solvent-free conditions at room temperature. After 30 min, primary amine 3 (2 mmol) was added to the mixture gently and the mixture was stirred for 15 min. After this time TMSCN 4 (2 mmol) was added to the mixture and stirred for 15 min. After completion of the reaction, as indicated by TLC, isocyanides 5 was added to mixture in the presence of catalyst. In the first step of this research, the reaction of 2,4-dihydroxyacetophenone 1, isopropenylacetylene 2, methyl amine 3a, trimethylsilyle cyanide 4 and tert-butyl isocyanides 5a was used as a sample reaction to attain the best reaction conditions. The results showed this reaction performed with catalyst and did not have any product without catalyst after 12 h. In conclusion, we investigate multicomponent reaction of 2,4-dihydroxyacetophenone 1, isopropenylacetylene 2, primary amines 3, trimethylsilyl cyanide 4 and isocyanides along with ZnO-NRs as reusable catalyst at room temperature under solvent-free conditions which generates α-amino nitrile benzofuran derivatives in high yields. The advantages of our method are high atom economy, green reaction conditions, higher yield, shorter reaction times, and easy work-up, which are in good agreement with some principles of green chemistry. The compounds 8c exhibit excellent DPPH radical scavenging activity and FRAP compared to synthetic antioxidants BHT and TBHQ.


A meta-structure for DSM-5 and ICD-11 pathological traits and the differentiation of personality functioning at different trait levels in older adults.
Categorical criteria are not well suited to inform personality disorder (PD) diagnoses in older adults. More promising are the ICD-11 and DSM-5 alternative models. Both conceptualize PD by level of severity and maladaptive traits. Severity is conditional for making a PD diagnosis. Trait levels portray stylistic differences in PD expression. Yet, in older adults the hierarchical trait structure is unknown. Neither is the differentiation of the severity criterion from maladaptive traits confirmed. A series of exploratory factor analyses with progressively greater numbers of factors were conducted to examine the hierarchical trait structure in 293 community dwelling older adults. The on average differentiation of a single higher order personality functioning factor from trait factors at succeeding levels of the hierarchy was estimated with Cohen q effect size. Six meaningful trait levels were identified. From the fourth trait level on the general personality functioning factor shared less than 15% variance on average with the trait factors. Trait factors at the sixth level corresponded to both DSM-5 and ICD-11 pathological traits. A future nosology integrating DSM-5 and ICD-11 trait proposals would be applicable in older adults. Personality functioning can be differentiated from traits, so separate assessment of traits and severity is worthwhile.


Mouse models for pathogenic African trypanosomes: unravelling the immunology of host-parasite-vector interactions.
African trypanosomiasis is a parasitic disease that affects a variety of mammals, including humans, on the sub-Saharan African continent. To understand the diverse parameters that govern the host-parasite-vector interactions, mouse models for the disease have proven to be a cornerstone. Despite the fact that most trypanosomes cannot be considered natural pathogens for rodents, experimental infections in mice have shed a tremendous amount of light on the general biology of these parasites and their interaction with and evasion of the mammalian immune system. Different aspects including inflammation, vaccine failure, antigenic variation, resistance/sensitivity to normal human serum and the influence of tsetse compounds on parasite transmission have all been addressed using mouse models. In more recent years, the introduction of various 'knock-out' mouse strains has allowed to analyse the implication of various cytokines, particularly TNF, IFNγ and IL-10, in the regulation of parasitaemia and induction of pathological conditions during infection.


Association between common iron store markers and hemoglobin in children with chronic kidney disease.
Serum ferritin and transferrin saturation (TSAT) are used to assess iron status in children with chronic kidney disease (CKD), but their sensitivity in identifying those at risk of lower hemoglobin (HGB) values is unclear. We assessed the association of iron status markers (ferritin, TSAT, and serum iron) with age- and gender-related HGB percentile in mild-to-moderate CKD in 304 children in the Chronic Kidney Disease in Children (CKiD) Study. Standardized HGB percentile values were examined by KDOQI-recommended ferritin (≥ 100 ng/ml) and TSAT (≥ 20 %) thresholds. Regression tree methods were used to identify iron status markers and clinical characteristics most associated with lower HGB percentiles. The cohort was 62 % male, 23 % African American, and 12 % Hispanic, median age 12 years, and median HGB 12.9 g/dl. 34 % had low TSAT and 93 % low ferritin as defined by KDOQI. Distribution of HGB percentile values was lower in those with ferritin ≥ 100 ng/ml, while TSAT ≥ 20 % was associated with only modest increase in HGB percentile. In regression tree analysis, lower glomerular filtration rate (GFR), serum iron <50 μg/dl and ferritin ≥ 100 ng/ml were most strongly associated with lower HGB percentile. The level of GFR was significantly associated with HGB. Higher serum ferritin was associated with lower HGB in this cohort. Low serum iron in the context of normal/increased ferritin and low HGB may be a useful indicator of iron-restricted erythropoiesis.


Secondary osteosarcoma arising after treatment for childhood hematologic malignancies.
Secondary osteosarcoma arising after the treatment of hematologic malignancies other than Hodgkin's lymphoma is rare. We report two cases of secondary osteosarcoma arising after treatment for childhood hematologic malignancies (non-Hodgkin's lymphoma and lymphoblastic leukemia). A 10-year-old boy, at the age of 3, was diagnosed with non-Hodgkin's lymphoma. He received chemotherapy, radiation, and bone-marrow transplantation and then was in complete remission. At 6 years, he complained of increasing pain of the right thigh and was diagnosed with osteoblastic osteosarcoma. A 26-year-old man, at the age of 6, was diagnosed as having acute lymphoblastic leukemia (ALL). He received chemotherapy, radiation, and peripheral blood stem cell transplantation (PBSCT). At 11 years after PBSCT, he visited with the complaint of left lumbar swelling. He was diagnosed with chondroblastic osteosarcoma. In both cases alkaline phosphatase (ALP) had already increased prior to the onset of the symptom. We should rule out secondary osteosarcoma at the abnormal elevation of ALP during clinical follow-up of patients after treatment of childhood hematologic malignancies.


The MSDIN family in amanitin-producing mushrooms and evolution of the prolyl oligopeptidase genes.
The biosynthetic pathway for amanitins and related cyclic peptides in deadly Amanita (Amanitaceae) mushrooms represents the first known ribosomal cyclic peptide pathway in the Fungi. Amanitins are found outside of the genus in distantly related agarics Galerina (Strophariaceae) and Lepiota (Agaricaceae). A long-standing question in the field persists: why is this pathway present in these phylogenetically disjunct agarics? Two deadly mushrooms, A. pallidorosea and A. subjunquillea, were deep sequenced, and sequences of biosynthetic genes encoding MSDINs (cyclic peptide precursor) and prolyl oligopeptidases (POPA and POPB) were obtained. The two Amanita species yielded 29 and 18 MSDINs, respectively. In addition, two MSDIN sequences were cloned from L. brunneoincarnata basidiomes. The toxin MSDIN genes encoding amatoxins or phallotoxins from the three genera were compared, and a phylogenetic tree constructed. Prolyl oligopeptidase B (POPB), a key enzyme in the biosynthetic pathway, was used in phylogenetic reconstruction to infer the evolutionary history of the genes. Phylogenies of POPB and POPA based on both coding and amino acid sequences showed very different results: while POPA genes clearly reflected the phylogeny of the host species, POPB did not; strikingly, it formed a well-supported monophyletic clade, despite that the species belong to different genera in disjunct families. POPA, a known house-keeping gene, was shown to be restricted in a branch containing only Amanita species and the phylogeny resembled that of those Amanita species. Phylogenetic analyses of MSDIN and POPB genes showed tight coordination and disjunct distribution. A POPB gene tree was compared with a corresponding species tree, and distances and substitution rates were compared. The result suggested POPB genes have significant smaller distances and rates than the house-keeping rpb2, discounting massive gene loss. Under this assumption, the incongruency between the gene tree and species tree was shown with strong support. Additionally, k-mer analyses consistently cluster Galerina and Amanita POPB genes, while Lepiota POPB is distinct. Our result suggests that horizontal gene transfer (HGT), at least between Amanita and Galerina, was involved in the acquisition of POPB genes, which may shed light on the evolution of the α-amanitin biosynthetic pathway.


Characteristics and Outcomes of Parkinson's Disease Individuals Hospitalized with COVID-19 in a New York City Hospital System.
The coronavirus disease 2019 (COVID-19) pandemic has caused worse health outcomes among elderly populations with specific pre-existing medical conditions and chronic illnesses. There are limited data on health outcomes of hospitalized Parkinson's disease (PD) individuals infected with COVID-19. To determine clinical characteristics and outcomes in hospitalized PD individuals infected with COVID-19. Individuals admitted to NewYork-Presbyterian with a diagnosis of PD were retrospectively identified using an electronic medical record system. Clinical characteristics and mortality were abstracted. Twenty-five individuals with PD, mostly male (76%) with a median age of 82 years (IQR 73-88 years), were hospitalized for COVID-19 infection. A total of 80% of individuals had mid-stage to advanced PD (Hoehn and Yahr 3-5) and 80% were on symptomatic pharmacologic therapy, most commonly levodopa (72%). The most common comorbidities were hypertension (72%) and mild cognitive impairment or dementia (48%). A total of 44% and 12% of individuals presented with altered mental status and falls, respectively. Mortality rate was 32% compared to 26% for age-matched controls (P = 0.743). Individuals who died were more likely to have encephalopathy during their admission (88% vs. 35%; P < 0.03). PD individuals who require hospitalization for COVID-19 infection are likely to be elderly, have mid-stage to advanced disease, and be on pharmacologic therapy. Hypertension and cognitive impairment are common comorbidities in these individuals and encephalopathy during hospitalization is associated with risk of death. Altered mental status and falls are clinical presentations of COVID-19 infection in PD that clinicians should be aware of. A diagnosis of PD is not a risk factor for COVID-19 mortality.


Induction of two different modes of cell death, apoptosis and necrosis, in rat liver after a single dose of thioacetamide.
A sequential study of the appearance of liver cell death after thioacetamide (TH) administration was performed in male Wistar rats. Within 3 hours of a single dose of TH, occurrence of cell death by apoptosis was evident around the centrilobular area. Light as well as electron microscopic examination demonstrated the presence of eosinophilic globules, often containing nuclear remnants (apoptotic bodies); they frequently were found within the cytoplasm of intact hepatocytes. The number of apoptotic bodies (ABs) was further enhanced at 6 hours, resulting in a 70-fold increase over the control values. Although necrosis or inflammation could not be observed at this time, as monitored by microscopic analysis as well as by determination of serum glutamate pyruvate transaminase levels, centrilobular necrosis accompanied by massive inflammatory reaction was evident at 12 hours and even more pronounced at 24 to 36 hours. Evidence of liver regeneration was found to occur at 48 hours, and the liver regained its normal architecture between 72 and 96 hours. Studies performed to analyze the activity of 'tissue' transglutaminase (tTG), a presumptive marker of apoptosis, showed that, 1 hour after treatment, TH caused a drastic dose-dependent inhibition of the enzyme activity. This early inhibition was followed by a rapid recovery in tTG activity that paralleled the induction of apoptosis in the liver. Treatment with cycloheximide (CH) 2 hours after TH partially inhibited the incidence of ABs at 6 hours (approximately 30% inhibition). The present study indicates that two different modes of cell death, apoptosis and necrosis, may be induced in a sequential fashion by a single dose of TH.


Decoding flat bands from compact localized states.
The flat band system is an ideal quantum platform to investigate the kaleidoscope created by the electron-electron correlation effects. The central ingredient of realizing a flat band is to find its compact localized states. In this work, we develop a systematic way to generate compact localized states by designing destructive interference patterns from 1-dimensional chains. A variety of 2-dimensional new flat band systems are constructed with this method. Furthermore, we show that the method can be extended to generate the compact localized states in multi-orbital systems by carefully designing the block hopping scheme, as well as in quasicrystal and disorder systems.


Does vocational training in family medicine have an impact on antibiotic prescribing pattern?
Antibiotics overuse is common and is the major cause of antibiotic resistance. Rational use of antibiotics by GPs is essential as most health problems are exclusively dealt within primary care. Postgraduate family medicine (FM) training has become established in various countries over the last few decades but little is known about the effect of FM training on antibiotic prescribing. To determine whether GPs with FM training prescribe less antibiotics than those without training. GPs working in a pluralistic primary health care system took part in the 2007-08 primary care morbidity and management survey in Hong Kong and collected information of all consecutive patient encounters during predetermined weeks of data collection. Characteristics of GPs, training status, patient morbidity and antibiotic prescribing pattern were compared using multivariate regression analyses. One hundred and nine GPs, of whom 67 had FM training, participated in the study and recorded 69 973 health problems. The overall antibiotic prescribing rate was 8.5% and that of GPs with FM training was 5.4% compared with the 13.3% among those without. Multivariate logistic regression showed that GPs with FM training were less likely to prescribe antibiotics (odds ratio 0.68, P < 0.05). They had lower antibiotic prescribing rates when managing upper respiratory tract infections, acute bronchitis and cough but higher in treating infective conjunctivitis and acute laryngitis. Postgraduate FM training in Hong Kong is associated with significantly lower antibiotic prescribing rates. This supports the importance of FM training in rationalizing the use of antibiotics in Hong Kong.


Calcium pumps: why so many?
Ca(2+)-ATPases (pumps) are key to the regulation of Ca(2+) in eukaryotic cells: nine are known today, belonging to three multigene families. The three endo(sarco)plasmic reticulum (SERCA) and the four plasma membrane (PMCA) pumps have been known for decades, the two Secretory Pathway Ca(2+) ATPase (SPCA) pumps have only become known recently. The number of pump isoforms is further increased by alternative splicing processes. The three pump types share the basic features of the catalytic mechanism, but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca(2+). The molecular understanding of the function of all pumps has received great impetus from the solution of the three-dimensional (3D) structure of one of them, the SERCA pump. This landmark structural advance has been accompanied by the emergence and rapid expansion of the area of pump malfunction. Most of the pump defects described so far are genetic and produce subtler, often tissue and isoform specific, disturbances that affect individual components of the Ca(2+)-controlling and/or processing machinery, compellingly indicating a specialized role for each Ca(2+) pump type and/or isoform.


Repetitive Transcranial Magnetic Stimulation (rTMS) as a Promising Treatment for Craving in Stimulant Drugs and Behavioral Addiction: A Meta-Analysis.
Addiction is a mental disorder with limited available treatment options. The therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) on it, by targeting craving in particular, has been explored with heterogenous results. This meta-analysis uses updated evidence to assess overall rTMS efficacy on craving, differential effects between addiction types clustered into three groups (depressant (alcohol, cannabis, opiate), stimulant (nicotine, cocaine, methamphetamine), and behavioral addiction (gambling, eating disorder)), and stimulation settings. Studies on substance use, gambling, and eating disorders are included, with unrestricted stimulation settings, by searching the PubMed, Embase, PsycINFO, and Cochrane databases up to 30 April 2020. A total of 34 eligible studies (42 units of analysis) were identified. Because of highly significant heterogeneity in primary results, a sensitivity analysis was performed on a remaining sample of 26 studies (30 units of analysis). Analyses performed using random effects model revealed a small effect size favoring active rTMS over shamTMS stimulation in the reduction in craving. We found a significant difference between addiction types, with a persistent small effect only for stimulant and behavioral groups. In these groups we found no difference between the different combinations of target and frequency of stimulation, but a significant correlation between number of sessions and craving reduction. In conclusion, efficacy of rTMS on craving in stimulant and behavioral addiction was highlighted, but recommendations on optimal stimulation settings and its clinical application await further research.


Inhibition of CREB Binding and Function with a Dual-Targeting Ligand.
CBP/p300 is a master transcriptional coactivator that regulates gene activation by interacting with multiple transcriptional activators. Dysregulation of protein-protein interactions (PPIs) between the CBP/p300 KIX domain and its activators is implicated in a number of cancers, including breast, leukemia, and colorectal cancer. However, KIX is typically considered "undruggable" because of its shallow binding surfaces lacking both significant topology and promiscuous binding profiles. We previously reported a dual-targeting peptide (MybLL-tide) that inhibits the KIX-Myb interaction with excellent specificity and potency. Here, we demonstrate a branched, second-generation analogue, CREBLL-tide, that inhibits the KIX-CREB PPI with higher potency and selectivity. Additionally, the best of these CREBLL-tide analogues shows excellent and selective antiproliferation activity in breast cancer cells. These results indicate that CREBLL-tide is an effective tool for assessing the role of KIX-activator interactions in breast cancer and expanding the dual-targeting strategy for inhibiting KIX and other coactivators that contain multiple binding surfaces.


Bioconjugatable, PEGylated Hydroporphyrins for Photochemistry and Photomedicine. Narrow-Band, Near-Infrared-Emitting Bacteriochlorins.
Synthetic bacteriochlorins absorb in the near-infrared (NIR) region and are versatile analogues of natural bacteriochlorophylls. The utilization of these chromophores in energy sciences and photomedicine requires the ability to tailor their physicochemical properties, including the incorporation of units to impart water solubility. Herein, we report the synthesis, from two common bacteriochlorin building blocks, of five wavelength-tunable, bioconjugatable and water-soluble bacteriochlorins along with two non-bioconjugatable benchmarks. Each bacteriochlorin bears short polyethylene glycol (PEG) units as the water-solubilizing motif. The PEG groups are located at the 3,5-positions of aryl groups at the pyrrolic β-positions to suppress aggregation in aqueous media. A handle containing a single carboxylic acid is incorporated to allow bioconjugation. The seven water-soluble bacteriochlorins in water display Qy absorption into the NIR range (679-819 nm), sharp emission (21-36 nm full-width-at-half-maximum) and modest fluorescence quantum yield (0.017-0.13). Each bacteriochlorin is neutral (non-ionic) yet soluble in organic (e.g., CH2Cl2, DMF) and aqueous solutions. Water solubility was assessed using absorption spectroscopy by changing the concentration ∼1000-fold (190-690 µM to 0.19-0.69 µM) with a reciprocal change in pathlength (0.1-10 cm). All bacteriochlorins showed excellent solubility in water, except for a bacteriochlorin-imide that gave slight aggregation at higher concentrations. One bacteriochlorin was conjugated to a mouse polyclonal IgG antibody for use in flow cytometry with compensation beads for proof-of-principle. The antibody conjugate of B2-NHS displayed a sharp signal upon ultraviolet laser excitation (355 nm) with NIR emission measured with a 730/45 nm bandpass filter. Overall, the study gives access to a set of water-soluble bacteriochlorins with desirable photophysical properties for use in multiple fields.


[Incidence of cleft lip and palate in Kirov region. Organization of multidisciplinary center for CLP infants rehabilitation].
The incidence of cleft lip and/or palate (CLP) in Kirov region is 1:1078 newborns. More than half of the patients (52%) have both cleft lip and palate thus requiring more complex and time consuming treatment. Multidisciplinary approach to CLP patients rehabilitation used in tertiary care center is described in the study.


Protective effect of cinnamic acid in endotoxin-poisoned mice.
In this work, we aimed to evaluate the protective effect of cinnamic acid (CD) on lipopolysaccharide (LPS; Escherichia coli 055:B5)-induced endotoxin-poisoned mice and clarify the underlying mechanisms. The mice were administrated CD 5 d before 15 mg/kg LPS challenge. 12 hr later, thymus was separated for determination of thymus indexes. Lung and spleen tissues were collected for histologic examination and the wet/dry weight ratio of lung was calculated, and serum was acquired for tumor necrosis factor-α (TNF-α), interleukin (IL)-18, and IL-1β measurement. Moreover, the expression of NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome was determined in lung. CD increased the thymus indexes and decreased lung wet/dry weight ratio. In addition, CD improved the lung and spleen histopathological changes induced by LPS and decreased the number of neutrophils in lung tissues. CD also inhibited the pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) production in serum. Furthermore, CD suppressed the LPS-induced NLRP3, Caspase-1, and IL-1β mRNA expression in lung, as well as the expression of NLRP3 and Caspase-1 (p20) protein. CD may have protective effects in endotoxin-poisoned mice via inhibiting the activation of NLRP3 inflammasome, and can be considered as a potential therapeutic candidate for diseases involved in endotoxin poisoning such as sepsis.


Early rehabilitative treatment in patients with traumatic brain injuries: outcome at one-year follow-up.
The aim of this study was to analyze the outcome at one-year follow-up of patients with traumatic brain injuries (TBI) after 4 years of application of our organizing model and compare our results with the international data in terms of disability (functional independence measure [FIM], disability rating scale [DRS] scores) and social integration (community integration questionnaire [CIQ], work reentry) We started a routine based on the presence of the physiatrist in the Intensive Care Unit (ICU) and Neurosurgery 3 times per week to evaluate all patients with TBI, program and control physiotherapeutic treatments and transfers to rehabilitative centers. Data were collected considering 80 TBI patients sequentially discharged from our department, from August 1999 to December 2003. The sample was composed of patients with severe brain injury evaluated at rehabilitation admission, rehabilitation discharge and one-year follow-up. We compared our data with those of the Traumatic Brain Injury Model System Data Base (TBI MSDB) and Gruppo Italiano per lo Studio delle Cerebrolesioni Acquisite Riabilitazione (GISCAR). Disability at one-year follow-up was better than at discharge: increase in FIM value, in DRS value. Social reintegration and return to work were not optimal: CIQ value was 16 and only 38% of patients returned to work at follow-up. Disability and social integration mean scores in our sample were similar to those obtained in TBI MSDB and so were the values of onset-admission interval (OAI) and length of stay (LOS). Differences were found with the Italian GISCAR database where mean OAI and LOS were higher than in our sample (55 and 86 days vs 18 and 37 days). Our data show that this kind of organizing model for the rehabilitative evolution of TBI patients can positively influence the cost-efficiency rate of rehabilitation process reducing care costs in terms of ICU and rehabilitation LOS without affecting outcome in terms of disability and reintegration.


Transformation by basic fibroblast growth factor requires high levels of expression: comparison with transformation by hst/K-fgf.
Basic fibroblast growth factor is a potent mitogen for a variety of cell types and has been suggested to have transforming activity. To test this hypothesis, we have introduced a human bFGF cDNA into NIH 3T3 cells either by DNA transfection or by retrovirus infection. We have compared the properties of cell lines obtained with cells prepared similarly but expressing the hst/K-fgf growth factor. While bFGF does not contain an amino terminal signal sequence and is not secreted from cells in which it is synthesized, hst/K-fgf does contain a signal sequence and is secreted from cells. Our results show that the transformed phenotype correlates directly with the level of bFGF expression, since all transformed clones expressed high levels of bFGF, while nontransformed clones expressed comparatively low levels of bFGF. In contrast, even low levels of hst/K-fgf expression resulted in a transformed phenotype. These results suggest that bFGF is an inefficient transforming protein and that this may relate to its lack of secretion.


Pattern of endocardial activation during sustained ventricular tachycardia.
Fifty-five patients with sustained ventricular tachycardia due to prior myocardial infarction underwent intraoperative endocardial activation mapping during ventricular tachycardia to guide subendocardial resection. The mapping data were analyzed to determine the pattern of endocardial activation during tachycardia. Of a total of 122 tachycardias, 101 had a pattern of activation assigned: in 90 (90%), endocardial activation spread centrifugally from a tachycardia site of origin, and 11 (10%) had a continuous loop of electrical activity around an aneurysm. All patients had at least one tachycardia having the centrifugal spread pattern. Tachycardias with a continuous loop pattern had a shorter mean cycle length than those with a centrifugal spread pattern (260 +/- 33 versus 338 +/- 81 ms, p less than 0.002) and a longer duration of endocardial activation relative to the tachycardia cycle length (100 +/- 0 versus 58 +/- 19%, p less than 0.001). There was no difference in preoperative patient characteristics, operative survival or cure of tachycardia between patients having any tachycardias of the continuous loop pattern and those having only centrifugal spread tachycardias. Thus, the vast majority of ventricular tachycardias in this group of patients are characterized by a centrifugal spread of endocardial activation from a site of origin less than 6 cm2 in size. Mapping-guided ablative surgery may remove the entire tachycardia circuit in these patients and a critical portion of the circuit in the minority of patients with continuous loop tachycardias.