Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ).
Since the first description of bisphosphonate-related osteonecrosis of the jaw (BRONJ), numerous research groups have focused on possible pathological mechanisms including the suppression of the bone turnover of the jaw, antiangiogenic effects and soft tissue toxicity. In our review we focused on summarizing the role of the soft tissues in the development and progression of BRONJ. The biological behavior of fibroblasts can be significantly influenced by bisphosphonates (BP) such as a concentration dependent reduction of cell viability. High concentrations of BP can induce apoptosis and necrosis of the cells. Comparable effects could be detected for keratinocytes. Compared to non-nitrogen containing bisphosphonates, nitrogen-containing BP have worse effects on cell biology by blocking the mevalonate pathway. Further, the cell architecture and expression levels of several genes and proteins are significantly disturbed by BP. These inhibitory effects of BP are in accordance with BP-related reduced angiogenesis and neovascularization and could underline the hypothesis that inhibition of fibroblasts and keratinocytes results in delayed wound healing and can induce and trigger BRONJ.


Barriers to prevention of cervical cancer in the city of Porto Velho, Rondônia, Brazil.
Identify the related factors with the no adhesion of women in preventive practices of cervical cancer (CC), in a coverage area of a Family Health Team in the city of Porto Velho (Rondônia, Brazil). Descriptive, cross-sectional study held in 2013. It was applied a questionnaire containing questions related to the health belief model (HBM) of the instrument "Champion's Health Belief Model Scale", validated and culturally adapted to Brazil, to 286 women. 87.7% of women state that they have been submitted to prevention of CC; Regarding the parameters of the HBM, it was found that 74.5% of the women had low scores for the perception of susceptibility to the disease; equal percentage of women had an moderate perception of severity; 52.8% have an moderate perception of the benefits gained from the examination of prevention; and 51.4% have moderate perception of barriers to perform the same test. the process involving the prevention of CC involves the supply of services and availability of skilled professionals. However, the adoption of preventive behavior depends not only on external factors, but also own subjective factors to women.


Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Korea.
Pyrazinamide (PZA) is one of the most important drugs for the treatment of Mycobacterium tuberculosis infection. However, the increasing frequency of PZA-resistant strains limits its effectiveness. In Korea, most PZA-resistant strains also exhibit both isoniazid and rifampin resistance making it essential to identify these resistant strains accurately and rapidly for effective treatment of mycobacterial infection. In this study, the characteristics and frequency of mutations of the pncA gene encoding pyrazinamidase were investigated in PZA-resistant clinical isolates from Korea. Automated DNA sequencing was used to evaluate the usefulness of DNA-based detection of PZA resistance. Among 95 PZA-resistant clinical isolates, 92 (97%) exhibited mutations potentially affecting either the production or the activity of the enzyme. Mutations were found throughout the pncA gene including the upstream region. Single nucleotide replacement appeared to be the major mutational event (69/92), although multiple substitutions as well as insertion and deletion of nucleotides were also identified. The high frequency of pncA mutations observed in this study supports the usefulness of DNA-based detection of PZA-resistant M. tuberculosis. Having verified the scattered and diverse mutational characteristics of the pncA gene, automated DNA sequencing seems to be the best strategy for rapid detection of PZA-resistant M. tuberculosis.


Genetic polymorphisms for 19 autosomal STR loci of Chongqing Han ethnicity and phylogenetic structure exploration among 28 Chinese populations.
The allele frequencies and forensic statistical parameters of 19 autosomal short tandem repeat (STR) loci (D8S1179, D21S11, D7S820, CSF1P0, D3S1358, THOl, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, FGA, D6S1043, Penta D, Penta E, and D12S391) included in the Goldeneye™ DNA ID system 20A kit were obtained in 671 Chinese Han individuals residing in Chongqing, Southwest China. All 19 STR loci were identified in agreement with the Hardy-Weinberg equilibrium. A total of 238 alleles were observed with corresponding allele frequencies that varied from 0.0007 to 0.5119. The combined power of discrimination and the combined probability of exclusion for 19 STR loci in the Chongqing Han population were 0.99999999999999999999998954 and 0.99999998387, respectively. The findings indicated that the 19 autosomal STR loci were highly polymorphic in the Chongqing Han population and can be used as a powerful tool in personal identification and parentage testing. Our genetic study enriched the Chinese local forensic reference database. Population comparisons and phylogenetic analyses revealed that genetic heterogeneity widely existed among the Chongqing Han, Xinjiang Uyghur, and Kazakh populations as well as demonstrated that genetic similarity was tightly associated with those of close geographic origin or of the same ethnic origin.


Techniques for establishing schedules with wheel running as reinforcement in rats.
In three experiments, access to wheel running was contingent on lever pressing. In each experiment, the duration of access to running was reduced gradually to 4, 5, or 6 s, and the schedule parameters were expanded gradually. The sessions lasted 2 hr. In Experiment 1, a fixed-ratio 20 schedule controlled a typical break-and-run pattern of lever pressing that was maintained throughout the session for 3 rats. In Experiment 2, a fixed-interval schedule of 6 min maintained lever pressing throughout the session for 3 rats, and for 1 rat, the rate of lever pressing was positively accelerated between reinforcements. In Experiment 3, a variable-ratio schedule of 20 or 35 was in effect and maintained lever pressing at a very stable pace throughout the session for 2 of 3 rats; for 1 rat, lever pressing was maintained at an irregular rate. When the session duration was extended to successive 24-hr periods, with food and water accessible in Experiment 3, lever pressing settled into a periodic pattern occurring at a high rate at approximately the same time each day. In each experiment, the rats that developed the highest local rates of running during wheel access also maintained the most stable and highest rates of lever pressing.


Effects of tadalafil (PDE5 inhibitor) and roflumilast (PDE4 inhibitor) on airway reactivity and markers of inflammation in ovalbumin-induced airway hyperresponsiveness in guinea pigs.
Selective phosphodiesterase (PDE) 4 inhibitors have recently been introduced into the therapy of chronic obstructive pulmonary disease. However, suppression of airway reactivity and eosinophilic inflammation by increased intracellular cAMP could be beneficial in bronchial asthma as well. PDE5 inhibitors are used for the therapy of erectile dysfunction, pulmonary hypertension, and other cardiovascular diseases, but an expression of PDE5 in several immune cells suggests its perspectives in inflammation, as well. To bring a new information on the therapeutically relevant potential of PDE4 and PDE5 inhibitors in allergic inflammation, this study evaluated the effects of 7-days administration of PDE5 inhibitor tadalafil and PDE4 inhibitor roflumilast in experimentally-induced allergic inflammation and compared their action with effects of a corticosteroid dexamethasone. In the study, male adult guinea pigs were used. Control group was non-sensitized, while other animals were ovalbumin-sensitized over two weeks and thereafter treated intraperitoneally for 7 days with tadalafil or roflumilast (daily dose 1.0 mg/kg b.w. each), with their combination (0.5 mg/kg b.w. each), with dexamethasone (1.0 mg/kg b.w.), or with vehicle. Both tadalafil and roflumilast reduced the specific airway resistance after nebulization of histamine (a marker of in vivo airway reactivity), and decreased the in vitro airway reactivity to cumulative doses of histamine and acetylcholine in tracheal strips (significant for roflumilast) and in lung tissue strips (significant for both agents), analyzed by organ bath method. These changes were associated with decreased numbers of circulating leukocytes and eosinophils and lower production of interleukins 4 and 5, nuclear factor kappa B and tumor necrosis factor alpha in the lung. Similar effects were observed also for dexamethasone. Roflumilast and tadalafil, but not their combination with reduced doses, lowered lung TBARS, a marker of lipid oxidation. Selective PDE5 inhibition alleviated allergic airway inflammation, but it was less potent than PDE4 inhibition, whereas anti-inflammatory action of the PDE inhibitors was comparable to the effects of dexamethasone.


Emergency Medicine Training Programs in Low- and Middle-Income Countries: A Systematic Review.
Despite the growing interest in the development of emergency care systems and emergency medicine (EM) as a specialty globally, there still exists a significant gap between the need for and the provision of emergency care by specialty trained providers. Many efforts to date to expand the practice of EM have focused on programs developed through partnerships between higher- and lower-resource settings. To systematically review the literature to evaluate the composition of EM training programs in low- and middle-income countries (LMICs) developed through partnerships. An electronic search was conducted using four databases for manuscripts on EM training programs - defined as structured education and/or training in the methods, procedures, and techniques of acute or emergency care - developed through partnerships. The search produced 7702 results. Using a priori inclusion and exclusion criteria, 94 manuscripts were included. After scoring these manuscripts, a more in-depth examination of 26 of the high-scoring manuscripts was conducted. Fifteen highlight programs with a focus on specific EM content (i.e. ultrasound) and 11 cover EM programs with broader scopes. All outline programs with diverse curricula and varied educational and evaluative methods spanning from short courses to full residency programs, and they target learners from medical students and nurses to mid-level providers and physicians. Challenges of EM program development through partnerships include local adaptation of international materials; addressing the local culture(s) of learning, assessment, and practice; evaluation of impact; sustainability; and funding. Overall, this review describes a diverse group of programs that have been or are currently being implemented through partnerships. Additionally, it highlights several areas for program development, including addressing other topic areas within EM beyond trauma and ultrasound and evaluating outcomes beyond the level of the learner. These steps to develop effective programs will further the advancement of EM as a specialty and enhance the development of effective emergency care systems globally.


Identification of New Potent Human Uncoupling Protein 1 (UCP1) Agonists Using Virtual Screening and in vitro Approaches.
Recent studies suggested that activation of Uncoupling Protein 1 (UCP1) has become an appealing therapeutic strategy against obesity and diabetes. In our research, the 3D structure of UCP1 was constructed through homology modelling, refined through molecular dynamics simulation, and evaluated by Ramachandran plot, the molecular docking of UCP1 activators brought about the proposal of an interaction mode inside the UCP1 active site. Remarkably, Reside Lys126 formed hydrogen bond; residues Pro121, Val125, Tyr146, Tyr149 and Arg150 formed hydrophobic interaction, which are key amino acids within UCP1 site. Then a pharmacophore model was generated consisting of three hydrophobic groups, a negative center and an additional hydrophobic group. Pharmacophore-based virutal screening of Specs database yield 5 hits. In vitro assay indicated ZINC 04660290 significantly increased the protein expression of UCP1 and decreased the fat droplet in a dose-dependent manner. Besides, pharmacokinetic properties were predicted for those five compounds through ADME/T prediction. All of these will guide us to design new UCP1 activators for the treatment of obesity and diabetes.


Differential localizations of the transient receptor potential channels TRPV4 and TRPV1 in the mouse urinary bladder.
We studied the localization and physiological functions of the transient receptor potential (TRP) channels TRPV1 (TRP vanilloid 1) and TRPV4 (TRP vanilloid 4) in the mouse bladder, because both channels are thought to be mechanosensors for bladder distention. RT-PCR specifically amplified TRPV4 transcripts from the urothelial cells, whereas TRPV1 transcripts were barely detectable. ISH experiments showed that TRPV4 transcripts were abundantly expressed in the urothelium, whereas TRPV1 transcripts were not detectable in the urothelial cells. Immunoblotting and IHC studies showed that TRPV4 proteins were mainly localized at the basal plasma membrane domains of the basal urothelial cells. In contrast, TRPV1-immunoreactivities were found not in the urothelial cells but in the nerve fibers that innervate the urinary bladder. In Ca(2+)-imaging experiments, 4alpha-phorbol 12,13-didecanoate, a TRPV4 agonist, and hypotonic stimuli induced significant increases in intracellular calcium ion concentration ([Ca(2+)](i)) in isolated urothelial cells, whereas capsaicin, a TRPV1 agonist, showed no marked effect on the cells. These findings raise the possibility that, in mouse urothelial cells, TRPV4 may contribute to the detection of increases in intravesical pressure related to the micturition reflex.


Engineering a "steric doorstop" in rhodopsin: converting an inverse agonist to an agonist.
The crystal structures of rhodopsin depict the inactive conformation of rhodopsin in the dark. The 11-cis retinoid chromophore, the inverse agonist holding rhodopsin inactive, is well-resolved. Thr118 in helix 3 is the closest amino acid residue next to the 9-methyl group of the chromophore. The 9-methyl group of retinal facilitates the transition from an inactive metarhodopsin I to the active metarhodopsin II intermediate. In this study, a site-specific mutation of Thr118 to the bulkier Trp was made with the idea to induce an active conformation of the protein. The data indicate that such a mutation does indeed result in an active protein that depends on the presence of the ligand, specifically the 9-methyl group. As a result of this mutation, 11-cis retinal has been converted to an agonist. The apoprotein form of this mutant is no more active than the wild-type apoprotein. However, unlike wild-type rhodopsin, the covalent linkage of the ligand can be attacked by hydroxylamine in the dark. The combination of the Thr118Trp mutation and the 9-methyl group of the chromophore behaves as a "steric doorstop" holding the protein in an open and active conformation.


Colorectal endoscopic submucosal dissection: Recent technical advances for safe and successful procedures.
Endoscopic submucosal dissection (ESD) is very useful in en bloc resection of large superficial colorectal tumors but is a technically difficult procedure because the colonic wall is thin and endoscopic maneuverability is poor because of colonic flexure and extensibility. A high risk of perforation has been reported in colorectal ESD. To prevent complications such as perforation and unexpected bleeding, it is crucial to ensure good visualization of the submucosal layer by creating a mucosal flap, which is an exfoliated mucosa for inserting the tip of the endoscope under it. The creation of a mucosal flap is often technically difficult; however, various types of equipment, appropriate strategy, and novel procedures including our clip-flap method, appear to facilitate mucosal flap creation, improving the safety and success rate of ESD. Favorable treatment outcomes with colorectal ESD have already been reported in many advanced institutions, and appropriate understanding of techniques and development of training systems are required for world-wide standardization of colorectal ESD. Here, we describe recent technical advances for safe and successful colorectal ESD.


When is a residue not a residue?
Residues of veterinary products in food animals have been the subject of much debate in recent years. This paper attempts to define and classify what is meant by the term 'residue' and to discuss the toxicological significance of various types of residues and how they may be controlled to ensure that no hazard results to consumers.


Validating the DemTect with 18-fluoro-2-deoxy-glucose positron emission tomography as a sensitive neuropsychological screening test for early alzheimer disease in patients of a memory clinic.
The first study to validate the diagnostic value of the DemTect, a short neuropsychological screening test for dementia (8-10 min), using 18-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) in patients of a memory clinic. DemTect results were compared to the clinical diagnosis and to FDG-PET as a reference method for the early in vivo detection of Alzheimer's disease (AD). 38 patients (age 65.2 +/- 9.8 years, 16 men, 22 women) were investigated using clinical standard examination, FDG-PET, and cranial magnetic resonance imaging. According to NINCDS-ADRDA and Petersen's criteria, 18 patients had dementia of the Alzheimer type (DAT) and 13 patients received the diagnosis of mild cognitive impairment (MCI). Compared to the clinical diagnosis, a DemTect cutoff score of < or =11 points demonstrated good sensitivity (83.3%) and specificity (70.0%) for the detection of DAT, whereas the best cutoff score for MCI was < or =13 points with comparable sensitivity (84.6%) and specificity (85.7%). With regard to FDG-PET, the DemTect demonstrated excellent sensitivity (93%) and low specificity (50%) for the detection of AD-typical patterns of cerebral glucose metabolism (cutoff < or =13 points). DemTect is a favorable neuropsychological screening instrument for detecting cognitive dysfunction even in predementia stages of AD. For definite cross-sectional diagnosis, further diagnostic evaluation with higher specificity, e.g. comprehensive neuropsychological examination, FDG-PET or other biomarkers, is necessary.


Gcm2 regulates the maintenance of parathyroid cells in adult mice.
Glial cells missing homolog 2 (GCM2), a zinc finger-type transcription factor, is essential for the development of parathyroid glands. It is considered to be a master regulator because the glands do not form when Gcm2 is deficient. Remarkably, Gcm2 expression is maintained throughout the fetal stage and after birth. Considering the Gcm2 function in embryonic stages, it is predicted that Gcm2 maintains parathyroid cell differentiation and survival in adults. However, there is a lack of research regarding the function of Gcm2 in adulthood. Therefore, we analyzed Gcm2 function in adult tamoxifen-inducible Gcm2 conditional knockout mice. One month after tamoxifen injection, Gcm2-knockout mice showed no significant difference in serum calcium, phosphate, and PTH levels and in the expressions of calcium-sensing receptor (Casr) and parathyroid hormone (Pth), whereas Ki-67 positive cells were decreased and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) positive cell number did not change, as compared with those of controls. Seven months after tamoxifen injection, Gcm2-knockout mice showed shrinkage of the parathyroid glands and fewer parathyroid cells. A significant decrease was noted in Casr- and Pth-expressing cells and serum PTH and Ca levels, whereas serum phosphate levels increased, as compared with those of controls. All our results concluded that a reduction of Gcm2 expression leads to a reduction of parathyroid cell proliferation, an increase in cell death, and an attenuation of parathyroid function. Therefore, we indicate that Gcm2 plays a prominent role in adult parathyroid cell proliferation and maintenance.


Tracing thought through time and space: a selective review of bibliometrics in social work.
Bibliometrics is a field of research that examines bodies of knowledge within and across disciplines. Citation analysis, a component of bibliometrics, focuses on the quantitative assessment of citation patterns within a body of literature. Citation analysis has been used in social work to examine the quantity and the impact of the work of individuals and academic institutions. This paper presents a selective review of these uses of bibliometrics within social work.


Renal complications of cancer therapies.
Cancer patients often exhibit preexisting renal impairment and are simultaneously at risk for developing further kidney injury due to direct or indirect complications of oncological therapies. The nature of kidney injury is highly dependent on the therapy regimen used, and the spectrum of possible kidney stressors has widened as a result of the development of new therapeutic modalities such as molecular therapy or immunotherapy. Indirect renal complications are often due to volume depletion or other therapy-related side effects. Direct toxicity from "classic" chemotherapy treatments such as cisplatin usually leads to acute tubular necrosis, whereas treatment with protein kinase inhibitors is more likely to cause disorders such as thrombotic microangiopathy. Immunotherapy often affects kidneys through the development of acute interstitial nephritis. Because of the high risk of nephrological complications in oncological patients, close monitoring of renal function and the early involvement of a nephrologist are strongly recommended.


Kinesin family member 20B regulates tongue cancer progression by promoting cell proliferation.
Oral cancer refers to the malignant tumors that occur in the oral cavity, of which 80% are squamous cell carcinomas. The incidence of oral cancer accounts for ~5% of the incidence of systemic malignancies, with rapid progression, extensive infiltration and poor prognosis. In the present study, Kinesin family member (KIF)20B, a member of Kinesin‑6 family, was identified as a potential biomarker which could promote cancer progression. A total of 82 patients were recruited and KIF20B expression levels were investigated by immunohistochemistry, and were divided into high and low groups based on the median of KIF20B expression levels. The clinicopathological features and survival‑associated data of the two groups were analyzed and the results were provided as a table and by a Kaplan‑Meier plot, respectively. Additionally, KIF20B was successfully silenced in two tongue cancer cell lines, CAL‑27 and TCA‑8113. MTT and colony formation assay were performed to determine the changes of cell proliferation in knocked down‑KIF20B cell lines. In addition, proliferation‑associated proteins Ki67 and PCNA were investigated, by western blotting. In animal experiments, subcutaneous tumor formation was performed with control cells and cells with knocked down KIF20B, to determine the inhibitory effect of KIF20B in vivo. Firstly, it was found that there was significantly high expression levels of KIF20B in tongue cancer patients (P<0.05). Patients with high expression of KIF20B had poorer clinicopathological results including tumor differentiation level, lymph node metastasis and clinical stages. The overall survival and relapse‑free survival of high‑expression group were also poor. Secondly, after successful establishment of cells with knocked down KIF20B, this resulted in a notable reduction in cell proliferation in vitro. Subsequent western blotting further confirmed that Ki67 and PCNA expression levels had a significant decline. Finally, it was demonstrated that knocking down KIF20B could inhibit tumor volume growth in vivo. In conclusion, the high level of KIF20B in oral squamous cell carcinoma was significantly associated with poor clinicopathological features and survival. KIF20B might promote cancer development through enhancing cell proliferation in vitro, and might be a potential biomarker of oral squamous cell carcinoma.


A two-vessel aortic arch: Rare configuration with bilateral brachiocephalic arteries.
We present a case of type B aortic dissection with a rare aortic arch branching variation whereby two separate brachiocephalic trunks arise from the arch. This case also highlights the potential implications of this variant in the management of thoracic aortic dissections and aneurysms.


Amidase activity and thermal stability of human thrombin.
Previous studies of amidase activity of human alpha-thrombin have yielded variable results and the decrease of this activity as a function of time and temperature has never been quantified. As this protease is an efficient tool in biochemistry and biotechnology thanks to its extreme selectivity, amidase activity and stability of thrombin were investigated with the synthetic substrate Tos-Gly-Pro-Arg-pNa. Enzyme activity as a function of temperature showed an optimum peak at 45 degrees C. The pH dependence of the activity showed a maximum around 9.5. The addition of NaCl promoted an increase of the activity. Stability of thrombin decreased rapidly when increasing the temperature from 25-45 degrees C and when diluting the enzyme. The presence of glycerol and ethylene glycol promoted a small increase of thrombin half life, whereas polyethylene glycol had a more pronounced positive effect even at very low concentrations.


Tissue Expander Placement to Prevent the Adverse Intestinal Effects of Radiotherapy in Malignant Pelvic Tumors.
We herein report the findings of 3 patients with primary Ewing sarcoma in a pelvic lesion who underwent the placement of a tissue expander (TE) before radiation therapy to prevent the adverse effects of radiotherapy. The simulation study showed that the TE drastically reduced volume of the intestine that was irradiated at all dose levels. All patients could receive the scheduled dose of radiotherapy without any acute and late complications such as diarrhea, melena, the dislodging of the TE, infection, or the formation of fistulae. In the 4-year (minimum) observation period, we did not observe intestinal complications in any of our patients. TE placement is considered to be a safe and effective method for preventing the adverse effects of radiotherapy in pediatric malignant pelvic tumors.


Mouse one-cell embryos undergoing a radiation-induced G2 arrest may re-enter S-phase in the absence of cytokinesis.
PCC (premature chromosome condensation) can be used for visualizing and scoring damage induced by radiation in the chromatin of cells undergoing a G1 or G2 arrest. A method involving the fusion of irradiated single embryonic cells with single MI oocytes was used to induce PCC in mouse zygotes of the BALB/c strain, which suffer a drastic G2 arrest after X-irradiation (dose used 2.5 Gy). Other G2-arrested embryos were exposed in vitro to the phosphatase inhibitor calyculin A. Both methods furnished excellent chromosome preparations of the G2-arrested embryos. The mean number of chromosome fragments did not change significantly during G2 arrest, suggesting that zygotes of this strain are unable to repair DNA damage leading to such aberrations. Forty to fifty percent of the irradiated embryos were unable to cleave after G2 arrest and remained blocked at the one-cell stage for a few days before dying. PCC preparations obtained from such embryos suggested that about 30% of them had undergone a late mitosis not followed by cytokinesis and had entered a new DNA synthesis. These results are discussed in the light of recent observations in irradiated human cells deficient in the p53/14-3-3sigma pathway.


Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors.
To evaluate the single- and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors. In single-dose pharmacokinetic study, 16 patients were administered VSLI (1.5, 2.0, or 2.3 mg·m(-2)) through intravenous infusion. Another 6 patients receiving vincristine sulfate (VCR, 2.0 mg) were taken as the control. In multiple-dose pharmacokinetic study, 12 patients were administered VSLI (1.5 or 1.8 mg·m(-2)) through intravenous infusion weekly for 4 consecutive weeks. The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After intravenous infusion of the single dose of VSLI, the plasma concentrations were characterized by bi-exponential decline curves. No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups. Compared with the patients receiving VCR, the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC), and a decrease in plasma clearance rates. On the 4th cycle in the multiple-dose study, the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ). The calculated pharmacokinetic parameters from the subjects in the multiple- and single-dose (1.5 mg·m(-2)) groups had no significant differences. Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR, VSLI-associated adverse events were similar to those associated with conventional VCR. VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR. No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks. VSLI was generally tolerated in the subjects. The phase II dose of VSLI may be recommended as 4 doses of 1.5 mg·m(-2) for treatment of patients with advanced solid tumors.


Mucosal distribution of eosinophilic granulocytes within the gastrointestinal tract of horses.
To establish reference values for the range of the number of eosinophils found in equine gastrointestinal mucosa and to describe the distribution of this cell within the equine gastrointestinal mucosa. Gastrointestinal mucosal specimens from 14 adult horses euthanatized for reasons other than gastrointestinal disease. Gastrointestinal mucosal specimens were collected and grouped according to their anatomic regions. For histologic examination slides were stained with Luna's eosinophil stain to determine eosinophil accumulation and distribution. The mucosa was divided into 5 sections for each anatomic location, and the percentage of eosinophils in each of the 5 sections relative to the total eosinophil count in all sections was determined. Additionally, the number of eosinophils per square millimeter of mucosa was calculated as a measure of the degree of eosinophil accumulation. Lowest numbers of eosinophils were found in the stomach, and numbers increased from there to the cecum, then decreased from the ascending colon (right ventral colon, left ventral colon, pelvic flexure, left dorsal colon, and right dorsal colon) to small colon. In all gastrointestinal sections, most eosinophils were located near the muscularis mucosae and were rarely found near or on the luminal surface of the mucosa. The distribution of eosinophils in the gastrointestinal tract of horses followed a pattern within the mucosa and between different sections of the gastrointestinal tract. The derived reference values and distribution data could be used to detect changes in eosinophil response in the equine gastrointestinal mucosa caused by diseases states.


Genetics of acheiropodia (the handless and footless families of Brazil). VI. Formal genetic analysis.
A genetic analysis is presented of data from 22 Brazilian sibships with cases of acheiropodia (the handless and footless families of Brazil). Segregation analysis performed using a 16K CDC 3100 computer showed a segregation frequency of .245 +/- .040, which is close to the expected value of .25. No sporadic cases were detected. The ascertainment of the probands was through multiple incomplete selection (pi = .55 +/- .07). The data are consistent with the hypothesis of an extremely rare autosomal recessive gene as the etiological factor in acheiropodia. Prevalence is estimated as 29 +/- 4, which is the same as the number of high risk cases; gene frequency equals .0009 +/- .0005, and the incidence at birth is 4 times 10(-6) by the indirect method or 7 times 10(-6) by the direct method. The frequency of heterozygotes at birth is assumed to be 0.18% (450 times the frequency of affected). Population size is approximately 10 million, and the number of founders on a unique-mutation hypothesis is estimated as about 500. All these estimates are first approximations and must be accepted with caution.


Morphological diversity of anatomical strepsirrhinism and the evolution of the lemuriform toothcomb.
The hypothesis that the vomeronasal organ has an important functional relationship with, and led to the evolution of, the prosimian toothcomb has not been well tested. This paper examines the diversity of anatomical strepsirrhinism across several mammalian taxa to determine if fossil and living strepsirrhine primates exhibit any derived characters that may highlight the functional link between the vomeronasal organ and the toothcomb, and to examine the potential importance of anatomical strepsirrhinism to toothcomb origins. Results indicate that extant gregarious lemuriforms are derived in having a relatively wide interincisal gap, providing an unobstructed line of communication between the vomeronasal organ and anterior rostral structures such as the toothcomb. This finding is consistent with the proposal that anatomical strepsirrhinism is functionally related to use of the toothcomb in grooming. However, the importance of the vomeronasal organ to toothcomb origins is less clear. If the morphology of adapiforms and non-gregarious lemuriforms is representative of the morphology of basal lemuriforms, then it can be inferred that early lemuriforms did not possess the wide-gap autapomorphy; hence, anatomical evidence discussed here cannot be used to rule out non-social hypotheses of toothcomb origins.


Microsatellite markers in avocado (Persea americana Mill.): genealogical relationships among cultivated avocado genotypes.
Twenty-five microsatellite markers uniquely differentiated 35 avocado cultivars and two wild relatives. Average heterozygosity was high (60.7%), ranging from 32% in P. steyermarkii to 84% in Fuerte and Bacon. In a subset of 15 cultivars, heterozygosity averaged 63.5% for microsatellites, compared to 41.8% for restriction fragment length polymorphisms (RFLPs). A neighbor-joining tree, according to average shared allele distances, consisted of three clusters likely corresponding to the botanical races of avocado and intermediate clusters uniting genotypes of presumably racially hybrid origin. Several results were at odds with existing botanical assignments that are sometimes rendered difficult by incomplete pedigree information, the complexity of the hybrid status (multiple backcrossing), or both. For example, cv. Harvest clustered with the Guatemalan race cultivars, yet it is derived from the Guatemalan x Mexican hybrid cv. Gwen. Persea schiedeana grouped with cv. Bacon. The rootstock G875 emerged as the most divergent genotype in our data set. Considerable diversity was found particularly among accessions from Guatemala, including G810 (West Indian race), G6 (Mexican race), G755A (hybrid Guatemalan x P. schiedeana), and G875 (probably not P. americana). Low bootstrap support, even upon exclusion of (known) hybrid genotypes from the data matrix, suggests the existence of ancient hybridization or that the botanical races originated more recently than previously thought.


Sequence variants of the DFNB31 gene among Usher syndrome patients of diverse origin.
It has been demonstrated that mutations in deafness, autosomal recessive 31 (DFNB31), the gene encoding whirlin, is responsible for nonsyndromic hearing loss (NSHL; DFNB31) and Usher syndrome type II (USH2D). We screened DFNB31 in a large cohort of patients with different clinical subtypes of Usher syndrome (USH) to determine the prevalence of DFNB31 mutations among USH patients. DFNB31 was screened in 149 USH2, 29 USH1, six atypical USH, and 11 unclassified USH patients from diverse ethnic backgrounds. Mutation detection was performed by direct sequencing of all coding exons. We identified 38 different variants among 195 patients. Most variants were clearly polymorphic, but at least two out of the 15 nonsynonymous variants (p.R350W and p.R882S) are predicted to impair whirlin structure and function, suggesting eventual pathogenicity. No putatively pathogenic mutation was found in the second allele of patients with these mutations. DFNB31 is not a major cause of USH.


Transcatheter aortic valve implantation: Watch out for the leak, irrespective of aortic valve disease type.
Postprocedural aortic regurgitation (PAR) after transcatheter aortic valve implantation (TAVI) is associated with a worst clinical outcome. The presence of chronic aortic regurgitation in TAVI candidates increases PAR risk but not overall survival. Future valve prototypes will likely reduce the degree and frequency of this complication.


Unravelling the dynamics of soil microbial communities under the environmental selection and range shift process in afforestation ecosystems.
The process of forest range shift not only affects the vegetation aboveground but also influences the dynamics of belowground microbial communities. To investigate the changes in soil under forest range shift, we examined the natural forest soil microbiome along with its corresponding physicochemical properties, as well as the afforestation of natural forest by seedlings and sowing. By utilizing natural forests and employing different afforestation methods, we simulated the three stages of forest range shift: the staging stage, regeneration, and colonization. We employed network analysis and phylogenetic assemblages to examine the structure of soil microbial communities during these three stages in a macro-environmental change context. Ordination and regression analyses were also used to explore the correlation between microorganisms, environmental factors, and changes in their niches. The findings revealed that different afforestation (range shift) types led to distinct microbial compositions. Seedling afforestation exhibited similarities to mature forests, suggesting a significant influence on below-ground microorganisms. In contrast, sowing-based afforestation resulted in small changes in soil microbes, indicating a legacy effect on grassland soils. The impact of the rhizosphere on microbial composition remained consistent across the three forest types. Overall, this study underscores the significance of forest range shift in shaping soil microbial communities and emphasizes the need to consider these dynamics in forest management and restoration endeavours.


Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41.
On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A(1), NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure-activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A(12)), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A(12) could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.


Chemoconvulsant-induced seizure susceptibility: toward a common genetic basis?
Despite the efforts employed, understanding the genetic architecture underlying epilepsy remains difficult. To reach this aim, convulsive epilepsies are classically modeled in mice, where genetic studies are less constricting than in humans. Pharmacogenetic approaches are one major source of investigation where kainic acid, pentylenetetrazol, and the ss-carboline family represent compounds that are used extensively. Several quantitative trait loci (QTLs) influencing the convulsant effects of these drugs have been mapped using either recombinant inbred strains (RIS) or segregating F2 populations (or both). In our laboratory, we have recently mapped two QTLs for methyl 6, 7-dimethoxy-4-ethyl-ss-carboline-3-carboxylate (DMCM), and seizure response using an F2 method. One is located on the distal part of Chromosome 1, a region implicated in a number of other studies. Here, we address the general importance of this chromosomal fragment for influencing seizure susceptibility.


Internet psychotherapy and the future of personalized treatment.
Internet-delivered cognitive behavioral therapy (iCBT) was developed to overcome some of the barriers in accessing best practice face-to-face CBT. iCBT affords many benefits, such as high fidelity, greater accessibility, convenience, and reduced cost to patients and health-care systems. Recent meta-analyses of iCBT for depressive and anxiety disorders demonstrate large effect size for superiority of iCBT over control conditions (ES>.95; number needed to treat (NNT) = 2) and data collected in routine practice supports the effectiveness of these programs. Tailoring treatment to match patient variables may be one means to increase adherence and optimize clinical outcomes. However, we propose that a "personalized medicine" approach will require looking beyond patient characteristics and comorbidities to consideration of the cognitive processes that subserve depression and anxiety symptomatology.


Reduced Periprocedural Analgesia After Replacement of Water for Injection with Glucose 5% Solution as the Infusion Medium for 90Y-Resin Microspheres.
The primary aim of our study was to compare the need for periinterventional on-demand analgesia when water for injection (WFI) was replaced with glucose 5% (G5) for 90Y-resin microsphere administration. Forty-one patients who received 77 radioembolization procedures with G5 (2014-2015) were retrospectively matched with 41 patients (77 radioembolization procedures) who received radioembolization with WFI (2011-2014) at our center. The need for on-demand pain medication was chosen as an objective and accessible measure of periprocedural pain experienced by patients. Patients were well matched according to sex, age, tumor type and involvement, and prior antiangiogenic therapies. Periinterventional analgesic requirements were significantly lower for radioembolization procedures performed with G5 than WFI: 5 of 77 (6.5%) versus 29 of 77 (37.7%), P ≤ 0,001, respectively. Early stasis (defined as slowed antegrade flow, before total vascular stasis) occurred in 12 of 154 (7.8%) radioembolization procedures overall and was not different (P ≤ 0.229) between the 2 groups (4/77 [5.2%] vs. 8/77 [10.4%]). Slow pulsatile administration of 90Y-resin microspheres with WFI is associated with a low rate of stasis. Replacement of WFI with G5 significantly reduces the need for periprocedural analgesia. These data favor the use G5 for 90Y-resin microsphere implantation in daily practice.


Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation.
As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socio-economic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.


Determination of regional flavor differences in U.S. Cheddar cheeses aged for 6 mo or longer.
Cheddar cheese is a widely popular food in the United States. This product is produced in facilities across the United States and often marketed based on region of manufacture, implying that regional differences in flavor character of the cheese exist. This study was conducted to determine if regional differences in flavor exist in the aged U.S. Cheddar cheeses. Three times per year for 2 y, triplicate 18-kg blocks of Cheddar cheese (< 60 d old) were obtained from 19 manufacturing facilities located in 4 major cheese- producing regions/states: California, Northwest, Midwest, and Northeast. A trained sensory panel documented the flavor characteristics of cheeses after 6-, 9-, 12-, 18-, and 24-mo ripening at 7 degrees C. Regional differences were observed for specific flavors for cheeses manufactured in the Northwest, Midwest, and Northeast across ripening (P < 0.05), but the specific flavors responsible for these effects were not consistent across ripening. Similarly, cheese make procedure effects were also observed for specific flavors across ripening (P < 0.05), but these differences were also not consistent across ripening. The impact of region and cheese make procedure on flavor of the aged Cheddar cheeses was small in comparison to consistently documented, facility-specific flavor differences (P < 0.0001). Flavor profiles of aged Cheddar cheeses were most strongly influenced by practices specific to manufacturing facility rather than region of manufacture.


The neuroprotective effect of magnesium sulfate in preterm fetal mice.
To investigate the use of magnesium sulfate (MgSO4) as a neuroprotective agent in a mouse model of inflammation-associated and noninflammation-associated preterm birth. On embryonic day 15 of gestation, lipopolysaccharide (LPS) and mifepristone (RU486) were used, respectively, to create mouse models of inflammation and noninflammation-associated preterm birth. After intraperitoneal injection of LPS, RU486, or normal saline solution (NS), dams were randomized to intraperitoneal MgSO4 or NS injection. From the 6 treatment groups (NS+NS, LPS+NS, NS+MgSO4, LPS+MgSO4, RU486+NS and RU486+MgSO4), fetal brains were collected for Western blot analysis and neuronal cultures. Protein expression of S100B was assessed, and immunohistochemistry was performed to detect NeuN. The numbers of NeuN-labeled cells were counted using confocal laser scanning microscopy. The expression of S100B significantly differed among the groups and was decreased in the LPS+MgSO4 group compared to the LPS+NS group. The expression of S100B did not differ between the RU486+NS and RU486+MgSO4 groups. NeuN-labeled cells were increased in the LPS+MgSO4 group compared with the LPS+NS group. NeuN-labeled cells were decreased in the RU486+MgSO4 group compared with the RU486+NS group. We observed that prenatal treatment with MgSO4 was associated with decreased expression of S100B and increased numbers of NeuN-labeled cells in an inflammation-associated preterm mouse model but not in a noninflammation-associated preterm mouse model. Our results suggest that prenatal treatment of MgSO4 reduces inflammation-associated brain injury in fetal mice.


Resveratrol can only partially attenuate ethanol-induced oxidative stress in embryonic chick brains.
Ethanol (EtOH) exposure promotes increased levels of reactive oxygen species that degrade unsaturated long-chain membrane fatty acids within embryonic chick brains and is associated with apoptosis and reduced embryo viability. In vitro studies have demonstrated that resveratrol, a known antioxidant, attenuated EtOH-induced damage. In order to test whether or not resveratrol can attenuate EtOH-induced embryonic damage, fertile chicken eggs were injected daily with EtOH (6.05 mmol/kg egg) and various concentrations of trans-resveratrol (0-29.5 mmol/kg egg) during the first three days of embryonic development. At 11 days of embryonic development, viable embryos were collected, brains isolated, and brain membrane fatty acid composition analyzed. Embryonic EtOH exposure promoted fewer viable embryos at 11 days of development as compared to controls. Embryonic EtOH exposure also promoted reduced levels of unsaturated long-chain membrane fatty acids, increased levels of saturated short-chain membrane fatty acids, and elevated brain lipid hydroperoxides (LPO) levels. Embryonic exposure to moderate (2.95 nmol/kg egg) and high (29.5 nmol/kg egg) levels of trans-resveratrol attenuated EtOH-induced changes in brain membrane fatty acid composition but failed to attenuate EtOH-induced increases in brain LPO levels and increased brain Casp-3 activities.


Cutaneous undifferentiated pleomorphic sarcoma is a pleomorphic dermal sarcoma.
Pleomorphic dermal sarcoma is a cutaneous soft tissue sarcoma that presents as a rapidly enlarging tumor, typically on a sun-exposed location of elderly individuals. The neoplasm shares many similar features - clinical, pathologic, immunohistochemical and genomic - with atypical fibroxanthoma. However, adverse histologic characteristics (deep subcutaneous invasion, tumor necrosis, lymphovascular invasion, and/or perineural invasion) differentiate pleomorphic dermal sarcoma from atypical fibroxanthoma and may account for the more aggressive biologic behavior of pleomorphic dermal sarcoma: local recurrence and metastases. The features of a woman with pleomorphic dermal sarcoma are described. Her sarcoma presented as a rapidly growing ulcerated red nodule on the left side of her face. Imaging studies were performed prior to surgery. The tumor was extirpated with a wide local excision and she received postoperative radiotherapy. There has been no recurrence or metastasis at one-year follow-up. Pleomorphic dermal sarcoma has previously been referred to as a malignant fibrous histiocytoma (until the term became antiquated) and an undifferentiated pleomorphic sarcoma. However, the latter term includes not only neoplasms from the skin but also sarcomas from internal organs, retroperitoneal and osteoid origin. Therefore, when classifying this undifferentiated soft tissue sarcomas of cutaneous origin, the term pleomorphic dermal sarcoma may be preferred.


Erectile Dysfunction in Young Myocardial Infarction Survivors: Evaluation, Follow Up.
Erectile dysfunction significantly affects quality of life in young men. Authors have evaluated erectile function in men with coronary artery disease (CAD) and the relationship between the degree of erectile dysfunction (ED) and the age of their first acute myocardial infarction (AMI). The incidence of erectile dysfunction in three groups of patients of AMI survivors was investigated: AMI survivors younger than 45 years, AMI survivors older than 65 years, and normal male population aged between 30 and 60 years. Erectile function was assessed by the International Index of Erectile Function (IIEF-5) questionnaire. In post-AMI male patients younger than 45 years ( n = 76), mild ED occurred in 26% and severe in 7%. In the older AMI group, mild ED occurred in 52% and severe in 38%. In the control group age matched to younger survivors, 96% denied ED and only one control patient had a score of 20 on the IIEF-5. A paradoxical result was observed in patients using beta blockers (BB), who had better scores than the group without BB. Statin treatment had a positive influence on the score in questionnaires. Those on statins had an average score of 21.0 ± 4.9 vs. without statin 17.7 ± 5.7, p = .03. The current findings identified that the prevalence of ED is relatively high in young patients with CAD and is related to treatment of the CAD. The overall increase in ED presence suggests that the background of their coronary event is not due to destabilization of single focused atheroma but may reflect a generalized atherosclerotic process.


Continuous three-dimensional radiation dosimetry in tissue-equivalent phantoms using electron paramagnetic resonance in L-alpha-alanine.
A new tissue-equivalent phantom material has been developed which also acts as a dosimeter. The new phantom material has a similar elemental composition to that of soft tissue and has a density 1.1 g/cm3. The phantom has an agar-gel base, and contains crystallized L-alpha-alanine which traps radiation-induced free radicals. Samples from the phantom were analyzed by an electron paramagnetic resonance (EPR) spectrometer and the intensity of the EPR signal was related to the absorbed dose. When calibrated, the phantom material acts as a dosimeter, with applications in radiation therapy.


Cervical spinal cord injury by a low-impact trauma as an unnoticed cause of cardiorespiratory arrest.
Cardiorespiratory arrest (CA) secondary to traumatic cervical spinal cord injury can occur in minor accidents with low-impact trauma and may be overlooked as the cause of CA in patients admitted in the coronary care unit. We present two patients admitted to the coronary care unit because of suspected CA of cardiac origin. Both patients were found in CA with asystole, one after collapsing in a shopping mall and falling down a few steps and the other in the street next to his bicycle. They underwent early pharmacologically induced coma and hypothermia precluding neurological examination. Both patients remained in coma after rewarming, with preserved brainstem reflexes but absent motor response to pain. One patient had post-anoxic myoclonus in the face without limb involvement. In both patients, median nerve somatosensory evoked potentials demonstrated bilateral absence of thalamocortical N19 responses and abnormal cervicomedullary junction potentials (N13 wave). Extensive diagnostic work-up did not find a cardiac cause of the CA, pulmonary thromboembolism, or intracranial haemorrhage. In both patients, cervical spinal cord injury was diagnosed incidentally 5 and 6 days after CA, when a brain magnetic resonance imaging performed to assess post-anoxic brain injuries detected spinal cord hyperintensities with fracture and luxation of the odontoid. Both patients died 11 and 8 days after CA. Low-impact traumatic cervical spinal cord injury should be considered in the diagnostic work-up of patients with CA of unknown cause.


Medical Futility and Involuntary Passive Euthanasia.
Conflicts between providers and patients or their families surrounding end-of-life care are both regrettable and extremely challenging, interpersonally and ethically, for all involved. These conflicts often implicate the concept of medical futility. The concept of futility is too often conflated with distinct concepts that are more ethically salient, including the fiduciary responsibility to assess surrogate decision-making, and distributive justice. By distinguishing these concepts from futility, it becomes clear that there are some situations in which forgoing life-sustaining treatment over objection is permissible, and perhaps even obligatory. But the justification lies in the constellation of rights and responsibilities surrounding surrogate decision-making, or in distributive justice, but not futility. Once futility is disambiguated from these other concepts, the practice of withholding or withdrawing life-sustaining treatment over the objection of a valid surrogate or a competent patient, based on the alleged futility of such treatment, is more clearly described as involuntary passive euthanasia.


Energy Criticality Avoidance-Based Delay Minimization Ant Colony Algorithm for Task Assignment in Mobile-Server-Assisted Mobile Edge Computing.
Mobile edge computing has been an important computing paradigm for providing delay-sensitive and computation-intensive services to mobile users. In this paper, we study the problem of the joint optimization of task assignment and energy management in a mobile-server-assisted edge computing network, where mobile servers can provide assisted task offloading services on behalf of the fixed servers at the network edge. The design objective is to minimize the system delay. As far as we know, our paper presents the first work that improves the quality of service of the whole system from a long-term aspect by prolonging the operational time of assisted mobile servers. We formulate the system delay minimization problem as a mixed-integer programming (MIP) problem. Due to the NP-hardness of this problem, we propose a dynamic energy criticality avoidance-based delay minimization ant colony algorithm (EACO), which strives for a balance between delay minimization for offloaded tasks and operational time maximization for mobile servers. We present a detailed algorithm design and deduce its computational complexity. We conduct extensive simulations, and the results demonstrate the high performance of the proposed algorithm compared to the benchmark algorithms.


How Is Fe-S Cluster Formation Regulated?
Iron-sulfur (Fe-S) clusters are fundamental to numerous biological processes in most organisms, but these protein cofactors can be prone to damage by various oxidants (e.g., O2, reactive oxygen species, and reactive nitrogen species) and toxic levels of certain metals (e.g., cobalt and copper). Furthermore, their synthesis can also be directly influenced by the level of available iron in the environment. Consequently, the cellular need for Fe-S cluster biogenesis varies with fluctuating growth conditions. To accommodate changes in Fe-S demand, microorganisms employ diverse regulatory strategies to tailor Fe-S cluster biogenesis according to their surroundings. Here, we review the mechanisms that regulate Fe-S cluster formation in bacteria, primarily focusing on control of the Isc and Suf Fe-S cluster biogenesis systems in the model bacterium Escherichia coli.


A phase I/II randomized trial of clofarabine or fludarabine added to idarubicin and cytarabine for adults with relapsed or refractory acute myeloid leukemia.
The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m2 was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = .50). In both arms, more than half of patients who had received only one prior line of therapy achieved remission. The median event-free survival for CIA and FIA was 2.0 and 1.9 months (p = .48), and the median overall survival was 6.3 and 4.7 months, respectively (p = .28). No significant differences in adverse events or early mortality rates were observed. Overall, CIA and FIA resulted in similar response rates and survival in patients with relapsed/refractory AML.


[Alternative immunization schedule and combined vaccines in paediatric practice].
European countries individually implement their national immunisation schedules adjusted to their economic situation, epidemiological risks and other socio-political factors. The polish schedule of compulsory vaccination includes an obligatory part financed by the state and the recommended one financed individually by parents of patients themselves. The officially registered multi component vaccines my become an alternative for the obligatory schedules. Benefits of combined vaccine comprise: reduced number injections per visit and reduced number of exposures to possible injection pain; less or no exposure to thiomersal; less time spent in doctor visit, less waste and increased injection safety with fewer syringes, reduced immunisation programme costs and facilitated addition data collection through easier documentation and simplified implementation of immunisation programmes.


Marital therapy for the elderly.
Little attention has been paid to marital therapy for the elderly in spite of its relevance to morale and emotional problems. Physical illness is of particular significance in altering the dynamics of the marital relationship. Retirement and financial problems, as well as changes in sexual activity and gender roles, are also important. However, radical changes in patterns of behaviour cannot be expected. Therapeutic techniques must be altered for this age group, and the therapist must be active, giving and concretely helpful. As with therapy for younger couples, children may need to be involved in the therapy sessions. Family physicians should be a main source of help for marital problems among the elderly. However, because problems related to countertransference must be faced, working with the elderly will not be for everyone.


The synthesis of biodegradable graft copolymer cellulose-graft-poly(L-lactide) and the study of its controlled drug release.
According to the concept of green chemistry and sustainable development, a new biodegradable copolymer comprised of hydrophobic poly(l-lactide) (PLLA) segments and hydrophilic cellulose segment (cellulose-g-PLLA) was designed and synthesized. The structure of the copolymer was characterized by (1)H NMR, FT-IR, (13)C NMR, DSC and WAXD. The cytotoxicity study shows that cellulose-g-PLLA exhibits good biocompatibility. The copolymer can self-assemble into micelles in water with the hydrophobic PLLA segments at the cores of micelles and the hydrophilic cellulose segments as the outer shells. Transmission electron microscopy (TEM) shows that the micelles exhibit nanospheric morphology within a size range of 30-80nm. The drug loaded micelles formed by the copolymer in aqueous media show sustained drug release which indicates their potential applicability in drug carrier.


Application of x-ray phase contrast imaging to microscopic identification of Chinese medicines.
In the last decade, x-ray phase contrast imaging (XPCI) has received considerable attention as a novel imaging technique, which has proved to be suitable for weakly absorbing materials such as biomedical samples and polymers. In this paper, the microstructures of traditional Chinese medicines (TCMs), which are used as judging criteria in the identification of TCMs, were investigated by XPCI based on a nano-focus x-ray tube. The results demonstrated that XPCI is a promising new method for the identification of TCMs, with advantages such as nondestructivity, no special sample preparation and suitability for thick samples.


Surveillance system assessment in Guinea: Training needed to strengthen data quality and analysis, 2016.
The 2014-2016 Ebola virus disease outbreak revealed the fragility of the Guinean public health infrastructure. As a result, the Guinean Ministry of Health is collaborating with international partners to improve compliance with the International Health Regulations and work toward the Global Health Security Agenda goals, including enhanced case- and community-based disease surveillance. We assessed the case-based disease surveillance system during October 1, 2015-March 31, 2016, in the Boffa prefecture of Guinea. We conducted onsite interviews with public health staff at the peripheral (health center), middle (prefectural), and central (Ministry of Health) levels of the public health system to document leadership structure; methods for maintaining case registers and submitting weekly case reports; disease surveillance feedback; data analysis; and baseline surveillance information on four epidemic-prone diseases (cholera, meningococcal meningitis, measles, and yellow fever). The surveillance system was simple and paper-based at health centers and computer spreadsheet-based at the prefectural and central levels. Surveillance feedback to stakeholders at all levels was infrequent. Data analysis activities were minimal at the peripheral levels and progressively more robust at the prefectural and central levels. Reviewing the surveillance reports from Boffa during the study period, we observed zero reported cases of the four epidemic-prone diseases in the weekly reporting from the peripheral to the central level. Similarly, the national District Health Information System 2 had no reported cases of the four diseases in Boffa but did indicate reported cases among all four neighboring prefectures. Based on the assessment findings, which suggest low sensitivity of the case-based disease surveillance system in Boffa, we recommend additional training and support to improve surveillance data quality and enhance Guinean public health workforce capacity to use these data.


Validation and pharmacokinetic application of a method for determination of doxazosin in human plasma by high-performance liquid chromatography.
A simple high-performance liquid chromatographic method for the determination of doxazosin in human plasma was developed and validated. Prazosin was used as internal standard. After extraction twice with ethyl acetate, chromatographic separation of doxazosin in human plasma was carried out using a reversed-phase Apollo C18 column (250 x 4.6 mm, 5 microm) with mobile phase of methanol-acetonitrile-0.04 m disodium hydrogen orthophosphate (22:22:56, v/v/v) adjusted to pH 4.9 with 0.9 m phosphoric acid and quantified by fluorescence detection operated with an excitation wavelength of 246 nm and an emission wavelength of 389 nm. The lower limit of quantification (LLOQ) of this assay was 1 ng/mL using 500 microL human plasma. Linearity was established over the range 1-25 ng/mL (r2 > 0.9994). The intra- and inter-day accuracy ranged from 90.5 to 104.4% and the coefficient of variation were not more than 8.6% for both intra- and inter-day precision, over the range of the calibration curve. The absolute recoveries of doxazosin and prazosin from human plasma were more than 91%. Doxazosin demonstrated acceptable short-term, long-term and freeze-thaw stability in human plasma. The assay has been successfully applied to plasma sample ana-lysis for pharmacokinetic study.


Lithium-induced Hashimoto's encephalopathy: a case report.
To report on a patient with Hashimoto's encephalopathy induced by lithium. PATIENT AND INTERVENTIONS: A 61-year-old woman with a type II bipolar disorder and a history of lithium-induced thyrotoxicosis associated with silent thyroiditis was hospitalized to treat a severe major depressive episode. Given long-term treatment with levothyroxine for hypothyroidism that had resulted from silent thyroiditis, endogenous hormone in thyroid follicles was assumed to be minimized by the negative feedback, decreasing risk of recurrent thyrotoxicosis if lithium were restarted. Lithium clearly relieved the patient's depressive symptoms, but after 40 days encephalopathy developed. Thyrotoxicosis was ruled out, and serum antithyroid antibody titers were elevated. In the cerebrospinal fluid, protein content was substantially elevated and antithyroid antibodies were detected. Encephalopathy resolved dramatically after course of intravenous pulse therapy with methylprednisolone. We believe that autoantibodies against antigens shared by the thyroid gland and the brain were induced by exposure to lithium, causing the patient to develop Hashimoto's encephalopathy.


The Distribution of Available Prevention and Management Interventions for Fetal Alcohol Spectrum Disorder (2007 to 2017): Implications for Collaborative Actions.
The global prevalence of Fetal Alcohol Spectrum Disorder (FASD) remains high despite the various preventive and management interventions that have been designed and implemented to tackle the issue in various settings. The aim of the scoping review is to identify and classify prevention and management interventions of FASD reported globally across the life span and to map the concentration of these interventions across the globe. We searched some selected databases with predefined terms. Framework and narrative approaches were used to synthesize and report on the findings. Thirty-two prevention intervention studies and 41 management interventions studies were identified. All the interventions were reported to be effective or showed promising outcomes for the prevention and management of FASD, except four. Although Europe and Africa have a relatively higher prevalence of FASD, the lowest number of interventions to address FASD were identified in these regions. Most of the interventions for FASD were reported in North America with comparatively lower FASD prevalence. The uneven distribution of interventions designed for FASD vis-à-vis the burden of FASD in the different regions calls for a concerted effort for knowledge and intervention sharing to enhance the design of contextually sensitive preventive and management policy in the different regions.


Model-based large-dynamic iterative piston correction using extended objects.
Cophasing is crucial for segmented or sparse aperture telescopes to achieve high resolution. In this Letter, we propose a novel, to the best of our knowledge, model-based piston correction method that can remove large-scale piston errors within a few iterations using extended objects. The relation between the piston error and a metric function is derived theoretically under broadband illumination. The metric function is based on the image's power spectral density at the spatial frequency where the sidelobe peak of the modulation transfer function (MTF) appears. The piston error is iteratively estimated and corrected by introducing positive and negative piston biases. The dynamic range of piston correction can be as large as the coherence length of light. The correction accuracy in experiments is affected by the image noises and the accuracy of the introduced piston biases.


Monitoring Longitudinal Trends and Assessment of the Health Risk of Shigella flexneri Antimicrobial Resistance.
Shigella flexneri infection is the main cause of diarrhea in humans worldwide. The emergence of antimicrobial resistance (AMR) of S. flexneri is a growing public health threat worldwide, while large-scale studies monitoring the longitudinal AMR trends of isolates remain scarce. Here, the AMR gene (ARG) profiles of 717 S. flexneri isolates from 1920 to 2020 worldwide were determined. The results showed that the average number of ARGs in isolates has increased significantly, from 19.2 ± 2.4 before 1970 to 29.6 ± 5.3 after 2010. In addition, mobile genetic elements were important contributors to ARGs in S. flexneri isolates. The results of the structural equation model showed that the human development index drove the consumption of antibiotics and indirectly promoted the antibiotic resistance. Finally, a machine learning algorithm was used to predict the antibiotic resistance risk of global terrestrial S. flexneri isolates and successfully map the antibiotic resistance threats in global land habitats with over 80% accuracy. Collectively, this study monitored the longitudinal AMR trends, quantitatively surveilled the health risk of S. flexneri AMR, and provided a theoretical basis for mitigating the threat of antibiotic resistance.


Self-assembly of colloidal nanoscale particles: fabrication, properties and applications.
Self-assembly is a spontaneous process by which molecules to macroscopic entities assembled into one-, two- and three-dimensional ordered array. Even though, much attention has been focused on molecular self-assembly, numerous fascinating applications of self-assembling processes can be found at nanoscale to microscale level. Well-defined ordered structures prepared through the self-assembly of colloidal nanoscale to microscale particles, provide new opportunities for optimizing, tuning and/or enhancing the properties and performance of the materials. In this review, we have provided a concise and comprehensive account of the latest research and development activities in the fabrication, properties and applications of self-assembled structures from colloidal building blocks of various metals, semiconductors, oxides and polymers. The applicability, limitations and potential of different self-assembly techniques are also discussed.


Facile One-Step Electrodeposition Preparation of Cationic Pillar[6]arene-Modified Graphene Films on Glassy Carbon Electrodes for Enhanced Electrochemical Performance.
In the present work, we have developed a facile one-step route for preparing electrochemically reduced graphene oxide-cationic pillar[6]arene (ErGO-CP6) nanocomposite films on glassy carbon electrodes (GCEs) directly from graphene oxide-cationic pillar[6]arene (GO-CP6) colloidal solution by using a pulsed electrodeposition technique. The electrocatalytic activity of ErGO-CP6 was examined by studying the oxidations of five purine bases [adenine (A), guanine (G), xanthine (X), hypoxanthine (HX), and uric acid (UA)]. It enhanced the oxidation currents of A, G, X, HX, and UA when compared to unmodified ErGO films and bare GCE, which is considered to be the synergetic effects of the graphene (excellent electrical properties and large surface area) and CP6 molecules (high inclusion complexation and enrichment capability).


Characteristics and Results of the Management of Diffuse Large B-Cell Lymphomas: The Experience of Côte d'Ivoire.
Diffuse large B-cell lymphomas have been little studied in black Africans. The purpose of our study was to determine the characteristics and results of the management of these lymphomas. Patients and Methods. In a descriptive and analytic retrospective study we studied the medical records of 63 patients with diffuse large B-cell lymphoma hospitalized during the period from 1991 to 2007. The diagnosis was made after lymph node or organ biopsy. Response to treatment, OS, PFS, and toxicity were studied. The complete response has been analyzed univariate and multivariate analysis. Results. The median age was 42 years. The sex ratio was 2. The HIV serology was positive in 11 cases, and 8 patients had antiretroviral therapy. In 71% the lymphoma was at stages III and IV of Ann Arbor. IPI was ≥3 in 65%. Complete remission was achieved in 43%. Only 43% of patients had had a good compliance. Progression-free survival at 3 years was 32%, and overall survival at 3 years was 50%. 13% of patients were lost to follow up, and 51% of them died. In terms of analysis the complete remission rate was influenced by the stage of Ann Arbor (P < 0.0001), biological b symptoms (P < 0.01), the IPI (P < 0.0001), and the socioeconomic standing (P = 0.001). In multivariate analysis, only IPI and stage of Ann Arbor influence the complete remission.


Patterns and trends of nurses' well-being and patient outcomes in the Journal of Nursing Management.
The aim of this presentation is to provide a brief overview of general patterns and trends in publications in the Journal of Nursing Management with a focus on nurses' well-being and patient outcomes in the Journal of Nursing Management and to suggest ways in which this information could be utilised to inform the future strategic direction of and future research and publications within this topic. A search within the Scopus database (August 2021) revealed that there have been 2,911 publications in Journal of Nursing Management since it's foundation in 1993. Most of these papers are research articles (80%% n=2,343), predominantly from countries with English fluency. A search within Journal the using the CINAHL database (August 2021) using key search terms related to nurses, wellbeing, patient outcomes and patient satisfaction revealed 57 papers concerned, broadly speaking, with nurses' well-being. Two further papers were identified that related to nurses' well-being and patient satisfaction and one that explored well-being and patient outcomes. However, none of these three later papers explored the relationship between nurses' well-being and patient outcomes or satisfaction in any meaningful way, rather the discussion related to both concepts (outcomes and satisfaction) was broadly discussed, alluding to a relationship but not providing any concrete evidence of this. Emerging themes within the 57 papers were as follows: sources and effects of dissatisfaction and stress among nurses; effects of COVID; influencing factors; supportive factors and values-based leadership. Two approaches to measurement of nurse well-being were noted, a demand-support-control model (Alfaro-Díaz et al 2020) and the Warwick-Edinburgh Mental Well-being Scale (Cilar et al 2020). The findings also revealed that discussions on this topic within the Journal took place in the last two decades, with the first paper emerging in 2001. The majority of papers were published in the last 5 years. Nurses' well-being was generally not referred to specifically, but rather explored and/or discussed within the context of satisfaction/dissatisfaction and/or stress.


The diagnostic accuracy of MRI versus CT imaging for osteoid osteoma in children.
Advanced imaging often is obtained in children suspected of having osteoid osteoma. We hypothesized that magnetic resonance imaging gives a falsely aggressive appearance and that computed tomography is better for identifying osteoid osteoma. This is the first prospective blinded study comparatively assessing these imaging studies in children. Twelve preoperative magnetic resonance imaging scans of confirmed cases of osteoid osteoma were collected. Three radiologists blinded to the diagnosis reviewed these images. Only a clinical history of skeletal pain was given. Lesions were classified as benign-latent, benign-aggressive, or malignant. Radiologists were asked to list their primary diagnosis (with a confidence level from 1-10). Seven of these 12 children also had computed tomography scans that subsequently were reviewed in similar manner. With computed tomography scans, lesions were accurately identified as benign-latent (15/21 readings, 71%) and as osteoid osteoma (14/21 readings) more frequently than with magnetic resonance imaging scans (7/36 readings, 19%). Diagnostic study, Level III-1 (study of nonconsecutive patients--no consistently applied reference gold standard). See the Guidelines for Authors for a complete description of levels of evidence.


The Role of Parental ADHD in Sustaining the Effects of a Family-School Intervention for ADHD.
This study investigated the extent to which parental Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms impact child and parent outcomes following a multimodal family-school intervention, the Family School Success (FSS) program, when compared to an active-control condition (CARE). Participants were 139 children with ADHD (67% male; 91% non-Hispanic; 77% Caucasian; Grades 2-6) and their primary caretaker (91% female; ages 26-59) who participated in a randomized clinical trial evaluating the efficacy of FSS. Associations were examined between parent-reported ADHD symptoms at baseline and intervention outcomes reported by parents and teachers after treatment and at a 3-month follow-up, including child homework and classroom impairments, child ADHD and oppositional defiant disorder symptoms, parenting behaviors, and parent-teacher relationship quality. Across both treatment conditions, parental ADHD was not associated with parent or child outcomes at postassessment. However, differences emerged between the two treatment groups at follow-up for parents with ADHD, particularly when an empirically supported symptom cutoff was used to identify parents at risk for having ADHD. In FSS, but not in CARE, parental ADHD was associated with declines in treatment gains in the quality of the parent-teacher relationship and the child's homework performance. Parents at risk for ADHD had difficulty maintaining treatment effects for themselves and their child in the FSS intervention but not in CARE. The supportive and educational components central to the CARE intervention may be helpful in promoting the sustainability of psychosocial interventions for children with ADHD who have parents with elevated ADHD symptoms.


Serotonin, atherosclerosis, and collateral vessel spasm.
Studies on animal models demonstrate that platelet products contribute to vascular spasm in ischemic syndromes and that this is reversible with administration of ketanserin and thromboxane synthesis inhibitors. Laboratory animals (dogs, rabbits, and rats) that had femoral artery ligations exhibited supersensitivity to serotonin within days in their collateral blood vessels. This supersensitivity lasted at least 6 months. The response to serotonin was reversed by ketanserin, but not by 5HT-1 antagonists. Supersensitivity does not extend to norepinephrine, and alpha blockers do not influence the response to serotonin. It appears that platelet activation by endothelial injury contributes to ischemia through blood vessel occlusion and vascular spasm. When platelet activation occurs in vivo, blood vessel occlusion and vascular spasm are reversible in part by using ketanserin or agents that block thromboxane synthesis or its action. Combining both classes of agents reverses spasm completely. These findings support existing evidence that platelet products contribute to vascular disease, and provide an approach to improved management with currently available pharmacologic agents.


[Clinical characteristics in multiple endocrine neoplasia type 1 in Japan: a review of 106 patients].
A review of 106 patients with multiple endocrine neoplasia (MEN) type 1 reported between 1966-1989 in Japan was conducted in order to clarify the natural history of this disease. Sporadic MEN 1 was found in 61 patients, and familial MEN 1 was found in 45 patients from 15 families. The mean ages at diagnosis of the two groups were 46.2 and 41.3 years, respectively, and the male to female ratio was 3:4. With regards to the involvement of the pituitary, parathyroid and endocrine pancreas, the combination of three endocrine glands was 31%, and that of two was 48%, in which the pituitary, parathyroid and endocrine pancreas had tumorous lesions in 60%, 88% and 63%, respectively. The first clinical manifestations of MEN 1 were the symptoms of hyperparathyroidism (32%), pituitary tumors (26%), peptic ulcer (28%) and hypoglycemia (13%). These symptoms appeared between 6 and 57 years of age (mean 34 years). The main clinical symptoms of the pituitary tumors were acromegaly and gigantism (37%), galactorrhea-amenorrhea syndrome (20%), Cushing's disease (10%) and visual disturbance due to compression of the tumor (20%). The clinical manifestations of hyperparathyroidism were mainly asymptomatic hypercalcemia (41%), nephrolithiasis (42%) and osteitis fibrosa (5%). In the patients with pancreatic tumor, Zollinger-Ellison syndrome (52%) and hypoglycemic symptoms (42%) were found. Tumors in the adrenal cortex, thyroid, carcinoid and lipoma were detected in association with MEN 1 in the frequencies of 28%, 21%, 9% and 5%, respectively. Death was reported in 37 patients between 9 and 86 years of age (mean 50.0 years). The cause of death was gastrointestinal bleeding and perforation (45%), surgery (24%) and disseminated carcinomatosis (18%). Recently, the gene predisposing to this syndrome has been assigned to chromosome 11 (11q13) in non-Japanese cases but not yet in Japanese MEN 1 patients.


Detection of subclinical central nervous system abnormalities in two patients with mucolipidosis III by the use of motor and somatosensory evoked potentials.
We have studied motor, somatosensory, brainstem auditory and visual evoked potentials in two patients with ML III without overt neurologic symptoms. Both our patients showed abnormal central motor functions upon magnetic cortical stimulation; in addition, in one of them, we observed a decreased conduction velocity of the nervous impulse in the central tract of the upper limb somatosensory pathway, from the cervical spinal cord to sensory cortex. Our results suggest that central motor pathways are affected in both children and also that the central somatosensory system is involved in one of them. We propose that the electrophysiological techniques might be of help to detect, locate and monitor minimal neurological lesions of mild lysosomal disorders like ML III.


Hypothetical mortality risk associated with spiral tomography of the maxilla and mandible prior to endosseous implant treatment.
Radiation dose delivered from the SCANORA radiography unit during the cross-sectional mode for dentotangential projections was determined. With regard to oral implantology, patient situations of an edentulous maxilla and mandible as well as a single tooth gap in regions 16 and 46 were simulated. Radiation doses were measured between 0.2 and 22.5 mGy to organs and tissues in the head and neck region when the complete maxilla or mandible was examined. When examining a single tooth gap, only 8% to 40% of that radiation dose was generally observed. Based on these results, the mortality risk was estimated according to a calculation model recommended by the Committee on the Biological Effects of Ionizing Radiations. The mortality risk ranged from 31.4 x 10(-6) for 20-year-old men to 4.8 x 10(-6) for 65-year-old women when cross-sectional imaging of the complete maxilla was performed. The values decreased by 70% when a single tooth gap in the molar region of the maxilla was radiographed. The figures for the mortality risk for examinations of the complete mandible were similar to those for the complete maxilla, but the mortality risk decreased by 80% if only a single tooth gap in the molar region of the mandible was examined. Calculations according to the International Commission on Radiological Protection carried out for comparison did not reveal the decrease of the mortality risk with age and resulted in a higher risk value in comparison to the group of 35-year old individuals in calculations according to the Committee on the Biological Effects of Ionizing Radiations.


Interaction of CpG-oligodeoxynucleotides with Toll like receptor 9 induces apoptosis and modulates metaloproteinase-2 activity in human intestinal epithelium.
Recent reports have indicated different effects of immunostimulatory sequences containing CpG-Oligodeoxynucleotides (ODN) on various immune cells. However, the exact role of CpG-ODN in the human gut is unclear. In the present study, we assessed potential effects of CpG-ODN on non lymphoid cell (intestinal epithelial cell line HT-29) on a dose-response and time-course basis. Intestinal epithelial cell line HT-29 was treated with CpG-ODN (CpG 2006) and lipopolysaccharide (LPS) at 5, 10, 25, 50 microg/ ml and 1, 5, 10 microg/ ml concentrations, respectively. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, Metaloproteinase-2 (MMP-2) activity (using gelatin zymography) and apoptosis (using annexin-v flowcytometry method) assays were performed. Chloroquine treatment was also used for its inhibitory effect on endosomal acidification process to verify specific CpG-ODN and Toll Like Receptor 9 (TLR9) interactions. Cytotoxicity analysis of CpG-ODN showed that CpG-ODN increased significantly the proliferation of CpG-ODN treated cells, as compared to untreated cells, at concentrations of 10-25 microg/ml (p < 0.05). Overall MMP-2 activity analysis showed significant differences between treated and untreated cells. However, minimal changes were observed when MMP-2 activity was assessed per cell. Moreover, CpG-ODN treated cells demonstrated an increasing apoptosis rate of 0.8 %, 6.46 % and 14.21% at concentrations of 5, 10, 25 microg/ml, respectively. Collectively, our data indicated that intestinal epithelial cell line HT-29 is highly responsive to CpG effect in vitro and exhibits modified activities. The direct CpG-ODN and TLR-9 interactions in HT-29 cells could provide new approaches in malignant tumor therapeutic strategies.


Treponema pallidum subsp. pallidum with an Artificially impaired TprK antigenic variation system is attenuated in the Rabbit model of syphilis.
The TprK protein of the syphilis agent, Treponema pallidum subsp. pallidum (T. pallidum), undergoes antigenic variation in seven discrete variable (V) regions via non-reciprocal segmental gene conversion. These recombination events transfer information from a repertoire of 53 silent chromosomal donor cassettes (DCs) into the single tprK expression site to continually generate TprK variants. Several lines of research developed over the last two decades support the theory that this mechanism is central to T. pallidum's ability for immune avoidance and persistence in the host. Structural and modeling data, for example, identify TprK as an integral outer membrane porin with the V regions exposed on the pathogen's surface. Furthermore, infection-induced antibodies preferentially target the V regions rather than the predicted β-barrel scaffolding, and sequence variation abrogates the binding of antibodies elicited by antigenically different V regions. Here, we engineered a T. pallidum strain to impair its ability to vary TprK and assessed its virulence in the rabbit model of syphilis. A suicide vector was transformed into the wild-type (WT) SS14 T. pallidum isolate to eliminate 96% of its tprK DCs. The resulting SS14-DCKO strain exhibited an in vitro growth rate identical to the untransformed strain, supporting that the elimination of the DCs did not affect strain viability in absence of immune pressure. In rabbits injected intradermally with the SS14-DCKO strain, generation of new TprK sequences was impaired, and the animals developed attenuated lesions with a significantly reduced treponemal burden compared to control animals. During infection, clearance of V region variants originally in the inoculum mirrored the generation of antibodies to these variants, although no new variants were generated in the SS14-DCKO strain to overcome immune pressure. Naïve rabbits that received lymph node extracts from animals infected with the SS14-DCKO strain remained uninfected. These data further support the critical role of TprK in T. pallidum virulence and persistence during infection.


Dominance style of female white-faced capuchins.
Dominance style, the level of tolerance displayed by dominant individuals toward subordinate ones, is exhibited along a continuum from despotic to relaxed. It is a useful concept to describe the nature of dominance relationships in macaque species and it bridges among multiple features of dominance hierarchies, aggression, kinship and conflict resolution. Capuchins share many behavioral similarities with Old World monkeys and like macaques, may exhibit a suite of covarying characteristics related to dominance. Here, we provide an assessment of dominance style by examining measures of aggression and kin bias in 22 adult female white-faced capuchin monkeys (Cebus capucinus) in three social groups at Santa Rosa Sector, Costa Rica. We found that bidirectionality of aggression was low (mean = 6.9% ± SE 1.6). However, there were few significant correlations between kin relatedness and social behavior (approaching, grooming, proximity, and co-feeding), even though the intensity of kin bias in grooming was moderate and higher in the larger group. We conclude that patterns of aggression and kin-biased behavior in our study animals are dissimilar to the patterns of covariation observed in macaque species. While unidirectional aggression suggests a despotic dominance style, the moderate expression of kin bias suggests an intermediate to relaxed classification when compared with results from an analysis of 19 macaque species. Additional studies of capuchin species and behaviors associated with dominance style (i.e., conciliatory tendencies) would help to create a comparative framework for the genus Cebus, and allow for more detailed cross-species comparison of dominance relationships across all primates.


Inverse probability of treatment-weighted competing risks analysis: an application on long-term risk of urinary adverse events after prostate cancer treatments.
To illustrate the 10-year risks of urinary adverse events (UAEs) among men diagnosed with prostate cancer and treated with different types of therapy, accounting for the competing risk of death. Prostate cancer is the second most common malignancy among adult males in the United States. Few studies have reported the long-term post-treatment risk of UAEs and those that have, have not appropriately accounted for competing deaths. This paper conducts an inverse probability of treatment (IPT) weighted competing risks analysis to estimate the effects of different prostate cancer treatments on the risk of UAE, using a matched-cohort of prostate cancer/non-cancer control patients from the Surveillance, Epidemiology and End Results (SEER) Medicare database. Study dataset included men age 66 years or older that are 83% white and had a median follow-up time of 4.14 years. Patients that underwent combination radical prostatectomy and external beam radiotherapy experienced the highest risk of UAE (IPT-weighted competing risks: HR 3.65 with 95% CI (3.28, 4.07); 10-yr. cumulative incidence = 36.5%). Findings suggest that IPT-weighted competing risks analysis provides an accurate estimator of the cumulative incidence of UAE taking into account the competing deaths as well as measured confounding bias.


Possibilities of a viral etiology for human breast cancer. A review.
Previous studies related mouse mammary tumor virus (MMTV) to human breast cancer. However, the presence of human endogenous retroviruses (HERs) confounded these results. We selected a 660-bp sequence of the MMTV env gene with low homology to HER (or any other known gene) and searched for a sequence homologous to it, using the polymerase chain reaction (PCR). The 660-bp sequence was detected in 131 (39%) of 335 unselected breast cancers, in 2 (6.9%) of 29 fibroadenomas, and in 2 (1.65%) of 121 normal breast specimens. The sequence was not present in normal tissues, or in other human cancers or cell lines. Cloning and sequencing of the 660-bp sequence revealed that it is 95-98% homologous to MMTV env gene, but not the known HERs or other viral or human gene. Southern blot hybridization using labeled cloned sequences demonstrated that the 660-bp sequence was present in very low copy number as a 6-8 kb EcoRI fragment only in breast cancer samples and in some of the human breast cancer cell lines that were positive by PCR. Preliminary experiments using reverse transcriptase (RT)-PCR indicated that expression of the 660-bp sequence can be detected in 65% of the positive tumors. We were also able to identify in breast cancer DNA a segment of 1.6 kb comprising LTR and env gene sequences, which are homologous to MMTV, but not to the HERs. The origin of the MMTV-like sequences in tumor DNA could be the result of integrated MMTV-like sequences derived from a human mammary virus.


Hypersensitivity to antipyretics: pathogenesis, diagnosis, and management.
Antipyretics are commonly prescribed drugs and hypersensitivity occurs at rates of 0.01% to 0.3%. Hypersensitivity can be due to immune mechanisms that include type I to IV hypersensitivity. Type I hypersensitivity results from specific immunoglobulin E production following sensitisation on first exposure. Subsequent exposures elicit degranulation of mast cells, culminating an immediate reaction. Non-type I hypersensitivity is a delayed reaction that involves various effector cells, resulting in maculopapular rash, fixed drug eruptions, drug reaction with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Antipyretics also cause non-immune hypersensitivity via cyclooxygenase inhibition. Apart from hypersensitivity to parent compounds, hypersensitivity to excipient has been reported. Clinical manifestations of antipyretic hypersensitivity involve the skin, mucosa, or multiple organs. Diagnosis of hypersensitivity requires a detailed history taking and knowledge of any underlying disorders. Differential diagnoses include infection, inflammatory conditions, and antipyretics acting as co-factors of other allergens. Investigations include specific immunoglobulin E assays, lymphocyte transformation test, basophil activation test, and skin prick test. Lack of standardisation and a scarcity of available commercial reagents, however, limit the utility of these tests. A drug provocation test under close supervision remains the gold standard of diagnosis. A trial of the culprit drug or other structurally different antipyretics can be considered. Patients with confirmed hypersensitivity to antipyretics should consider either avoidance or desensitisation. Other theoretical options include subthreshold or low-dose paracetamol, cyclooxygenase-2 inhibitors, pre-medication with antihistamines with or without a leukotriene receptor antagonist, co-administration of prostaglandin E2 analogue, traditional Chinese medicine, or desensitisation if antipyretics are deemed desirable. Safety and efficacy of unconventional treatments warrant future studies.


Chiral N-Fmoc-beta-amino alkyl isonitriles derived from amino acids: first synthesis and application in 1-substituted tetrazole synthesis.
A novel class of optically active N-Fmoc-protected amino isonitriles has been described for the first time. Conversion of the carboxyl group of Fmoc-beta-amino acids into an isocyano group has resulted in a new class of N-urethane-protected amino isonitriles. All the isonitriles have been isolated as stable solids, purified, and completely characterized. A synthetic application of the obtained isonitriles has also been demonstrated through the synthesis of 1-substituted tetrazole analogues of amino acids via a 2 + 3 cycloaddition with trimethylsilyl azide.