Endovascular Management of Flush Common Iliac Artery Occlusive Disease: Challenges and Solutions.
The aim of this study was to assess the difficulties met with possible recommendations in management of flush common iliac artery occlusive disease (FCIAOD). This a prospective study assessing FCIAOD along the period of 24 months. We defined FCIAOD as more than 90% occlusion of diameter of common iliac artery (CIA) with less than 2 mm patent iliac stump from its origin from the abdominal aorta. Our study included 51 cases. Technical success was achieved in 47 patients (92%); 82.5% of cases were done via two accesses (65% of cases were done using bilateral femoral). Primary stenting was done in all cases. Sixty-eight percent of cases were treated by unilateral stents (81.3% of them were done using self-expandable) and 32% of cases were treated by kissing stents (50% using self-expandable). Prestent dilatation was selectively used in 77% of cases. Follow-up (12 months) revealed primary patency of 82.5% and secondary patency was 98% with no amputation done. Mortality rate was 4%. Endovascular treatment provides a successful option for the management of FCIAOD with a technical success rate of 92%, the option of selective use of prestent dilatation. FCIAOD does not preclude the use of unilateral stent in CIA, which can be completed to kissing stents if needed.


Monogenetic causes of chilblains, panniculitis and vasculopathy: the Type I interferonopathies.
Type I interferonopathies are a clinically heterogeneous group of inherited disorders of the innate immune system characterized by constitutive activation of the type I interferon signaling pathway. Cutaneous vasculopathy, lipodystrophy, interstitial lung disease and brain calcifications are the typical manifestations characterizing affected patients. The pathogenic mechanism commonly underlying these disorders is the abnormal activation of immune pathways involved in recognition of non-self-oligonucleotides. These natural defenses against virus consent humans to survive the infections. Target therapies capable of inhibiting type I interferon signaling pathway seem effective in these patients, albeit with possible incomplete responses and severe side effects.


Nitric oxide modulates hypoxic pulmonary smooth muscle cell proliferation and apoptosis by regulating carbon monoxide pathway.
To explore the role of carbon monoxide (CO) in the regulation of hypoxic pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis by nitric oxide (NO). PASMC of Wistar rats was cultured in vitro in the presence of a NO donor, sodium nitroprusside, or an inhibitor of heme oxygenase (HO), zinc protoporphyrin-IX, or under both normoxic and hypoxic conditions. Nitrite and carboxyhemoglobin in PASMC medium were detected with spectrophotometry. The proliferating and apoptotic percentage of PASMC was measured by flow cytometry. The expression of HO-1 mRNA in PASMC was analyzed by fluorescent real-time quantitative PCR, and the proliferating cell nuclear antigen and caspase-3 were examined by immunocytochemical analysis. The results showed that hypoxia suppressed NO generation from PASMC, which promoted hypoxic PASMC proliferation and induced apoptosis. Meanwhile, hypoxia induced HO-1 expression in PASMC and promoted CO production from PASMC, which inhibited PASMC proliferation and regulated PASMC apoptosis. NO upregulated the expression of HO-1 mRNA in hypoxic PASMC; NO also inhibited proliferation and promoted apoptosis of hypoxic PASMC, possibly by regulating the production of CO. The results indicated that CO could inhibit proliferation and regulate apoptosis of PASMC, and NO inhibited proliferation and promoted apoptosis of hypoxic PASMC, possibly by regulating the production of CO.


Endocrine and immunohistochemical studies on thyrotropin (TSH)-secreting pituitary adenomas: responses of TSH, alpha-subunit, and growth hormone to hypothalamic releasing hormones and their distribution in adenoma cells.
Endocrine and immunohistochemical studies were performed in two cases of TSH-secreting pituitary adenomas. The patients had elevated serum TSH and alpha-subunit concentrations despite high serum thyroid hormone levels. In addition, one patient (no. 1) had elevated serum GH levels with clinical evidence of acromegaly. GH-releasing hormone infusion increased serum levels of TSH, alpha-subunit and GH in the two patients. TRH injection increased serum TSH levels in both patients and, concomitantly, serum alpha-subunit and GH levels in patient 1. Basal TSH levels and their responses to TRH changed reciprocally to changes in serum thyroid hormone levels, although TRH-induced GH release did not. The administration of GnRH also increased serum TSH, alpha-subunit, and GH levels in patient 1. In accordance with these in vivo results, pituitary adenoma cells in culture obtained from patient 1 responded to GH-releasing hormone, TRH, or GnRH to secrete TSH, alpha-subunit, and GH. Incubation of cells with dexamethasone resulted in inhibition of TSH and stimulation of GH secretion without a significant change in alpha-subunit secretion. On the basis of light microscopic and electron microscopic double gold immunohistochemistry, the tumor from patient 1 was a bimorphous adenoma composed of two separate cell types: cells with TSH beta-subunit (TSH beta) and alpha-subunit, and those with GH and alpha-subunit. The remainder consisted mainly of cells with TSH beta and alpha-subunit. The coproduction of the unusual combination of two hormones such as GH and alpha-subunit in a single-type of adenoma cell and the coexistence of thyrotrophs and somatotrophs in one pituitary adenoma along with the aberrant responses of TSH beta, alpha-subunit, and GH to multiple hypothalamic hormones suggest the dedifferentiation of pituitary cells to multipotential progenitor cells by neoplastic transformation.


Survival outcome of local versus radical resection for jejunoileal gastrointestinal stromal tumors: a propensity score-matched population-based analysis.
Survival after local resection (LR) versus radical resection (RR) has been revealed comparable for patients with rectal and duodenal gastrointestinal stromal tumors (GISTs), but is unknown for jejunoileal (JI) GISTs. This study aimed to compare the long-term survival between patients with JI GISTs who underwent LR and RR, and to find out the prognostic factors for JI GISTs. Patients diagnosed with JI GISTs in 1975-2019 were identified from Surveillance, Epidemiology, and End Results (SEER) database and grouped according to surgical modality. Propensity score matching (PSM) was performed to balance the LR and RR groups. Overall survival (OS) and disease-specific survival (DSS) were compared in the full and matched cohorts using Kaplan-Meier (KM) analysis. Subgroup sensitivity analyses were also performed. Risk factors associated with DSS were analyzed in multivariate Cox analysis following model selection. 1107 patients diagnosed with JI GISTs were included in the study cohort. After PSM, OS and DSS were comparable in LR and RR groups. Consistently, the two groups had similar DSS in all subgroup analyses. Moreover, multivariate Cox analysis identified lymphadenectomy, older age, larger tumor size, distant metastasis, high and unknown mitotic rate, but not LR, as independent prognostic risk factors for JI GISTs. We conducted the first population-based comparison between the effect of different surgical modes on survival for patients with JI GISTs. LR can be carried out safely without compromising oncological outcome, and should be considered as a treatment option in selected patients with JI GISTs.


Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence.
Posttranslational modification such as phosphorylation of p53 plays important roles in activating p53 responses to various cellular and genotoxic stresses. Cell line studies have shown that phosphorylation of Ser46 is correlated with the activation of p53 apoptotic activity. To address the physiological roles of Ser46 phosphorylation, we employed homologous recombination and LoxP/Cre-mediated deletion to introduce Ser46 to Ala missense mutation into the human p53 knock-in (HUPKI) allele in mice (p53hki(S46A)). p53 stabilization in response to various types of DNA damage is modestly reduced in p53hki(S46A) embryonic stem (ES) cells, mouse embryonic fibroblasts (MEFs) and thymocytes. In addition, p53-dependent apoptosis is partially impaired in p53hki(S46A) thymocytes and E1A/Ras-expressing mouse embryonic fibroblasts (MEFs) after DNA damage. Consistent with this finding, transcription of p53 target apoptotic genes is preferentially affected by S46A mutation after DNA damage. p53hki(S46A) MEFs proliferate and reach senescence normally but can be spontaneously immortalized more easily than wild type MEFs. In addition, p53hki(S46A) MEFs more readily escapes from Ras-induced senescence. Therefore, Ser46 phosphorylation activates p53-dependent apoptosis induced by DNA damage and cellular senescence induced by oncogenic stress.


Bacterial keratitis following laser in situ keratomileusis for hyperopia.
A 42-year-old Bahraini man had uneventful laser in situ keratomileusis for hyperopia (OD: +3.00 +0.75 x 155 degrees; OS: +2.00 +0.50 x 155 degrees). Three weeks later, he presented with localized keratitis in his right eye, with localized keratitis at the flap margin with stromal edema. Uncorrected visual acuity was 20/80 OD with no improvement with pinhole, and was 20/20 OS. Corneal smear culture showed a positive growth of Staphylococcus aureus. The patient was immediately treated with subconjunctival gentamicin and intensive topical ofloxacin 0.3% with systemic cephalosporin. The patient recovered from keratitis within 2 weeks and his uncorrected visual acuity OD improved to 20/20. Keratitis following LASIK should be treated promptly so that it does not lead to permanent reduction in visual acuity.


Infection transmission among lung transplant couples.
The risk of transmission of infections in partnerships between 2 transplant recipients is unknown. The aim of this study was to evaluate transmission in such couples. In this single-center study, lung transplant (LTx) couples were identified among outpatients between 1988 and 2016. Infection rates per year and survival were compared to matched LTx-recipients not living in a transplant partnership. Twelve transplant couples were analyzed with cumulative 65 years of relationship. Overall infections were similar between LTx-couples and matched LTx-patients. No significant differences were noted in bacterial infections (.12 vs .27 per year), community-acquired viral (CARV) infections (.26 vs .22 per year), rejection treatments (.22 vs .12 per year), or hospitalizations (.26 vs .46 per year) in transplant couples and matched controls, respectively. There was no transmission of any microbial colonization from 1 partner to the other. Five cases of simultaneously detected CARV infections occurred (metapneumovirus [3], H1N1 [1], and respiratory syncytial virus [RSV; 1]). Three couples exhibited cytomegalovirus (CMV) reactivation in both partners at the same time with confirmed seronegativity before transplantation. In this case series of 12 lung transplant couples, the partnerships between 2 transplant recipients have no greater risk of bacterial infection and colonization transmission in comparison with recipients not living in a transplant relationship. However, transplant couples should be informed about the risk for transmission of viral infections, which could impact the development of chronic lung allograft dysfunction (CLAD).


Dissemination of multidrug-resistant, class 1 integron-carrying Acinetobacter baumannii isolates in Taiwan.
In this study, 283 multidrug-resistant Acinetobacter baumannii (MDR-AB) bloodstream isolates were collected between 1996 and 2004, from three teaching hospitals located in different regions of Taiwan. Susceptibility data showed that strains carrying class 1 integrons were significantly more resistant (p <0.01) to all tested antibiotics (except aztreonam and chloramphenicol) than strains lacking integrons, Seven types of gene cassette were identified among these strains, including two that have not been previously reported. The vast majority of the cassettes encoded aminoglycoside resistance genes, including aacA4, aacC1, aac(6')-II, aadA1, aadA2, aadA4 and aadDA1. Sixteen distinct ribotypes were identified in MDR-AB isolates carrying class 1 integrons. Only one strain was found to produce an extended-spectrum beta-lactamase, i.e. VEB-3. In the 18 imipenem-resistant strains, two carbapenenmase genes, bla(VIM-11) and bla(OXA-58), were found concomitantly in one isolate. An island-wide epidemic clone and an endemic clone from a hospital located in the northern region were identified by ribotyping. On the basis of the susceptibility data among the different ribogroups, the epidemic clone was associated more significantly with resistance to cefepime and ampicillin-sulbactam than was the endemic clone. In conclusion, the presence of class 1 integrons was significantly associated with resistance in MDR-AB, and the epidemic, class 1 integron-carrying MDR-AB clone was found to be widespread in Taiwan.


Nonmyeloablative blood stem cell transplantation as adoptive allogeneic immunotherapy for metastatic renal cell carcinoma.
Allogeneic stem cell transplantation has emerged as a potentially curative form of immunotherapy for patients with hematological malignancies that are resistant to conventional chemo/radiotherapy. Donor T cell populations targeting allogeneic minor histocompatibility antigens expressed on the patient's malignant cells are felt to be the driving force of the graft-versus-leukemia reaction, although to date only a handful of these antigens have been fully characterized. Recent data from experimental animal models and limited clinical data in humans suggest that graft-versus-tumor effects, analogous to the graft-versus-leukemia reaction, may be generated against malignancies of epithelial origin. This article reviews the results of a pilot trial demonstrating graft-versus-renal cell carcinoma effects following nonmyeloablative stem cell transplantation, highlighting the potential of allogeneic immunotherapy for treating cancer.


The luteinizing hormone receptor.
The luteinizing hormone receptor (LHR) is a member of the subfamily of glycoprotein hormone receptors within the superfamily of G protein-coupled receptor (GPCR)/seven-transmembrane domain receptors. Over the past eight years, major advances have been made in determining the structure and function of the LHR and its gene. The hormone-binding domain has been localized to exons 1-7 in the extracellular (EC) domain/region of the receptor, which contains several leucine-rich repeats. High-affinity binding of LH and human chorionic gonadotrophin (hCG) causes secondary hormone or receptor contacts to be established with regions of the EC loop/transmembrane module that initiate signal transduction. Models of hormone-receptor interaction have been derived from the crystal structures of hCG and of the ribonuclease inhibitor, which also contains leucine-rich repeats. Such models provide a framework for the interpretation of mutational studies and for further experiments. The extracellular domain of the receptor has been overexpressed in vitro, which will facilitate crystallographic resolution of the structure of the receptor-binding site. The transmembrane domain/loop/cytoplasmic module transduces the signal for coupling to G proteins. Several constitutive, activating mutations that cause human disease have been found in helix VI and adjacent structures. These mutations have provided valuable information about mechanisms of signal transfer and G protein coupling. The structure of the LHR gene has been elucidated, and the regulation of its transcription is beginning to be understood. Valuable insights into receptor evolution have been derived from analysis of sequence homologies, the gene structure of glycoprotein hormone receptors and other members of the GPCR family, and the glycoprotein hormone receptor-like precursors identified in several invertebrate species.


Biochemical switching device: monocyclic enzyme system.
The switching characteristics of a monocyclic enzyme system, in which two enzymes share substrates or co-factors in a cyclic manner, such as, --> X(1) + B + E(1) right arrow over left arrow A + E(1) + X(2) -->, --> X(3) + A + E(2) right arrow over left arrow B + E(2) + X(4) --> (E(1), E(2) are enzymes, X(1), X(3) are substrates, X(2), X(4) are products, A, B are cofactors), were demonstrated using computer simulations. The detailed mathematical models of biochemically possible cyclic enzyme systems were built up and the effects of rate constants and the effects of initial concentrations of enzymes and cofactors on switching characteristics were discussed. The cyclic enzyme system could function as a switching circuit when the initial concentrations of enzymes or cofactors are over a certain threshold value. Based on the present results, we further discuss the dynamic characteristics of a biochemical reactor system (bioreactor) involving this cyclic enzyme system as a switching controller.


Osimertinib for an Advanced NSCLC Patient with Two Common EGFR Mutations and a Concomitant MET Exon 14 Skipping Mutation: A Case Report.
Lung cancer remains the leading cause of cancer-related mortality. Studies have revealed that a combination of crizotinib and EGFR tyrosine kinase inhibitors (TKIs) could be an effective treatment option for patients with sensitizing EGFR mutations and de novo or acquired MET amplification. Until now, there have been few reports of the response in patients harboring three mutations. A patient was diagnosed with advanced lung adenocarcinoma harboring EGFR Del19, L858R mutation and METex14. She received osimertinib, and repeated imaging revealed further tumor progression. Sixty-six days later, combined treatment with osimertinib and crizotinib was initiated. Unfortunately, the patient succumbed to death at home after 17 days. This report firstly provided a lung adenocarcinoma patient with two common EGFR mutations (Del19 and L858R) and METex14. Our case raises a reminder about the tolerance and safety of combination therapy, especially in older peoples.


The sero-prevalence of antibodies to trypanosoma cruzi in Latin American refugees and immigrants to Canada.
Chagas' disease is caused by infection with the protozoan agent Trypanosoma cruzi. An estimated sixteen to eighteen million people are infected in Latin America. Outside of endemic regions, Chagas' disease may be transmitted through the transfusion of infected blood components, congenital infection and organ transplantation. We sought to determine the sero-prevalence of antibodies to T. cruzi in a community sample of Latin American refugees and immigrants to Canada. This was a sero-prevalence study in Latin American refugees and immigrants living in Canada. Eligible subjects were born in South America, Central America or in Mexico. Participants were recruited from a variety of community settings, as well as from medical clinics. Serum was tested by enzyme-linked immunoassay for antibodies to T. cruzi. A total of 102 participants were enrolled. One sample tested positive for antibodies for T. cruzi. The seroprevalence in our sample was 1.0% (95% CI: 0.2%- 5.3%). We found a low sero-prevalence of Chagas' disease in a community sample of Latin American immigrants and refugees. Physicians who treat Latin American immigrants should consider the risk profile and clinical status of the individual in their decision to screen for Chagas' disease.


Solid tumor models for the assessment of different treatment modalities. XXII. The alternate utilization of radiotherapy and chemotherapy.
Major increases in the time between administration of two modalities, radiation and cyclophosphamide (CP), from 1 to 7 days and in the overall time of delivery of 3 courses of combined therapy from 24 to 35 days were carried out in rats with hepatoma 3924A without major loss of therapeutic effectiveness. Cure rates of 50% or greater could be maintained even though treatment was given over much longer time periods. The radiation was given as hyperfractionated, split-course schedules which were devised by increasing the number of 250 rad fractions over a 2-day period. In one series of experiments these 2-day schedules were given at 11-day intervals for 3 courses on days 0 and 1, 11 and 12, 22 and 23; and CP (150 mg/kg) was given 1 day after each of the 3 radiation courses on days 2, 13, and 24. In the second series of experiments radiation was given on days 0 and 1, 14 and 15, 28 and 29; and this was alternated with 3 single doses of CP given 1 week after each of the 3 courses of radiation, on days 7, 21 and 35. Increasing the total radiation dose from 6000 to 7500 rad in the series given CP 1 day after each of three courses of radiation results in an increase in total tumor cure rates from 50% to 60%. The tumor cure rate in the series given CP 7 days after radiation increased from 10% to 70% when the total radiation dose was increased from 6000 to 7500 rad. Increasing the total radiation dose from 6000 to 7500 rad increased the magnitude of the acute skin reaction as well as the duration of recovery. However, the skin reactions for both the 6000 and 7500 rad were acceptable. Host toxicity and normal tissue reaction were within acceptable limits for both modalities. The results of these studies, therefore, indicate that excessive toxicity, one of the major deterrents to the effective combined utilization of these two primary means of cancer management, may be avoided by temporal separation of delivery while maintaining tumor cure rates of 50% or greater.


[Fever and rash in the adult patient].
Fever with rash is a frequent reason for consultation. A detailed medical history and thorough physical examination are essential since laboratory tests often lack specificity. Certain infectious and non-infectious causes are considered medical emergencies and must always be investigated upon initial evaluation. In the case of a history of recent travel the differential diagnosis has to be broadened but it should not be forgotten that resurgent « childhood » viral diseases like measles can be acquired while traveling.


Rapid and specific post-synthesis modification of DNA through a biocompatible condensation of 1,2-aminothiols with 2-cyanobenzothiazole.
Post-synthesis modification of DNA is an important way of functionalizing DNA molecules. Herein, we describe a method that first enzymatically incorporates a cyanobenzothiazole (CBT)-modified thymidine. The side-chain handle CBT can undergo a rapid and site-specific cyclization reaction with 1,2-aminothiols to afford DNA functionalization in aqueous solution. Another key advantage of this method is the formation of a single stereo/regioisomer in the process, which allows for precise control of DNA modification to yield a single component for aptamer selection work and other applications.


Microfluidic immunomagnetic cell separation using integrated permanent micromagnets.
In this paper, we demonstrate the possibility to trap and sort labeled cells under flow conditions using a microfluidic device with an integrated flat micro-patterned hard magnetic film. The proposed technique is illustrated using a cell suspension containing a mixture of Jurkat cells and HEK (Human Embryonic Kidney) 293 cells. Prior to sorting experiments, the Jurkat cells were specifically labeled with immunomagnetic nanoparticles, while the HEK 293 cells were unlabeled. Droplet-based experiments demonstrated that the Jurkat cells were attracted to regions of maximum stray field flux density while the HEK 293 cells settled in random positions. When the mixture was passed through a polydimethylsiloxane (PDMS) microfluidic channel containing integrated micromagnets, the labeled Jurkat cells were selectively trapped under fluid flow, while the HEK cells were eluted towards the device outlet. Increasing the flow rate produced a second eluate much enriched in Jurkat cells, as revealed by flow cytometry. The separation efficiency of this biocompatible, compact micro-fluidic separation chamber was compared with that obtained using two commercial magnetic cell separation kits.


Rice C2-domain proteins are induced and translocated to the plasma membrane in response to a fungal elicitor.
Hundreds of proteins involved in signaling pathways contain a Ca(2+)-dependent membrane-binding motif called the C2-domain. However, no small C2-domain proteins consisting of a single C2-domain have been reported in animal cells. We have isolated two cDNA clones, OsERG1a and OsERG1b, that encode two small C2-domain proteins of 156 and 159 amino acids, respectively, from a fungal elicitor-treated rice cDNA library. The clones are believed to have originated from a single gene by alternative splicing. Transcript levels of the OsERG1 gene are dramatically elevated by a fungal elicitor prepared from Magnaporthe grisea or by Ca(2+) ions. The OsERG1 protein produced in Escherichia coli binds to phospholipid vesicles in a Ca(2+)-dependent manner and is translocated to the plasma membrane of plant cells by treatment with either a fungal elicitor or a Ca(2+) ionophore. These results suggest that OsERG1 proteins containing a single C2-domain are involved in plant defense signaling systems.


Education on organ donation and transplantation in primary school; teachers' support and the first results of a teaching module.
Organ and tissue donation can also involve children. Because of its sensitivity, this topic requires careful decision making. Children have the ability to carefully reflect on this subject and enjoy participating in family discussions about it. Therefore, what children need is proper information. When schools are used to educate children about this subject, information about teacher support for this type of lesson along with its effects on the depth of family discussions is important. A questionnaire was sent to all 7,542 primary schools in the Netherlands. The goal was to gather information on teachers' perspectives about a neutral lesson devoted to organ and tissue donation, and also on the best age to start giving such a lesson. The second part of our study examined the effects of a newly developed lesson among 269 primary school pupils. The school response was 23%. Of these, 70% were positive towards a lesson; best age to start was 10-11 years. Pupils reported 20% more family discussions after school education and enjoyed learning more about this topic. There is significant support in primary schools for a school lesson on organ and tissue donation. Educational programs in schools support family discussions.


Value of radionuclide assessment with thallium 201 scintigraphy in carnitine deficiency cardiomyopathy.
The case of a 30 month-old boy who presented with isolated severe dilated cardiomyopathy is reported. The diagnosis of systemic carnitine deficiency was confirmed by low serum and tissue carnitine levels. During oral L-carnitine therapy, dramatic improvement of the cardiac function was assessed by radionuclide methods. Myocardial thallium 201 uptake was closely correlated with cardiac function studied by angioscintigraphy. These methods are simple, easily reproducible, non-invasive and involve little radiation. In a case of cardiomyopathy, we suggest an immediate trial of oral carnitine treatment; the efficacy of the therapy can be confirmed by isotopic tests with thallium 201 scintigraphy.


Bipartite tetracysteine display reveals allosteric control of ligand-specific EGFR activation.
Aberrant activation of the epidermal growth factor receptor (EGFR), a prototypic receptor tyrosine kinase, is critical to the biology of many common cancers. The molecular events that define how EGFR transmits an extracellular ligand binding event through the membrane are not understood. Here we use a chemical tool, bipartite tetracysteine display, to report on ligand-specific conformational changes that link ligand binding and kinase activation for full-length EGFR on the mammalian cell surface. We discover that EGF binding is communicated to the cytosol through formation of an antiparallel coiled coil within the intracellular juxtamembrane (JM) domain. This conformational transition is functionally coupled to receptor activation by EGF. In contrast, TGFα binding is communicated to the cytosol through formation of a discrete, alternative helical interface. These findings suggest that the JM region can differentially decode extracellular signals and transmit them to the cell interior. Our results provide new insight into how EGFR communicates ligand-specific information across the membrane.


Revealing the structure of stereociliary actin by X-ray nanoimaging.
Hair cell stereocilia are crucial for hearing and the sense of balance. They include an array of accurately packed, parallel actin filaments and act as levers, which transform mechanical deformation into neuronal signals. The length of vestibular stereocilia reaches several micrometers, whereas, for individual microfilaments, the diameter and therefore the characteristic length scale in the lateral direction is on the order of a few nanometers. These orders of magnitude render X-rays an ideal tool for investigating actin packing, and numerous studies on reconstituted in vitro systems have revealed important information. Here we report on the characterization of intact stereocilia using two nanoscale X-ray techniques. We use X-ray ptychography to image stereocilia with quantitative phase contrast and high dose efficiency, showing stereocilia with diameters and lengths in the expected range. We further employ X-ray nanodiffraction using a nanofocused X-ray beam on the same order of magnitude as the width of a stereocilium. Despite the small probe volume we can clearly visualize the stereocilia bundles. From the individual diffraction patterns we determine the local orientation of the actin structures and can clearly correlate them with the corresponding visible-light fluorescence images. Furthermore, azimuthal integration of individual diffraction patterns reveals distinct intensity curves, showing modulations of the signal, which reflect the relevant length scales and pronounced order in the biological system. The applied techniques are not limited to the studies on stereocilia but have the potential of being applied to many biological and soft-matter systems, in particular if a pronounced degree of order is present.


[Effectiveness of treatment of varicose veins assessed by epidemiological comparative studies].
Effectiveness of varicose veins (VV) management, due to high prevalence of this condition, is an important medical, social and economical issue. The aim of the study was to compare cost effectiveness of VV treatment by comparison of the results of two epidemiological surveys performed in Warsaw Bródno population, in 1982-1984 (group I, n=4997) and 1998-2000 (group 11, n=3556). Analysis compared prevalence of varicose veins, venous ulcers, deep vein thrombosis (DVT) in relation to number of VV procedures performed, and cost of conservative and surgical treatment, subjective patients' assessment of treatment results. Varicose veins prevalence has not changed significantly in group I was 15.7% (men 9.3%, women 20.1%) vs. 13.7% (men 8.7%, women 15.9%) in group II. Similarly, prevalence of venous ulcers (0.76% vs 0.73%), and previous DVT among VV patients (8.9% vs 8.9%) have not changed in both groups. Percentage of patients treated surgically in relation to all VV patients (19.7% vs 26.1%), as well as treated conservatively (45.2% vs 48.8%) increased, the latter mainly due to significant increase of ratio of patients treated with phlebotropic drugs. Patients'assessment of conservative and surgical treatment has improved dramatically, cost of treatment remained similar. Despite significant surgical and conservative treatment efforts, prevalence of essential venous diseases in hospital catchment area remained unchanged. Amount of patients satisfied both with surgical and conservative treatment increased, perhaps mainly due to better efficacy of phlebotropic drugs and better access to specialist care. On the other hand, significant amount of patients doesn't start any treatment at all. We conclude that preventive varicose veins surgery during early stage of disease may not diminish prevalence of serious venous complications.


Comments on: "The Role of Muscle Mass Gain Following Protein Supplementation Plus Exercise Therapy in Older Adults with Sarcopenia and Frailty Risks: A Systematic Review and Meta-Regression Analysis of Randomized Trials".
We recently read with great interest the article titled "The Role of Muscle Mass Gain Following Protein Supplementation (PS) plus Exercise Therapy in Older Adults with Sarcopenia and Frailty Risks: A Systematic Review and Meta-Regression Analysis of Randomized Trials" [...].


Eosinophilic cystitis: eight cases report and literature review.
Historically, eosinophilic cystitis is a rare disorder of bladder inflammation with eosinophils infiltration diagnosed by pathologic examination. The etiology is unclear despite the past identification of many factors contributing to this disease. Eight patients with eosinophilic cystitis were reported. The intact history, clinical manifestation, radiological examination and response to therapy were all evaluated. The results showed that 7 patients developed hematuria, 6 patients were with dysuria, 4 patients with frequency and 4 patients with urine retention. Seven patients had abnormal urinalysis but no positive finding in culture. Radiological findings revealed that one patient had bladder mass lesions and upper urinary tract dilation. Cystoscopic examination was performed in every patient and showed mass-like, edematous, ulcerative or hyperemic mucosa lesions. Cold-cup biopsy or transurethral resection of bladder lesions were all performed and could be the first priority to be considered. However, partial or total cystectomy should be taken into consideration when simple treatment failed to resolve this problem. Additionally, antihistamines, steroids or antibiotics are given to control the clinical symptoms. The results of these treatments were good except for one case who suffered from recurrence but recovered after simple operation and oral therapy. Although good results were found concerning treatment, long-term follow-up is necessary.


Estimates of loudness, loudness discomfort, and the auditory dynamic range: normative estimates, comparison of procedures, and test-retest reliability.
The purpose of this series of experiments was to establish normative reference values for absolute and relative judgements of loudness discomfort and for the auditory dynamic range (DR), and to evaluate intersubject variability and intra-subject test-retest reliability for the respective measures of loudness discomfort. To establish the normal auditory DR, audiometric thresholds and loudness discomfort levels (LDLs) were measured from a group of 59 normal-hearing adults without sound tolerance problems. The resulting estimates of the LDL and DR were on the order of 100 dB HL and 95 dB, respectively. A subset (n = 18) of this larger group participated in further studies in which loudness growth functions and the upper limit of the auditory DR were measured by categorical scaling judgments. The findings revealed no significant differences between the test methods for absolute (LDL) and relative (categorical scaling) judgements of loudness discomfort, intersubject variability, or intrasubject test-retest reliability, and suggest that the simple LDL estimate of loudness discomfort is an efficient and valid clinical measure for characterizing the "threshold of discomfort."


Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists' awareness.
Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.


Can causality assessment fulfill the new European definition of adverse drug reaction? A review of methods used in spontaneous reporting.
Causality assessment is a fundamental biomedical technique for the signal detection performed by Pharmacovigilance centers in a Spontaneous reporting system. Moreover, it is a crucial and important practice for detecting preventable adverse drug reactions. Among different methods for causality assessment, algorithms (such as the Naranjo, or Begaud Methods) seem for their operational procedure and easier applicability one of the most commonly used methods. With the upcoming of the new European Pharmacovigilance legislation including in the definition of the adverse event also effects resulting from abuse, misuse and medication error, all well-known preventable causes of ADRs, there was an emerging need to evaluate whether algorithms could fulfill this new definition. In this review, twenty-two algorithmic methods were identified and none of them seemed to fulfill perfectly the new criteria of adverse event although some of them come close. In fact, several issues were arisen in applying causality assessment algorithms to these new definitions as for example the impossibility to answer the rechallenge question in case of medication error or AEFI (Adverse Event Following Immunization). Moreover, the exact conditions at which events occurred, as for example dosage or mode of administration should be considered to better assess causality in conditions of abuse/overdose, or misuse as well as in conditions of lack of expected efficacy reports for biotechnological drugs and adverse event occurring after mixing of vaccines. Therefore, this review highlights the need of updating algorithmic methods to allow a perfect applicability in all possible clinical scenarios accordingly or not with the terms of marketing authorization.


Abdominal compartment syndrome associated with endovascular and open repair of ruptured abdominal aortic aneurysms.
Abdominal compartment syndrome (ACS) is a known complication of ruptured abdominal aortic aneurysm (rAAA) repair and can occur with either endovascular (EVAR) or open repair. We hypothesize that the underlying mechanism for the development of ACS may differ for patients treated with EVAR or open operation. All patients who presented with rAAA at a tertiary care medical center between January 2005 and December 2010 were included in the study. Demographic factors, type of repair (open vs EVAR), development of ACS, intraoperative and postoperative fluid requirements, estimated blood loss, length of stay, and morbidity and mortality were recorded. Student t-test and Fisher exact test were performed. A P value < .05 was considered significant. Seventy-three patients, 62 men and 11 women with an average age of 70.5 years, were treated for rAAA. Forty-four (60%) underwent open repair; 29 (40%) had EVAR. Overall mortality was 42% (31 of 73), with mortality being 31% (9 of 29) in EVAR and 48% (21 of 44) in open repair. ACS developed in 21 patients (29%), more frequently in open repair than in EVAR (15 of 44 [34%] vs 6 of 29 [21%]; P = NS). Mortality was higher in patients who developed ACS compared with those without ACS (13 of 21 [62%] vs 17 of 52 [33%]; P = .022). This finding was especially pronounced in the EVAR group, in which mortality in patients with ACS was 83% (5 of 6) compared with 17% (4 of 23) without ACS (P = .005). Intraoperative fluid requirements were significantly higher in EVAR patients who developed ACS compared with those without ACS, including packed red blood cells (5600 mL vs 1100 mL; P < .0001), total blood products (9300 mL vs 1500 mL; P < .001), crystalloid (11,200 mL vs 4500 mL; P < .001), and estimated blood loss (5000 mL vs 660 mL; P = .006). In patients treated with open repair, there were no significant differences in intraoperative fluid requirements between those who developed ACS and those without ACS. However, patients who developed ACS after open repair required significantly more crystalloid on the first and second postoperative days (first postoperative day, 8300 mL vs 5600 mL [P = .01]; second postoperative day, 6500 mL vs 3800 mL [P = .004]). This study demonstrates that the development of ACS after repair of rAAA is associated with increased mortality, especially in EVAR-treated patients. The higher intraoperative blood and blood product requirements associated with ACS in EVAR patients suggest that one potential cause of early ACS is continued hemorrhage from lumbar and inferior mesenteric vessels through the ruptured aneurysm sac. Hence, open ligation of such vessels should be considered in patients developing early ACS after EVAR for rAAA.


The Effectiveness of a Simulation Program to Enhance Readiness to Engage in Difficult Conversations in Clinical Practice.
Health care providers are often tasked with communicating difficult, emotionally charged news, including delivering an unwelcome diagnosis and planning end-of-life care. Patients and family members often cannot recall specifics of these conversations, although their perceptions of how information was communicated by health care providers impact not only their evaluation of the quality of care received, but also their abilities to cope with the communicated bad news. What can be done to better prepare novice clinicians to have these types of conversations? This quality improvement project used a simulation-based difficult conversation workshop given to adult-gerontology acute care nurse practitioner students in their final year of study. The workshop comprised both standardized patient actors and a structured communication curriculum. A pretest/posttest was conducted to show that this intervention was effective in increasing student confidence to facilitate difficult conversations in clinical practice.


Gene expression of VIP receptor in rat lymphocytes.
In the present report we analyze by reverse transcription (RT) and polymerase chain reaction (PCR) the expression of vasoactive intestinal peptide receptors (VIP-R) in rat thymocytes and peripheral T and B lymphocytes. We have obtained a specific VIP-R cDNA product of 311 bp identical in size to that obtained from lung. These results have been confirmed by Southern hybridization analysis. VIP receptor gene expression in central and peripheral lymphoid organs support the notion that VIP is a immunomodulatory peptide.


CCKB/gastrin receptor antagonists: recent advances and potential uses in gastric secretory disorders.
Cholecystokinin (CCK) and the structurally related peptide, gastrin, have numerous effects on tissues in the central nervous system and gastrointestinal tract. Recent studies show these effect are mediated by a CCKA and CCKB receptor. Knowledge of the physiological role and role of CCKB receptors in pathologic processes has been particularly limited by the availability of selective, potent receptor antagonists. Recently, new members of five different classes of non-peptide CCKB receptor antagonists are reported and are reviewed briefly. these include compounds isolated from Streptomyces (tetronothiodin, virginiamycin analogues), ureido-acetamide analogues (RP 69758, RP 72540, RP 73870), newer benzodiazepine analogues (L-368,935, L-740,093, YM022), pyrazolidimine analogues (LY 262,691) and glutamic acid analogues (CR2194). Many of these compounds have greater than 1000-fold selectivity for the CCKB over the CCKA receptor and some have greater than 10,000-fold selectivity. The pharmacology and effects of CCKB receptor antagonists on gastric acid secretion is briefly reviewed. Furthermore, the possible clinical usefulness of CCKB receptor antagonists in treating disorders of gastric acid secretion, in inhibiting the trophic effects of gastrin and in other clinical conditions is briefly discussed.


Protein kinase C-dependent up-regulation of CD5 surface expression on normal and lymphoblastoid T cells.
As an approach to study the mechanisms regulating the surface expression of CD5 antigen on T cells, the effects of agents that activate different lymphocyte functions were examined. Active tumour promoter agents (TPA), such as phorbol ester analogues [phorbol 12-myristate 13-acetate (PMA), phorbol 12, 13-dibutyrate (PBu2)] and mezerein, were able to increase the expression of CD5 on the cell surface of all T-cell lines), as deduced from immunofluorescence and immunoprecipitation analysis. The TPA-induced CD5 up-regulation occurred in a dose-and time-dependent manner and was dependent on protein and RNA synthesis. From the other stimuli tested, the T-cell mitogens [phytohaemagglutinin (PHA) and concanavalin A (Con A)], as well as monoclonal antibodies (mAb) against the CD3 complex, also increased CD5 expression, although to a lesser degree. In all cases the increments were shown to be dependent on protein kinase C (PKC), as evidenced by their inhibition with staurosporine, a potent inhibitor of PKC activation. These data suggest that CD5 up-regulation on T cells can be a physiological event that depends on PKC activation.


RFLP analysis with cDNA probes for DQ/DP region in HLA identical sibling marrow transplants: lack of correlation with GvHD.
The role of HLA-DP as transplantation antigen in contributing to GvHD is a matter of current debate. HLA-DP, is encoded centromeric to DR-DQ and its alleles are in weak linkage disequilibrium with the rest of the MHC; thus a certain number of HLA matched pairs could be actually DP incompatible to study a possible correlation between HLA-DP matching and GvHD, 24 HLA identical BMT/donor-recipient sibling pairs (serologically tested for HLA Class I and DR antigens) were tested for DQ and DP genes using restriction fragment length polymorphism (RFLP) analysis. DNA extracts were digested according to a standard procedure with two different restriction enzymes (HIND III and MSP I) and hybridised with DQ (alpha and beta) and DP (alpha and beta) specific probes. Highly stringent hybridization and washing conditions were used to prevent cross-hybridizations. Twenty four out of 24 pairs proved to be DQ and DP identical. GvHD developed in 16 out of 24 (66.6%) recipients. These data suggest that DNa analysis of DQ-DP regions, with the probes and enzymes used, does not give predictive informations for GvHD in HLA genotypically identical pairs.


A new in-cage treatment system for control of northern fowl mites on laying hens.
Commercially available plastic and other types of flexible tubing were tested to determine their relative permeability to an emulsifiable concentrate (EC) of permethrin acaricide. Bioassays employing northern fowl mites, Ornithonyssus sylviarum (Canestrini and Fanzago), indicated that .3 mg permethrin/cm2 surface area penetrated vinyl plastic tubing that had been filled with 42.5% active ingredient EC for 14 days. Vinyl tubing circuits were installed in wire poultry cages, either in the form of suspended loops or woven through the rear cage wall, and permethrin EC was introduced by means of a small pump. Significant reductions in northern fowl mite populations on hens caged therein were apparent after 48 days posttreatment. This approach has merit as a long-term, labor-economical form of mite control on caged poultry.


Improved Soluble ScFv ELISA Screening Approach for Antibody Discovery Using Phage Display Technology.
Phage display technology (PDT) is a powerful tool for the isolation of recombinant antibody (Ab) fragments. Using PDT, target molecule-specific phage-Ab clones are enriched through the "biopanning" process. The individual specific binders are screened by the monoclonal scFv enzyme-linked immunosorbent assay (ELISA) that may associate with inevitable false-negative results. Thus, in this study, three strategies were investigated for optimization of the scFvs screening using Tomlinson I and J libraries, including (1) optimizing the expression of functional scFvs, (2) improving the sensitivity of ELISA, and (3) preparing different samples containing scFvs. The expression of all scFv Abs was significantly enhanced when scFv clones were cultivated in the terrific broth (TB) medium at the optimum temperature of 30 °C. The protein A-conjugated with horseradish peroxidase (HRP) was found to be a well-suited reagent for the detection of Ag-bound scFvs in comparison with either anti-c-myc Ab or the mixing procedure. Based on our findings, it seems there is no universal media supplement for an improved expression of all scFvs derived from both Tomlinson I and J libraries. We thus propose that expression of scFv fragments in a microplate scale is largely dependent on a variety of parameters, in particular the scFv clones and relevant sequences.


Regulation of Zn and Fe transporters by the GPC1 gene during early wheat monocarpic senescence.
During wheat senescence, leaf components are degraded in a coordinated manner, releasing amino acids and micronutrients which are subsequently transported to the developing grain. We have previously shown that the simultaneous downregulation of Grain Protein Content (GPC) transcription factors, GPC1 and GPC2, greatly delays senescence and disrupts nutrient remobilization, and therefore provide a valuable entry point to identify genes involved in micronutrient transport to the wheat grain. We generated loss-of-function mutations for GPC1 and GPC2 in tetraploid wheat and showed in field trials that gpc1 mutants exhibit significant delays in senescence and reductions in grain Zn and Fe content, but that mutations in GPC2 had no significant effect on these traits. An RNA-seq study of these mutants at different time points showed a larger proportion of senescence-regulated genes among the GPC1 (64%) than among the GPC2 (37%) regulated genes. Combined, the two GPC genes regulate a subset (21.2%) of the senescence-regulated genes, 76.1% of which are upregulated at 12 days after anthesis, before the appearance of any visible signs of senescence. Taken together, these results demonstrate that GPC1 is a key regulator of nutrient remobilization which acts predominantly during the early stages of senescence. Genes upregulated at this stage include transporters from the ZIP and YSL gene families, which facilitate Zn and Fe export from the cytoplasm to the phloem, and genes involved in the biosynthesis of chelators that facilitate the phloem-based transport of these nutrients to the grains. This study provides an overview of the transport mechanisms activated in the wheat flag leaf during monocarpic senescence. It also identifies promising targets to improve nutrient remobilization to the wheat grain, which can help mitigate Zn and Fe deficiencies that afflict many regions of the developing world.


A new therapeutic protocol for the treatment of keloid scars: a retrospective study.
There are few means to treat large keloid scars, as exeresis-even if partial-impedes direct closure without tension in the absence of a flap or a skin graft. This study evaluates the efficacy, indications for use and limitations of a new therapeutic protocol, combining an extralesional keloid excision left to heal by secondary intention with a paraffin dressing and glucocorticoid ointment, followed by monthly intrascar injections of corticosteroids upon full re-epithelialisation. A retrospective study of patients treated for keloid scars by using the new therapeutic protocol. Scars were categorised as either healed or recurring. Their recurrence was scored according to the changes in functional signs and the scar volume. A total of 36 scars were studied. The mean follow-up was 14.1 months. Healing occurred in a mean of 6.8 weeks. The mean surface area was 21.6cm2. Healing rate was 30.5%. Scar volume was improved in 60% of recurrent cases and functional signs in 56%. Based on adherence with the corticotherapy, two patient groups could be discerned. For patients in the 'adherent' group, the healing rate was 40%, and scar volume was improved in 75% of recurrent cases and the functional signs in 83% of cases. The healing rate in this study was close to that reported in the literature. Excision-healing by secondary intention could therefore be offered to patients for whom adherence is uncertain. The protocol in this study offers a straightforward, fast, accessible solution that does not appear to entail any risk of additional keloids. It could potentially offer a treatment option in case of failure of other treatments, large keloid scars or scalp keloids.


An ent-kaurene-derived diterpenoid virulence factor from Xanthomonas oryzae pv. oryzicola.
Both plants and fungi produce ent-kaurene as a precursor to the gibberellin plant hormones. A number of rhizobia contain functionally conserved, sequentially acting ent-copalyl diphosphate and ent-kaurene synthases (CPS and KS, respectively), which are found within a well-conserved operon that may lead to the production of gibberellins. Intriguingly, the rice bacterial leaf streak pathogen Xanthomonas oryzae pv. oryzicola (Xoc) contains a homologous operon. Here, we report biochemical characterization of the encoded CPS and KS, and the impact of insertional mutagenesis on virulence and the plant defense response for these genes, as well as that for one of the cytochromes P450 (CYP112) found in the operon. Activity of the CPS and KS found in this phytopathogen was verified - that is, Xoc is capable of producing ent-kaurene. Moreover, knocking out CPS, KS or CYP112 led to mutant Xoc that exhibited reduced virulence. Investigation of the effect on marker gene transcript levels suggests that the Xoc diterpenoid affects the plant defense response, most directly that mediated by jasmonic acid (JA). Xoc produces an ent-kaurene-derived diterpenoid as a virulence factor, potentially a gibberellin phytohormone, which is antagonistic to JA, consistent with the recent recognition of opposing effects for these phytohormones on the microbial defense response.


Translation, Cultural Adaptation, and Psychometric Properties of the Danish Version of the Anti-Clot Treatment Scale.
Background The Anti-Clot Treatment Scale (ACTS) is a 17-item, 2-factor (Burdens and Benefits), patient-reported outcome instrument to evaluate patient satisfaction with oral anticoagulant treatment. Objectives This study aimed to translate and culturally adapt the English version of the ACTS into Danish and to subsequently validate the Danish version in a population of patients treated with dabigatran etexilate for atrial fibrillation. Methods The ACTS was translated into Danish and culturally adapted. This prospective phase 4 study included 232 respondents who completed the Danish ACTS after 1 month of treatment with dabigatran etexilate for atrial fibrillation. Psychometric properties were evaluated. For test-retest reliability, the ACTS was measured twice, 2 weeks apart, in a subgroup of 50 stable patients. Results Generally, a high level of treatment satisfaction was found. Confirmatory factor analysis showed a suboptimal fit for the two-factor model of the original version. Using modification indices of confirmatory factor analysis, a four-factor model had the best fit. Cronbach's α for internal consistency was acceptable at 0.78. There was good test-retest reliability with intraclass correlation at 0.80. Smallest detectable changes (SDCs) for individual patients were 5.89 points for the total ACTS, 5.57 for the reverse Burdens, and 3.34 for Benefits scores. Group SDCs were 0.39, 0.37, and 0.22 respectively. Substantial ceiling effects limit the ability to detect improvement at the high end of the scale. Conclusion The Danish version of the ACTS has inadequate structural validity. Reliability was acceptable. Ceiling effects challenge detection of improvement of treatment satisfaction in clinical practice in this patient population.


Jorunnamycins A-C, new stabilized renieramycin-type bistetrahydroisoquinolines isolated from the Thai nudibranch Jorunna funebris.
Jorunnamycins A-C (1a-c), three stabilized renieramycin-type bistetrahydroisoquinolines, were isolated from the mantles, the visceral organs, and the egg ribbons of the Thai nudibranch Jorunna funebris that was pretreated with potassium cyanide (KCN), along with five known compounds, renieramycins M (2m), N (2n), O (2o), and Q (2q) and mimosamycin (3). The structures of 1a-c were elucidated from spectroscopic data and by chemical conversion of renieramycin M (2m) into 1c via 1a. The chemical stability and the oxidative degradation generating simple isoquinoline alkaloids of a carbinolamine analog 1d, which was easily prepared by reacting 1c with silver nitrate in aqueous acetonitrile, are discussed. The results of cytotoxicity studies are also presented.


Tannin extracted from Penthorum chinense Pursh, a potential drug with antimicrobial and antibiofilm effects against methicillin-sensitive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.
Staphylococcus aureus is an opportunistic pathogen. Due to the widespread use and abuse of antibiotics, various drug-resistant strains of S. aureus have emerged, with methicillin-resistant Staphylococcus aureus (MRSA) being the most prevalent. Bacterial biofilm is a significant contributor to bacterial infection and drug resistance. Consequently, bacterial biofilm formation has emerged as a therapeutic strategy. In this study, the chemical constituents, antimicrobial and antibiofilm properties of tannins isolated from Penthorum chinense Pursh (TPCP) were investigated. In vitro, TPCP exhibited antimicrobial properties. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA were 156.25 and 312.5 μg/mL, and 312.5 and 625 μg/mL, respectively. According to the growth curves, TPCP significantly inhibited the growth of MSSA and MRSA. The results of the crystal violet biofilm assay in conjunction with confocal laser scanning and scanning electron microscopy demonstrated that TPCP destroyed preformed MSSA and MRSA biofilms. TPCP significantly decreased the secretion of exopolysaccharides and extracellular DNA. Subsequently, the mechanism was investigated using RT-PCR. Examining the expression of icaA, cidA, sigB, agrA, and sarA genes in MRSA, we discovered that TPCP inhibited biofilm formation by affecting the quorum-sensing system in bacteria. Our study demonstrates that TPCP exerts antibacterial effects by disrupting the formation of bacterial biofilms, suggesting that TPCP has clinical potential as a novel antibacterial agent for the prevention and treatment of MSSA and MRSA infections.


Glycan reductive isotope-coded amino acid labeling (GRIAL) for mass spectrometry-based quantitative N-glycomics.
A general and simple labeling method, termed glycan reductive isotope-coded amino acid labeling (GRIAL), was developed for mass spectrometry-based quantitative N-glycomics.


Wegener's granulomatosis (WG) and insulin dependent diabetes mellitus (IDDM).
We report a case of a 14 year-old girl with Wegener's granulomatosis (WG) complicated by its direct brain invasion and insulin dependent diabetes mellitus (IDDM). This case was diagnosed as WG early in its onset and successfully treated. As for IDDM of this case, the presence of HLA-DR4 and the islet cell surface antibody (ICSA) was demonstrated. To our knowledge, this is the first case report on IDDM associated with WG. We consider that WG may precipitate the development of IDDM in a genetically predisposed subject.


Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project.
Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend = 0.01). An increasing trend (ptrend = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT.


Cost-effectiveness of intraoperative facial nerve monitoring in middle ear or mastoid surgery.
Despite the utility of intraoperative facial nerve monitoring in reducing the risk of iatrogenic facial nerve injury during neurotologic surgery, its routine use during primary or revision surgery remains controversial. One of the major barriers to its acceptance is cost. This study evaluates the cost-effectiveness of intraoperative facial nerve monitoring during middle ear or mastoid surgery. A simple decision analytic cost-effectiveness model and a societal approach were used to evaluate three cohorts of individuals who received (1) intraoperative facial nerve monitoring for both primary and revision middle ear or mastoid surgeries, or (2) facial nerve monitoring for revision surgeries only, or (3) no monitoring for any middle ear or mastoid surgeries. Our results strongly favored the use of intraoperative facial nerve monitoring in all patients undergoing middle ear or mastoid surgery, adding about $222.73 to $528.00 US dollars to the total cost. The strategy to monitor primary and revision surgeries had the greatest effectiveness and lowest cost, with an average quality-adjusted life-year (QALY) of 45.68 at an average cost of $238 US dollars. Facial nerve monitoring in revision patients only had similar QALYs (45.67) and higher costs ($292.1). Finally, the strategy not to monitor had the lowest QALY (45.65) and highest cost ($449.8). The analysis was robust across a wide range of changes in both costs and probabilities. Facial nerve monitoring is cost-effective, and its routine use should be adopted to reduce the risk of iatrogenic facial nerve injury during otologic surgery.


High-performance, stretchable, wire-shaped supercapacitors.
A general approach toward extremely stretchable and highly conductive electrodes was developed. The method involves wrapping a continuous carbon nanotube (CNT) thin film around pre-stretched elastic wires, from which high-performance, stretchable wire-shaped supercapacitors were fabricated. The supercapacitors were made by twisting two such CNT-wrapped elastic wires, pre-coated with poly(vinyl alcohol)/H3PO4 hydrogel, as the electrolyte and separator. The resultant wire-shaped supercapacitors exhibited an extremely high elasticity of up to 350% strain with a high device capacitance up to 30.7 F g(-1), which is two times that of the state-of-the-art stretchable supercapacitor under only 100% strain. The wire-shaped structure facilitated the integration of multiple supercapacitors into a single wire device to meet specific energy and power needs for various potential applications. These supercapacitors can be repeatedly stretched from 0 to 200% strain for hundreds of cycles with no change in performance, thus outperforming all the reported state-of-the-art stretchable electronics.


A Novel Bacteriophage Targeting Cronobacter sakazakii Is a Potential Biocontrol Agent in Foods.
Cronobacter sakazakii is an important pathogen that causes high mortality in infants. Due to its occasional antibiotic resistance, a bacteriophage approach might be an alternative effective method for the control of this pathogen. To develop a novel biocontrol agent using bacteriophages, the C. sakazakii-infecting phage CR5 was newly isolated and characterized. Interestingly, this phage exhibited efficient and relatively durable host lysis activity. In addition, a specific gene knockout study and subsequent complementation experiment revealed that this phage infected the host strain using the bacterial flagella. The complete genome sequence analysis of phage CR5 showed that its genome contains 223,989 bp of DNA, including 231 predicted open reading frames (ORFs), and it has a G+C content of 50.06%. The annotated ORFs were classified into six functional groups (structure, packaging, host lysis, DNA manipulation, transcription, and additional functions); no gene was found to be related to virulence or toxin or lysogen formation, but >80% of the predicted ORFs are unknown. In addition, a phage proteomic analysis using SDS-PAGE and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) revealed that seven phage structural proteins are indeed present, supporting the ORF predictions. To verify the potential of this phage as a biocontrol agent against C. sakazakii, it was added to infant formula milk contaminated with a C. sakazakii clinical isolate or food isolate, revealing complete growth inhibition of the isolates by the addition of phage CR5 when the multiplicity of infection (MOI) was 10(5).


Relaxivity of liposomal paramagnetic MRI contrast agents.
Paramagnetic liposomes, spherical particles formed by a lipid bilayer, are able to accommodate a high payload of Gd-containing lipid and therefore can serve as a highly potent magnetic resonance imaging contrast agent. In this paper the relaxation properties of paramagnetic liposomes were studied as a function of composition, temperature and magnetic field strength. The pegylated liposomes with a diameter of approximately 100 nm were designed for favorable pharmacokinetic properties in vivo. The proton relaxivity, i.e. the T1 relaxation rate per mmol of Gd(III) ions, of liposomes with unsaturated DOPC phospholipids was higher than those with saturated DSPC lipids. Addition of cholesterol was essential to obtain monodisperse liposomes and led to a further, although smaller, increase of the relaxivity. Nuclear magnetic relaxation dispersion measurements showed that the relaxivity was limited by water exchange. These results show that these paramagnetic liposomes are very effective contrast agents, making them excellent candidates for many applications in magnetic resonance imaging.


[Expression of matrix metalloproteinase-2,matrix metalloproteinase-9 and vascular endothdial growth factor in retinoblastoma and its clinical significance].
To study the expression of matrix metalloproteinase-2(MMP-2), matrix metalloproteinase-9(MMP-9) and vascular endothelial growth factor(VEGF) in retinoblastoma (RB) and its relationship with the differentiation and optic nerve infiltration of RB. Immunohistochemical technique was used to detect the protein expression of MMP-2, MMP-9 and VEGF in 40 RB cases. The MMP-2, MMP-9 protein and VEGF protein expression were detected as positive in 52.5%, 57.5% and 72.5% of 40 RB cases respectively. The expression of MMP-2, MMP-9 and VEGF was significantly higher in the undifferentiated pattern than in the rosetted pattern(p<0.05); and the expression of MMP-2, MMP-9 and VEGF was significantly higher in tumors with optic nerve invasion than in those without optic nerve invasion(p<0.05). In RB, the expression of MMP-2, MMP-9 had a positive correlation with the expression of VEGF. In RB, high expression of MMP-2, MMP-9 and VEGF is related to the invasion and metastasis of RB. The expression of MMP-2, MMP-9 is positively correlated with the expression of VEGF. The expression of MMP-2, MMP-9 and VEGF may act as a biological marker for the invasion and metastasis of RB. The method may help screen and identify the cases with high risk for metastasis and to predict the prognosis of patients.


Design and Synthesis of New Sulfonic Acid Functionalized Ionic Liquids as Catalysts for Esterification of Fatty Acids with Bioethanol.
In this study, three types of sulfonic acid group functionalized ionic liquids (SAILs) with a different number of catalytic groups and lipophilicity were synthesized and characterized by FT-IR, NMR, and MS analyses. Their catalytic activities were studied in a model esterification of oleic acid with ethanol; heating in a microwave reactor was also used. The experimental results indicated that SAIL, with the lipophilic alkyl chain, performed the best due to its increased solubility in the reaction mixture. Microwave heating was found to be more effective than conventional heating. Recycling experiments show that these novel SAILs can be reused without significant loss of the catalytic activity.


Grain-scale modeling and splash parametrization for aeolian sand transport.
The collision of a spherical grain with a granular bed is commonly parametrized by the splash function, which provides the velocity of the rebounding grain and the velocity distribution and number of ejected grains. Starting from elementary geometric considerations and physical principles, like momentum conservation and energy dissipation in inelastic pair collisions, we derive a rebound parametrization for the collision of a spherical grain with a granular bed. Combined with a recently proposed energy-splitting model [Ho et al., Phys. Rev. E 85, 052301 (2012)PLEEE81539-375510.1103/PhysRevE.85.052301] that predicts how the impact energy is distributed among the bed grains, this yields a coarse-grained but complete characterization of the splash as a function of the impact velocity and the impactor-bed grain-size ratio. The predicted mean values of the rebound angle, total and vertical restitution, ejection speed, and number of ejected grains are in excellent agreement with experimental literature data and with our own discrete-element computer simulations. We extract a set of analytical asymptotic relations for shallow impact geometries, which can readily be used in coarse-grained analytical modeling or computer simulations of geophysical particle-laden flows.


Thyroid hormone regulation of miR-21 enhances migration and invasion of hepatoma.
Thyroid hormone (T(3)) signaling through the thyroid hormone receptor (TRα1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (miR-21) is activated by T(3) through a native T(3) response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T(3) stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T(3). The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T(3). Attenuation and overexpression of miR-21 induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of β-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRα1, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P = 0.005) between the tumor/nontumor ratios of TRα1 and miR-21 expression, whereas a negative correlation (P = 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T(3) and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion.


CLIPR-59 is a lipid raft-associated protein containing a cytoskeleton-associated protein glycine-rich domain (CAP-Gly) that perturbs microtubule dynamics.
We recently have identified a new cytoplasmic linker protein (CLIP), CLIPR-59, which is involved in the regulation of early endosome/trans-Golgi network dynamics. In contrast with CLIP-170, CLIPR-59 is not localized to microtubules at steady state but is associated with the trans-Golgi network and the plasma membrane. Here we show that the last 30 amino acids (C30) are sufficient for membrane targeting and that two cysteines in the C30 domain are palmitoylated. We demonstrate that CLIPR-59 is associated with lipid rafts via its C-terminal palmitoylated domain. In vitro experiments suggest that CLIPR-59 and its microtubule-binding domain alone have a better affinity for unpolymerized tubulin or small oligomers than for microtubules. In contrast with the CLIP-170 microtubule-binding domain, the CLIPR-59 microtubule-binding domain diminishes microtubule regrowth after nocodazole washout in vivo, showing that this domain can prevent microtubule polymerization. In contrast with the role of linker between membranes and microtubules that was proposed for CLIP function, CLIPR-59 thus may have an "anti-CLIP" function by preventing microtubule-raft interactions.


Dynamic strength of the quadriceps muscle and sports activity.
The study objectives were to examine the dynamic strength of the quadriceps muscle in athletes, and investigate its association with participation in sport. The study comprised 168 active competitive non-pregnant athletes, aged 14-24 years. The dynamic strength of their quadriceps muscle was measured, and they answered a questionnaire about sports activity and occupation. The dynamic strength of the quadriceps muscle was significantly higher in men than in women, and was positively associated with body weight, years of jogging, years of soccer, and weekly hours of basketball. In conclusion, the dynamic strength of the quadriceps muscle seems to be associated with sports activity. The results suggest sport specific adaptation, which may reflect high levels of running and jumping activity.


Ground water rights, spatial variation, and transboundary conflicts.
The goal for any property rights system is to achieve equity, efficiency, and certainty. Trying to achieve these goals for ground water is difficult because a ground water right is not exclusive. To make matters more complicated, ground water is often under the jurisdiction of more than one political unit. The result is transboundary conflicts. Two critical elements must be included in any system of ground water rights. The system must define how the ground water can be used and define the relationships that each user and each use has with the other users and uses in the system. Unfortunately, these relationships are seldom completely defined and are made more complex by the transboundary scales at which they operate. As ground water moves horizontally across boundaries, different users or different jurisdictions have sequential control, creating conflicts between the first users and subsequent ones. Other problems occur because of vertical relationships, with more than one person or entity having control over ground water at the same time. This simultaneous exercise of authority can create conflicts between an individual who possesses a right to use ground water and a state or federal agency that regulates the same water. Transboundary conflicts occur at different scales and include conflicts between neighboring property owners as well as conflicts between countries. Scale, the property rights structure, and the nature of the relationship between users influence the way transboundary ground water conflicts are resolved.


Artificial lungs: are we there yet?
New oxygenator technologies widened the application of extracorporeal life support significantly in the last decade. Currently the use is still limited within intensive care units. Compared to ventricular assist devices for heart failure, lung replacement technology is lagging behind, not allowing discharge on device. Challenges to achieve a true artificial lung for long term use are discussed in this article.


Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation.
FOXP3 has been identified as a key regulator of immune homeostasis. Mutations within the FOXP3 gene result in dysregulated CD4+ T-cell function and elevated cytokine production, leading to lymphoproliferative disease. FOXP3 expression in CD4+ T cells is primarily detected with the CD4+ CD25+ regulatory T-cell population. In humans the protein is detected as a doublet following immunoblot analysis. The lower band of the doublet has been identified as a splice isoform lacking a region corresponding to exon 2. The aim of this study was to investigate whether the splice variant form lacking exon 2 and a new novel splice variant lacking both exons 2 and 7, were functional inhibitors of CD4+ T-cell activation. The data generated showed that full-length FOXP3 and both splice variant forms of the protein were functional repressors of CD4+ T-cell activation.


Oncology Nursing Research: Moving Toward Equitable and Inclusive Science.
One of the challenges for nurse scientists, particularly those of us educated in traditional academic models, is the question of how to make certain that our research addresses critical barriers to achieving health and healthcare equity. Traditional research inculcation taught us to focus on discrete, answerable questions, using an attainable sample given the financial and practical limitations inherent in research implementation. Although these techniques were part of an agreed-upon scientific method, the restrictions can lead to an answer to a circumscribed question but fail to articulate the broader issues inherent in designing and implementing human research that moves from inquiry to impact. Although our strong history in oncology nursing research includes a range of health concerns and responses to cancer, including biologic, socio-cultural, sex and gender, and, more recently, financial, I think that we, as oncology nurse scientists, agree that the focus of our research needs to more explicitly address pernicious aspects of health that lead to health disparities: racism and structural discrimination. Racism and structural barriers cloud all aspects of oncology: early detection, the design and uptake of promising therapeutics, quality of life, and financial well-being during active treatment and survivorship. How do we take the essential steps to not only measure but also address these critical barriers to reduce disparities and bring about more equitable and salubrious outcomes in oncology nursing research?


Surface tensions, surface potentials, and the Hofmeister series of electrolyte solutions.
A theory is presented which allows us to accurately calculate the surface tensions and the surface potentials of electrolyte solutions. Both the ionic hydration and the polarizability are taken into account. We find a good correlation between the Jones-Dole viscosity B coefficient and the ionic hydration near the air-water interface. The kosmotropic anions such as fluoride, iodate, sulfate, and carbonate are found to be strongly hydrated and are repelled from the interface. The chaotropic anions such as perchlorate, iodide, chlorate, and bromide are found to be significantly adsorbed to the interface. Chloride and bromate anions become weakly hydrated in the interfacial region. The sequence of surface tensions and surface potentials is found to follow the Hofmeister ordering. The theory quantitatively accounts for the surface tensions of 10 sodium salts for which there is experimental data.


Clostridium difficile disease in solid organ transplant recipients: a recommended treatment paradigm.
Organ transplant recipients have an increased incidence of Clostridium difficile disease and lower clinical response rates compared with the general population. Transplant specific treatment approaches are not defined. Therefore, a review of therapeutics in the transplant population is needed. A literature review on the current therapies for C. difficile was performed focusing on the evidence in transplant recipients and immunosuppressed populations. Transplant patients warrant an aggressive approach to treatment. The authors propose a suggested treatment paradigm for therapy.


Role of the surgical position in the development of postoperative low back pain.
The aetiology of postoperative back pain is contentious. Although the role of the surgical position has not been fully established, the lithotomy position is often implicated. In order to investigate this common surgical complication further, a prospective study has been performed on 101 hysterectomy patients. The supine (52 patients) and the lithotomy (49 patients) positions have been compared and contrasted within this series. Ten patients in the supine group (20%) and seven patients in the lithotomy group (14%) developed postoperative low back pain (p > 0.1). The mean duration of symptoms postoperatively for the whole series was 7 months. We conclude that postoperative backache is an under-estimated complication of surgery and that this problem occurs equally whether the supine or the lithotomy positions are used.


Primary drug resistance to both rifampicin and dapsone in a paucibacillary leprosy patient.
A thirty-one year old male patient was diagnosed and treated for a pure or better primary neuritic case of leprosy with dapsone (100 mg daily for 2 years) and rifampicin (600 mg daily for 6 months). From the very outset, the patient did not show any improvement; on the top of it, he subsequently, developed a cutaneous patch, which on histopathological examination, revealed classical features of BT leprosy. Acid-fast bacilli were absent both in skin slit smear and histologic section. A primary resistance to both dapsone and rifampicin, even in paucibacillary patient, is speculated.


Genetic and epigenetic markers in colorectal cancer screening: recent advances.
Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.


Identification of genetic variants in pharmacogenetic genes associated with type 2 diabetes in a Mexican-Mestizo population.
Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic pathologies in the world. In developing countries, such as Mexico, its prevalence represents an important public health and research issue. Determining factors triggering T2DM are environmental and genetic. While diet, exercise and proper weight control are the first measures recommended to improve the quality of life and life expectancy of patients, pharmacological treatment is usually the next step. Within every population there are variations in interindividual drug response, which may be due to genetic background. Some of the most frequent first line T2DM treatments in developing countries are sulfonylureas (SU), whose targets are ATP-sensitive potassium channels (KATP). Single nucleotide polymorphisms (SNPs) of the KATP coding genes, potassium voltage-gated channel subfamily J member 11 (KCNJ11) and ATP binding cassette subfamily C member 8 (ABCC8) have been associated with SU response variability. To date, there is little information regarding the mechanism by which these SNPs work within Mexican populations. The present study describes the distribution of three SNPs [KCNJ11 rs5219 (E23K), ABCC8 rs757110 (S1369A) and rs1799854 (-3C/T)] among Mestizo Mexican (MM) T2DM patients, and compares it with published data on various healthy subjects and T2DM populations. Through this comparison, no difference in the KCNJ11 rs5219 and ABCC8 rs757110 allelic and genotypic frequencies in MM were observed compared with the majority of the reported populations of healthy and diabetic individuals among other ethnic groups; except for African and Colombian individuals. By contrast, ABCC8 rs1799854 genomic and allelic frequencies among MM were observed to be significantly different from those reported by the 1000 Genomes Project, and from diabetic patients within other populations reported in the literature, such as the European, Asian and Latin-American individuals [T=0.704, G=0.296; CC=0.506, CT=0.397, TT=0.097; 95% confidence interval (CI); P≤0.05]; except for South Asian and Iberian populations, which may reflect the admixture origins of the present Mexican population. This genetic similarity has not been observed in the other Latin-American groups. To the best of our knowledge, this is the first study of ABCC8 rs757110 and rs1799854 SNP frequencies in any Mexican population and, specifically with diabetic Mexicans. Knowledge of the genetic structure of different populations is key to understanding the interindividual responses to drugs, such as SU and whether genotypic differences affect clinical outcome.


Factors influencing diagnosis delay of advanced breast cancer in Moroccan women.
Delay in the diagnosis of breast cancer in symptomatic women of 3 months or more is associated with advanced stage and low survival. We conducted this study to learn more about the extent and reasons behind diagnosis delay of advanced breast cancer in Moroccan women. A group of patients with advanced breast cancer were interviewed at the National Institute of Oncology in Rabat during the period from February to December 2014. Diagnosis delay was devised into patient delay and system delay. Patient delay was defined as time from first symptoms until first medical consultation. System delay was defined as time from first presentation to a health care provider until definite diagnosis or treatment. Prospective information and clinical data were collected on a form during an interview with each patient and from medical records. In all, 137 patients were interviewed. The mean age of women was 48.3 ± 10.4 years. The median of consultation time was 6[4,12] months and the median of diagnosis time was 1[1,3] months. Diagnosis delay was associated to a personal reason in 96 (70.1 %) patients and to a medical reason in 19 (13.9 %) patients. A number of factors predicted diagnosis delay: symptoms were not considered serious in 66 (55.9 %) patients; traditional therapy was applied in 15 (12.7 %) patients and fear of cancer diagnosis and/or treatment in 14 (11.9 %) patients. A use of traditional methods was significantly associated with rural residence and far away from basic health center (p = 0.000). Paradoxically, a family history of breast cancer was significantly higher in who report a fear of cancer diagnosis and/or treatment to diagnosis delay (p < 0.001). Also, a significantly higher risk of more than 6 months delay was found among rural women (P = 0.035) and women who live far away from specialized care center (P = 0.001). Diagnosis delay is very serious problem in Morocco. Diagnosis delay was associated with complex interactions between several factors and with advanced stages. There is a need for improving breast cancer information in our populations and training of general practitioners to reduce advanced breast cancer by promoting early detection.


In Vitro Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin.
Carvedilol is mainly metabolized in the liver to O-glucuronide (O-Glu). We previously found that the glucuronidation activity of racemic carvedilol in pooled human liver microsomes (HLM) was increased, R-selectively, in the presence of amiodarone. The aim of this study was to clarify the mechanisms for the enhancing effect of amiodarone on R- and S-carvedilol glucuronidation. We evaluated O-Glu formation of R- and S-carvedilol enantiomers in a reaction mixture of HLM including 0.2% bovine serum albumin (BSA). In the absence of amiodarone, glucuronidation activity of R- and S-carvedilol for 25 min was 0.026, and 0.51 pmol/min/mg protein, and that was increased by 6.15 and 1.60-fold in the presence of 50 µM amiodarone, respectively. On the other hand, in the absence of BSA, or when BSA was replaced with human serum albumin, no enhancing effect of amiodarone on glucuronidation activity was observed, suggesting that BSA played a role in the mechanisms for the enhancement of glucuronidation activity. Unbound fraction of S-carvedilol in the reaction mixture was greater than that of R-carvedilol in the absence of amiodarone. Also, the addition of amiodarone caused a greater increase of unbound fraction of R-carvedilol than that of S-carvedilol. These results suggest that the altered protein binding by amiodarone is a key mechanism for R-selective stimulation of carvedilol glucuronidation.


Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease.
See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.


Cancer incidence and mortality: trends in the United Kingdom and constituent countries, 1993 to 2004.
This article examines trends in cancer in the UK and constituent countries over the period 1993-2004 for all cancers combined and the four most common cancers: breast, prostate, lung and colorectal. The results show that the UK male incidence rate increased for prostate cancer, and decreased for lung cancer. The UK female incidence rate increased for breast cancer, and decreased for colorectal cancer. The UK mortality rates fell for the three most common cancers in males, and for breast and colorectal in females. These results provide insight into current trends in incidence and mortality to enable services to be directed appropriately.


Multiple parasite infections and their relationship to self-reported morbidity in a community of rural Côte d'Ivoire.
Concomitant parasitic infections are common in the developing world, yet most studies focus on a single parasite in a narrow age group. We investigated the extent of polyparasitism and parasite associations, and related these findings to self-reported morbidity. Inhabitants of 75 randomly selected households from a single village in western Côte d'Ivoire provided multiple faecal specimens and a single finger prick blood sample. The Kato-Katz technique and a formol-ether concentration method were employed to screen faecal samples for Schistosoma mansoni, soil-transmitted helminths and intestinal protozoa. Giemsa-stained blood smears were analysed for malaria parasites. A questionnaire was administered for collection of demographic information and self-reported morbidity indicators. Complete parasitological data were obtained for 500/561 (89.1%) participants, similarly distributed among sex, with an age range from 5 days to 91 years. The prevalences of Plasmodium falciparum, hookworms, Entamoeba histolytica/E. dispar, and S. mansoni were 76.4%, 45.0%, 42.2%, and 39.8%, respectively. Three-quarters of the population harboured three or more parasites concurrently. Multivariate analysis revealed significant associations between several pairs of parasites. Some parasitic infections and the total number of parasites were significantly associated with self-reported morbidity indicators. Our data confirm that polyparasitism is very common in rural Côte d'Ivoire and that people have clear perceptions about the morbidity caused by some of these parasitic infections. Our findings can be used for the design and implementation of sound intervention strategies to mitigate morbidity and co-morbidity.


Computed Tomography Pulmonary Angiography during Pregnancy: Radiation Dose of Commonly Used Protocols and the Effect of Scan Length Optimization.
To evaluate the radiation dose for pregnant women and fetuses undergoing commonly used computed tomography of the pulmonary arteries (CTPA) scan protocols and subsequently evaluate the simulated effect of an optimized scan length. A total of 120 CTPA datasets were acquired using four distinctive scan protocols, with 30 patients per protocol. These datasets were mapped to Cristy phantoms in order to simulate pregnancy and to assess the effect of an effective radiation dose (in mSv) in the first, second, or third trimester of pregnancy, including a simulation of fetal dose in second and third trimesters. The investigated scan protocols involved a 64-slice helical scan at 120 kVp, a high-pitch dual source acquisition at 100 kVp, a dual-energy acquisition at 80/140 kVp, and an automated-kV-selection, high pitch helical scan at a reference kV of 100 kVref. The effective dose for women and fetuses was simulated before and after scan length adaptation. The original images were interpreted before and after scan length adaptations to evaluate potentially missed diagnoses. Large inter-scanner and inter-protocol variations were found; application of the latest technology decreased the dose for non-pregnant women by 69% (7.0-2.2 mSv). Individual scan length optimization proved safe and effective, decreasing the fetal dose by 76-83%. Nineteen (16%) cases of pulmonary embolism were diagnosed and, after scan length optimization, none were missed. Careful CTPA scan protocol selection and additional optimization of scan length may result in significant radiation dose reduction for a pregnant patient and her fetus, whilst maintaining diagnostic confidence.


Distribution of glycoproteins containing fucose in normal and psoriatic keratinocytes.
Electron microscope autoradiography has been used to compare the fucose-containing glycoproteins of normal and psoriatic epidermis. Normal keratinocytes and uninvolved psoriatic cells have most of their fucose on the plasma membrane, whereas involved psoriatic cells retain more within the cytoplasm. The fucose distribution in other epidermal cell types is also described.