Pathways to health: a cluster randomized trial of nicotine gum and motivational interviewing for smoking cessation in low-income housing.
Despite high smoking rates among those living in poverty, few cessation studies are conducted in these populations. This cluster-randomized trial tested nicotine gum plus motivational interviewing (MI) for smoking cessation in 20 low-income housing developments (HDs). Intervention participants (10 HDs, n = 66) received educational materials, 8 weeks of 4 mg nicotine gum, and 5 MI sessions on quitting smoking. Comparison participants (10 HDs, n = 107) received 5 MI sessions and educational materials addressing fruit and vegetable consumption. Participants had a mean age of 46.3 years and were predominantly female (70%) and African American (83%). Biochemically-verified 7-day abstinence rates at 8 weeks were 6.1% and 5.6% in the intervention and comparison arms, respectively (p = ns); and at 26 weeks were 7.6% and 9.3%, respectively (p = ns). Results suggest that nicotine gum plus MI were not effective for smoking cessation in low-income housing. Programs are needed to enhance the effectiveness of pharmacotherapy and counseling in underserved populations.


Therapeutic potential of serum and glucocorticoid inducible kinase inhibition.
Expression of serum-and-glucocorticoid-inducible kinase-1 (SGK1) is low in most cells, but dramatically increases under certain pathophysiological conditions, such as glucocorticoid or mineralocorticoid excess, inflammation with TGFβ release, hyperglycemia, cell shrinkage and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase and mammalian target of rapamycin. SGK1 sensitive functions include activation of ion channels (including epithelial Na(+) channel ENaC, voltage gated Na(+) channel SCN5A transient receptor potential channels TRPV4 - 6, Ca(2+) release activated Ca(2+) channel Orai1/STIM1, renal outer medullary K(+) channel ROMK, voltage gated K(+) channels KCNE1/KCNQ1, kainate receptor GluR6, cystic fibrosis transmembrane regulator CFTR), carriers (including Na(+),Cl(-) symport NCC, Na(+),K(+),2Cl(-) symport NKCC, Na(+)/H(+) exchangers NHE1 and NHE3, Na(+), glucose symport SGLT1, several amino acid transporters), and Na(+)/K(+)-ATPase. SGK1 regulates several enzymes (e.g., glycogen synthase kinase-3, ubiquitin-ligase Nedd4-2) and transcription factors (e.g., forkhead transcription factor 3a, β-catenin, nuclear factor kappa B). The phenotype of SGK1 knockout mice is mild and SGK1 is apparently dispensible for basic functions. Excessive SGK1 expression and activity, however, contributes to the pathophysiology of several disorders, including hypertension, obesity, diabetes, thrombosis, stroke, fibrosing disease, infertility and tumor growth. A SGK1 gene variant (prevalence ∼ 3 - 5% in Caucasians and ∼ 10% in Africans) is associated with hypertension, stroke, obesity and type 2 diabetes. SGK1 inhibitors have been developed and shown to reduce blood pressure of hyperinsulinemic mice and to counteract tumor cell survival. Targeting SGK1 may be a therapeutic option in several clinical conditions, including metabolic syndrome and tumor growth.


Evidence for hybridization and introgression within a species-rich oak (Quercus spp.) community.
Analysis of interspecific gene flow is crucial for the understanding of speciation processes and maintenance of species integrity. Oaks (genus Quercus, Fagaceae) are among the model species for the study of hybridization. Natural co-occurrence of four closely related oak species is a very rare case in the temperate forests of Europe. We used both morphological characters and genetic markers to characterize hybridization in a natural community situated in west-central Romania and which consists of Quercus robur, Q. petraea, Q. pubescens, and Q. frainetto, respectively. On the basis of pubescence and leaf morphological characters ~94% of the sampled individuals were assigned to pure species. Only 16 (approximately 6%) individual trees exhibited intermediate morphologies or a combination of characters of different species. Four chloroplast DNA haplotypes were identified in the study area. The distribution of haplotypes within the white oak complex showed substantial differences among species. However, the most common haplotypes were present in all four species. Furthermore, based on a set of 7 isozyme and 6 microsatellite markers and using a Bayesian admixture analysis without any a priori information on morphology we found that four genetic clusters best fit the data. There was a very good correspondence of each species with one of the inferred genetic clusters. The estimated introgression level varied markedly between pairs of species ranging from 1.7% between Q. robur and Q. frainetto to 16.2% between Q. pubescens and Q. frainetto. Only nine individuals (3.4%) appeared to be first-generation hybrids. Our data indicate that natural hybridization has occurred at relatively low rates. The different levels of gene flow among species might be explained by differences in flowering time and spatial position within the stand. In addition, a partial congruence between phenotypically and genetically intermediate individuals was found, suggesting that intermediate appearance does not necessarily mean hybridization. However, it appears that natural hybridization did not seriously affect the species identity in this area of sympatry.


Excimer laser for psoriasis: a review of theories regarding enhanced efficacy over traditional UVB phototherapy.
Fiber-optically targeted ultraviolet B (UVB) therapy has been shown to clear plaques of psoriasis in a significantly fewer number of treatments and reduce overall cumulative UVB dose than traditional UVB phototherapy. This article reviews existing theories in the literature attempting to explain the superior efficacy of targeted UVB. Medline was used to perform a comprehensive review of the literature from 1965 to present. Only information from the English language journals are reported in this study. The theories proposed to explain the higher efficacy of the excimer (XeCl) laser relative to traditional UVB include the ability to use higher intensities of ultraviolet (UV) light and a more efficient induction of T cell apoptosis. The possible explanations for the superior efficacy of the excimer laser over traditional UVB therapy for psoriasis include: 1) a higher intensity UV light to plaques, which is more effective in clearing psoriasis; 2) penetration into the dermis where it may induce T cell apoptosis, potentially to a greater extent than the wavelength or given energy level predicts; and 3) the difference in the delivery of UVB light may result in cell death and skin immune system suppression more effectively than traditional UVB.


Association of the blood eosinophil count with end-organ symptoms.
Eosinophilia may cause organ dysfunction, but an exact relation between eosinophil blood counts and adverse outcomes has not been described. The aim of the study is to associate in one model both normal and increased blood eosinophil counts to the subsequent development of common conditions in internal medicine, in which eosinophil granulocytes may play a role for the symptoms. From the Copenhagen Primary Care Differential Count (CopDiff) Database, we identified 359,950 individuals with at least one differential cell count (DIFF) during 2000-2007. From these, one DIFF was randomly chosen. From the Danish National Patient Register we ascertained organ damage, within four years following the DIFF. Using multivariable logistic regression, odds ratios were calculated and adjusted for previous eosinophilia, sex, age, year, month, CRP and comorbid conditions. Risks for skin- and respiratory disease were increased from above the median eosinophil count of 0.16 × 109/l and reached a plateau around 1.0 × 109/l. Furthermore, risks of most outcomes also increased when the eosinophil count approached zero. The observed U-shaped association with a plateau of risks around 1 × 109/l indicates that the risk for symptoms due to eosinophilia do not increase proportionate at higher counts. This study demonstrates for the first time that there is indeed an increased risk below median count of 0.16 × 109/l for an increased risk for the same manifestations. Clinically, it means that a normal or even low count of eosinophils do not rule out a risk for organ affection by eosinophils, and may contribute to explain, why patients may have normal eosinophil counts in e.g. asthma or allergy and still have symptoms from the lungs and skin, most likely explained by the extravasation of eosinophils.


Results of extracorporeal membrane oxygenation in neonates with sepsis. The Extracorporeal Life Support Organization experience.
Use of extracorporeal membrane oxygenation for treatment of respiratory failure caused by sepsis is controversial because of concerns over survival benefit and hemorrhage-related complications. To evaluate the impact of the primary diagnosis of sepsis on outcome, we reviewed data from 6853 neonates in the Extracorporeal Life Support Organization Registry and defined two groups: group 1 (n = 1060), all patients undergoing extracorporeal membrane oxygenation with a primary diagnosis of sepsis; group 2 (n = 5793), those with any other primary diagnosis. A multivariate logistic regression analysis that considered 15 variables present before extracorporeal membrane oxygenation (including age, sex, birth weight, prior cardiopulmonary arrest, arterial blood gas results, and ventilator settings) was used to compare outcomes between groups. Survival was not different between the two groups (77%, group 1; 82%, group 2; p = 0.2480), although lung recovery was less frequent in the patients with sepsis (p = 0.0185). Group 1 had a higher incidence of complications including seizures (odds ratio 1.446, p = 0.0346), cerebral infarct or hemorrhage (2.310, p = 0.0001), need for dialysis (1.478, p = 0.0131), hypernatremia (2.089, p = 0.0019), hyperbilirubinemia (2.423, p = 0.0001), and dobutamine use (1.918, p = 0.0001). Neonates with sepsis are more likely to have neurologic, renal, and metabolic complications from extracorporeal membrane oxygenation but may still achieve a survival benefit equivalent to those without sepsis. From these data, extracorporeal membrane oxygenation should not be withheld from neonates solely on the basis of sepsis. Rather, management strategies should focus on limiting the incidence or severity of the common complications.


Molecular Mechanism for Improving Emulsification Efficiency of Soy Glycinin by Glycation with Soy Soluble Polysaccharide.
Glycation with carbohydrates has been considered to be an effective strategy to improve the emulsifying properties of plant storage globulins, but the knowledge is inconsistent and even contradictory. This work reported that the glycation with soy soluble polysaccharide (SSPS) progressively improved the emulsification efficiency of soy glycinin (SG) in a degree-of-glycation (DG)-dependent manner. The glycation occurred in both the acidic (A) and basic (B) polypeptides to a similar extent. The physicochemical and structural properties of glycated SG samples with different DG values of 0-35% were characterized. The emulsifying properties of unglycated and glycated SG were performed on the emulsions at an oil fraction of 0.3 and a protein concentration in the aqueous phase, produced using microfluidization as the emusification process. The glycation with increasing the DG led to a progressive decrease in solubility and surface hydrophobicity but remarkably increased the magnitude of ζ-potential. Dynamic latter scattering and spectroscopic results showed that the glycation resulted in a gradual dissociation of the 11S-form SG at the quaternary level (into different [AB] subunits), in a DG-dependent way, while their tertiary ([AB] subunits) and secondary structure were slightly affected. Besides the emulsification efficiency, the glycation progressively accelerated the droplet flocculation and facilitated the adsorption of the proteins at the interface and formation of bridged emulsions. The results demonstrated that the improvement of the emulsification efficiency of SG by the glycation with SSPS was largely attributed to the enhanced conformation flexibility at the [AB] subunit level as well as facilitated formation of bridged emulsions. It was also confirmed that once the glycated SG adsorbed at the interface, it would readily dissociated into subunits; the dissociated [AB] subunits exhibited an outstanding Pickering stabilization. The findings would be of importance for providing new knowledge about the molecular mechanism for the modification of emulsifying properties of oligomeric globulins by the glycation with polysaccharides.


[The advantages of a programme for training carers of persons with dementia: a pilot study by specialised nurses].
The care of patients with dementia usually has to be undertaken by persons with no formal training. However, the chances of treatment being effective depends on them. Specialist non hospital nurses, who are accessible and close to these patients, are in a privileged position to develop programmes to train carers. In our country no studies have been done to evaluate the efficacy of such programmes. To evaluate the efficacy of a programme for training carers of patients with irreversible dementia. The programme was designed and carried out by specialist nurses, based on a neurology clinic outside the hospital. Ten carers who came consecutively to the clinic were invited to participate in the programme. Before and after the programme we evaluated cognitive, functional behaviour and affective aspects of the patient and/or carer. As far as the patient was concerned no changes were found in either cognitive or functional aspects. Although the behaviour problems were reduced, they caused less stress to the carer after the training sessions. At the same time the affectivity of the patients improved. It is possible to carry out effective training programmes for carers of demented patients, with relatively little expense. Affectivity, both of the patient and the carer is the aspect most improved by this training. Large scale trials are necessary to show improvement of other aspects, and to compare different types of training programmes.


Submersed macrophytes play a key role in structuring bacterioplankton community composition in the large, shallow, subtropical Taihu Lake, China.
Within-lake horizontal heterogeneity of bacterioplankton community composition (BCC) was investigated in the large and shallow subtropical Taihu Lake (2338 km(2), maximum depth < 3 m). Samples were collected at 17 sites along a trophic gradient ranging from mesotrophic to hypertrophic areas in August and September 2004. These sites cover two alternative stable states of shallow lakes, which are basically characterized by the dominance or the lack of submerged macrophytes. In the case of Taihu Lake, the macrophyte-dominated state is characterized by clear water and immobilized sediment, and the state largely lacking macrophytes is characterized by the dominance of phytoplankton, frequent wind-driven re-suspension of sediments, and a high turbidity. Three different methods, i.e. denaturing gradient gel electrophoresis (DGGE), reverse line blot hybridization (RLB) with probes targeting 17 freshwater bacterial groups, and 16S rRNA gene cloning and sequencing, were used for analysis of BCC. The BCC varied strongly between the two alternative ecological states, but less pronounced between phytoplankton-dominated sites even spanning chlorophyll a gradients from 16.5 (mesotrophic) to 229.8 microg l(-1) (hypertrophic). The 16S rRNA gene library representing the turbid water state contained many sequences closely related to sequences previously obtained from soil or freshwater sediment samples. Furthermore, sequences representing two new lineages of freshwater Actinobacteria were obtained from the investigated samples. Comparative statistical analyses of BCC along the investigated ecological gradients revealed that the dominance of submersed macrophytes was the most influential factor on BCC, responsible for a major part of the observed within-habitat heterogeneity of BCC in Taihu Lake.


Studies of extraction and transport system for highly charged ion beam of 18 GHz superconducting electron cyclotron resonance ion source at Research Center for Nuclear Physics.
An 18 GHz superconducting electron cyclotron resonance ion source is installed to increase beam currents and to extend the variety of ions especially for highly charged heavy ions which can be accelerated by cyclotrons of Research Center for Nuclear Physics (RCNP), Osaka University. The beam production developments of several ions from B to Xe have been already done [T. Yorita, K. Hatanaka, M. Fukuda, M. Kibayashi, S. Morinobu, H.Okamura, and A. Tamii, Rev. Sci. Instrum. 79, 02A311 (2008) and T. Yorita, K. Hatanaka, M. Fukuda, M. Kibayashi, S. Morinobu, H.Okamura, and A. Tamii, Rev. Sci. Instrum. 81, 02A332 (2010)] and the further studies for those beam extraction and its transport have been done in order to increase the beam current more. The plasma electrode, extraction electrode, and einzel lens are modified. Especially extraction electrode can be applied minus voltage for the beam extraction and it works well to improve the extracted beam current. The extraction voltage dependences of transmission and emittance also have been studied for beam current improvement which is injected into azimuthally varying field cyclotron at RCNP.


Hyperhomocysteinemia and protein damage in chronic renal failure and kidney transplant pediatric patients--Italian initiative on uremic hyperhomocysteinemia (IIUH).
Plasma homocysteine, a new cardiovascular risk factor in both children and adults, is higher in chronic renal failure or kidney transplant patients. This alteration has been linked, in chronic renal failure, to plasma protein damage, represented by increased L-isoaspartyl residues. We measured plasma homocysteine levels and plasma protein damage in pediatric patients from four different Italian regions with conservatively treated renal failure; hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), or transplants, to establish the presence of protein damage and the relative role of hyperhomocysteinemia. High performance liquid chromatography (HPLC) separation measured total plasma homocysteine levels, using precolumn derivatization with ammonium 7-fluorobenzo-2-oxa-1, 3-diazole-4-sulphonate (SBD-F). Plasma protein L-isoaspartyl residues were quantitated using human recombinant protein carboxyl methyl transferase (PCMT). In all patient groups, homocysteine levels were significantly higher with respect to the control (Control: 6.87 +/- 0.73 microM) conservatively treated, 14.19 +/- 1.73 microM; hemodialysis, 27.03 +/- 4.32 microM; CAPD, 22.38 +/- 3.73 microM; transplanted, 20.22 +/- 2.27 microM, p < 0.001 vs. control]. Plasma protein damage was significantly higher in conservatively treated, hemodialysis (HD) and CAPD patients, while in transplant patients it was no different from the control. We concluded that in pediatric patients of different Italian geographical origin, plasma homocysteine levels were significantly higher in all groups with respect to healthy children; therefore contributing to the elevated cardiovascular risk present in these patients. Plasma protein L-isoaspartyl content was higher in renal failure patients, but kidney transplant patients had normal levels, indicating that this kind of protein damage relates more to the toxic action of uremic retention solutes, than to plasma homocysteine levels.


[Clinical and radiological study of Suruí indigenous children and adolescents, Amazon Region, Brazil].
The average incidence coefficient of tuberculosis in Suruí Indians from Rondônia was 2.500/100.000 inhabitants in 1991-2002. About 50% of these cases were reported in children < 15 years-old. This study aimed to describe the clinical and radiological characteristics of children and adolescents identified as TB case contacts. A score system for the diagnosis of childhood TB was used and the procedures adopted by local health services were in accordance with national guidelines. 52 chest X-rays of 37 indigenous subjects were analyzed; of these, 51.9% were abnormal. Some X-rays showed more than two lesions, making a total of 36 independent events. Infiltrates (38.9%), calcifications (38.9%), cavitations (11.1%) and atelectasis/pleural effusion (11.1%) were observed. Among the abnormal images, 22.2% were probably indicated active TB and 33.3% showed sequelae. Confrontation with the guidelines revealed 52.6% of divergent procedures. The presence of latent tuberculosis infection (LTBI) and active TB between children and adolescents are indicators of active and progressive transmission of Mycobacterium tuberculosis. The X-rays showed high frequencies of infiltrates and calcifications, which are compatible with primary infection in early childhood. However, these lesions are not different from those observed among other groups and do not suggest immune deficiencies. The divergences presented show that the best moment for the treatment of LTBI went unnoticed by local personnel. In conclusion, the use of a score system is fundamental for the correct diagnosis of TB in childhood, as is conducting bacilloscopy and sputum culture in adolescents able to expectorate.


[Vesicovaginal fistula in an 8-year-old girl].
We report a case of vesicovaginal fistula in an 8-year-old girl caused by a foreign body in the vagina. The foregoing condition was associated with vesical lithiasis. Correction of the fistula was performed during the same surgical procedure for stone removal, without waiting for 3-6 months to elapse as advocated by most of the authors. A review of the literature revealed only one such case has been reported earlier.


Cervical Cancer Treatment Delays and Associated Factors in a Cohort of Women From a Developing Country.
To estimate treatment delays and associated factors among women diagnosed with cervical cancer who were treated at the main cancer center in Rio de Janeiro, Brazil. A retrospective cohort study was performed comprising 865 women newly diagnosed with cervical cancer between 2012 and 2014. Times from diagnosis to treatment initiation (less than or equal to 60 days) and from diagnosis to treatment ending (less than or equal to 120 days) were analyzed according to the Brazilian law for the treatment of patients with cancer. Associations between treatment delays and sociodemographic, economic, lifestyle, clinical, and treatment variables were estimated using logistic regression models, with 95% CIs. The average age was 48 (± 13.7) years, and the median age was 47 years; 36.2% of patients had stage IIIB to IVA disease. The median time from diagnosis to treatment initiation was 114 days, which was statistically higher among women with stage IIB to IVA (105.5 days) compared with those with earlier stages (119 days). The delay in treatment initiation occurred in 92.8% of participants; the median time from diagnosis to treatment ending was 274 days, with a delay (more than 120 days) for 92.6% of patients. The median time interval from diagnosis to the first visit to the cancer center was 28 days, with a delay of more than 30 days for 46.6% of patients. Age (odds ratio [OR], 1.05; 95% CI,1.02 to 1.08), stage IIIB to IVA (OR, 0.38; 95% CI, 0.16 to 0.90), time to first visit to the cancer center (OR, 11.52; 95% CI, 4.32 to 30.66), chemoradiation treatment (OR, 4.56; 95% CI, 1.81 to 11.47), and adequate treatment (OR, 2.57; 95% CI, 1.26 to -5.40) were independently associated with delay of treatment initiation. Significant delays in treatment initiation and ending were observed in this studied population. The treatment initiation delay was positively associated with age, time interval more than 30 days from diagnosis to first specialist assessment at the cancer center, treatment with chemoradiation, and adequate treatment.


Energy utilisation of broiler chickens in response to guanidinoacetic acid supplementation in diets with various energy contents.
This experiment was conducted to investigate the effects of guanidinoacetic acid (GAA) on productive performance, intestinal morphometric features, blood parameters and energy utilisation in broiler chickens. A total of 390 male broiler chicks (Ross 308) were assigned to six dietary treatments based on a factorial arrangement (2×3) across 1-15 and 15-35-d periods. Experimental treatments consisted of two basal diets with standard (STD; starter: 12·56 MJ/kg and grower: 12·97 MJ/kg) and reduction (LME; starter: 11·93 MJ/kg and grower: 12·33 MJ/kg) of apparent metabolisable energy (AME) requirement of broiler chickens each supplemented with 0, 0·6 and 1·2 g/kg GAA. Supplemental 1·2 g/kg GAA decreased the negative effects of feed energy reduction on weight gain across starter, growing and the entire production phases (P<0·05). Energy retention as fat and total energy retention were increased when birds received LME diets supplemented with 1·2 g/kg GAA (P<0·05). Net energy for production (NEp) and total heat production increased in birds fed LME diets containing 1·2 g/kg GAA (P<0·05). A significant correlation was observed between dietary NEp and weight gain of broilers (r 0·493; P=0·0055), whereas this relationship was not seen with AME. Jejunal villus height and crypt depth were lower in birds fed LME diets (P<0·05). Serum concentration of creatinine increased in broilers fed LME diets either supplemented with 1·2 g/kg GAA or without GAA supplementation (P<0·05). Supplemental GAA improved performance of chickens fed LME diet possibly through enhanced dietary NEp. The NEp could be preferred over the AME to assess response of broiler chickens to dietary GAA supplementation.


Officers, trustees, directors beware! IRS-imposed 'intermediate' sanctions can be severe.
The IRS pushed for intermediate sanctions for some time. It now has them, and we should assume that it will use them. If you're an insider to a 501(c)(3) or 501(c)(4) organization, who is compensated by or has business dealings with the organization, or if you are an officer, director, or trustee of such an organization, study the intermediate sanctions law and congressional comment on it. Think through its possible applications and ramifications. With the assistance of legal counsel, you may also want to carefully review your organization's indemnification policies and understand how they relate to intermediate sanctions taxes. Finally, keep your ear to the ground for further IRS interpretations and application of this important new tax law.


Leading with integrity. How to balance conflicting values.
Reports of lapses in organizational integrity and ethical behavior are disturbing and point to the need for leaders committed to organizational integrity. In recent years, organizations have increased their attention to codes of compliance and compliance programs, but these programs focus on minimal requirements and are not a manifestation of integrity. Leaders must create integrity-based ethics programs, which direct corporate actions and goals and assist in shaping organizational relationships and decisions based on mission, vision, and core values. Organizational leaders must hold values that may be in conflict in a balanced tension. Such conflicting values include the Hippocratic tradition and population-based healthcare, caring for patients and families and containing costs, and competition and collaboration. Leaders can model integrity by addressing conflicting values overtly in decision-making processes.


Surgical revascularization for acute coronary syndrome: comparative surgical and long-term results.
The purpose of this study was to evaluate the adequate timing of coronary artery bypass grafting (CABG) for acute coronary syndrome (ACS). In our institution, emergency CABG has been avoided when possible for ACS patients favoring stabilization with medical therapies, including intra-aortic balloon pumping or percutaneous coronary intervention. After thorough preoperative examinations, an urgent CABG is performed. A total of 67 patients with ACS underwent CABG, comprised of 33 patients receiving an emergency CABG (emergent group: E-G) and 34 patients receiving an urgent CABG (urgent group: U-G). The early and long-term results were evaluated retrospectively. Preoperatively, the incidences of acute myocardial infarction and cardiogenic shock were significantly higher in E-G. No significant differences were found in the intraoperative factors except for the number of distal anastomoses (2.5 in E-G vs. 3.1 in U-G, p=0.01). The hospital mortality was 9.1% in E-G, and 2.9% in U-G, with no significant difference between the groups. Moreover, no patient in U-G necessitated emergency CABG while waiting for surgery. The patency rate of the grafts was 100% in E-G, and 96.2% in U-G. The 5-year survival rate excluding in-hospital death was 80.3% in E-G, and 78% in U-G (p>0.05). The 5-year cardiac event-free rate was 80.3% in E-G, and 80.9% in U-G (p>0.05). An emergency CABG can be reserved for ACS patients when symptoms and hemodynamic state are stabilized with medical therapies. Improvements in long-term results can be expected after high quality and complete surgical revascularization.


Cord blood banking and transplant in Europe. Eurocord.
The number of cord blood transplants has been increasing very quickly with more than 250 cases reported to Eurocord Registry and more than 500 patients transplanted via the New York Cord Blood Bank. Cord blood transplants have been performed either with related or unrelated cord blood. Several cord blood banks established a group called Netcord whose goal is the standardization of the procedures, the organization of internal audits for accreditation and qualification, and the communication and exchange by internet of donor search on an international basis. More than 15,000 units of frozen cord blood are currently available and this number is increasing rapidly worldwide. Analysis of the clinical results has shown that related cord blood transplants give better results than unrelated cord blood transplants. Factors associated with better survival in related and unrelated cord blood transplants were lower age, diagnosis, with better results in inborn errors and in good risk children with acute leukemia. A larger number of nucleated cells in the transplant and the recipient being negative for CMV serology were also favourable risk factors for survival. Engraftment was improved with higher numbers of cells and HLA identity. Graft versus Host disease was reduced when compared to transplants of adult allogeneic bone marrow or peripheral blood progenitor cells. HLA disparities did not influence GVH; the only factor associated with increased GVH was positive CMV serology in the recipient. This study shows that cord blood is an alternative source of hematopoietic stem cells for allogeneic transplantation in children and in some adults. HLA disparity is not a limiting factor but the number of cells infused is important; currently the use of a number of nucleated cells inferior to 1 x 10(7)/kg is not recommended. Several questions remain including the criteria of choice of the donor, the indications in children and in adults, the comparison of cord blood transplants to other sources of hematopoietic stem cells and the role of growth factors and expansion for improving the speed of engraftment.


Engineered Fibrin Gels for Parallel Stimulation of Mesenchymal Stem Cell Proangiogenic and Osteogenic Potential.
Mesenchymal stem/stromal cells (MSCs) are under examination for use in cell therapies to repair bone defects resulting from trauma or disease. MSCs secrete proangiogenic cues and can be induced to differentiate into bone-forming osteoblasts, yet there is limited evidence that these events can be achieved in parallel. Manipulation of the cell delivery vehicle properties represents a candidate approach for directing MSC function in bone healing. We hypothesized that the biophysical properties of a fibrin gel could simultaneously regulate the proangiogenic and osteogenic potential of entrapped MSCs. Fibrin gels were formed by supplementation with NaCl (1.2, 2.3, and 3.9% w/v) to modulate gel biophysical properties without altering protein concentrations. MSCs entrapped in 1.2% w/v NaCl gels were the most proangiogenic in vitro, yet cells in 3.9% w/v gels exhibited the greatest osteogenic response. Compared to the other groups, MSCs entrapped in 2.3% w/v gels provided the best balance between proangiogenic potential, osteogenic potential, and gel contractility. The contribution of MSCs to bone repair was then examined when deployed in 2.3% w/v NaCl gels and implanted into an irradiated orthotopic bone defect. Compared to acellular gels after 3 weeks of implantation, defects treated with MSC-loaded fibrin gels exhibited significant increases in vessel density, early osteogenesis, superior morphology, and increased cellularity of repair tissue. Defects treated with MSC-loaded gels exhibited increased bone formation after 12 weeks compared to blank gels. These results confirm that fibrin gel properties can be modulated to simultaneously promote both the proangiogenic and osteogenic potential of MSCs, and fibrin gels modified by supplementation with NaCl are promising carriers for MSCs to stimulate bone repair in vivo.


[Use of a freeze-drief culture of Leuconostoc mesenteroides for the synthesis of dextran].
The influence of a prolonged storage of the freeze-dried culture Leuconostoc mesenteroides strain SF-4 on its capacity for the dextrane synthesis has been studied. The culture has maintained its normal viability for 12 years (the observation time) without changes in the cell morphology and capacity for the dextrane synthesis. The structure of dextrane synthesized by the revived culture L. mesenteroides has been similar to that of dextrane synthesized by the culture L. mesenteroides preserved via passages.


Shared and syndrome-specific adaptive difficulties in preschoolers with Williams syndrome and autism spectrum disorder: a cross-syndrome study.
Understanding adaptive functioning profiles in children with Williams syndrome (WS) and autism spectrum disorder (ASD) is critical to inform treatment strategies. However, knowledge in this area is limited and inconclusive. The current study aimed to characterise the early adaptive profiles of young children with WS (n = 18; Mage = 47 months) and ASD (n = 26; Mage = 45 months) matched on chronological age and developmental age using the Vineland Scales of Adaptive Behavior, Second Edition. Results suggest that young children with WS and ASD do not differ on their overall level of adaptive functioning but that those with WS show relative strengths in the Socialisation scale compared with children with ASD. No other subscales differed between groups. Within groups, the WS group showed a profile of Communication, Daily Living Skills and Motor < Socialisation, whereas the ASD group did not evidence differences across subscales. Consideration of the shared and syndrome-specific adaptive profiles provides relevant insight on intervention targets and strategies. Given the shared challenges across the two clinical groups, implications and future directions are discussed.


Performance of the coughassist insufflation-exsufflation device in the presence of an endotracheal tube or tracheostomy tube: a bench study.
The CoughAssist is a mechanical insufflator-exsufflator designed to assist airway secretion clearance in patients with ineffective cough. The device may benefit intubated and tracheotomized patients. We assessed the impact of various artificial airways on peak expiratory flow (PEF) with the CoughAssist. We measured PEF and pressure at the airway opening in a lung model during insufflation-exsufflation with the CoughAssist, at 3 set pressures: 30/-30, 40/-40, and 50/-50 cm H(2)O, first without (control), and then with different sizes (6.5 to 8.5 mm inner diameter) of endotracheal tube (ETT) and tracheostomy tube (6, 7, and 8 mm inner diameter), compliance settings of 30 and 60 mL/cm H(2)O, and resistance settings of 0 and 5 cm H(2)O/L/s). We analyzed the relationship between PEF and pressure with linear regression. With compliance of 30 mL/cm H(2)O and 0 resistance the slope of the control relationship between PEF and pressure was statistically significantly greater than during any conditions with ETT or tracheostomy tube. Therefore, in comparison to the control, the relationship of PEF to pressure significantly went in the direction from top to bottom as the ETT or tracheostomy tube became narrower. The findings were the same with compliance of 30 mL/cm H(2)O and resistance of 5 cm H(2)O/L/s. With compliance of 60 mL/cm H(2)O the highest set pressure values were not achieved and some relationships departed from linearity. The control slope of the relationship between PEF and pressure with compliance of 60 mL/cm H(2)O and 0 resistance did not significantly differ with any ETT or tracheostomy tube. The artificial airways significantly reduced PEF during insufflation-exsufflation with CoughAssist; the narrower the inner diameter of the artificial airway, the lower the PEF for a given expiratory pressure.


Mutations affecting the cytochrome d-containing oxidase complex of Escherichia coli K12: identification and mapping of a fourth locus, cydD.
A mutant of Escherichia coli K12 has been isolated affected in a gene, designated cydD, distinct from the three previously described loci involved in the synthesis of assembly of the cytochrome bd oxidase complex. The mutant, obtained by nitrosoguanidine mutagenesis, lacks the spectroscopically detectable components of this oxidase, namely cytochromes b558, b595 and d. Cytochrome oxidase o is the sole CO-binding cytochrome in membranes of the mutant, but the soluble haemoprotein b-590 and catalase activity appear unaffected. Discrimination between Cyd+ and Cyd- strains is facilitated by the development of a defined low-phosphate medium that allows the inclusion of Zn2+ as well as azide, inhibitors of respiratory electron transfer particularly via cytochrome o. Mapping with F-prime factors and by P1 cotransductional frequencies shows the mutation to map near 19.3 min on the E. coli chromosome, distinct from cydC, which maps at 18.9 min. The gene order in this region was tested in a three-factor cross and demonstrates the order zbj::Tn10(YYC199)-cydD-aroA, consistent with cotransduction frequencies.


Monosodium glutamate-induced oxidative damage and genotoxicity in the rat: modulatory role of vitamin C, vitamin E and quercetin.
Monosodium glutamate (MSG) continues to function as a flavor enhancer in West African and Asian diets. The present study examines the modulatory effects of dietary antioxidant vitamin C (VIT C), vitamin E (VIT E) and quercetin on MSG-induced oxidative damage in the liver, kidney and brain of rats. In addition, the effect of these antioxidants on the possible genotoxicity of MSG was investigated in a rat bone marrow micronuclei model. MSG administered intraperitoneally at a dose of 4 mg/g body wt markedly increase malondialdehyde (MDA) formation in the liver, the kidney and brain of rats. Simultaneous administration of VIT C, VIT E and quercetin to MSG-treated rats significantly reduced this increase in MDA induced by MSG. VIT E reduced lipid peroxidation most in the liver followed by VIT C and then quercetin, while VIT C and quercetin showed a greater ability to protect the brain from membrane damage than VIT E. The decreased glutathione (GSH) level elicited by MSG in the three organs corresponded with marked increase in the activity of glutathione-S-transferase (GST). While MSG increased (P < 0.001) the activities of superoxide dismutase and catalase in the liver, it decreased significantly the activities of these enzymes in the kidney and the brain. The three antioxidants were effective at ameliorating the effects of MSG on GSH levels and the enzymes in the three organs examined. While MSG increased the activity of glucose-6-phosphatase in the liver and kidneys of rats (P < 0.001), the activity of the enzyme was abysmally low in the brain. There were marked increases in the activities of alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase in rats treated with MSG. The antioxidants tested protected against MSG-induced liver toxicity significantly. MSG at a dose of 4 mg/g significantly (P < 0.01) induced the formation of micronucleated polychromatic erythrocytes (MNPCEs). Co-treatment of rats with VIT C and quercetin inhibited the induction of MNPCEs by MSG (P < 0.001). VIT E failed to protect against MSG-induced genotoxicity. The results indicate that dietary antioxidants have protective potential against oxidative stress induced by MSG and, in addition, suggest that active oxygen species may play an important role in its genotoxicity.


Structural dynamics of green fluorescent protein alone and fused with a single chain Fv protein.
Structural information on intracellular fusions of the green fluorescent protein (GFP) of the jellyfish Aequorea victoria with endogenous proteins is required as they are increasingly used in cell biology and biochemistry. We have investigated the dynamic properties of GFP alone and fused to a single chain antibody raised against lipopolysaccharide of the outer cell wall of gram-negative bacteria (abbreviated as scFv-GFP). The scFv moiety was functional as was proven in binding assays, which involved the use of both fluorescence correlation spectroscopy observing the binding of scFv-GFP to gram-negative bacteria and a surface plasmon resonance cell containing adsorbed lipopolysaccharide antigen. The rotational motion of scFv-GFP has been investigated with time-resolved fluorescence anisotropy. However, the rotational correlation time of scFv-GFP is too short to account for globular rotation of the whole protein. This result can only be explained by assuming a fast hinge motion between the two fused proteins. A modeled structure of scFv-GFP supports this observation.


Combined hybridization capture and shotgun sequencing for ancient DNA analysis of extinct wild and domestic dromedary camel.
The performance of hybridization capture combined with next-generation sequencing (NGS) has seen limited investigation with samples from hot and arid regions until now. We applied hybridization capture and shotgun sequencing to recover DNA sequences from bone specimens of ancient-domestic dromedary (Camelus dromedarius) and its extinct ancestor, the wild dromedary from Jordan, Syria, Turkey and the Arabian Peninsula, respectively. Our results show that hybridization capture increased the percentage of mitochondrial DNA (mtDNA) recovery by an average 187-fold and in some cases yielded virtually complete mitochondrial (mt) genomes at multifold coverage in a single capture experiment. Furthermore, we tested the effect of hybridization temperature and time by using a touchdown approach on a limited number of samples. We observed no significant difference in the number of unique dromedary mtDNA reads retrieved with the standard capture compared to the touchdown method. In total, we obtained 14 partial mitochondrial genomes from ancient-domestic dromedaries with 17-95% length coverage and 1.27-47.1-fold read depths for the covered regions. Using whole-genome shotgun sequencing, we successfully recovered endogenous dromedary nuclear DNA (nuDNA) from domestic and wild dromedary specimens with 1-1.06-fold read depths for covered regions. Our results highlight that despite recent methodological advances, obtaining ancient DNA (aDNA) from specimens recovered from hot, arid environments is still problematic. Hybridization protocols require specific optimization, and samples at the limit of DNA preservation need multiple replications of DNA extraction and hybridization capture as has been shown previously for Middle Pleistocene specimens.


Multi-species single-cell transcriptomic analysis of ocular compartment regulons.
The retina is a widely profiled tissue in multiple species by single-cell RNA sequencing studies. However, integrative research of the retina across species is lacking. Here, we construct the first single-cell atlas of the human and porcine ocular compartments and study inter-species differences in the retina. In addition to that, we identify putative adult stem cells present in the iris tissue. We also create a disease map of genes involved in eye disorders across compartments of the eye. Furthermore, we probe the regulons of different cell populations, which include transcription factors and receptor-ligand interactions and reveal unique directional signalling between ocular cell types. In addition, we study conservation of regulons across vertebrates and zebrafish to identify common core factors. Here, we show perturbation of KLF7 gene expression during retinal ganglion cells differentiation and conclude that it plays a significant role in the maturation of retinal ganglion cells.


"They stand in the middle now": Pathways to meeting psychological needs by adolescents who are refugees from sub-Saharan Africa.
This study explored the psychological needs of refugee youth from sub-Saharan Africa resettled in a large city in Southwest United States. We utilized the framework of Basic Psychological Needs Theory (Deci & Ryan, 2000) which proposes that competence, relatedness, and autonomy are universal psychological needs. We examined the challenges to meeting these needs and resolutions to these challenges. Integral to understanding these needs was to place them in the context of a bicultural model of adaptation. Of particular interest was discovering how these young people negotiate and reconcile home and host cultural demands while meeting needs. From July 2019 to August 2020, semistructured individual interviews (N = 44) were completed with youth, parents, and cultural experts. Data were analyzed using a hybrid inductive and deductive approach and thematic content analysis. Active engagement, assertion, and self-advocacy were delineated as important pathways to achieve competence. Relatedness needs were served by inclusive ties, and frequently included other "outsiders." Autonomy came from self-sufficiency, agency, and "voice." Altruism was common, extending beyond ethnic community, and promoted competence, relatedness, and empowerment. Conflicts between family and host culture were managed by accepting parental authority. Parents contributed to integrating home and host cultures by flexibly interpreting traditional rules. Our findings illustrate the strengths of these youth who manage tremendous challenges to meeting their psychological needs. We highlight how in the process of cultural adaptation they retain ties to their home culture. They choose diversity in their relationships and find agency and purpose by supporting others. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Functional and Anatomic Consequences of Diabetic Pregnancy on Memory in Ten-Year-Old Children.
Pregnancies complicated by diabetes mellitus impair offspring memory functions during infancy and early childhood. The purpose of this study was to investigate the long-term consequences of such pregnancies on memory and memory-related brain regions in 10-year-old children. Nineteen children of diabetic mothers (CDMs) and 35 children of nondiabetic mothers participated in this 10-year follow-up study. Memory performance was assessed using a continuous recognition memory task during which children made old/new judgments in response to pictures of concrete and abstract objects presented after different lags or delays. In addition, the volume of the hippocampal formation (HF) was measured using high-resolution structural images. At 10 years of age, recognition memory performance of CDMs did not differ from children of nondiabetic mothers. Similarly, the volume of the HF did not differ between groups. However, the size of the HF in CDMs predicted the time those children needed to provide accurate responses in the continuous recognition memory task. CDMs do not show memory impairments by 10 years of age, despite evidence for such impairments early in life. However, subtle differences in underlying neural processes may still be present. These results have important implications for long-term cognitive development of CDMs.


Expression of NCAM containing VASE in neurons can account for a developmental loss in their neurite outgrowth response to NCAM in a cellular substratum.
Binding of the neural cell adhesion molecule (NCAM) in neurons to NCAM on non-neuronal cells can stimulate axonal growth. A developmentally regulated loss of this response is associated with the insertion of 10 amino acids (called VASE) into the fourth Ig domain in up to 50% of the NCAM receptors in neurons. In the present study we have transfected PC12 cells with the major neuronal isoforms of human NCAM and tested cells expressing these isoforms for their ability to respond to NCAM in a cellular substratum. Whereas both the 140- and 180-kD isoforms of NCAM can act as functional receptors for neurite outgrowth, the presence of the VASE sequence in a minority of the receptors specifically inhibited this response. A synthetic peptide containing the VASE sequence inhibits neurite outgrowth from PC12 cells and primary neurons stimulated by NCAM. The same peptide has no effect on integrin dependent neurite outgrowth or neurite outgrowth stimulated by N-cadherin or L1. We discuss the possibility that the VASE peptide inhibits the NCAM response by preventing NCAM from binding to the FGF receptor in the plasma membrane.


CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities.
Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors.


Aversive workplace conditions and absenteeism: taking referent group norms and supervisor support into account.
Past research reveals inconsistent findings regarding the association between aversive workplace conditions and absenteeism, suggesting that other, contextual factors may play a role in this association. Extending contemporary models of absence, we draw from the social identity theory of attitude-behavior relations to examine how peer absence-related norms and leader support combine to explain the effect of aversive workplace conditions on absenteeism. Using a prospective design and a random sample of transit workers, we obtained results indicating that perceived job hazards and exposure to critical incidents are positively related to subsequent absenteeism, but only under conditions of more permissive peer absence norms. Moreover, this positive impact of peer norms on absenteeism is amplified among employees perceiving their supervisor to be less supportive and is attenuated to the point of nonsignificance among those viewing their supervisor as more supportive.


Adsorption of Catalytic Nanoparticles onto Polymer Substrates for Controlled Deposition of Microcapsule Metal Shells.
Efficient encapsulation of small chemical molecules and their controlled targeted delivery provides a very important challenge to be overcome for a wide range of industrial applications. Typically rapid diffusion of these actives across capsule walls has so far prevented the development of a versatile widely applicable solution. In an earlier publication, we have shown that thin metal shells are able to permanently retain small molecules. The critical step in the microcapsule synthesis is the formation of a strongly adsorbed, dense monolayer of catalytic nanoparticles on the surface as this affects the secondary metal film quality. Control over Pt-nanoparticle adsorption density and a clear understanding of Pt-nanoparticle adsorption kinetics is therefore paramount. Maximising the density of heterogeneous catalysts on surfaces is generally of interest to a broad range of applications. In this work, transmission electron microscopy (TEM) and quartz crystal microbalance (QCM) are used to demonstrate that the concentration of nanoparticle polymer stabilizer used during particle synthesis and nanoparticle suspension concentration can be used to control nanoparticle surface adsorption density. We demonstrate that excess polymer, which is often used in nanoparticle synthesis but rarely discussed as an important parameter in the literature, can compete with and thus drastically affect the adsorption of the Pt-nanoparticles.


Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice.
The Sir2 (silent information regulator 2) family of NAD-dependent deacetylases regulates aging and longevity across a wide variety of organisms, including yeast, worms, and flies. In mammals, the Sir2 ortholog Sirt1 promotes fat mobilization, fatty acid oxidation, glucose production, and insulin secretion in response to nutrient availability. We previously reported that an increased dosage of Sirt1 in pancreatic beta cells enhances glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance in beta cell-specific Sirt1-overexpressing (BESTO) transgenic mice at 3 and 8 months of age. Here, we report that as this same cohort of BESTO mice reaches 18-24 months of age, the GSIS regulated by Sirt1 through repression of Ucp2 is blunted. Increased body weight and hyperlipidemia alone, which are observed in aged males and also induced by a Western-style high-fat diet, are not enough to abolish the positive effects of Sirt1 on beta cell function. Interestingly, plasma levels of nicotinamide mononucleotide (NMN), an important metabolite for the maintenance of normal NAD biosynthesis and GSIS in beta cells, are significantly reduced in aged BESTO mice. Furthermore, NMN administration restores enhanced GSIS and improved glucose tolerance in the aged BESTO females, suggesting that Sirt1 activity decreases with advanced age due to a decline in systemic NAD biosynthesis. These findings provide insight into the age-dependent regulation of Sirt1 activity and suggest that enhancement of systemic NAD biosynthesis and Sirt1 activity in tissues such as beta cells may be an effective therapeutic intervention for age-associated metabolic disorders such as type 2 diabetes.


Optimising the ISAR-HP to screen efficiently for functional decline in older patients.
The Identification of Seniors At Risk-Hospitalised Patients (ISAR-HP) has recently been included in guidelines as a frailty indicator to identify patients for comprehensive geriatric assessment. Previous studies showed that the conventional cut-off score incorrectly classifies a high percentage of patients as high risk. We aimed to optimise the predictive value of ISAR-HP by using different cut-offs in older acutely hospitalised patients. A prospective follow-up study was performed in two Dutch hospitals. Acutely hospitalised patients aged ≥ 70 years were included. Demographics, illness severity parameters, geriatric measurements and the ISAR-HP scores were obtained at baseline. The primary outcome was a combined end point of functional decline or mortality during 90-day follow-up. In total 765 acutely hospitalised older patients were included, with a median age of 79 years, of whom 276 (36.1%) experienced functional decline or mortality. The conventional ISAR-HP cut-off of ≥ 2 assigned 432/765 patients (56.5%) as high risk, with a positive predictive value (PPV) of 0.49 (95%CI 0.45-0.54) and a negative predictive value of 0.81 (95%CI 0.76-0.85). Thus, 51% of those whom the ISAR-HP denoted as high risk did not experience the outcome of interest. Raising the cut-off to ≥ 4 assigned 205/765 patients (26.8%) as high risk, with a marginally increased PPV to 0.55 (95%CI 0.48-0.62). The ISAR-HP with the conventional cut-off of ≥ 2 incorrectly identifies a large group of patients at high risk for functional decline or mortality and raising the cut-off to 4 only marginally improved performance. Caution is warranted to ensure efficient screening and follow-up interventions.


Making "time" for preventive services.
Although the implementation of clinical preventive services is a high priority on the national agenda and physicians acknowledge the importance of these services, implementation rates remain far below the target years after the recommendations have been released. Physicians repeatedly report that the reason for not providing preventive services is that they do not have "time." In this article, we identify attributes of the health-services system that create this phenomenon. We present evidence that formal delivery systems for preventive services must be developed if the "time" problem is to be solved, and we review why preventive-services systems need to be integrated into the current health-services system. Finally, we list the attributes that we believe a preventive-services system must have if it is to be successful. The success of clinical trials of such systems indicates that our goals of preventive services can be achieved if all persons who have an investment in clinical preventive services commit themselves to developing and supporting these systems.


Determinants of the human immunodeficiency virus type 1 p15NC-RNA interaction that affect enhanced cleavage by the viral protease.
During human immunodeficiency virus type 1 (HIV-1) virion assembly, cleavage of the Gag precursor by the viral protease results in the transient appearance of a nucleocapsid-p1-p6 intermediate product designated p15NC. Utilizing the p15NC precursor protein produced with an in vitro transcription-translation system or purified after expression in Escherichia coli, we have demonstrated that RNA is required for efficient cleavage of HIV p15NC. Gel mobility shift and nitrocellulose filter binding experiments indicate that purified p15NC protein specifically binds its corresponding mRNA with an estimated Kd of 1.5 nM. Binding was not affected by the presence or absence of zinc or EDTA. Moreover, mutagenesis of the cysteine residues within either of the two Cys-His arrays had no effect on RNA binding or on RNA-dependent cleavage by the viral protease. In contrast, decreased binding of RNA and diminished susceptibility to cleavage in vitro were observed with p15NC-containing mutations in one or more residues within the triplet of basic amino acids present in the region between the two zinc fingers. In addition, we found that 21- to 24-base DNA and RNA oligonucleotides of a particular sequence and secondary structure could substitute for p15 RNA in the enhancement of p15NC cleavage. Virus particles carrying a mutation in the triplet of NC basic residues (P3BE) show delayed cleavage of p15NC and a defect in core formation despite the eventual appearance of fully processed virion protein. These results define determinants of the p15NC-RNA interaction that lead to enhanced protease-mediated cleavage and demonstrate the importance of the triplet of basic residues in formation of the virus core.


Osteoporotic bone microstructure by collagenase etching.
Collagenase etching has been used to show the microstructure of bone from patients suffering from primary osteoporosis. Both polished and unpolished surfaces of trabecular bone from femoral heads were treated with collagenase solution before study in the scanning electron microscope. The polished surfaces show the mineral component of this bone as small rounded units approximately 10-20 nm across, which aggregate to form a continuous phase of contiguous spheroidal particles approximately 100 nm across. Lamellations are clearly seen to be due to the removal of collagen fibres up to approximately 200 nm across, fibres in adjacent lamellae being arranged approximately perpendicular to each other. The unpolished surfaces also show small rounded units, which aggregate into rods of mineral approximately 100 nm across. Although these rods form a connected system, they are loosely packed, compatible with their being interspersed with the collagen fibres in vivo. This model for the detailed microstructure of bone is consistent with specimens from a number of other sources and shows no features unique to osteoporosis.


Genetic characterization of patients with Bernard-Soulier syndrome and their relatives from Southern Iran.
Bernard-Soulier syndrome (BSS) is a rare recessively inherited bleeding disorder caused by the deficiency of the platelet glycoprotein (Gp) complex Ib/IX/V that is the von Willebrand factor receptor on platelets. In patients suffering from BSS platelet adhesion is typically impaired, while platelet aggregation is normal; macrothrombocytopenia is a common feature. In this study three different families from Southern Iran were investigated. GpIb/IX/V platelet expression as detected by flow cytometry was less than 2% of normal in six cases and 12% in the remaining one. Platelet count was 35,000 platelets/microliter and iron deficiency anemia was common. All patients suffered from mucocutaneous bleeding at presentation and were born from consanguineous marriages. Genetic analysis demonstrated the presence of the same GpIX Phe55Ser missense mutation in two families and of a single base insertion (GP1BA C3221 ins), a never described mutation causing a frameshift in the GpIbalpha gene, in the third family. Among the family members studied several heterozygotes were identified. None of them, with one exception, had macrothrombocytopenia. In one family a slight reduction of GpIb/IX/V expression was observed.


Double Emulsion Droplets as a Plausible Step to Fatty Acid Protocells.
It is assumed that life originated on the Earth from vesicles made of fatty acids. These amphiphiles are the simplest chemicals, which can be present in the prebiotic soup, capable of self-assembling into compartments mimicking modern cells. Production of fatty acid vesicles is widely studied, as their growing and division. However, how prebiotic chemicals require to further yield living cells encapsulated within protocells remains unclear. Here, one suggests a scenario based on recent studies, which shows that phospholipid vesicles can form from double emulsions affording facile encapsulation of cargos. In these works, water-in-oil-in-water droplets are produced by microfluidics, having dispersed lipids in the oil. Dewetting of the oil droplet leaves the internal aqueous droplet covered by a lipid bilayer, entrapping cargos. In this review, formation of fatty acid protocells is briefly reviewed, together with the procedure for preparing double emulsions and vesicles from double emulsion and finally, it is proposed that double emulsion droplets formed in the deep ocean where undersea volcano expulsed materials, with fatty acids (under their carboxylic form) and alkanols as the oily phase, entrapping hydrosoluble prebiotic chemicals in a double emulsion droplet core. Once formed, double emulsion droplets can move up to the surface, where an increase of pH, variation of pressure and/or temperature may have allowed dewetting of the oily droplet, leaving a fatty acid vesicular protocell with encapsulated prebiotic materials.


The Ex Vivo Time of Fresh Autologous Cartilage Before Transplantation and Cartilage Absorption Degree.
This study aims to determine the relationship between the time of autogenous cartilage in vitro and the degree of absorption in animal experiments. New Zealand white rabbits were randomly divided into 3 groups according to the time of cartilage in vitro: 1-hour group, 2-hour group, and 3-hour group. A volume of ear cartilage was taken and transplanted into the back, according to the group. After 1 month, the volume was taken out and remeasured. Then, these were compared by scanning electron microscopy and hematoxylin and eosin staining. The cartilage bulk absorption level of different groups is different (P < 0.05). There was statistical significance when the 3-hour group was compared with the other 2 groups (P < 0.05). This shows that cartilage volume absorption level becomes higher after 3 hours. Scanning electron microscopy revealed that before and after transplantation, the arrangement of collagen fibers and the gap between these fibers changed. Hematoxylin and eosin staining revealed that there were some morphological changes in chondrocytes, and the degree of chondrocyte apoptosis increased with time, which was accompanied by granulation tissue formation. In addition, the cartilage tissue survived after transplantation. The change in cartilage volume was more obvious after 3 hours of autogenous fresh cartilage transplantation, when compared with that of the first 2 hours. The longer the time of light microscopy was, the longer the apoptosis of cartilage cells, the more serious the destruction of collagen fibers and the cartilage matrix, and the greater the absorption of cartilage and the new chondrocytes.


Transvenous cardiac implantable electronic devices and hemodialysis catheters: recommendations to curtail a potentially lethal combination.
Abnormal renal function is an independent risk factor for cardiac implantable electronic device (CIED) infection. The risk of CIED infection increases as the degree of renal dysfunction worsens with the highest risk observed in patients with stage V chronic kidney disease. A significant portion of these patients use a tunneled hemodialysis catheter (TDC) for dialysis therapy. These devices are associated with very high rates of catheter-related bacteremia (1.6-5.5 episodes of bacteremia per 1000 catheter days), and have been known to cause infection of CIED indwelling in the bloodstream. In this context, the cardiac device is exposed to the risk of infection due to the presence of renal failure and episodes of bacteremia related to TDCs. Both increase the risk of CIED infection. Once infected, a cardiac rhythm device carries a marked increase in morbidity and mortality. In this context, the combination of a TDC and a CIED indwelling in the bloodstream becomes a potentially deadly combination. Recent data have emphasized that epicardial CIED implantation reduces cardiac device infection in TDC patients. This report highlights the risk of CIED infection in renal patients, presents TDC's contribution to the cardiac device infection, and suggests recommendations to minimize the risk of CIED infection in chronic hemodialysis patients dialyzing with a TDC.


Common variants at 30 loci contribute to polygenic dyslipidemia.
Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.


Effect of Lactobacillus fermentum TKSN041 on improving streptozotocin-induced type 2 diabetes in rats.
With the increasing incidence of type 2 diabetes, it is imperative to identify how to effectively prevent or treat this disease. Studies have shown that some lactic acid bacteria can improve type 2 diabetes with almost no side effects. Therefore, in this experimental study, we explored the preventive and therapeutic effects of Lactobacillus fermentum TKSN041 (L. fermentum TKSN041) on streptozotocin-induced type 2 diabetes in rats. The results showed that L. fermentum TKSN041 could reduce the amount of water intake, reduce weight loss, and control the increase in the fasting blood glucose level of diabetic rats. The organ index and tissue section results showed that L. fermentum TKSN041 could reduce the damage caused by diabetes to the liver, kidney, spleen, pancreatic, and brain tissue. Furthermore, L. fermentum TKSN041 decreased the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), aminotransferase (AST), alanine aminotransferase (ALT), glycated serum proteins (GSP), malondialdehyde (MDA), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and endothelin 1 (ET-1) in serum and increased the serum levels of high-density lipoprotein cholesterol (HDL) and interleukin 10 (IL-10). Finally, L. fermentum TKSN041 up-regulated the mRNA and protein expressions of NF-kappa-B inhibitor-α (IκB-α), AMP-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), liver kinase B1 (LKB1), and glucose transporter 4 (GLUT4) and down-regulated those of nuclear factor-κBp65 (NFκB-p65) and tumor necrosis factor alpha (TNF-α). Furthermore, LF-TKSN041 up-regulated the mRNA expressions of peroxisome proliferator-activated receptor γ (PPAR-γ) and down-regulated neuropeptide Y (NPY), sterol regulatory element-binding protein-1 (SREBF-1), and vascular endothelial growth factor (VEGF). These results suggest that L. fermentum TKSN041 may be a useful intervention factor for the prevention or treatment of type 2 diabetes induced by STZ. Clinical trials are needed to further demonstrate its effectiveness.


ATM protein synthesis patterns in sporadic breast cancer.
The gene mutated in ataxia-telangiectasia (A-T), designated ATM (for "A-T mutated"), is believed to be associated with an increased risk of developing breast cancer. Most patients with A-T have null mutations of the ATM gene that appear to give rise to a truncated nonfunctional ATM protein. Therefore, the increased risk of breast cancer reported in A-T heterozygotes appears to be the result of haplo-insufficiency of ATM in breast tissues. This study aimed to determine whether reduced synthesis of ATM was also an important factor in sporadic breast cancer. Paraffin wax embedded tissues from patients with breast invasive ductal carcinoma (IDC) (n = 42), patients with ductal carcinoma in situ (DCIS) (n = 17), and others with lymph node metastases (n = 14) were studied. A streptavidin-biotin-peroxidase system was used to stain tissue sections for the ATM protein using the ATM-4BA and CT-1 polyclonal and monoclonal antibodies, respectively. The protein truncation test was used to screen for mutations in the ATM gene in those patients who had greatly reduced ATM protein immunoreactivity in the primary carcinoma (n = 3). Most metastatic breast carcinomas in lymph nodes (71%) had greatly reduced or absent ATM protein synthesis, which was significant when compared with that observed in non-metastatic invasive breast carcinomas (p = 0.029; chi 2 test). Although not significant (p = 0.045; chi 2 test), some sporadic breast carcinomas (14 of 42) also had reduced or absent ATM protein immunoreactivity. The protein truncation test did not reveal any gross ATM gene abnormality in the cases tested, indicating that the patients were not A-T heterozygotes, who are predisposed to breast cancer. A reduction in immunohistochemically detectable ATM protein in sporadic breast carcinoma implicates ATM in the progression of the disease.


Steroid 5alpha-reductase 1 polymorphisms and testosterone/dihydrotestosterone ratio in male patients with hypospadias.
Defects in the steroid 5alpha-reductase type 2 (SRD5A2) activity cause decreased formation of dihydrotestosterone (DHT) from testosterone (T), resulting in defective masculinization of external genitalia; the T/DHT ratio is increased. We investigated 10 patients with elevated T/DHT ratios in whom mutations in the SRD5A2 and AR genes had been excluded to find out whether structural alterations of the SRD5A1 gene could contribute to their genital malformations. Single-strand conformation polymorphism analysis and direct sequencing were used to detect variations in the SRD5A1 gene of the patients and of 49 adult fertile men who served as controls. The sequence analysis of exon 3 of the SRD5A1 gene indicated an adenine-to-guanine change (ACA vs. ACG), both triplets encoding the amino acid residue threonine. The ACG sequence was detected in 57% of all subjects and was equally distributed in patients and controls. The T/DHT ratio was significantly higher in controls with the ACG variant as compared with those having the ACA variant. However, no particular sequence aberration was found in the SRD5A1 genes of either group. Mutant SRD5A1 isoenzyme does not seem to play a crucial role in the development of hypospadias.


Integrative analysis of gene amplification in Drosophila follicle cells: parameters of origin activation and repression.
In metazoans, how replication origins are specified and subsequently activated is not well understood. Drosophila amplicons in follicle cells (DAFCs) are genomic regions that undergo rereplication to increase DNA copy number. We identified all DAFCs by comparative genomic hybridization, uncovering two new amplicons in addition to four known previously. The complete identification of all DAFCs enabled us to investigate these in vivo replicons with respect to parameters of transcription, localization of the origin recognition complex (ORC), and histone acetylation, yielding important insights into gene amplification as a metazoan replication model. Significantly, ORC is bound across domains spanning 10 or more kilobases at the DAFC rather than at a specific site. Additionally, ORC is bound at many regions that do not undergo amplification, and, in contrast to cell culture, these regions do not correlate with high gene expression. As a developmental strategy, gene amplification is not the predominant means of achieving high expression levels, even in cells capable of amplification. Intriguingly, we found that, in some strains, a new amplicon, DAFC-22B, does not amplify, a consequence of distant repression of ORC binding and origin activation. This repression is alleviated when a fragment containing the origin is placed in different genomic contexts.


A new non-tumescent endovenous ablation method for varicose vein treatment: Early results of N-butyl cyanoacrylate (VariClose®).
Objective This report aims to present the early results of a retrospective study of the use of N-butyl cyanoacrylate (VariClose®)-based non-tumescent endovenous ablation for the treatment of patients with varicose veins. Method One hundred and eighty patients with varicose veins due to incompetent saphenous veins were treated with the VariClose® endovenous ablation method between May 2014 and November 2014. The patient sample consisted of 86 men and 94 women, with a mean age of 47.7 ± 11.7 years. The patients had a great saphenous vein diameter greater than 5.5 mm and a small saphenous vein diameter greater than 4 mm in conjunction with reflux for more than 0.5 s. Patients with varicose veins were evaluated with venous duplex examination, Clinical, Etiological, Anatomical and Pathophysiological classification (CEAP), and their Venous Clinical Severity Scores were recorded. Results The median CEAP score of patients was three, and the saphenous vein diameters were between 5.5 and 14 mm (mean of 7.7 ± 2.1 mm). A percutaneous entry was made under local anesthesia to the great saphenous vein in 169 patients and to the small saphenous vein in 11 patients. Duplex examination immediately after the procedure showed closure of the treated vein in 100% of the treated segment. No complications were observed. The mean follow-up time was 5.5 months (ranging from three to seven months). Recanalization was not observed in any of the patients during follow-up. The average Venous Clinical Severity Scores was 10.2 before the procedure and decreased to 3.9 after three months (p < 0.001). Conclusion The application of N-butyl cyanoacrylate (VariClose®) is an effective method for treating varicose veins; it yielded a high endovenous closure rate, with no need for tumescent anesthesia. However, long-term results are currently unknown.


A new approach in the treatment of skeletal open bite: vertically activated bite block.
This study examined the effects of the vertically activated bite block, a new appliance designed for maxillary molar intrusion in open bite malocclusion, on the dentofacial structures in 1 adolescent patient and 1 adult patient. The vertically activated bite block consists of 2 parts, the main block and an auxiliary segment. The auxilliary segment is separated bilaterally from the main block in the posterior region and connected bilaterally to the main block in the palatal region by open jackscrews. Closing the jackscrews moves the auxiliary segment toward the palate, thereby inducing molar intrusion. The present study achieved a reduction in open bite, using the VABB through: (1) active intrusion of the maxillary molars; (2) control of posterior vertical alveolar development and/or compensatory eruption of the mandibular molars; (3) stimulation of anterior vertical alveolar development by restriction of the tongue; and (4) anterior repositioning of mandible. Achieving these dentoalveolar and skeletal changes are required treatment objectives in cases of skeletal open bite. As a result of attaining these objectives, the open bite was eliminated in 1 early growth and 1 late growth patient by 14 mm and 6 mm, respectively.


Velocity distribution of Gold nanoparticles trapped on an optical waveguide.
The velocity distributions of 250nm diameter gold nanospheres trapped in the evanescent fields of optical waveguides are studied. The automated analysis of a large number of particles and temporal frames is described. It is used to show that the envelope of the particles' speed follows the mode intensity profile of the evanescent field along a length of the waveguide and across its width. Modal beating in a dual-moded waveguide is mapped by analysis of nanoparticle distributions above the waveguide. A modal power of _150mW at l=1066nm in a Cs+ ion-exchanged monomode waveguide results in speeds of up to 500microm/s.


HIPAA and patient care: the role for professional judgment.
Federal health privacy regulations, commonly known as the Health Insurance Portability and Accountability Act (HIPAA) regulations, came into effect in April 2003. Many clinicians and institutions have relied on consultants and risk managers to tell them how to implement these regulations. Much of the controversy and confusion over the HIPAA regulations concern so-called incidental disclosures. Some interpretations of the privacy regulations would limit essential communication and compromise good patient care. This article analyzes misconceptions regarding what the regulations say about incidental disclosures and discusses the reasons for such misunderstandings. Many misconceptions arise from gaps in the regulations. These gaps are appropriately filled by professional judgment informed by ethical guidelines. The communication should be necessary and effective for good patient care, and the risks of a breach of confidentiality should be proportional to the likely benefit for the patient's care. The alternative for communication should be impractical. We offer specific recommendations to help physicians think through what incidental disclosures in patient care are ethically permissible and what safeguards ought to be taken. Physicians should work with risk managers and practice administrators to develop policies that promote good communication in patient care, while taking appropriate steps to protect patient privacy.


The Interplay between Autophagy and Aging.
Numerous studies have established a link between autophagy and aging; however, the relationship has not been clearly defined. Aging is a very complex process caused by the accumulation of various factors due to the gradual failure of cellular maintenance. Recent studies have shown that autophagy reduces the stress responses induced by starvation, reactive oxygen species, and the accumulation of intracellular proteins and organelles through cytoprotection, clearance of damaged mitochondria, and lysosomal degradation. Here, we summarize our current understanding of the relationship between autophagy and the aging process.


Prenatal diagnosis of BMD in Morocco: evolution and limits.
The muscular dystrophy is a group of inherited disorders characterized in the most of cases by progressive muscle weakness. The best known are X-linked disorder Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). BMD is a milder form of the disease with a later age of onset and a slower clinical progression. The DMD gene, located on Xp21, is the largest human gene in the human genome (2.3 Mb). DMD gene consists of 79 exons and codes for dystrophin protein. A 9-year-old boy, who experienced symptoms of the disease, was admitted to the Casablanca University Children's Hospital. The patient, with no known family history of significant muscle disease, was first examined at 4 years of age because of walking difficulties and a limited hands force. Blood tests revealed elevated serum levels of creatine kinase (7.60 U/L). The electromyogram showed myopathic changes, consisting of polyphasic potentials, and the muscular biopsy revealed dystrophic aspect. Analysis of the dystrophin-encoding gene by PCR deletion analysis of the dystrophin gene was performed by multiplex PCR primer sets of Chamberlain and Beggs. The analysis showed a deletion of exons 45 to 49. Mother genetic testing showed the heterozygosis deletion.


Glucagon-Like Peptide-1 Receptors in the Gustatory Cortex Influence Food Intake.
The gustatory cortex (GC) region of the insular cortex processes taste information in manners important for taste-guided behaviors, including food intake itself. In addition to oral gustatory stimuli, GC activity is also influenced by physiological states including hunger. The specific cell types and molecular mechanisms that provide the GC with such abilities are unclear. Glucagon-like peptide 1 (GLP-1) is produced by neurons in the brain, where it can act on GLP-1 receptor-expressing (GLP-1R+) neurons found in several brain regions. In these brain regions, GLP-1R agonism suppresses homeostatic food intake and dampens the hedonic value of food. Here, we report in mice of both sexes that cells within the GC express Glp1r mRNA and further, by ex vivo brain slice recordings, that GC GLP-1R+ neurons are depolarized by the selective GLP-1R agonist, exendin-4. Next we found that chemogenetic stimulation of GLP-1R+ neurons, and also pharmacological stimulation of GC-GLP-1Rs themselves, both reduced homeostatic food intake. When mice were chronically maintained on diets with specific fat contents and then later offered foods with new fat contents, we also found that GLP-1R agonism reduced food intake toward foods with differing fat contents, indicating that GC GLP-1R influences may depend on palatability of the food. Together, these results provide evidence for a specific cell population in the GC that may hold roles in both homeostatic and hedonic food intake.SIGNIFICANCE STATEMENT The present study demonstrates that a population of neurons in the GC region of the insular cortex expresses receptors for GLP-1Rs, these neurons are depolarized by agonism of GLP-1Rs, and GC GLP-1Rs can influence food intake on their activation, including in manners depending on food palatability. This work is significant by adding to our understanding of the brain systems that mediate ingestive behavior, which holds implications for metabolic diseases.


Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment.
Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment.


KIAA0101 (OEACT-1), an expressionally down-regulated and growth-inhibitory gene in human hepatocellular carcinoma.
Our previous cDNA array results indicated KIAA0101 as one of the differentially expressed genes in human hepatocellular carcinoma (HCC) as compared with non-cancerous liver. However, it is necessary to study its expression at protein level in HCC and its biological function for HCC cell growth. Western blot and tissue array were performed to compare KIAA0101 protein expression level in paired human HCC and non-cancerous liver tissues from the same patients. Investigation of its subcellular localization was done by using dual fluorescence image examination and enriched mitochondrial protein Western blot analysis. The in vitro cell growth curve was used for examining the effect of over-expression of KIAA0101 in HCC cells. FACS was used to analyze the cell cycle pattern in KIAA0101 expression positive (+) and negative (-) cell populations isolated by the pMACSKKII system after KIAA0101 cDNA transfection. Western blot showed KIAA0101 protein expression was down-regulated in HCC tissues as compared with their counterpart non-cancerous liver tissues in 25 out of 30 cases. Tissue array also demonstrated the same pattern in 161 paired samples. KIAA0101 was predominantly localized in mitochondria and partially in nuclei. KIAA0101 cDNA transfection could inhibit the HCC cell growth in vitro. In cell cycle analysis, it could arrest cells at the G1 to S phase transition. KIAA0101 protein expression was down-regulated in HCC. This gene could inhibit the HCC cell growth in vitro and presumably by its blocking effect on cell cycle.


Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.
Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks. This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administration's (FDA's) end point for IBS-C (responder: a patient who reported (i) improvement of ≥ 30 % from baseline in average daily worst abdominal pain score and (ii) increase of ≥ 1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥ 6 / 12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored. In all, 804 patients (mean age = 44 years, female = 90 % , white = 78 % ) were evaluated; 33.7 % of linaclotide-treated patients were FDA end point responders, vs. 13.9 % of placebo-treated patients ( P < 0.0001) (number needed to treat = 5.1, 95 % confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9 % of linaclotide-treated patients vs. 34.5 % of placebo-treated patients (number needed to treat = 7.0, 95 % CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6 % of linaclotide-treated patients, vs. 22.6 % of placebo patients (number needed to treat = 4.0, 95 % CI: 3.2, 5.4). Remaining primary end points ( P < 0.0001) and all secondary end points ( P < 0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5 % of linaclotide patients vs. 0.2 % of placebo patients. Linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.


Sequence dependent proton conduction in self-assembled peptide nanostructures.
The advancement of diverse electrochemistry technologies depends on the development of novel proton conducting polymers. Inspired by the efficacy of proton transport through proteins, we show in this work that self-assembling peptide nanostructures may be a promising alternative for such organic proton conducting materials. We demonstrate that aromatic amino acids, which participate in charge transport in nature, unprecedentedly promote proton conduction under both high and low relative humidity conditions for d,l α-cyclic peptide nanotubes. For dehydrated networks long-range order of the assemblies, induced by the aromatic side chains, is shown to be a dominating factor for promoting conductivity. However, for hydrated networks this order of effect is less significant and conductivity can be improved by the introduction of proton donating carboxylic acid peptide side chains in addition to the aromatic side chains despite the lower order of the assemblies. Based on these observations, a novel cyclic peptide that incorporates non-natural naphthyl side chains was designed. Self-assembled nanotubes of this peptide show greatly improved dehydrated conductivity, while maintaining high conductivity under hydrated conditions. We envision that the demonstrated modularity and versatility of these bio inspired nanostructures will make them extremely attractive building blocks for the fabrication of devices for energy conversion and storage applications, as well as other applications that involve proton transport, whether dry or wet conductivity is desired.


Effectiveness and safety of traditional Chinese medical therapy for cancer-related fatigue: a systematic review and Meta-analysis of randomized controlled trials.
To assess the effectiveness and safety of traditional Chinese medical therapy for cancer-related fatigue. We systematically searched eight electronic databases up to June 2017 for randomized clinical trials of traditional Chinese medical therapy for cancer-related fatigue. Two authors independently extracted data and assessed the risk bias of the included trials using the Cochrane Handbook. Data were analyzed by RevMan 5.2 software. A total of 23 trials involving 1832 participants identified with cancer-related fatigue were included. Twenty trials reported a beneficial effect of traditional Chinese medical therapy on cancer-related fatigue. On pooling the data from Chinese herbal medicine therapy and acupuncture or moxibustion therapy, respectively, significant differences were found between experimental groups and control groups. Fatigue improvement rates showed significant differences between traditional Chinese medical therapy and control groups [odds ratio (OR), 7.62; 95% confidence interval (CI), 3.75-15.49; P < 0.000 01; and OR, 3.78; 95% CI, 2.29-6.23; P < 0.000 01). Fatigue change scores also showed significant differences between the two groups (mean difference, -0.91; 95% CI, -0.16 to -0.65; P < 0.000 01). Eleven trials demonstrated that traditional Chinese medical therapy improved the quality of life of cancer patients. No severe adverse effects occurred in traditional Chinese medical therapy groups. Meta-analysis showed that Chinese medical therapy seems to be effective and safe in the treatment of cancer-related fatigue.


Pulmonary embolization of vascular occlusion coils in dogs with patent ductus arteriosus.
Transcatheter coil embolization of patent ductus arteriosus (PDA) was performed in 206 dogs between 1994 and 2003 at Texas A&M University, of which 7 (3%) had embolization of coils to the pulmonary vasculature. Thoracic radiographs indicated that coils were located in the right pulmonary artery in 6 of the 7 dogs. Pulmonary perfusion scans were available for review in 5 dogs, and moderate perfusion defects were observed in the right caudal lung lobe in 4 dogs within 24 hours of embolization. Perfusion deficits observed initially in 2 of the dogs resolved on perfusion scans performed at 6 months and 3.1 years. One dog did not have evidence of focal perfusion defects on a perfusion scan performed 4.5 months after embolization. All pulmonary embolizations occurred during the procedure. Attempts at retrieval of coils were unsuccessful in the 2 dogs in which it was attempted. No short- or long-term clinical complications were observed in any of the dogs with pulmonary embolization. We conclude that pulmonary embolization of vascular occlusion coils is an uncommon event and is not typically associated with adverse clinical effects in dogs with PDA.


Generation of genipin cross-linked fibrin-agarose hydrogel tissue-like models for tissue engineering applications.
The generation of biomimetic and biocompatible artificial tissues is the basic research objective for tissue engineering (TE). In this sense, the biofabrication of scaffolds that resemble the tissues' extracellular matrix is an essential aim in this field. Uncompressed and nanostructured fibrin-agarose hydrogels (FAH and NFAH, respectively) have emerged as promising scaffolds in TE, but their structure and biomechanical properties must be improved in order to broaden their TE applications. Here, we generated and characterized novel membrane-like models with increased structural and biomechanical properties based on the chemical cross-linking of FAH and NFAH with genipin (GP at 0.1%, 0.25%, 0.5% and 0.75%). Furthermore, the scaffolds were subjected to rheological (G, G', G″ modulus), ultrastructural and ex vivo biocompatibility analyses. Results showed that all GP concentrations increased the stiffness (G) and especially the elasticity (G') of FAH and NFAH. Ultrastructural analyses demonstrated that GP and nanostructuration of FAH allowed us to control the porosity of FAH. In addition, biological studies revealed that higher concentration of GP (0.75%) started to compromise the cell function and viability. Finally, this study demonstrated the possibility to generate natural and biocompatible FAH and NFAH with improved structural and biomechanical properties by using 0.1%-0.5% of GP. However, further in vivo studies are needed in order to demonstrate the biocompatibility, biodegradability and regeneration capability of these cross-linked scaffolds.


Case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis C after liver retransplantation.
A recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) can lead to accelerated allograft injury and fibrosis. The aim of this article is to report the first ever use of daclatasvir (DCV; also known as BMS-790052), a potent orally administered nonstructural 5A replication complex inhibitor, in combination with peginterferon α (PEG-IFNα) and ribavirin in an LT recipient. A 49-year-old female developed a severe recurrent HCV genotype 1b infection 4 months after transplantation with severe cholestasis on biopsy, an HCV RNA level of 10,000,000 IU/mL, an alkaline phosphatase level of 1525 IU/mL, and a total bilirubin level of 8.4 mg/dL. Despite partial virological suppression with PEG-IFNα and ribavirin, progressive allograft failure ensued and culminated in retransplantation at 9 months. Three months after the second transplant, DCV (20 mg/day), PEG-IFNα2a (180 μg/week), and ribavirin (800 mg/day) were prescribed for early recurrent cholestatic HCV. Serum HCV RNA became undetectable at week 3 of treatment and remained undetectable during 24 weeks of triple therapy and during the posttreatment follow-up. DCV was well tolerated, and the trough drug levels were within the targeted range throughout the treatment. The cyclosporine trough levels were also stable during and after therapy. In conclusion, the lack of anticipated drug-drug interactions between DCV and calcineurin inhibitors and the potent antiviral efficacy of DCV make this agent (in combination with PEG-IFN and ribavirin) an attractive antiviral regimen worthy of further study in LT recipients with recurrent HCV.