Molecular conformation of ubiquitinated structures and the implications for regulatory function.
The molecular conformation of ubiquitinated structures and the validity of the N-end rule were examined by simulating the molecular mechanics to ascertain the global energy-minimized structure. We examined the chemical linkage involved in attaching the ubiquitin carboxyl terminus to the N-terminus of three different x-hexapeptides, where x is the amino group of the acceptor peptide--either valine, arginine or glutamic acid--(x-K linkage) and to the epsilon-amino group of lysine of the acceptor hexapeptide x-glu1-his2-lys3-gly4-lys5-val6 (K-K linkage) through the formation of an isopeptide bond. Changes in conformation and molecular stability of the multi-ubiquitinated structures were determined by energy-minimization procedures using the SYBYL program developed by Tripos Associates. In the x-K linkage, the ubiquitin molecule is stretched in the beta-pleated sheets and beta-turns while the alpha-helices expand, as the molecule continues to unfold linearly. In the K-K linkage, the ubiquitin molecules have turned into a u-shaped, semi-circular alignment, contracting into a compact, folded structure.


Biological evaluation of 3-hydroxybenzyl alcohol, an extrolite produced by Aspergillus nidulans strain KZR-132.
The aim of the study was to purify and characterize a bioactive compound from Aspergillus nidulans strain KZR-132 and its biological evaluation. A bioactive extolite was purified from A. nidulans strain KZR-132, and its chemical structure was elucidated as 3-hydroxylbenzyl alcohol (3-HBA) based on 1 H and 13 C NMR, FT-IR and mass spectroscopic analysis. The antimicrobial efficacy of 3-HBA was established against Gram-positive, Gram-negative bacteria and different Candida strains. It also showed promising antibiofilm activity against various tested microbial strains. Reactive oxygen species induced by 3-HBA treatment on different Candida strains killed most of the cells and showed necrotic effect. It also exhibited dose-dependent antioxidant and anti-inflammatory activities. This bioactive extrolite produced by A. nidulans isolated from a niche habitat was demonstrated to possess significant biotechnological and pharmacological potential since it exhibited broad-spectrum antimicrobial and antibiofilm activities which are reported for the first time. The overall study demonstrates that 3-HBA produced by A. nidulansKZR-132 is a promising bioactive metabolite and possibly can function as a pharmacologically suitable broad-spectrum antimicrobial drug candidate against various dreaded human-related bacterial and fungal pathogens.


Value of diffusion tensor imaging in differentiating malignant from benign parotid gland tumors.
To evaluate whether diffusion tensor imaging (DTI) can be used to differentiate malignant parotid gland tumors from the benign ones. The study population comprised 59 parotid gland tumors (24 Warthin's tumors, 19 pleomorphic adenomas, seven other benign tumors, and nine malignant tumors). Single-shot echo-planar DTI was performed with motion-probing gradients along 30 noncollinear directions (b=1000s/mm2) at 3.0T. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values for benign and malignant tumors were compared using the Mann-Whitney U test. Receiver-operating characteristic (ROC) curve analysis was performed to assess the ability of the ADC and FA values to differentiate malignant tumors from the benign ones. ADC values showed no significant difference between malignant (0.93±0.21×10-3mm2/s) and benign tumors (1.19±0.50×10-3mm2/s) (p=0.225). FA values of malignant tumors were significantly higher than those of benign tumors (0.26±0.06 vs. 0.17±0.05, p<0.001). The area under the ROC curve of FA was significantly greater than that under the curve of ADC (0.884 vs. 0.628, p=0.010). DTI, particularly FA, can help differentiate malignant parotid gland tumors from the benign ones.


Predictors of subjective fatigue among individuals with rheumatoid arthritis.
To examine a range of variables potentially associated with rheumatoid arthritis (RA)-related fatigue and to determine which variables best predict subjective fatigue. Measures of fatigue, disease activity, pain, and various psychosocial factors were gathered from 73 individuals with RA. Correlations between fatigue and other variables were examined, and the "best" predictors of fatigue were determined with multiple regression analyses. Many of the variables that were significantly correlated with fatigue had a psychosocial character. Moreover, the "best" predictors of increased fatigue were higher levels of pain, more depressive symptoms, and female sex. Longer symptom duration, less perceived adequacy of social support, and less disease activity were significant predictors of fatigue, over and above the "best" model. RA-related fatigue appears to be strongly associated with psychosocial variables, apart from disease activity per se. Correspondingly, treatment of fatigue may be enhanced by interventions that address relevant cognitive and behavioral dimensions.


Symptomatic ocular metastases in lung cancer.
A survey was carried out of ocular manifestations of lung cancer. A retrospective analysis was performed of all lung cancer patients diagnosed between 1991 and 2005 at Taipei Veterans General Hospital, Taipei, Taiwan. Sixteen lung cancer patients with symptomatic ocular metastases were identified. The incidence was less than 1%. The low incidence among these patients contrasts with previous reports of an incidence of about 6-7%, and suggests that most patients with ocular metastasis may be asymptomatic and remain undiagnosed. The most frequent ocular symptoms were changes in visual acuity. Metastases most frequently originated from adenocarcinomas and the choroids were the most common sites of metastases. Ten of the 16 ocular metastases were early events, identified prior to or at the initial diagnosis of the lung cancer. Only three of the 16 ocular metastatic events presented as solitary distant metastases. Although symptomatic ocular metastases are rare, they should be considered in lung cancer patients presenting with alterations in visual acuity.


Ultrafast Enhancement of Ferromagnetic Spin Exchange Induced by Ligand-to-Metal Charge Transfer.
We theoretically predict and experimentally demonstrate a nonthermal pathway to optically enhance superexchange interaction energies in a material based on exciting ligand-to-metal charge-transfer transitions, which introduces lower-order virtual hopping contributions that are absent in the ground state. We demonstrate this effect in the layered ferromagnetic insulator CrSiTe_{3} by exciting Te-to-Cr charge-transfer transitions using ultrashort laser pulses and detecting coherent phonon oscillations that are impulsively generated by superexchange enhancement via magneto-elastic coupling. This mechanism kicks in below the temperature scale where short-range in-plane spin correlations begin to develop and disappears when the excitation energy is tuned away from the charge-transfer resonance, consistent with our predictions.


CD40 restrains in vivo growth of Toxoplasma gondii independently of gamma interferon.
CD40-CD154 interaction is pivotal for resistance against numerous pathogens. However, it is not known if this pathway can also enhance in vivo resistance in gamma interferon (IFN-gamma)-deficient hosts. This is an important question because patients and mice with defects in type 1 cytokine response can control a variety of pathogens. While blockade of endogenous CD154 resulted in a remarkable increase in parasite load in IFN-gamma-/- mice infected with Toxoplasma gondii, in vivo administration of a stimulatory anti-CD40 monoclonal antibody markedly reduced parasite load. This latter effect took place even in T-cell-depleted mice and was accompanied by induction of macrophage toxoplasmacidal activity. CD40 stimulation restricted T. gondii replication independently of STAT1, p47 GTPases, and nitric oxide. In vivo CD40 ligation enhanced tumor necrosis factor alpha (TNF-alpha) production by T. gondii-infected macrophages. In addition, CD40 stimulation required the presence of TNF receptor 2 to reduce parasite load in vivo. These results suggest that CD40-CD154 interaction regulates IFN-gamma-independent mechanisms of host protection through induction of macrophage antimicrobial activity and modulation of TNF-alpha signaling.


Treatment and outcomes of symptomatic hyperammonemia following asparaginase therapy in children with acute lymphoblastic leukemia.
Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.


Multifocal neuroendocrine cell hyperplasia accompanied by tumorlet formation and pulmonary sclerosing pneumocytoma: A case report.
Pulmonary tumorlets are nodular hyperplastic neuroendocrine cells (NECs) that extend beyond the basement membrane. They often coexist with other lung diseases such as fibrosis and bronchiectasis, but rarely accompanied by pulmonary sclerosing pneumocytoma (PSP), which has not been reported in the literature. A 54-year-old woman was admitted to the hospital because she had symptoms of bloody sputum for more than 4 mo and hemoptysis for 1 wk. Computed tomography images showed atrophy accompanied by infections in the middle lobe of her right lung. Moreover, numerous nodules were identified in the middle lobe of the right lung. The patient underwent thoracoscopic pneumonectomy of the middle lobe of the right lung, and the resected mass was pathologically confirmed to have bronchiectasis, multifocal NEC hyperplasia accompanied by tumorlet, and PSP. Our report presents a rare clinical case of bronchiectasis complicated with multifocal NEC hyperplasia, tumorlet, and PSP.


Retracted: A Neighborhood and Machine Learning-Enabled Information Fusion Approach for the WSNs and Internet of Medical Things.
[This retracts the article DOI: 10.1155/2022/5112375.].


Effect of square-edged intraocular lenses on neodymium:YAG laser capsulotomy rates in the United States.
To model the effect of the introduction of square-edged intraocular lenses (IOLs) in the United States on neodymium:YAG (Nd:YAG) laser capsulotomy rates and to compare the model with actual capsulotomy rates. Ophthalmology Department, St. Thomas' Hospital, London, United Kingdom, and Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. The actual numbers of cataract surgeries and Nd:YAG laser capsulotomies performed in the U.S. were obtained from Medicare claims data for 1993 to 2003. The percentage market share of square-edged IOLs was obtained, and numbers of square-edged and round-edged IOLs implanted were calculated. Predicted laser capsulotomy rates were modeled on published postmortem and clinical data and compared with actual capsulotomy rates. Between 1993 and 2003, the number of cataract surgeries and Nd:YAG laser capsulotomies reimbursed by Medicare rose by 67.4% and 18.9%, respectively. After the introduction of square-edged IOLs in 1995, the market share grew to 48.5% in 2003. The total number of Nd:YAG capsulotomies reimbursed by Medicare in 2003 exceeded the number of capsulotomies predicted by the model by at least 23.9%. The estimated cost generated by the discrepancy between predicted and actual laser capsulotomies in 2003 was at least US $30 million. After the introduction of square-edged IOLs, Nd:YAG laser capsulotomy rates decreased, but not by as much as predicted. The additional cost to the Medicare system was more than US $30 million higher than the model predicted.


Concerns of Hereditary Breast Cancer in Pregnancy and Lactation.
Genetic testing should be offered to all women less than 40 years of age who are diagnosed with breast cancer, and patients with PABC are generally among them. However, there is no specific study about these cases, and whether genetic testing should be carried out during or after pregnancy is not known. Generally, testing before delivery should only be performed if positive results change management plans, such as undergoing fetal testing and choosing mastectomy instead of breast conserving surgery.


MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo.
Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo.


LncNONO-AS regulates AR expression by mediating NONO.
Spermatogenesis and healthy testicular development are prerequisites for male reproductive function. Androgen receptor (AR), an important receptor in testicular sertoli cells, is involved in androgen specific response and its dysfunction will lead to abnormal sperm development, resulting in male infertility. NONO (non-POU-domain-containing octamer binding protein) can act as a coactivator to enhance the transcription of AR, while AR may be regulated by NONO in testicular sertoli cells. LncRNAs are involved in almost every step of spermatogenesis. However, there are few studies focus on the relationship between lncRNAs and spermatogenesis in goat testis. Therefore, in this research, high throughput sequencing and bioinformatics analysis were performed on testicular tissues of Dazu black goats at different stages of development to obtain the target NONO lncRNA. It's called lncNONO-AS. This study further explored the biological functions of lncRNA through RNA pull down, overexpression, interference, fluorescence quantification, Western blot and other techniques on the basis of in vitro culture of testis sertoli cells, and we got the following results: The gene expression levels of NONO and AR in lncNONO-AS overexpression group were significantly higher than that in the empty vector group (P < 0.01). Compared with the untreated negative control group, the expression of NONO decreased from 1.00 to 0.68 (P < 0.01), and the expression of AR decreased from 1.01 to 0.34 (P < 0.01). The results showed that lncNONO-AS could regulate the expression of AR by mediating the expression of NONO.


Identification of endogenous retroviral sequences as potential donors for recombinational repair of mutant retroviruses: positions of crossover points.
Mutants of Moloney murine leukemia virus carrying deletions in essential regions of the genome can revert after infection of mouse cells by recombination with endogenous retroviral sequences. We have identified cloned DNAs containing potential donor sequences for two such recombination events and determined the nucleotide sequences in the relevant regions. Comparison of these sequences with that of the original mutants and the revertant viruses allowed a determination of the crossover points that were used in formation of the revertants. Each crossover occurred in short stretches (17-24 bp) of perfect homology between the two parent sequences.


[Epidemiology of diabetes mellitus in South America: The experience of Colombia].
According to the International Diabetes Federation, 8.3% of the world population suffers from diabetes mellitus, and it is expected that the number of individuals with the disease will increase to over 592 million. In South and Central America, it is estimated that the increase in the number of cases diagnosed in the period from 2013 to 2035 will be 59.8% (from 24 to 38.5 millions). According to the World Health Organisation, the prevalence of fasting hyperglycaemia in the region of the Americas in 2014 was 9.3% in men and 8.1% in women. The countries with the highest prevalence of diabetes mellitus in adults ≥18years were: Guyana, Surinam, Chile, and Argentina. In Colombia, the prevalence of type 2 diabetes mellitus is variable, depending on the population range assessed and the diagnostic criteria used.


High-density lipoprotein cholesterol, monthly variation and association with cardiovascular risk factors in 1000 forty-year-old Dutch citizens.
High density lipoprotein cholesterol (HDL chol) levels were measured in about 1000 forty-year-old residents of the town of Leiden, The Netherlands. Mean levels (+/- S.D.) in women were 48.0 +/- 11.0 mg/dl; in men 42.5 +/- 10.7 mg/dl. In March mean levels in women were about 5 mg/dl lower than in June (P less than 0.001); in men there was a similar difference between mean levels in April and June (P less than 0.002). HDL chol levels were negatively related to smoking habits, relative body weight, and in women to use of oral contraceptives. Weak positive and negative correlations between HDL chol and serum cholesterol, respectively, were found in subgroups with high and low HDL chol levels, respectively.


Radical 1-Fluorosulfonyl-2-alkynylation of Unactivated Alkenes.
Sulfonyl fluorides have found widespread use in chemical biology and drug discovery. The development of synthetic methods for the introduction of the sulfonyl fluoride moiety is therefore of importance. Herein, a transition-metal-free radical 1,2-difunctionalization of unactivated alkenes via FSO2 -radical addition with subsequent vicinal alkynylation to access β-alkynyl-fluorosulfonylalkanes is presented. Alkynyl sulfonyl fluorides are introduced as highly valuable bifunctional radical trapping reagents that also serve as FSO2 -radical precursors. The β-alkynyl-fluorosulfonylalkanes obtained in these transformations can be readily diversified by using SuFEx click chemistry to obtain sulfonates and sulfonamides.


Phylogenetic analysis of nasal avian schistosomes (Trichobilharzia) from aquatic birds in Mazandaran Province, northern Iran.
Nasal schistosomes are trematodes in the family Schistosomatidae, many members of which are causative agents of human cercarial dermatitis (HCD). Little is known about the species diversity and distribution of nasal dwelling schistosomes of water birds, particularly in countries outside of Europe; even less is known in countries like Iran. Nasal schistosomes are of particular interest since these species migrate via the central nervous system to the nasal cavity once they penetrate their host. Thus, there must be efforts to determine the incidence of HCD due to nasal schistosomes. HCD outbreaks are reported seasonally in Mazandaran Province, northern Iran, an area well known for rice cultivation leading to increased person contact with water and infected snails. Such places include favorable habitat for both domestic ducks year round, and wild migratory ducks in the winter through spring. Recent reports have detected the presence of both nasal and visceral schistosomes in ducks in this area but with little species characterization. In this study, we examine a diversity of aquatic birds to determine the distribution, prevalence and bird host use of nasal schistosomes. We apply for the first time a molecular identification and phylogenetic analysis of these schistosomes. From 2012 to 2014, the nasal cavity of 508 aquatic birds from Mazandaran Province were examined that included species in Anseriformes, Gruiformes, Charadriiformes and Phoenicopteriformes. Nasal schistosomes were found in 45 (8.9%) birds belonging to Anseriformes (Anas platyrhynchos and Anas clypeata). Phylogenetic analysis of the nuclear internal transcribed spacer 1 rDNA and the mitochondrial cytochrome oxidase1 gene of isolated eggs revealed that all samples grouped in a sister clade to the European Trichobilharzia regenti. However, Trichobilharzia from this study were more similar to a unique haplotype of Trichobilharzia, isolated from the nasals of an A. clypeata in France. The genetic and phenotypic differences between the species found herein and T. regenti from Europe, may prove with additional data to be a distinct species of Trichobilharzia.


Aurora-A kinase is differentially expressed in the nucleus and cytoplasm in normal Müllerian epithelium and benign, borderline and malignant serous ovarian neoplasms.
Aurora-A kinase is important for cellular proliferation and is implicated in the tumorigenesis of several malignancies, including of the ovary. Information regarding the expression patterns of Aurora-A in normal Müllerian epithelium as well as benign, borderline and malignant epithelial ovarian neoplasms is limited. We investigated Aurora-A expression by immunohistochemistry in 15 benign, 19 borderline and 17 malignant ovarian serous tumors, and 16 benign, 8 borderline, and 2 malignant ovarian mucinous tumors. Twelve fimbriae from seven patients served as normal Müllerian epithelium controls. We also examined Aurora-A protein expression by western blot in normal fimbriae and tumor specimens. All normal fimbriae (n = 12) showed nuclear but not cytoplasmic Aurora-A immunoreactivity by immunohistochemistry. Benign ovarian tumors also showed strong nuclear Aurora-A immunoreactivity. Forty-eight percent (13/27) of borderline tumors demonstrated nuclear Aurora-A immunoreactivity, while the remainder (52%, 14/27) lacked Aurora-A staining. Nuclear Aurora-A immunoreactivity was absent in all malignant serous tumors, however, 47% (8/17) demonstrated perinuclear cytoplasmic staining. These results were statistically significant when tumor class (benign/borderline/malignant) was compared to immunoreactivity localization or intensity (Fisher Exact Test, p < 0.01). Western blot analysis confirmed the greater nuclear Aurora-A expression in control Müllerian epithelium compared to borderline and malignant tumors. Aurora-A kinase is differentially expressed across normal Müllerian epithelium, benign and borderline serous and mucinous ovarian epithelial neoplasms and malignant serous ovarian tumors., with nuclear expression of unphosphorylated Aurora-A being present in normal and benign neoplastic epithelium, and lost in malignant serous neoplasms. Further studies of the possible biological and clinical implications of the loss of nuclear Aurora-A expression in ovarian tumors, and its role in ovarian carcinogenesis are warranted.


Prolonged esophageal pH monitoring in the evaluation of gastroesophageal reflux in children with chronic tubotympanal disorders.
Children with ear, nose and throat disorders are believed to have a high incidence of pathologic gastroesophageal reflux (GER). This study was designed to establish the frequency and ratio of pathologic GER in the development of chronic tubotympanal disorders. Twenty-seven children with chronic tubotympanal disorders (mean age, 2 to 13 years; average age, 6.8 years) underwent 24-hour continuous pH monitoring. Fourteen of the examined patients had secretory otitis, whereas 13 patients had recurrent otitis. From each 24-hour pH monitoring, 12-hour daytime and nighttime periods were selected. Eleven patients were tested using simultaneous dual pH monitoring (distal and proximal pH monitoring). Fifteen (55.6%) of 27 patients had pathologic GER. The authors did not find a relation between pathologic GER and different types of ear disorders. Daytime pH monitoring yielded significantly more episodes of reflux than did nighttime monitoring. The reflux index was substantially higher during the day. In the current study, distal pH monitoring showed that 6 of 11 patients had pathologic GER, whereas proximal pH monitoring showed that only only 3 of 11 patients had pathologic GER. The authors recommend that a pH study be performed in children with chronic tubotympanal disorders when standard treatment is ineffective. The method of choice for the diagnosis of pathologic GER in patients with chronic tubotympanal disorders should be pH monitoring of the esophagus and throat.


The Efficacy of Non-Vitamin K Antagonist Oral Anticoagulants in the Prevention of Left Atrial Thrombus in Patients With Atrial Fibrillation Compared With Vitamin K Antagonists: A Meta-Analysis.
There is still a paucity of data on the efficacy of non-vitamin K antagonist oral anticoagulants (NOACs) in the prevention of left atrial thrombus (LAT) formation before cardioversion or catheter ablation. To assess the efficacy of NOACs in the prevention of LAT in patients with non-valvular atrial fibrillation (NVAF) compared with vitamin K antagonists (VKAs), we conducted a meta-analysis. We searched PubMed, Embase, and the Cochrane Library databases. For meta-analysis, dichotomous variables were analyzed by using the odds ratios (OR) computed using the Mantel Haenszel method (random models). All results were reported with 95% confidence intervals (CI). A total of 13 studies (one randomized controlled investigation and 12 observational studies) were included in the meta-analysis. There was no statistically significant difference between the NOACs and VKAs groups with respect to the odds of LAT/LAAT formations (OR 0.79; 95% CI: 0.52-1.21; P = .29; (I2 = 14%). NOACs were as effective as VKAs in the prevention of LAT/LAAT formation in patients with NVAF. Though patients on NOACs therapy showed a lower incidence of LAT/LAAT formation compared with VKAs, it was not significant (P = .29).


Synthesis, structure-activity relationships and molecular modeling studies of new indole inhibitors of monoamine oxidases A and B.
New monoamine oxidase inhibitors were synthesized as indole analogues of a previously reported pyrrole series. Several compounds were potent MAO-A (12, 17, 19-22, 31, 36, and 37) or MAO-B (14, 20, 24, 38, 44, and 46) inhibitors, and had K(i) values in the nanomolar concentration range. In particular, 22 (K(i)=0.00092 microM, and SI=68,478) was exceptionally potent and selective as MAO-A inhibitor. In molecular modeling studies, compounds 22, 24, 44, and 46 positioned the indole ring into an aromatic cavity of MAO-A, and established pi-pi stacking interactions with Tyr407, Tyr444, and FAD cofactor. However, only compound 22 was able to form hydrogen bonds with FAD, a finding which was in accordance with its potent anti-MAO-A activity. Conversely, 22/MAOB complex was highly unstable during the MD simulation.


Effects of the antioxidant turmeric on lipoprotein peroxides: Implications for the prevention of atherosclerosis.
Extracts from the rhyzome of Curcuma longa are widely used as food additives in India and other Asiatic and Central American countries. It has been shown that these extracts ("turmeric"), as well as "curcumin" and related phenolic compounds isolated from Curcuma, have a powerful antioxidant action when tested in in vitro systems. Moreover, previous research from our laboratories has shown significant decreases in the levels of lipid peroxides in the blood of both mice and human subjects administered "turmeric." Our present research complements the previous data, showing that a daily intake of turmeric equivalent to 20 mg of the phenolic antioxidant curcumin for 60 days decreases the high levels of peroxidation of both the HDL and the LDL, in vivo, in 30 healthy volunteers ranging in age from 40 to 90 years. The effect was quite striking in the persons with high baseline values of peroxidized compounds in these lipoproteins, while no apparent change took place in the persons having low baseline values. In view of current concepts on the atherogenic role played by peroxidized HDL, and especially by peroxidized LDL, as inducers of foam and smooth cell proliferation in the arterial wall, this preliminary experiment suggests that the Curcuma phenolic antioxidants, because of their high antioxidant activity and lack of toxicity, might be a useful complement to standard hypo-lipidemic drugs in the prevention and treatment of atherosclerosis.


Immunohistochemical localisation of keratin and luminal epithelial antigen in myoepithelial and luminal epithelial cells of human mammary and salivary gland tumours.
Rabbit antisera to human 40-63 000 MW epidermal keratin, one batch with restricted distribution of reactivity from an initial (aK1) and one with "broad spectrum" distribution of reactivity from a late bleeding (aK), and to "luminal epithelial antigen" (aLEA) were applied to formalin fixed paraffin embedded sections of human normal and neoplastic mammary and salivary glands using an indirect immunoperoxidase method. aK1 reacted with myoepithelial cells, aLEA with luminal epithelial cells and aK with both cell types in normal mammary and salivary gland. In breast carcinomas the majority of intraluminal and infiltrating carcinoma cells reacted with aLEA but not with aK1 which reacted only with surrounding myoepithelial cells. aK reacted with both myoepithelial cells and with intraluminal and infiltrating tumour cells. In the salivary gland adenomas the majority of cells reacted with aK, and those cells arranged in a tubular fashion reacted with aLEA.


Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons.
Recent human genetics approaches identified the Aristaless-related homeobox (ARX) gene as the causative gene in X-linked infantile spasms, Partington syndrome, and non-syndromic mental retardation as well as in forms of lissencephaly with abnormal genitalia. The ARX predicted protein belongs to a large family of homeoproteins and is characterised by a C-terminal Aristaless domain and an octapeptide domain near the N-terminus. In order to learn more about ARX function, we have studied in detail Arx expression in the central nervous system during mouse embryonic development as well as in the adult. During early stages of development, Arx is expressed in a significant proportion of neurons in the cortex, the striatum, the ganglionic eminences and also in the spinal cord. In the adult, expression of Arx is still present and restricted to regions that are known to be rich in GABAergic neurons such as the amygdala and the olfactory bulb. A possible role for Arx in this type of neurons is further reinforced by the expression of Arx in a subset of GABAergic interneurons in young and mature primary cultures of cortical neuronal cells as well as in vivo. Moreover, these data could explain the occurrence of seizures in the great majority of patients with an ARX mutation, due to mislocalisation or dysfunction of GABAergic neurons. We also performed ARX wild-type and mutant over-expression experiments and found that the different ARX mutations tested did not modify the morphology of the cells. Moreover, no abnormal cell death or protein aggregation was observed, hence suggesting that more subtle pathogenic mechanisms are involved.


Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products.
Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection. Samples from 26 clinical trials totaling 460 transduced cell products from 375 subjects were evaluated. All cell products were negative for RCL. A total of 296 of the clinical trial participants were screened for RCL at least 1 month after infusion of the cell product. No research subject has shown evidence of RCL infection. These findings provide further evidence attesting to the safety of third-generation lentiviral vectors and that testing T cell products for RCL does not provide added value to screening the lentiviral vector product.


RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature.
RNA sequencing (RNA-seq) is a complementary diagnostic tool to exome sequencing (ES), only recently clinically available to undiagnosed patients post-ES, that provides functional information on variants of unknown significance (VUS) by evaluating its effect on RNA transcription. ES became clinically available in the early 2010s and promised an agnostic platform for patients with a neurological disease, especially for those who believed to have a genetic etiology. However, the massive data generated by ES pose challenges in variant interpretation, especially for rare missense, synonymous, and deep intronic variants that may have a splicing effect. Without functional study and/or family segregation analysis, these rare variants would be likely interpreted as VUS which is difficult for clinicians to use in clinical care. Clinicians are able to assess the VUS for phenotypic overlap, but this additional information alone is usually not enough to re-classify a variant. Here, we report a case of a 14-month-old male who presented to clinic with a history of seizures, nystagmus, cerebral palsy, oral aversion, global developmental delay, and poor weight gain requiring gastric tube placement. ES revealed a previously unreported homozygous missense VUS, c.7406A > G p.(Asn2469Ser), in VPS13D. This variant has not been previously reported in genome aggregation database (gnomAD), ClinVar, or in any peer-reviewed published literature. By RNA-seq, we demonstrated that this variant mainly impacts splicing and results in a frameshift and early termination. It is expected to generate either a truncated protein, p.(Val2468fs*19), or no protein from this transcript due to nonsense-mediated mRNA decay leading to VPS13D deficiency. To our knowledge, this is the first case utilizing RNA-seq to further functionally characterize a homozygous novel missense VUS in VPS13D and confirm its impact on splicing. This confirmed pathogenicity gave the diagnosis of VPS13D movement disorder to this patient. Therefore, clinicians should consider utilizing RNA-seq to clarify VUS by evaluating its effect on RNA transcription.


Angioid streaks associated with pseudoxanthoma elasticum in a 13-year-old patient.
This report describes a 13-year-old girl who presented with angioid streaks associated with pseudoxanthoma elasticum (PXE). Extensive retinal pigment epithelial (RPE) mottling, known as peau d'orange, characteristic of PXE, was also noted. The potential complication of choroidal neovascularization is described. Physicians should be aware that angioid streaks and their potentially sight-threatening complications can occur in this age group.


Quantitation of total antibody (tAb) from antibody drug conjugate (ADC) PYX-201 in rat and monkey plasma using an enzyme-linked immunosorbent assay (ELISA) and its application in preclinical studies.
PYX-201 is an investigative ADC oncology drug composed of a monoclonal human immunoglobulin G (IgG) antibody targeting the extra domain B splice variant of fibronectin (EDB + FN) conjugated to an auristatin payload through a cleavable linker. Effective measurement of PYX-201 tAb is the key to ADC drug PYX-201 preclinical pharmacokinetics (PK) assessment. PYX-201 monoclonal antibody (mAb) was used as the reference standard, goat anti-human IgG polyclonal antibody (pAb) or rabbit anti-human Kappa light chain mAb was employed as the capture antibody, and mouse mAb or goat pAb anti-human IgG the crystallizable fragment (Fc) (horseradish peroxidase (HRP)) was utilized as the detection antibody in this ELISA. This assay was validated with a dynamic range 250 - 10,000 ng/mL and 250 - 6000 ng/mL in rat and monkey K2EDTA plasma, respectively. PYX-201 tAb bioanalytical ELISA assay was reported for the first time in any biological matrix. This is the first time for a bioanalytical method to be validated for a tAb from an ADC drug targeting EDB + FN in any biological matrix.


Downregulation of vascular endothelial growth factor and integrinbeta3 by endostatin in a mouse model of retinal neovascularization.
Retinal neovascularization is among the leading causes of vision impairment throughout the world. Intraocular expression of vascular endothelial growth factor (VEGF), an angiogenic protein, and integrins, a group of cell adhesion molecules, is closely correlated with neovascularization in such neovascular diseases. The purpose of this study is to determine the effect of endostatin, a potent anti-angiogenic factor, on gene expression of vascular endothelial growth factor (VEGF) and integrinbeta3 in a mouse model of oxygen-induced retinopathy. C57BL/6 mice were given intravitreous injections of 1.0 microg endostatin at P12. At P17, retinal VEGF and integrinbeta3 mRNA levels were measured by real-time quantitative PCR in the hyperoxia mice and in the endostatin-treated mice. Analysis of 12 separate experiments revealed a 3.5-fold decrease in VEGF levels between hyperoxia mice and endostatin-treated mice (p<0.01) and a 2.5-fold decrease in integrinbeta3 levels between hyperoxia mice and endostatin-treated mice (p<0.01). These data suggest that intraocular expression of VEGF and integrinbeta3 mRNA is down-regulated by endostatin, which may provide a new therapeutic approach for ocular neovascularization.


The association between socioeconomic status and C-reactive protein in Bayesian perspective.
•This study analyzed the total health inequality on risks of chronic inflammation.•We used Bayesian multiple and distributional regression models.•Between-group posterior distributions show a robust educational gradient in health.•Within-group posterior distributions show polarized risks for individuals.


Delayed febrile effects of chlorpyrifos: is there cross-tolerance to bacterial lipopolysaccharide?
Oral chlorpyrifos (CHP) induces hypothermia followed by a fever that persists for several days in the rat. To understand the neuro-immune mechanisms of CHP-induced fever, we compared the tolerance and cross-tolerance between CHP and the fever elicited by lipopolysaccharide (LPS) (Escherichia coli). Female rats were administered the corn oil (CO) vehicle or CHP (10 mg/kg; p.o.) daily for 4 days while core temperature (Tc) and motor activity (MA) were monitored by telemetry. There was a reduction in Tc followed by an elevation the next day after each CHP treatment. The day after the last CHP treatment, rats were administered saline or 50 microg/kg LPS (i.p.). CHP-treated rats had a smaller LPS fever that was attributed to their elevated baseline Tc. In another study, rats were dosed with saline or LPS daily for three days. By the time of the third LPS injection there was no febrile response, indicating tolerance to LPS. Rats were then dosed with CO or CHP (10 mg/kg) 24 h after the third LPS treatment. LPS-tolerant rats displayed an accentuated hypothermic and febrile response to CHP. Plasma cholinesterase activity was unaffected by repeated LPS treatment, suggesting that the metabolism of CHP in the liver was unaffected by LPS. Overall, the neural-immune mechanisms for LPS fever is distinct from that of CHP in view of marked difference in mechanisms of tolerance.


The T-type calcium channel CaV3.2 regulates insulin secretion in the pancreatic β-cell.
Voltage-gated Ca2+ (CaV) channel dysfunction leads to impaired glucose-stimulated insulin secretion in pancreatic β-cells and contributes to the development of type-2 diabetes (T2D). The role of the low-voltage gated T-type CaV channels in β-cells remains obscure. Here we have measured the global expression of T-type CaV3.2 channels in human islets and found that gene expression of CACNA1H, encoding CaV3.2, is negatively correlated with HbA1c in human donors, and positively correlated with islet insulin gene expression as well as secretion capacity in isolated human islets. Silencing or pharmacological blockade of CaV3.2 attenuates glucose-stimulated cytosolic Ca2+ signaling, membrane potential, and insulin release. Moreover, the endoplasmic reticulum (ER) Ca2+ store depletion is also impaired in CaV3.2-silenced β-cells. The linkage between T-type (CaV3.2) and L-type CaV channels is further identified by the finding that the intracellular Ca2+ signaling conducted by CaV3.2 is highly dependent on the activation of L-type CaV channels. In addition, CACNA1H expression is significantly associated with the islet predominant L-type CACNA1C (CaV1.2) and CACNA1D (CaV1.3) genes in human pancreatic islets. In conclusion, our data suggest the essential functions of the T-type CaV3.2 subunit as a mediator of β-cell Ca2+ signaling and membrane potential needed for insulin secretion, and in connection with L-type CaV channels.


Accuracy of intraoperative pathological examination of SLN in cervical cancer.
Early cervical cancer patients with pelvic lymph node metastasis do not benefit from radical hysterectomy. Assessment of the SLN status is thus crucial before deciding to perform a radical hysterectomy as opposed to aortic dissection only followed by definitive radiation therapy. Accuracy of frozen section of SLN has been questioned and deserves further investigation. Stage IA-IB1 cervical cancer patients who underwent SLN then full pelvic dissection at the Claudius Regaud Cancer Center in Toulouse, France, were included. At least one SLN was identified in all 94 patients. Bilateral detection rate was 80.8%. Ectopic drainage area was found in 19 patients (20.2%). Sentinel lymph node involvement was found in 11 patients (11.7%). Sensitivity and NPV of frozen section pathological examination for the detection of macrometastatic disease was 100%, sensitivity for the detection of macro and micrometastatic disease, excluding ITC, was 88.9%, and NPV was 98.8%. Micrometastasis and isolated tumor cells (ITC) undetected at frozen section examination were found in 1 patient (1.06%) and 2 lymph nodes (1.24%), and in 2 patients (2.13%) and 2 lymph nodes (1.24%), respectively. Final pathology sensitivity of SLN was 100% for both macro and micrometastatic disease, including ITC. In our institution, intraoperative frozen examination of SLN accurately predicts the status of pelvic lymph nodes and is effective for selecting intraoperatively the group of patients who benefit from radical hysterectomy. In addition, our results suggest that patients with small tumors and bilateral detection of SLN can be spared full pelvic lymphadenectomy.


The effect on plasma prolactin, growth hormone and luteinising hormone concentrations of single oral doses or propranolol and tolamolol in normal man.
In a placebo controlled double-blind study in six healthy male volunteers the effects of single oral doses of 100 mg and 200 mg of tolamolol on plasma concentrations of prolactin, growth hormone and luteinising hormone were investigated. In a second placebo controlled single-blind study in a further six healthy male volunteers the effects of single oral doses of 200 mg tolamolol and 160 mg propranolol on the same plasma hormone concentrations were compared. A dose dependent increase in plasma prolactin concentration was demonstrated after tolamolol. The increase in plasma prolactin concentration was not evident after propranolol. Plasma growth hormone and luteinising hormone concentrations were not significantly changed by either propranolol or tolamolol.


Newly diagnosed atrial fibrillation and hospital utilization in heart failure: a nationwide cohort study.
Atrial fibrillation (AF) constitutes a major burden to health services, but the importance of incident AF in patients with heart failure (HF) is unclear. We examined the associations between incident AF and hospital utilization in patients with HF. In a nationwide matched-cohort study of HF patients, we identified patients diagnosed with incident AF between 2008 and 2018 in the Danish Heart Failure Registry (N = 4463), and we compared them to matched referents without AF (N = 17 802). Incident AF was associated with a multivariable-adjusted 4.8-fold increase (95% CI 4.1-5.6) and 4.3-fold increase (95% CI 3.9-4.8) in the cumulative incidence of inpatient and outpatient contacts within 30 days, respectively. At 1 year, the cumulative incidence ratios were 1.8 (95% CI 1.7-1.9) and 1.4 (95% CI 1.4-1.5). Incident AF was also associated with increases in the total numbers of inpatient and outpatient hospital contacts within 30 days (multivariable-adjusted rate ratio 1.4, 95% CI 1.4-1.5, and 1.6, 95% CI 1.6-1.7, respectively). At 1 year, the ratios were 2.2 (95% CI 2.1-2.3) and 2.0 (95% CI 1.9-2.1). The multivariable-adjusted proportion of bed-day use among HF patients with incident AF was 10.9-fold (95% CI 9.3-12.9) higher at 30 days and 5.3-fold (95% CI 4.3-6.4) higher at 1 year compared with AF-free referents. Incident AF in HF is associated with earlier hospital contact, more hospital contacts, and more hospital bed-days. More evidence on interventions that may prevent the risk and subsequent burden of AF in HF is urgently needed.


Clinical and Genomic Considerations for Variant Histology in Bladder Cancer.
Urothelial carcinoma demonstrates remarkable plasticity in its ability to differentiate into divergent histologic subtypes in both a pure and mixed form. This review presents the most current data pertaining to bladder cancer with variant histology. Recognition of bladder cancer variants has increased profoundly in the past two decades with their inclusion in the pathologic guidelines and increased awareness among pathologists and urologists. Most of the available literature consists of small single-institutional studies, but there is compelling evidence to support deviation from the normal urothelial carcinoma management pathways for certain subtypes. While traditionally diagnosed by microscopic appearance, next-generation sequencing and molecular profiling have enabled identification of genomic markers associated with specific variants that exist in tumors lacking classic histologic hallmarks. This genomic information holds promise for predicting response to specific treatments or even in the development of novel targeted therapies. Combining increased awareness of variant histology, its impact on clinical outcomes, and genomic data will result in a more nuanced treatment approach to reduce morbidity and optimize oncologic outcomes for our patients.


Statistical issues of QT prolongation assessment based on linear concentration modeling.
The ICH (2005) defined drug-induced prolongation of QT interval, i.e., the duration of depolarization and repolarization of ventricles, as evidenced by an upper bound of the 95% confidence interval around the mean effect on QTc (QT corrected for heart rate) of 10 ms. Furthermore, it defined that a negative thorough QT/QTc study is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms. This objective leads to the application of intersection-union tests by testing the mean difference between test treatment and placebo of QTc change from baseline at each of the matched time points at which the observations are collected. The nature of the higher false positive rate due to more observational time points leads to the concern of study efficiency. Based on the concept of clinical pharmacology, a concentration-response modeling approach is often adopted to assess the prolongation size of QTc interval induced by a drug without carefully examining the validity of the assumptions involved. In most of the applications, the model is assumed either to be linear, log-linear, or logistic. The supporter of the modeling often emphasizes the advantage of power improvement and reduction in estimation error. However, it has been often pointed out by statisticians and pharmacologists that modeling under an invalid uniformity assumption across study population often leads to severe bias in testing and estimation. In this article, we examine data sets of New Drug Applications to illustrate the bias and lack of validity of the linearity assumptions.


Peptide-containing innervation of the human intestinal mucosa. An immunocytochemical study on whole-mount preparations.
The three-dimensional distribution of the peptide-containing innervation in the human intestinal mucosa was studied by fluorescence immunohistochemistry on whole-mount mucosal preparations. An extensive VIP-immunoreactive nerve supply was demonstrated at all levels, but was markedly increased in density in the distal intestine, where it formed a particularly rich network in close contact with the luminal epithelium. In contrast, substance P-containing nerve fibres formed a looser and evenly distributed innervation at all levels. The muscularis mucosae was richly supplied by VIP- and substance P-containing fibres. Met-enkephalin immunoreactivity was confined to a few scattered nerve bundles running in the muscularis mucosae and around the bottom of epithelial crypts.


Use of Topical Rapamycin in Facial Angiofibromas in Indian Skin Type.
Facial angiofibromas (FA) are the most visible cutaneous manifestations in patients with tuberous sclerosis (TS), often resulting in stigmatization of the affected individuals. Recent studies have suggested that topical rapamycin may be an effective treatment for angiofibromas. To study the safety and efficacy of topical rapamycin in treatment of FA in Type IV-VI skin type. Five female patients with FA were included in the study, four of whom had TS, whereas one had isolated angiofibromas without systemic involvement. The age of the patients varied from 6 to 44 years. After baseline evaluation, they were advised to apply topical rapamycin (0.1-1%) in white soft paraffin base twice daily. Follow-up varied from 1 month to 6 months and is ongoing. A sustained improvement was observed with respect to erythema, size as well as extent of the lesions as early as within 2 weeks of starting treatment. No side effects were observed. A correlation between duration of angiofibromas and effectiveness of treatment was noted. Topical rapamycin appears to be a safe and effective alternative to surgical or laser-based treatments in patients with FA. This treatment shows potential to be a first-line management for FA and appears safe to start in early childhood.


Repeat pelvic osteotomy in cloacal exstrophy: applications and outcomes.
Pelvic osteotomies have been shown to enhance success rates for classic exstrophy patients when closed primarily or secondarily after initial failure. Primary closure of cloacal exstrophy also benefits from osteotomy but this has yet to be shown for re-closure of cloacal exstrophy failures. This study looks at the applications, complications, and long-term success rates in this very select group of patients. We extracted from an institutionally approved exstrophy database 15 patients who had undergone repeat pelvic osteotomy and analyzed patient history, complications and orthopedic outcomes. All patients who underwent reclosure at our institution remain closed. Major complications were seen in two patients and minor complications in four patients. Urinary continence was achieved in 10 patients with augmentation and continent stoma formation, urinary diversion was performed in two patients and three patients await a continence procedure. Repeat pelvic osteotomy in cloacal exstrophy is successful and the complication rate is low. Pelvic osteotomy is associated with enhanced success rates of primary and secondary closure with better cosmesis of the abdominal wall and genitalia. Intrasymphyseal plates along with gradual reduction of the extreme diastasis utitlizing an external fixation device can be beneficial prior to further genitourinary surgery.


Developing and testing evidence-based weight management in Australian pharmacies: A Healthier Life Program.
Pharmacies represent a valuable opportunity to deliver weight management services, rather than just the routine supply of weight-loss products. In order to provide optimal services and translation of evidence-based weight management in community pharmacy, a best practice model program was designed and pilot tested to facilitate implementation of such services in pharmacies in Australia. To develop and pilot a pharmacist-delivered, evidence-based, non-product-centred weight management service for community pharmacy in Australia. Setting Sydney, New South Wales, Australia. A pharmacy-based weight management service called the A Healthier Life Program (AHLP), for overweight and obese individuals, was developed based on current Australian weight management guidelines and recommendations made by key stakeholders. The pharmacist undertook training to acquire specific competencies to deliver the program. The AHLP involved six individual face-to-face sessions with the pharmacist over 3 months. The intervention targeted three areas: diet, physical activity and behavioural change. Weight, BMI, waist circumference, blood pressure, dietary intake, and physical activity levels at 3 months were compared with values at baseline. Qualitative feedback on participants' satisfaction and willingness to pay were also analysed. Eight pharmacies provided the AHLP between February and December 2013. Thirty-four participants were enrolled in the AHLP; mean age 50.7 years (SD 15.7) and mean BMI 34.3 kg/m(2) (SD 5.3). Of the 22 (65%) participants who completed the program, six had achieved the target weight loss of ≥5%. The mean change in weight was -3.5 kg (95% CI -4.8, -2.2) and waist circumference -2.0 cm (95% CI -2.8, -1.3) for program completers at 3 months. Furthermore, participants reported overall positive experiences of the program, and identified accessibility of the pharmacy and high comfort level with the pharmacist, as the major advantages. The AHLP was well received and participants achieved targeted weight loss. This study demonstrated that an evidence-based patient-centred weight management program can be implemented in Australian pharmacies.


Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies.
Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.


Insecticidal and cytotoxic effects of natural and hemisynthetic destruxins.
The insecticidal and cytotoxic effects of 13 natural and hemisynthetic destruxins have been studied. DE shows insecticidal effects similar to those of DA, while DE and DA are more active than all the other natural compounds and analogues tested. Brominated destruxin is a relatively active analogue displaying particular modalities of cytotoxic effects which reflect a certain originality of its mode of action. The linear molecule resulting from the opening of the DA cycle is not toxic. The most hydrophilic destruxins showing e.g. charged radicals (COO-) appear the least toxic probably because they do not penetrate easily the cellular membranes.


The management of burns in a developing country: an experience from the republic of Yemen.
Burns management and mortality rates have improved in even developing countries including some Arab states. This paper describes an experience with burn victims in the Yemen to draw attention to the victims' plight, the challenge posed to bodies, such as the International Society of Burn Injury (ISBI), and, the basic required corrective measures. Between 1996 and 1999, sponsored surgical teams paid four visits to four Yemen cities. The patients presented here are a consecutive series of the plastic surgery operations that the teams performed. No literature on burn care in the Yemen could be traced. The cities visited were Mokalla, Sayown, Taiz and Aden. Of 406 plastic procedures, 139 were for post-burn contracture release and are the focus of this paper. The victims were mostly children and the hand (49; 35%) was the most common site. Types of operation performed were release and split skin grafi, excision and full thickness skin grafi, release and local flap, and, multiple Z-plasty. This experience confirms the believe that, given initiative and efficient organization of available resources, developing countries such as the Yemen can also achieve better burn management. Solutions suggested are determining local health needs; onsite conferences, symposia and training programs; local personnel to visit burn centers overseas; burn research and prevention activities; and epidemiologic studies.


[Isolation of a HBV-PreS2 epitope from a random peptide library displayed on the bacterial flagellin].
To establish an improved procedure for isolation and identification of epitopes from a random peptide library displayed on the bacterial surface. Epitopes were screened from FliTrx random peptide library by a monoclonal antibody 3B9 against HBV-PreS2 protein. The enrichment was monitored in each round. Higher affinity clones were obtained by increasing the washing strength and randomly selected for sequencing and Western blot analysis. Clones specifically binding to antibody were enriched in each round. Ten sequences were obtained from sixteen sequenced clones, seven of them contained the common motif RXRGXY with high homogeneity to 135-140 amio acids in HBV-PreS protein and have positive results in Western blot analysis. The other three sequences have no typical motif RXRGXY and showed different Western blot results. It's easy and quick to drive epitopes from a random peptide library displayed on the bacterial surface.


Evidence for a modified V3 with dorsal and ventral halves in macaque monkeys.
Through more than 30 years of research, the nature of the third visual area, V3, and even its existence have been in question. Here, we used injections of up to five distinguishable tracers into both dorsal and ventral portions of V1 of macaque monkeys (representing the lower and upper visual quadrant, respectively) to provide compelling evidence for a V3 that is smaller than V2. This V3 includes both dorsal and ventral halves mirroring dorsal and ventral V2 in retinotopic organization. Of the approximately ten areas with V1 connections, V3 appears to account for about 20%.


Online Reputation Management for Urologists.
"It takes 20 years to build a reputation; it can be ruined in just five minutes." --Warren BuffetThis article will define online reputation management and outline techniques and steps to easily manage and control your online ratings. You do not want to take your reputation for granted. You want to be proactive in protecting your reputation as it is your most valuable asset. After reading this article you will understand the importance of online reputation management, the risk of ignoring this aspect of your reputation, and how every urologist can and should be involved in controlling his/her reputation. Medical as well as nonmedical publications were reviewed to identify the importance of online reputations of physicians, and what can be done to protect one's reputation. Research indicates that doctors do have control of their online reputations. As physicians, professionally we can live and die by our reputations. We need to take action to manage our online reputations before negative reviews appear on online review sites.


Parenchymal hypointense foci associated with developmental venous anomalies: evaluation by phase-sensitive MR Imaging at 3T.
The risk of hemorrhage in the context of developmental venous anomaly is considered to be very low, but it has never been evaluated by susceptibility-weighted MR imaging at 3T. The goal of the present study was to evaluate the prevalence of hypointense foci (ie, microhemorrhage or cavernous malformation) associated with DVA on phase-sensitive MR imaging, on the basis of principles similar to those of susceptibility-weighted MR imaging, and to evaluate the relationship between the hypointense foci and several factors, such as white matter hyperintense lesions adjacent to DVA on T2-weighted imaging, DVA morphology, and clinical symptoms. This study retrospectively evaluated 61 lesions in 59 consecutive patients with DVA who underwent MR imaging including phase-sensitive MR imaging. Two neuroradiologists independently assessed for the presence of hypointense foci and other factors such as DVA location, depth, size, direction of draining vein on phase-sensitive MR imaging, and white matter hyperintense lesion on T2-weighted imaging. Clinical symptoms were also assessed. Hypointense foci were observed in 62.3% (38/61) of lesions. White matter hyperintense lesion was more frequently observed in patients with hypointense foci (26/38) than in patients without hypointense foci (7/23) (P < .01). There was no significant association between hypointense foci and other factors. Our results support the hypothesis that microhemorrhage or cavernous malformation can be related to venous congestion caused by abnormal venous drainage. We conclude that phase-sensitive MR imagingis useful for the detection of microhemorrhage or cavernous malformation in patients with DVA, especially when associated with white matter hyperintense lesion.


Correction: The Holstein Friesian Lethal Haplotype 5 (HH5) Results from a Complete Deletion of TBF1M and Cholesterol Deficiency (CDH) from an ERV-(LTR) Insertion into the Coding Region of APOB.
[This corrects the article DOI: 10.1371/journal.pone.0154602.].


Smartphone application training program improves smartphone usage competency and quality of life among the elderly in an elder university in China: A randomized controlled trial.
Given that China has free universities dedicated solely to the elderly, such universities may be the perfect place to provide large numbers of elderly with a systematic program of self-management. Yet, testing health applications in this location has not occurred, partly because time-consuming training is required before applications can be used. This study aimed to develop and implement a smartphone training program for the elderly and to confirm the effects on smartphone competency and quality of life. A randomized controlled trial was conducted. Participants were randomly assigned to either the intervention group or the wait-list control group. A smartphone operation manual was provided to all participants. The intervention group received the smartphone training program once a week for 20 weeks. After the study was finished, participants in the wait-list control group were permitted to undergo the smartphone training program. Of the 344 participants were randomized at the elder university in Huzhou. After 20 weeks of the intervention, the intervention group showed significant improvement in smartphone usage competency (except health applications) and quality of life relative to the wait-list control group (P < 0.05). This study confirmed the effectiveness of the smartphone training program in the elder university setting. However, further research is needed to strengthen the intervention in the area of health applications.


Evaluation of novel modified tangential irradiation technique for breast cancer patients using dose-volume histograms.
We have previously reported that entire axillary lymph node regions could be irradiated by the modified tangential irradiation technique (MTIT). In this study, MTIT was compared with a conventional irradiation technique (CTIT) using dose-volume histograms to verify how adequately MTIT covers the breast and axillary lymph node region and the extent to which it involves the lung and heart. Forty-four patients with early-stage breast cancer were treated by lumpectomy, axillary dissection, and postoperative radiotherapy. Twenty-two patients were treated with MTIT and 22 with CTIT. In 25 patients, the breast tumor was on the left and in 19 on the right. During axillary dissection, surgical clips were left as markers at the border of the axillary lymph node region. MTIT was planned by setting the dorsal edge of the radiation field on a lateral-view simulator film at the dorsal edge of the humeral head and the cranial edge of the radiation field at the caudal edge of the humeral head. CTIT was planned to ensure radiation of the breast tissue without considering the axillary region. In this study, all patients underwent computed tomography, and the CT data were transmitted on-line to a radiotherapy planning system, in which the dose-distribution computed tomography images and dose-volume histograms were calculated by defining the breast, axillary region (levels I, II, and III), lung, and heart region. Dose-volume histogram analysis demonstrated that breast tissue was radiated with an 86.5-100% volume (median 96.5%) by MTIT and an 83-100% volume (median, 95%) by CTIT at >95% of the isocenter dose. The axillary lymph node regions at Levels I, II, and III were irradiated with 84-100% (median, 94.5%), 59-100% (median, 89%), and 70-100% (median, 89.5%) volumes, respectively, by MTIT and with 2-84% (median, 38%), 0-53% (median, 15%), and 0-31% (median, 0%) volumes, respectively, by CTIT at >70% of the isocenter dose. The ipsilateral lung was irradiated with a 5-22% volume (median, 11.5%) by MTIT and 5-15% volume (median 9%) by CTIT at >90% of the isocenter dose. In all 25 left-sided breast cancer patients, the volumes irradiated with an 80% isocenter dose were <30 cm(3). The results of our study demonstrated that the breast tissue was sufficiently irradiated with both CTIT and MTIT planning, the axillary lymph node areas irradiated by MTIT were much wider than those irradiated by CTIT at all levels, and the lung and heart volumes irradiated by MTIT were small.


A novel fluorescent array for mercury (II) ion in aqueous solution with functionalized cadmium selenide nanoclusters.
Mono-disperse CdSe nanoclusters have been prepared facilely and functionalized with l-cysteine through two steps by using safe and low cost substances. They are water-soluble and biocompatible. Especially these functionalized quantum dots can be stably soluble in water more than for 30 days, and the intensity of fluorescence and absorbance was decreased less than 15% of fresh prepared CdSe colloids. These functionalized CdSe QDs exhibited strong specific affinity for mercury (II) through QDs interface functional groups. Based on the quenching of fluorescence signals of functionalized CdSe QDs at 530 nm and no obvious wavelength shift or no new emission band in present of Hg (II) at pH 7.75 of phosphate buffer solution, a simple, rapid and specific array for Hg (II) was proposed. In comparison with conventional organic fluorophores, these nanoparticles are brighter, more stable against photobleaching, and do not suffer from blinking. Under optimum conditions, the response of linearly proportional to the concentration of Hg (II) between 0 and 2.0 x10(-6) mol L(-1), and the limit of detection is 6.0 x 10(-9) mol L(-1). The relative standard deviation of six replicate measurements is 1.8% for 1.0 x 10(-7) mol L(-1) Hg (II). The mechanism of reaction is also discussed. The proposed method was successfully applied for Hg (II) detection in four real samples with a satisfactory result that was obtained by cold vapor atomic fluorescence spectrometry (CV-AFS).


Community engagement in disaster preparedness and recovery: a tale of two cities--Los Angeles and New Orleans.
Awareness of the impact of disasters globally on mental health is increasing. Known difficulties in preparing communities for disasters and a lack of focus on relationship building and organizational capacity in preparedness and response have led to a greater policy focus on community resiliency as a key public health approach to disaster response. In this article, the authors describe how an approach to community engagement for improving mental health services, disaster recovery, and preparedness from a community resiliency perspective emerged from their work in applying a partnered, participatory research framework, iteratively, in Los Angeles County and the City of New Orleans.


RO/NF membrane treatment of veterinary pharmaceutical wastewater: comparison of results obtained on a laboratory and a pilot scale.
Emerging contaminants (ECs) are commonly derived from industrial wastewater, which is often a consequence of an inadequate treatment of the latter. Improperly pretreated pharmaceutical wastewater could cause difficulties in operations of wastewater treatment plants while incomplete elimination of ECs during the processing might result in their appearance in drinking water. This paper deals with membrane treatment of pharmaceutical wastewater on a laboratory and a pilot scale as well as with the removal of the following veterinary pharmaceuticals (VPs) (sulfamethoxazole, trimethoprim, ciprofloxacin, dexamethasone, and febantel). The pretreatment of pharmaceutical wastewater by means of coagulation and microfiltration (MF) prevented the irreversible fouling of the fine porous structure of the reverse osmosis (RO) and nanofiltration (NF) membranes which were used in the final stage of wastewater processing. The percentage of the removal of the selected VPs ranges from 94% to almost 100% in the case of NF and RO membranes in both scales. The recovery percentage concerning the pilot scale amounted to 88%. Membrane cleaning was successfully carried out in both scales. The differences in retention between laboratory and pilot tests are due to different raw wastewater quality and different recovery and hydrodynamic of the two systems. Fouling and concentration polarization were more pronounced in laboratory setup (frame-plate module) than in pilot unit (spiral module). The proposed integrated membrane treatment (coagulation, MF, NF, and RO) can be employed for treatment of wastewater originating from pharmaceutical factory. The obtained permeate can be safely discharged to sewer system or could be reused in manufacturing process.


[Hydroxysafflor yellow A inhibits rat vascular smooth muscle cells proliferation possibly via blocking signal transduction of MEK-ERK1/2].
To elucidate the effect of hydroxysafflor yellow A ( HYSA) on the proliferation of vascular smooth muscle cells (VSMCs) and the related mechanism. VSMCs derived from SD rats were treated with DMEC culture medium (Control), 10 ng/ml PDGF (PDGF group), pretreatment with HYSA at different doses (1, 5, 10, 20, 40, 60 µmol/L) for 24 h then cotreatment with PDGF. After 24 h, MTT assay, Western blot and immunohistochemical staining were performed to evaluate the inhibitory effects of HYSA on VSMCs proliferation. HYSA inhibited PDGF induced VSMCs proliferation in a dose-dependent manner, dowregulated proliferating cell nuclear antigen (PCNA) expression and blocked PDGF activated PDGFR-MEK-ERK1/2 signaling pathway. HYSA inhibits VSMCs proliferation possibly via downregulating the expression of PCNA and blocking MEK-ERK1/2 signal transduction in VSMCs.


Hydroxylamine addition and real-time aeration control in sewage nitritation system for reduced start-up period and improved process stability.
Sewage nitritation is a promising process for nitrogen removal, but its practical application is limited by long start-up period and unstable operation. In this study, hydroxylamine (NH2OH) addition and real-time aeration control strategies were adopted for the promotion of sewage nitritation in a sequencing batch reactor. Initially, 4.5 mg/L NH2OH was added into reactor every 24 h to establish nitritation, increasing the nitrite accumulation ratio (NAR) from 1.7% to 93% in 19 d. In the following period, NH2OH addition was stopped and nitritation remained stable over 55 d, with NAR of 97% by real-time aeration control. The aeration duration was determined by characteristic points on pH curve. The main genera of nitrite oxidizing bacteria, Nitrobacter and Nitrospira, were both eliminated from the system, supporting the long-term stability of nitritation. Overall, NH2OH addition and real-time aeration control is an excellent strategy for establishing and maintaining effective sewage nitritation.


Determination of leucine metabolism and protein turnover in sheep, using gas-liquid chromatography-mass spectrometry.
1. Whole-body protein synthetic rates in non-pregnant ewes were determined by the continuous infusion of L-[15N]- and [1-13C]leucine and measuring the plasma enrichment of leucine, alpha-ketoisocaproate (alpha-KIC) and expired carbon dioxide by gas-liquid chromatography-mass spectrometry. 2. The mean whole-body protein synthesis estimated from plasma leucine flux corrected for oxidation was 5.38 (SE 0.54) g/kg per d. 3. Under the conditions of the present study leucine oxidation was 0.323 (SE 0.067) mmol/kg per d and accounted for 10.71 (SE 2.26) % of plasma [13C]leucine flux. Deamination of leucine was 0.55 (SE 0.035) mmol/kg per d and accounted for approximately 17% of plasma [15N]leucine flux. 4. The rate of alpha-KIC reamination to leucine, calculated by subtracting 13C flux from 15N flux, was 0.228 (SE 0.101) mmol/kg per d. 5. The rate of whole-body protein degradation was 4.49 (SE 0.54) g/kg per d and there was a net protein gain of 0.89 (SE 0.21) g/kg per d.


"Hybrid" X--Y translocation chromosomes of Drosophila hydei and D. neohydei.
The Y chromosome of Drosophila carries fertility genes which, in part, develop lampbrush loops during the meiotic prophase. Hybrid males from crosses between D. hydei and D. neohydei are fertile although the morphology of the lampbrush loops differs between both species. With the aid of X ray induced "hybrid" X-Y translocation chromosomes the question has been studied whether Y chromosomal genes of D. neohydei can substitute deletions in the Y chromosome of D. hydei. Although the induction of translocation chromosomes almost regularly results in an inactivation of the translocated Y fragment within a few generations, one case of successful complementation has been demonstrated. Furthermore, a new lampbrush loop pair has been detected in D. neohydei which is morphologically similar to the "nooses" of D. hydei. Preliminary evidence for the location of the lampbrush loops on the Y chromosome of D. neohydei is discussed.


Isobaric laparoscopy using LaparoTenser system in surgical gynecologic oncology.
In this prospective analysis, the feasibility and outcome of isobaric laparoscopy in gynecologic oncology was evaluated. Total laparoscopic radical hysterectomy type A and B, with or without pelvic lymphadenectomy, according to the Querleu-Morrow classification was performed in 22 consecutive patients. Seven patients had early cervical cancer (adenocarcinoma stage 1B1 in 1, and squamous carcinoma stage 1B1 in 4, stage 1A2 in 1, and stage 1B2 in 1), and 15 patients had endometrial cancer (stage IA in 4, stage IB in 9, and stage IIIA in 2). Radical hysterectomy was performed using the LaparoTenser, a subcutaneous wall-lifting device. Visual analog score, duration of surgery, blood loss, complications, and postoperative course were recorded. Pathologic analysis confirmed the adequacy of the surgical specimens in type B radical hysterectomies and the number of lymph nodes removed. Low-pressure CO2 insufflation was us to improve field exposure in patients with high body mass index. Postoperatively, no patient reported substantial abdominal discomfort caused by lifting of the abdominal wall. Operative time, blood loss, and hospital stay were consistent with published data for CO2 laparoscopy. One complication related to insertion of the subcutaneous needle of the wall lifter occurred. We conclude that total laparoscopic radical hysterectomy can be successfully completed via isobaric laparoscopy using the LaparoTenser device in patients with early cervical and endometrial cancer. Gasless laparoscopy has become the first choice in our department to overcome the detrimental effects of pneumoperitoneum and represents a logical advance in the evolution of minimally invasive surgery. The LaparoTenser device is being used to perform increasingly complex procedures in high-risk patients and situations.


Associations of inner retinal layers with risk of incident dementia: An individual participant data analysis of four prospective cohort studies.
Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all-cause dementia and Alzheimer's disease (AD). We performed an individual participant data meta-analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all-cause dementia; n = 520 cases incident AD; follow-up time median [interquartile range] 11.3 [8.8-11.5] years). General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all-cause dementia and AD, respectively. Lower baseline macular ganglion cell-inner plexiform layer thickness was not significantly associated with these outcomes. These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia.


Control of ALK (wild type and mutated forms) phosphorylation: specific role of the phosphatase PTP1B.
Phosphorylation of proteins on tyrosine residues is regulated by the activities of protein tyrosine kinases and protein tyrosine phosphatases. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) essentially and transiently expressed during development of the central and peripheral nervous systems. ALK has been identified as a major neuroblastoma predisposition gene and activating mutations have been identified in a subset of sporadic neuroblastoma tumors. We previously established that the mutated receptors were essentially retained in the endoplasmic reticulum/Golgi compartments due to their constitutive activity. Intriguingly we demonstrated a stronger phosphorylation for the minor pool of receptor addressed to the plasma membrane. We decided to investigate the potential involvement of tyrosine phosphatase in dephosphorylation of this intracellular pool. In this study we first showed that general inhibition of tyrosine phosphatases resulted in a dramatic increase of the tyrosine phosphorylation of the wild type but also of the mutated receptors. This increase not only required the intrinsic kinase activity of the ALK receptor but also involved the Src tyrosine kinase family. Second we provided strong evidences that the endoplasmic reticulum associated phosphatase PTP1B is key player in the control of ALK phosphorylation. Our data shed a new light on the biological significance of the basal phosphorylation levels of both wild type and mutated ALK receptors and could be essential to further understand their roles in malignancies.


Complete genome sequences and phylogenetic analysis of encephalomyocarditis virus strains isolated from pigs and rats origin.
In order to evaluate the genetic variability of encephalomyocarditis virus (EMCV), the whole genomes of six EMCV field isolates originating from pigs and rats origin in different regions of central China, were phylogenetically and comparatively analyzed. Phylogenetic analysis of whole genome sequences, open reading frame (ORF), capsid coding region (CCR) and VP3/VP1 using neighbor-joining analysis revealed that these isolates belonged to lineage 1. Nucleotide sequences of six isolates showed more than 99% pairwise identity rates, and the sequences of isolates from pig and boar in the same region were completely identical with each other, without any genetic deletion or insertion. From comparative analysis of variability of each EMCV protein coding region, 3D and VP3 regions showed that the highest average identity rates, and was confirmed as highly conserved. In contrast, the protein coding regions 3A and 3B was confirmed to be highly variable region with the lowest average identity rate. Our data confirmed that the EMCV strains isolated from pigs and rats origin had high homology with each other, which implied rats may play an important role in EMCV transmission between domestic pigs and wild boars.


An analytic approach to identifying the sources of the low-frequency round window cochlear response.
The cochlear microphonic, traditionally thought of as an indication of electrical current flow through hair cells, in conjunction with suppressing high-pass noise or tones, is a promising method of assessing the health of outer hair cells at specific locations along the cochlear partition. We propose that the electrical potential recorded from the round window in gerbils in response to low-frequency tones, which we call cochlear response (CR), contains significant responses from multiple cellular sources, which may expand its diagnostic purview. In this study, CR is measured in the gerbil and modeled to identify its contributing sources. CR was recorded via an electrode placed in the round window niche of sixteen Mongolian gerbils and elicited with a 45 Hz tone burst embedded in 18 high-pass filtered noise conditions to target responses from increasing regions along the cochlear partition. Possible sources were modeled using previously-published hair cell and auditory nerve response data, and then weighted and combined using linear regression to produce a model response that fits closely to the mean CR waveform. The significant contributing sources identified by the model are outer hair cells, inner hair cells, and the auditory nerve. We conclude that the low-frequency CR contains contributions from several cellular sources.


Low-grade central osteosarcoma of the rib.
We report a case of low-grade central osteosarcoma of the rib, mimicking fibrous dysplasia protuberans or parosteal osteosarcoma. A 13-year-old boy presented with a densely ossified exophytic tumor in the left sixth rib. The surgically resected rib revealed an ossified tumor that had developed within bone and had formed an exophytic mass. Microscopic examination revealed parosteal osteosarcoma-like low-grade central osteosarcoma. Low-grade central osteosarcomas rarely affect the rib, and exophytic tumor formation is also rare. This tumor required differentiation from fibrous dysplasia protuberans and parosteal osteosarcoma because of its clinical presentation.


Introduction: molecular and biomechanical basis of osteoarthritis.
Osteoarthritis has developed into the most common chronic disease in the highly industrialized nations. Moreover, because of the prevalence of the disease in the elderly, this trend occurs worldwide as a consequence of increasing longevity due to the overall improvement in living conditions and health status. In contrast, research on osteoarthritis is still financially marginalized within biomedical research, so that the molecular and biophysical bases for disease initiation and progression are largely unmapped. The following sequence of five reviews highlights a remarkable change in that body of knowledge taking place at the beginning of the World Health Organization (WHO) 'Bone and Joint Decade 2001-2010'. The data and ideas presented in these articles reflect to some extent the guidelines set up by the WHO and by the National Institutes of Health of the USA and therefore allow a glimpse into the directions that research in osteoarthritis will take in the future.


[Claims management from the perspective of the lawyer : Top 7 errors in medical liability law].
The number of treatment error procedures against physicians in Germany has been relatively constant at a high level for years, even though the allegation of a faulty medical procedure is confirmed statistically only in approximately one quarter of the cases. Frequent and typical sources of error that can lead to the assertion of patient claims in the context of a medical treatment. Evaluation of existing statistics of individual courts and arbitration boards. From a legal point of view the most common mistakes under the medical liability law can be divided into seven categories, which are the subject of dispute in almost all judicial or extrajudicial treatment error procedures. Due to the civil legal evidence situation thereby errors in disclosure of information take the top spot. Even by observing a few legal requirements, numerous liability traps can be avoided in the context of medical treatment.


Blood flow in the perimalleolar skin in relation to posture in patients with venous hypertension.
The resting and standing perimalleolar skin blood flow and venoarteriolar response have been studied in 20 patients with postphlebitic limbs and 25 normal volunteers using laser-Doppler flowmetry. In postphlebitic limbs the venoarteriolar reflex was impaired and both the resting and standing skin blood flow were increased, suggesting the presence of local vasoparalysis similar to that previously observed in diabetics with peripheral neuropathy.


Nucleoside-Driven Specificity of DNA Methyltransferase.
We have studied the adenosine binding specificities of two bacterial DNA methyltransferases, Taq methyltransferase (M.TaqI), and HhaI methyltransferase (M.HhaI). While they have similar cofactor binding pocket interactions, experimental data showed different specificity for novel S-nucleobase-l-methionine cofactors (SNMs; N=guanosyl, cytidyl, uridyl). Protein dynamics corroborate the experimental data on the cofactor specificities. For M.TaqI the specificity for S-adenosyl-l-methionine (SAM) is governed by the tight binding on the nucleoside part of the cofactor, while for M.HhaI the degree of freedom of the nucleoside chain allows the acceptance of other bases. The experimental data prove catalytically productive methylation by the M.HhaI binding pocket for all the SNMs. Our results suggest a new route for successful design of unnatural SNM analogues for methyltransferases as a tool for cofactor engineering.


Severity and determinants of psychosocial comorbidities in granulomatosis with polyangiitis and their impact on quality of life.
Depression, anxiety, sleep disturbances, and fatigue are inadequately addressed comorbidities in granulomatosis with polyangiitis (GPA). We determined the prevalence, severity, determinants, and the impact of these comorbidities on quality-of-life (QoL) in GPA. This observational study included adult GPA patients; patients with RA and lupus were included as comparators. Patient Health Questionnaire-9 for depression, Generalized Anxiety Disorder 7-item scale for anxiety, Epworth Sleepiness Scale for sleep disturbances, and Fatigue Severity Scale for fatigue were administered prospectively to estimate prevalence and severity. QoL and disability were estimated using PROMIS-HAQ, HAQ-health and HAQ-pain. Correlations among these parameters were assessed. Stepwise regression analyses were performed to identify determinants of depression, anxiety, excessive sleepiness, and fatigue. One hundred eighty-one patients-62 GPA [mean age 43 (13) years], 57 RA and 62 SLE- were included. The prevalence of depression (47%), excessive sleepiness (21%), and fatigue (39%) in GPA were comparable to RA and lupus; anxiety was less prevalent (29% versus 46% and 53%, p = 0.02). Severity was mostly mild-moderate. Younger age [OR = 0.93 (0.89-0.98)], higher BMI [OR = 1.2 (1.0-1.4)], and greater disease damage [OR = 2.0 (1.3-3.3)] independently predicted presence of depression. Higher BMI [OR = 1.3 (1.1-1.5)] and concomitant FMS [OR = 80.9 (5.1-1289.2)] were independently associated with excessive sleepiness. No association with disease activity, duration, or gender was seen. GPA patients with depression, anxiety, excessive sleepiness, and fatigue had worse PROMIS-HAQ, HAQ-pain, and HAQ-health. In conclusion, depression, anxiety, sleep disturbances, and fatigue are common in GPA. Although their severity is mostly mild-moderate, they impair QoL significantly. Potentially modifiable determinants that can form targets for future interventions have been identified.


Correction: Variability in engagement and progress in efficacious integrated collaborative care for primary care patients with obesity and depression: Within-treatment analysis in the RAINBOW trial.
[This corrects the article DOI: 10.1371/journal.pone.0231743.].


Heavy metals concentration in soils of southeastern part of Ranga Reddy district, Andhra Pradesh, India.
There is a growing concern over the potential accumulation of heavy metals in soils owing to rapid industrial and urban development and increasing reliance on agrochemicals in the last several decades. These metals can infiltrate through the soil thereby causing groundwater pollution. Surface soil samples (5 to 15 cm) collected from southeastern part of Ranga Reddy district were analyzed for 14 heavy metals (As, Ba, Co, Cr, Cu, Mo, Ni, Pb, Rb, Sr, V, Y, Zn and Zr) using Philips PW 2440 X-ray fluorescence spectrometer. Results for heavy and trace elements are reported for the first time in soils for this region. The contamination of the soils was assessed on the basis of enrichment factor (EF), geoaccumulation index (I (geo)), contamination factor and degree of contamination. The results reveal that variations in heavy element concentrations in the soil analyzed have both geogenic and anthropogenic contribution, due to the long period of constant human activities in the study area. The concentration of the metals Ba, Rb, Sr, V, Y and Zr were interpreted to be mainly inherited from parent materials (rocks) and the As, Co, Cr, Cu, Mo, Ni, Pb and Zn concentrations show contribution from geogenic and anthropogenic sources. The major element variations in soils are determined by the composition of the parent material predominantly involving granites.


Evidence for a genetic aetiology in reading disability of twins.
Reading disability (dyslexia) is a major social, educational, and mental health problem. Although estimates of prevalence vary, up to 10-15% of school-age children have severe reading deficits in spite of average intelligence and adequate educational opportunity. That reading disability may have a constitutional basis has long been recognized, and results of twin and family studies suggest that one or more of its forms may be heritable; however, definitive evidence for a genetic aetiology has not been reported. Establishing a heritable basis for reading disability could suggest possible causes, give improved risk estimates, facilitate early diagnosis, and provide validity tests for ostensible subtypes. In this report, we apply a recently developed multiple regression analysis to data collected from a sample of 64 pairs of identical twins and 55 pairs of fraternal twins, in which at least one member of the pairs is reading disabled, and present evidence for a significant genetic aetiology.


Noncovalently bilayer-coated capillaries for efficient and reproducible analysis of proteins by capillary electrophoresis.
The suitability of noncovalently bilayer-coated capillaries for the analysis of proteins by capillary electrophoresis (CE) at medium pH was investigated. Fused-silica capillaries were coated simply by successively flushing with a polybrene (PB) and a poly(vinyl sulfonate) (PVS) solution. A protein test mixture was used to evaluate the performance of the coated capillaries. Comparisons with bare fused-silica capillaries were made. Several background electrolytes (BGEs) were tested in combination with the PB-PVS coating, showing that optimum performance was obtained for the proteins using high BGE concentrations. With a 300 mM Tris phosphate buffer (pH 7.0), good plate numbers (150,000-300,000), symmetrical peaks, and favorable migration-time repeatabilities (RSDs below 0.8%) were obtained for the proteins. Using bare fused-silica capillaries, the protein peaks were significantly broadened and the migration-time RSDs often exceeded 5%. It is concluded that the PB-PVS coating effectively minimizes adverse protein adsorption and provides a very stable electroosmotic flow (EOF). We also investigated the potential of a commercially available bilayer coating (CEofix) for protein analysis. It is demonstrated that with this coating, good plate numbers and peak symmetries for proteins can be achieved when the CEofix BGE ("accelerator") is replaced by a common BGE such as sodium or Tris phosphate. Apparently, the negatively charged polymer present in the "accelerator" interacts with the proteins causing band broadening. The utility of the bilayer coatings is further illustrated by the separation of proteins such as interferon-alpha 2b, myoglobin and carbonic anhydrase, by the analysis of a degraded insulin sample in time, and by the profiling of the glycoprotein ovalbumin. In addition, it is demonstrated that even in the presence of concentrations of human serum albumin in the sample of up to 60 mg/mL, the PB-PVS coating still provides reproducible protein separations of good performance.