Enhanced recovery after surgery (ERAS) versus conventional postoperative care in patients undergoing abdominal hysterectomies.
In the present study, we aimed to compare the postoperative compliance and complications between ERAS and conventional postoperative care in patients undergoing abdominal hysterectomies. This is the prospective, randomized, controlled trial, which involved 62 patients, who underwent abdominal hysterectomy between December 2016 to February 2017. A total of 30 patients formed the ERAS group. A total of 32 patients who received conventional perioperative care and matched for age, body mass index (BMI) and American Society of Anesthesiologists score were assigned as a control group. Groups were compared in terms of patient characteristics [age, body mass index, ASA Score, parity, diagnosis, type of surgery, and perioperative intravenous fluids], postoperative compliance (postoperative intravenous fluids, time to first flatus, first defecation, ambulation, eating solid food, and postoperative hospital stay), and postoperative complications. Peri- and post-operative administrated intravenous fluids were significantly lower in the ERAS group (p < 0.001 for both). Time to first flatus (p = 0.001), time to first defecation (p < 0.001), and time to eating solid food (p < 0.001) were all significantly shorter in the ERAS group. Post-operative early mobilization on the first postoperative day was achieved in eight (26.7%) patients in the ERAS group. There were no significant differences in complications. One (3.3%) patient in the ERAS Group and 11 (34.4%) patients in the Conventional Group required hospital readmission after discharge (p = 0.002). The ERAS protocol seems to be a simple tool for reducing the incidence of postoperative complications and shortening hospitalization.


Recombinant human bone morphogenetic protein-2: a novel osteoinductive alternative to autogenous bone graft?
Autogenous bone grafts from the iliac crest have long been the gold standard for repair and reconstruction of bone; however harvesting of the grafts from the iliac crest is associated with donor site morbidity, particularly chronic pain. The bone morphogenetic proteins (BMPs) are soluble bone matrix glycoproteins that induce the differentiation of osteoprogenitor cells into osteogenic cells and have the potential to act as autogenous bone graft substitutes. BMP-2, which can be produced with recombinant technology, is highly osteoinductive, inducing bone formation by stimulating the differentiation of mesenchymal cells into chrondroblasts and osteoblasts. At present, more than 1,000 patients have received rhBMP-2 in clinical trials for acute open tibial fracture and interbody fusion procedures for the treatment of degenerative disc disease. Data suggest that rhBMP-2 therapy may offer an effective alternative to autogenous bone graft for recalcitrant bone unions and spinal fusion, obviating donor site morbidity.


Requirements for nucleocapsid-mediated regulation of reverse transcription during the late steps of HIV-1 assembly.
HIV-1 is a retrovirus replicating within cells by reverse transcribing its genomic RNA (gRNA) into DNA. Within cells, virus assembly requires the structural Gag proteins with few accessory proteins, notably the viral infectivity factor (Vif) and two copies of gRNA as well as cellular factors to converge to the plasma membrane. In this process, the nucleocapsid (NC) domain of Gag binds to the packaging signal of gRNA which consists of a series of stem-loops (SL1-SL3) ensuring gRNA selection and packaging into virions. Interestingly, mutating NC activates a late-occurring reverse transcription (RT) step in producer cells, leading to the release of DNA-containing HIV-1 particles. In order to decipher the molecular mechanism regulating this late RT, we explored the role of several key partners of NC, such as Vif, gRNA and the cellular cytidine deaminase APOBEC3G that restricts HIV-1 infection by targeting the RT. By studying combinations of deletions of these putative players, we revealed that NC, SL1-SL3 and in lesser extent Vif, but not APOBEC3G, interplay regulates the late RT.


Management of patients and subjects at risk for multiple endocrine neoplasia type 1: MEN 1. GENEM 1. Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1.
Multiple endocrine neoplasia type 1 (MEN 1) is characterized by the combined occurrence, to variable degree, of hyperparathyroidism (HPT) (85.7% of cases according to the French Registry of GENEM 1), tumors of the endocrine pancreas (49.6%), pituitary adenomas (38.4%) and, less frequently, adrenal tumors (9.6%) and neuroendocrine tumors (5.8%). Currently, diagnosis of MEN 1 is done in the fourth decade of life, but familial screening (using genetic tools whose diagnostic accuracy approaches 100%) has lowered the age of diagnosis. Screening for MEN 1 in a patient harboring an apparently sporadic tumor will depend on the endocrine gland involved. Extensive screening for MEN 1 in the presence of HPT will be conducted only when the familial history is suggestive, when parathyroid glands are hyperplastic or when multiple parathyroid adenomas have been found at surgery. All patients with an endocrine pancreas tumor need to be investigated for the presence of other endocrine lesions of MEN 1. Extensive screening for MEN 1 is only recommended when a patient with a pituitary tumor or an adrenal tumor has a familial history suggestive of MEN 1. Otherwise regular measurement of blood calcium and PTH levels seem sufficient. Extensive screening for endocrine lesions when MEN 1 is suspected involves hormone measurements and imaging procedures. For the diagnosis of HPT, calcemia and PTH 1-84 must be measured. In the absence of clinical symptoms, basal measurement of serum gastrin, glucose, insulin, glucagon, VIP, somatostatin and pancreatic polypeptide levels are combined with abdominal ultrasonography. When symptoms suggest the Zollinger-Ellison syndrome, the secretin stimulation test is recommended. The diagnosis of a pituitary tumor is made by pituitary imaging and selected hormone assays (mainly PRL). To detect an adrenal tumor, CT scan is recommended, combined with serum potassium, urinary free cortisol and androgen measurement. When the diagnosis of MEN 1 is made, clinical and hormonal follow-up (once a year) and imaging surveillance (every 3-5 years) may be sufficient to detect new other endocrinopathies (unless suggestive clinical symptoms arise). Surgical management of each endocrine lesion must be done by skilled surgeons according to therapeutic protocols which have been discussed in detail. Genetic screening is an integral part of familial screening which may be conducted in collateral and in the offspring of MEN 1 patients. Obviously ethical principles (informed consent, etc.) must be respected. As it is now possible to detect presymptomatic gene carriers with a high degree of accuracy, follow-up is needed to make appropriate management decisions. The marked anxiety provoked by screening in an overtly asymptomatic healthy subject must not be underestimated. Conversely, a negative genetic diagnosis helps to reassure the subject and avoid repetitive and costly follow-up.


Micro CT pilot evaluation of removability of two endodontic sealers.
This study compared the removability of AH Plus and EndoSequence BC sealers using in vitro micro-computed tomography. Ten single-canal, extracted human teeth were cleaned and shaped with ProTaper NEXT rotary files to size X5 (50/0.06) (Dentsply-Sirona). Canals were obturated with a single cone gutta-percha and either AH Plus (Dentsply-Sirona) (Group A) or EndoSequence BC (Brasseler) (Group B). ProTaper Universal Retreatment files (Dentsply-Sirona) were used to remove obturation materials after 90 days at 37oC/100% humidity. Each tooth was scanned using micro-computed tomography (SkyScan 1272; Bruker) at an isotropic resolution of 6 μm from which the percent of material removed was calculated. Two-sample t-tests and one-way ANOVA were used for analysis. The percent removal of materials in the coronal third was 92.9% ± 7.3% (Group A) and 93.2% ± 6.1% (Group B). Removal in the middle third was 94.9% ± 8.5% (Group A) and 96.5% ± 6.1% (Group B). Apical third removal was 76.2% ± 27.9% (Group A) and 70.1% ± 30.8% (Group B). No statistically significant differences were determined between the two sealers or among the sectional thirds within each group (P > 0.05). AH Plus and EndoSequence BC sealers exhibit the same removability at all canal levels of 70% to 96%, with better removal coronally.


Sequential monitoring of randomization tests: stratified randomization.
In many clinical trials, it is desirable to establish a sequential monitoring plan, whereby the test statistic is computed at an interim point or points in the trial and a decision is made whether to stop early due to evidence of treatment efficacy. In this article, we will set up a sequential monitoring plan for randomization-based inference under the permuted block design, stratified block design, and stratified urn design. We will also propose a definition of information fraction in these settings and discuss its calculation under these different designs.


Draft Genome Assembly of Neisseria lactamica Type Strain A7515.
We present the scaffolded genome assembly of Neisseria lactamica type strain A7515 (ATCC 23970) as submitted to NCBI under accession no. JOVI00000000. This type strain of the lactose-fermenting Neisseria species is often used in quality control testing and intra-genus phylogenetic analyses. The assembly includes four contigs placed into a single scaffold.


[Retrospective analysis of invasive fungal infection in surgical intensive care unit].
To conduct a retrospective analysis of the invasive fungal infection (IFI) in surgical intensive care unit (SICU). The IFI data of the patients who were admitted in SICU during January 2003 to December 2008 was retrospectively analyzed. A total of 3743 patients were admitted into SICU. Among them, 271 patient's SICU duration was more than 48 hours, who had fungi examination. Seventy-five patients were diagnosed IFI, the morbidity was 2.00% (75/3743), the incidence of fungemia was 0.27% (10/3743), the mortality of IFI patients was 49.33% (37/75). The morbidity rate of each year was almost the same. The mortality of 2007 and 2008 was higher than before (both P < 0.05). Thirty-four of all the 75 IFI patients got urinary tract infected, 37 got fungal pneumonia, 10 got fungemia, 1 got catheter-related fungal infection, 2 got fungal infection in abdomen, 2 got biliary tract infected. Eighty-six fungi strains which caused fungal infection were spotted. Candida albicans was the most common isolate (46.51%). Other isolates were Candida glabrata (22.09%), Candida tropicalis (13.95%), Candida parapsilosis (8.14%), Candida krusei (3.49%), Trichosporon (4.65%), Aspergillus (1.16%). Assist ventilation, combination of bacterial infection, treatment by broad spectrum antibiotics or more than three kinds of antibiotics were the most important risk factors of IFI in SICU. Prophylactic antifungal treatment may be useful. The morbidity of IFI in our SICU was comparatively low, and the same of the incidence of fungemia. The mortality of IFI patients was markedly high. The main sites of infection were lung and urinary tract, and the pathogenic fungi strains were mostly Candidas. Assist ventilation, combination of bacterial infection, broad spectrum antibiotics treatment were the most important risk factors of IFI in SICU.


A computational hypothesis for allostasis: delineation of substance dependence, conventional therapies, and alternative treatments.
The allostatic theory of drug abuse describes the brain's reward system alterations as substance misuse progresses. Neural adaptations arising from the reward system itself and from the antireward system provide the subject with functional stability, while affecting the person's mood. We propose a computational hypothesis describing how a virtual subject's drug consumption, cognitive substrate, and mood interface with reward and antireward systems. Reward system adaptations are assumed interrelated with the ongoing neural activity defining behavior toward drug intake, including activity in the nucleus accumbens, ventral tegmental area, and prefrontal cortex (PFC). Antireward system adaptations are assumed to mutually connect with higher-order cognitive processes occurring within PFC, orbitofrontal cortex, and anterior cingulate cortex. The subject's mood estimation is a provisional function of reward components. The presented knowledge repository model incorporates pharmacokinetic, pharmacodynamic, neuropsychological, cognitive, and behavioral components. Patterns of tobacco smoking exemplify the framework's predictive properties: escalation of cigarette consumption, conventional treatments similar to nicotine patches, and alternative medical practices comparable to meditation. The primary outcomes include an estimate of the virtual subject's mood and the daily account of drug intakes. The main limitation of this study resides in the 21 time-dependent processes which partially describe the complex phenomena of drug addiction and involve a large number of parameters which may underconstrain the framework. Our model predicts that reward system adaptations account for mood stabilization, whereas antireward system adaptations delineate mood improvement and reduction in drug consumption. This investigation provides formal arguments encouraging current rehabilitation therapies to include meditation-like practices along with pharmaceutical drugs and behavioral counseling.


Drug-coated balloons for the treatment of in-stent restenosis in diabetic patients: A review of currently available scientific data.
After the introduction of drug eluting stent (DES) the rate of in-stent restenosis (ISR) has decreased if compared to the BMS era; however, treatment of patients with ISR remained a major issue for the interventional cardiologist. DES has been largely used with good results also as second layer for the treatment of ISR, but the overall percentage of patients suffering from restenosis still remains high, especially in some subgroups of patients as ones with diabetes mellitus (DM). In this clinical scenario, drug coated balloon (DCB) has been gaining an important role for the treatment of ISR. In fact, it allows to release an antiproliferative drug, namely paclitaxel, without the addition of a second metallic strut, which can lead to a persistent inflammatory stimulus and further narrow the vessel. This could be an advantage in patients with an already increased systemic inflammatory burden and stiffer vessels as those with DM. Despite differences in terms of efficacy and safety between DES and DCB have already been evaluated in different clinical trials, just few of these focused on diabetic patients. The aim of this paper is to review the available data for treatment of ISR both with DES, DCB, and a comparison between these two devices, in patients affected by DM. © 2017 Wiley Periodicals, Inc.


Rapidly Progressing Autoimmune Hemolytic Anemia in a Pediatric Patient With COVID-19.
SARS-CoV-2 is a novel virus that is known to have a predilection for complications associated with the respiratory system. Although COVID-19 has a wide spectrum of manifestations, the pathophysiology of severe illness remains poorly understood but is thought to be associated with fulminant cytokine release. While severe complications secondary to COVID-19 in the pediatric population are considered rare, they do happen. Children with and without comorbidities have required intensive care unit admissions for respiratory distress and, more notably, multisystem inflammatory syndrome in children (MIS-C). While MIS-C is associated with hematologic complications, such as thrombocytopenia and coagulopathies, it is not associated with blood hemolysis. In this report, we describe a case of a 23-month-old previously healthy female, who presented with lethargy and positive COVID-19 PCR status. This case illustrates the rapid and fatal sequela caused by autoimmune hemolytic anemia (AIHA) from COVID-19. It stresses the importance of thorough workup and management of AIHA secondary to COVID-19 illness. Currently, there is limited understanding of AIHA from COVID-19 illness in children. Our aim is to describe this rare complication of COVID-19 illness in pediatric patients and discuss the best practices to manage it.


Treating nerves: a call to arms.
The process of proving that new treatments for peripheral nerve diseases work has often been slow and inefficient. The lack of adequate evidence for some existing treatments has been highlighted by Cochrane systematic reviews. This article uses four different conditions to illustrate the need for more research. Both corticosteroid injections and surgical decompression of the median nerve are efficacious in carpal tunnel syndrome, but whether corticosteroid injections avoid the need for operation needs to be discovered. Corticosteroids are efficacious for Bell's palsy, but the role of antiviral agents needs clarification, which should come from ongoing trials. Intravenous immunoglobulin (IVIg) and plasma exchange are both efficacious in Guillain-Barré syndrome, but corticosteroids are not. More trials are needed to discover the best dose of IVIg in severe cases and whether mild cases need treatment. In chronic inflammatory demyelinating polyradiculoneuropathy, corticosteroids, IVIg and plasma exchange are all efficacious, at least in the short term, but trials are needed to discover whether and which other immunosuppressive agents help. The Peripheral Nerve Society has formed a standing committee, the Inflammatory Neuropathy Consortium (http://pns.ucsd.edu/INC.htm), to facilitate the trials needed to answer the remaining questions in the inflammatory neuropathies.


Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.
Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.


Feasibility and acceptability of using medical and nursing students to provide Implanon NXT at the community level in Kinshasa, Democratic Republic of Congo.
The use of implants has steadily increased in Kinshasa since 2013 but clinic-based access to this family planning method is limited due to distance and costs barriers. The objective of this study was to examine the feasibility and acceptability of providing Implanon NXT at the community level using medical and nursing students (M/N) as distributors, as part of a strategy to improve contraceptive uptake in the Democratic Republic of Congo. A cohort of 531 women who chose to receive Implanon NXT from a M/N student during community-based campaign days participated in three rounds of a quantitative survey administered at the time of insertion of the method, and at 6 and 12 months later. We conducted descriptive analysis to assess the feasibility and acceptability of providing the method through M/N students in terms of method choice, user profiles, contraceptive history, experience with insertion and side effects, continuation / discontinuation of the method, and overall satisfaction with FP services as well as students' preparedness and capacity to safely offer the method, and their satisfaction with the experience.. The study demonstrated the feasibility of training students for community-based provision of Implanon NXT and 95% of them were satisfied with their experience. Acceptability of both the method and the service delivery strategy was high among participants, including among young and first-time contraceptive users. Out of the 441 women with a known outcome at 12 months, 92% still had Implanon NXT inserted, despite some of them reporting experiencing side effects. The vast majority (79%) would "strongly recommend" obtaining NXT from a M/N student if a friend wanted to avoid pregnancies. The provision of Implanon NXT at the community-level is a promising solution to address some of the barriers to accessing this method for women living in Kinshasa. However, strengthening pre-insertion counseling, particularly on expected side-effects and the possibility of early removal, is necessary to increase informed choice for the women and potentially limit method discontinuation.


Cleavage of type I and type II procollagens by type I/II procollagen N-proteinase. Correlation of kinetic constants with the predicted conformations of procollagen substrates.
The kinetic constants were examined for the cleavage of several types of procollagen by type I/II procollagen N-proteinase. The Km values were essentially the same (0.2 microM) for chick type I procollagen, human type I procollagen, and chick type II procollagen. However, the Vmax values differed over a 14-fold range. As reported previously, the enzyme did not cleave denatured type I or II procollagen. Also, it did not cleave human type III procollagen which contains the same scissle -Pro-Gln- bond as the pro-alpha 1(I) chain of type I procollagen. To explain the observations, Chou-Fasman rules were used to compare the secondary structures of the cleavage sites in the procollagens. The results supported a previous suggestion (Helseth, D. L., Jr., Lechner, J. L., and Veis, A. (1979) Biopolymers 18, 3005-3014) that the region carboxyl-terminal to cleavage site in the pro-alpha 1(I) chain of type I procollagen was in a hairpin conformation consisting of a beta-sheet, beta-turn, and beta-sheet. In both chick and human type I procollagen, the hairpin loop in the pro-alpha 1(I) chain consisted of about 18 amino acids. The cleavage site itself was in a short alpha-helical structure of four or five amino acids. The pro-alpha 2(I) chains had a similar hairpin loop of about 14 amino acids and alpha-helix of four or five amino acids containing the cleavage site. Chick type II procollagen, which had the highest Vmax value, had a longer hairpin structure of 22 amino acids, and the cleavage site was in a longer alpha-helical domain of 10 amino acids. In contrast, type III procollagen had a random-coil conformation in the same region. The results help to explain the unusual substrate requirements of type I/II N-proteinase. They also help explain why mutations that produce in-frame deletions of amino acids 84 or more residues carboxyl-terminal to the cleavage site make the protein resistant to the enzyme.


Transport of Triplet Excitons along Continuous 100 nm Polyfluorene Chains.
Triplet excitons created in poly-2,7-(9,9-dihexyl)fluorene (pF) chains with end trap groups in solution are efficiently transported to and captured by the end groups. The triplets explore the entire lengths of the chains, even for ∼100 nm long chains, enabling determination of the completeness of end-capping. The results show that the chains are continuous: they may contain transient barriers or traps, such as those from fluctuations of dihedral angles, but they are free of major defects that stop motion of the triplets. Quantitative determinations are aided by the addition of a strong electron donor, TMPD, which removes absorption bands of the end-trapped triplets. For chains having at least one end trap, triplet capture is quantitative on the 1 μs time scale imposed by the use of the donor. Fractions of chains having no end traps were 0.15 for pF samples with anthraquinone (AQ) end traps and 0.063 with naphthylimide (NI) end traps. These determinations agreed with measurements by NMR for short (<40 polymer repeat units (PRU)) chains, where NMR determinations are accurate. The results find no evidence for traps or barriers to the transport of triplets, and places limits on the possible presence of defects as impenetrable barriers to less than one per 300 PRU. The present results present a paradigm different from the current consensus, derived from observations of singlet excitons, that conjugated chains are divided into "segments," perhaps by some kind of defects. For the present pF chains, the segmentation either does not apply to triplet excitons or is transient so that the defects are healed or surmounted in times much shorter than 1 μs. Triplets on chains without end trap groups transfer to chains with end traps on a slower time scale. Rate constants for these bimolecular triplet transfer reactions were found to increase with the length of the accepting chain, as did rate constants for triplet transfer to the chains from small molecules like biphenyl. A second set of polyfluorenes with 2-butyloctyl side chains was found to have a much lower completeness of end-capping.


Embryonal tumor with abundant neuropil and true rosettes: a systematic literature review and report of 2 new cases.
Embryonal tumor with abundant neuropil and true rosettes has been recently defined as a distinct central nervous system embryonal neoplasm, although it was initially regarded as a subtype of central nervous system primitive neuroectodermal tumor. To date 70 cases have been reported. We have performed a literature review and we present 2 new cases. Analysis of the reported data revealed that radiotherapy, tumor excision and high-dose adjuvant chemotherapy with sequential autologous hematopoietic stem cell rescue have a prognostic significance.


Mode of delivery and risk of developing allergic disease.
The aim of this study was to quantify the relationship between mode of delivery and subsequent incidence of allergic disease. The analysis is based on data derived from a birth cohort of 24,690 children who contributed data to the West Midlands General Practice Research Database. We found no convincing evidence to suggest that babies born by caesarean, forceps, or breech delivery had an increased risk of developing allergic disease.


Cross-species Exon Capture and Whole Exome Sequencing: Application, Utility and Challenges for Genomic Resource Development in Non-model Species.
Comprehending the genetic architecture of complex traits has many applications in evolution, ecology, conservation biology and plant and animal production systems. Underlying research questions in these fields are diverse species that often have limited genetic information available. In aquaculture, for example, genetic progress has been slow in many species due to a lack in such genetic information. In this study, zebrafish (as a well-studied model species) was used in cross-species transfer to develop genomic resources and identify candidate genes underling growth differentials in dusky kob. Dusky kob is a Sciaenid finfish and an emerging aquaculture species. The zebrafish All Exon Predesigned Probe-set capture protocol was used to enrich fractionated DNA samples from kob, classified as either large or small, before massive parallel sequencing on the Ion Torrent platform. Although vast quantities of sequence data were generated, only about 30% of contigs could be identified as zebrafish homologues. There were numerous species-specific sequences and inconsistent coverage of sequencing products across samples, likely due to non-specific binding of the probe-set as a result of the evolutionary divergence between zebrafish and kob. Nonetheless, more than 55,000 SNPs could be reliably identified and genotyped to the individual level. Using SNP genotypic divergence estimates, between large and small cohorts, a number of candidate genes associated with growth was also identified for future investigation. These findings contribute to the growing body of evidence demonstrating the utility of a cross-species capture approach in the development of important genomic resources for understanding traits of interest in species without reference genomes.


Lack of Geospatial Population Structure Yet Significant Linkage Disequilibrium in the Reservoir of Plasmodium falciparum in Bongo District, Ghana.
Malaria control in West Africa is impeded by the large reservoir of chronic asymptomatic Plasmodium falciparum infections in the human population. This study aimed to assess the extent of diversity in the P. falciparum reservoir in Bongo District (BD), Ghana, at the end of the dry season, the lowest point in malaria transmission over the course of the year. Analysis of the variation in 12 microsatellite loci was completed for 200 P. falciparum isolates collected from a cross-sectional survey of residents of all ages from two catchment areas in BD. Analysis of the multilocus haplotypes showed high levels of genetic diversity (He = 0.74), no population differentiation yet significant linkage disequilibrium (LD) (ISA = 0.0127, P = 0.006) in BD. Multilocus LD was significant between and within catchment areas even though every haplotype in the population was unique and the majority of individuals (84.0%) harbored multiple-clone infections. The linkage structure among multilocus haplotypes was not associated with sampling location. These data provide the first study with deep sampling of the P. falciparum reservoir in an area of seasonal malaria transmission in West Africa. The co-occurrence of high multiplicity of infection (multiple-clone infections) with significant multilocus LD is surprising given the likelihood of high recombination rates in BD. The results suggest that the linkage structure among multilocus haplotypes has not been shaped by geographic separation of parasite populations. Furthermore, the observed LD levels provide a baseline population genetic metric with putatively neutral markers to evaluate the effects of seasonality and malaria control efforts in BD.


[Locally advanced pancreatic cancer that enlarged after administration of gemcitabine and responded to oral TS-1--a case report].
We administered oral TS-1 alone for locally advanced pancreatic cancer that did not respond to gemcitabine (GEM). A 56-year-old man was admitted to our hospital because of obstructive jaundice due to stage III pancreatic head cancer. We performed chemotherapy using GEM at a dose of 1,000 mg/m(2) after reduction of jaundice by PTCD and stenting. Once the tumor was reduced, enlargement was confirmed after 8 months, and cholangitis appeared due to stent obstruction. After PTCD and stenting (stent in stent) were performed again,we administered oral TS-1 alone at a dose of 100 mg/body. We achieved antitumor activity again using TS-1. It is suggested that TS-1 is a useful second-line agent for pancreatic cancer.


Combining Non-Uniform Time Slice and Finite Difference to Improve 3D Ghost Imaging.
Three-dimensional ghost imaging (3DGI) using a detector is widely used in many applications. The performance of 3DGI based on a uniform time slice is difficult to improve because obtaining an accurate time-slice position remains a challenge. This paper reports a novel structure based on non-uniform time slice combined with finite difference. In this approach, finite difference is beneficial to improving sensitivity of zero crossing to accurately obtain the position of the target in the field of view. Simultaneously, non-uniform time slice is used to quickly obtain 3DGI on an interesting target. Results show that better performances of 3DGI are obtained by our proposed method compared to the traditional method. Moreover, the relation between time slice and the signal-noise-ratio of 3DGI is discussed, and the optimal differential distance is obtained, thus motivating the development of a high-performance 3DGI.


Ambivalence in cardiac transplantation candidates.
During three and a half years of psychiatric liaison with a cardiac transplantation program, the authors evaluated and followed 101 transplantation candidates. Ten exhibited pronounced ambivalence toward cardiac transplantation. Ambivalence appears to be associated with three factors: difficulties facing the seriousness of the cardiac illness, fear of the actual operation, and quality of life-concerns. An essentially nonpathological response, ambivalence can produce significant psychiatric symptoms and management problems in transplant candidates. Its resolution can be facilitated by psychotherapy, appropriate medication, peer support, and patience. Some patients may need particular assistance in understanding that refusal of transplantation is an acceptable alternative.


Altered beta-adrenergic sensitivity and protein binding to 1-propranolol in the elderly.
The elderly are reported to be less sensitive to the beta-blocking effects of propranolol. However, age-related changes in the stereoselective pharmacokinetics or protein binding of propranolol enantiomers could have confounded the results of previous studies because only 1-propranolol contributes significantly to the beta-blocking effects of the racemate. To avoid these confounding variables, we studied 10 young (mean 28 years) and 10 elderly (mean 64 years) subjects, and determined the cardiac beta-receptor sensitivity in terms of unbound, active 1-propranolol. The doses of isoproterenol required to increase heart rate (HR) by 25 beats/min were determined before and during a continuous infusion of propranolol. The serum concentration of 1-propranolol was determined by enantioselective high-performance liquid chromatography (HPLC), and the unbound fraction was determined by equilibrium dialysis. The apparent in vivo receptor dissociation constant for unbound 1-propranolol increased from 0.066 +/- 0.047 ng/ml in the young to 0.218 +/- 0.264 ng/ml in the older group (p less than 0.05). The unbound fraction was decreased in the older subjects (0.141 +/- 0.023 vs. 0.121 +/- 0.025, p less than 0.05) because of an increase in alpha 1-acid glycoprotein concentration (55 +/- 11 mg/dl vs. 72 +/- 19 mg/dl, p less than 0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (rs = 0.76, p less than 0.05) and to unbound 1-propranolol (rs = 0.45, p less than 0.05). We conclude that the older subjects have (a) decreased sensitivity to the beta-blocking effects of 1-propranolol and to the agonist effects of isoproterenol, and (b) a lower unbound fraction of 1-propranolol.


Predictors of Mortality in Hospitalized African American Covid-19 Cancer Patients.
Coronavirus disease 2019 (COVID-19) and associated outcomes manifest differently depending on patients' background and pre-existing conditions. It remains unclear how African Americans with and without cancer have been affected. To determine epidemiological, clinical comorbidities, and laboratory test results to identify markers associated with mortality in COVID-19 cancer patients. We reviewed all Covid-19 hospitalized patients records from Dec. 2019 to Oct. 2021 at Howard University Hospital. Patients having a history of, or active cancer status were reviewed. All the clinical, treatment, lab values, and pathological data were extracted. Statical analysis of the Covid-19 cancer patients and comparison with non-cancer Covid-19 patients was performed using univariate and multivariate analyses. Out of 512 COVID-19 infected patients, a total of 49 patients were identified with different types of cancer, with both active and previous history. Females consisted of 26 cancer patients (53%). African American race was predominant in both cases and controls, 83.6% and 66.7% respectively. Cancer patients were older than non-cancer patients (Mean Age-70.6 vs. 56.3 years) and had an increased length of hospital stay (Mean 13.9 vs 9.4 days). Among cancer patients, breast cancer was more prevalent in females and prostate cancer in males, (54% and 52% respectively). Comparison of patients with active vs. previous cancer showed no significant difference in the clinical outcome, death vs. discharge (P=0.34). A higher reduction in albumin level in cancer cases, from the time of admission to day five, was significantly associated with death during the same hospital stay compared to those discharged (n=24, 48.9%, p<0.001). In controls, Lymphopenia (n=436, 94.1%, p=0.05), AST (n=59, 12%, p=0.008) and Albumin (n=40, 10.7%, p=0.02) have shown an association with increased mortality. Albumin level has shown to have an inverse relationship with clinical outcomes among all COVID infected African American patients. Reduction in Albumin level during the hospital stay, particularly in COVID-19 cancer patients should be considered as a predictor of mortality. No significant difference was noticed in the clinical outcome in patients with previous versus active cancer. Further research with a large cohort size is needed to verify and identify other predictors of outcome in Covid-19 cancer patients and develop appropriate treatment modalities.


The effect of a herbal paste and oil extract on the lipid content of canine hair fibres.
Application of herbal paste and oil to a dog's coat and body before rinsing (often combining with shampooing) is a cosmetic therapy available in Japan. It is highly appreciated by users, who claim that the treatment makes the coat shinier, improves volume and eliminates tangles. However, there has been no scientific evaluation of such treatments. Improvement of hair condition is derived from oils such as sebum and conditioning oils because chemicals are not used. Therefore, we examined nonpolar lipids (the primary lipids in dog hair) and the botanical oils used in this therapy. Hair samples were obtained from six beagle dogs. Groups were based on different combinations of the following processes: rinsing, shampooing, herbal therapy and herbal therapy with oil extract. Analysis of lipids was performed by high performance thin layer chromatography. The processes of shampooing and herbal therapy were associated with an equivalent reduction in cholesterol ester and triglyceride (TG). However, hair treated by herbal therapy combined with oil extract had an almost three-fold higher TG content, even after shampooing. This study demonstrated that the herbal therapy was able to coat hair samples with TG that was not removed with rinsing. Further investigation is required to evaluate the possible benefits of the application of botanical products containing lipids, such as TG, on hair coat quality in dogs.


Therapeutic Mechanisms of Herbal Medicines Against Insulin Resistance: A Review.
Insulin resistance is a condition in which insulin sensitivity is reduced and the insulin signaling pathway is impaired. Although often expressed as an increase in insulin concentration, the disease is characterized by a decrease in insulin action. This increased workload of the pancreas and the consequent decompensation are not only the main mechanisms for the development of type 2 diabetes (T2D), but also exacerbate the damage of metabolic diseases, including obesity, nonalcoholic fatty liver disease, polycystic ovary syndrome, metabolic syndrome, and others. Many clinical trials have suggested the potential role of herbs in the treatment of insulin resistance, although most of the clinical trials included in this review have certain flaws and bias risks in their methodological design, including the generation of randomization, the concealment of allocation, blinding, and inadequate reporting of sample size estimates. These studies involve not only the single-flavored herbs, but also herbal formulas, extracts, and active ingredients. Numerous of in vitro and in vivo studies have pointed out that the role of herbal medicine in improving insulin resistance is related to interventions in various aspects of the insulin signaling pathway. The targets involved in these studies include insulin receptor substrate, phosphatidylinositol 3-kinase, glucose transporter, AMP-activated protein kinase, glycogen synthase kinase 3, mitogen-activated protein kinases, c-Jun-N-terminal kinase, nuclear factor-kappaB, protein tyrosine phosphatase 1B, nuclear factor-E2-related factor 2, and peroxisome proliferator-activated receptors. Improved insulin sensitivity upon treatment with herbal medicine provides considerable prospects for treating insulin resistance. This article reviews studies of the target mechanisms of herbal treatments for insulin resistance.


Matrix metalloproteinase degradable, in situ photocrosslinked nanocomposite bioinks for bioprinting applications.
The development of suitable bioinks with high printability, mechanical strength, biodegradability, and biocompatibility is a key challenge for the clinical translation of 3D constructs produced with bioprinting technologies. In this work, we developed a new type of nanocomposite bioinks containing thiolated mesoporous silica nanoparticles (MSN) that act as active fillers within norbornene-functionalized hydrogels. The MSNs could rapidly covalently crosslink the hydrogels upon exposure to UV light. The mechanical properties of the gels could be modulated from 9.3 to 19.7 kPa with increasing concentrations of MSN. The ability of the MSN to covalently crosslink polymeric networks was, however, significantly influenced by polymer architecture and the number of functional groups. Modification of the outer surface of MSNs with matrix metalloproteinase (MMP) sensitive peptides (MSN-MMPs) resulted in proteinase K and MMP-9 enzyme responsive biodegradable bioinks. Additional cysteine modified RGD peptide incorporation enhanced cell-matrix interactions and reduced the gelation time for bioprinting. The nanocomposite bioinks could be printed by using extrusion-based bioprinting. Our nanocomposite bioinks preserved their shape during in vitro studies and encapsulated MG63 cells preserved their viability and proliferated within the bioinks. As such, our nanocomposite bioinks are promising bioinks for creating bioprinted constructs with tunable mechanical and degradation properties.


Recent developments and future prospects of Vitreoscilla hemoglobin application in metabolic engineering.
In hypoxic conditions, bacteria express a kind of hemoglobin, which is proposed to enhance respiration and energy metabolism by promoting oxygen delivery. Bacteria hemoglobin from Vitreoscilla stercoraria - Vitreoscilla hemoglobin (VHb), when expressed in various hosts in oxygen-limited conditions, has been shown to improve growth, protein secretion, metabolite productivity and stress resistance of hosts, thus rendering the protein promising in metabolic engineering, especially in plant metabolism optimization. In this review, many well-studies areas are presented to illustrate the potential of VHb application in biotechnology industry, to discuss the cellular mechanisms of VHb function and to show the wide variety of approaches taken within the field.


Children's growth parameters vary by type of fruit juice consumed.
Excessive fruit juice consumption in young children has been associated with nonorganic failure to thrive and short stature in some children and with obesity in others. To evaluate, in a sample of healthy young children, whether the associations between fruit juice intakes and growth parameters differ by the type of fruit juice consumed. Cross-sectional study. General primary care health center in upstate New York. One hundred sixteen two-year-old children and one hundred seven five-year-old children, who were scheduled for a nonacute visit, and their primary care-takers or parents were recruited over a two-year period. For 163 children (73% of total), 14 days of dietary records were available. The dietary records were entered and analyzed using the Nutrition Data System (NDS). Type of fruit juice was classified according to Nutrition Coordinating Center food codes. Height was measured using a Harpenden Stadiometer. Weight was measured using a standard balance beam scale. The children consumed, on average, 5.5 fluid oz/day of fruit juices, which were classified by the NDS software as 35% apple juice, 31% orange juice, 25% grape juice and 9% other types and/or mixtures of fruit juice. Children with higher fruit juice intakes had lower total fat, saturated fat and cholesterol intakes. Child height was inversely related to apple juice intake (p=0.007) and grape juice intake (p=0.02), after adjustment for child age, gender and energy intake (excluding fruit juice) and maternal height. Apple juice intake was correlated with child body mass index (p<0.05) and ponderal index (p<0.005), after adjustment for the above covariates. Total cholesterol, LDL-cholesterol, triglyceride and lipoprotein(a) levels were not related to intakes of any of the fruit juices examined. The children's ratios of total cholesterol to HDL cholesterol were correlated with grape juice intakes, while HDL-cholesterol levels were inversely related to grape juice intakes. There were no significant relationships between fruit juice intake and measures of anemia (hematocrit or mean corpuscular volume). The previously reported associations between short stature and high intakes of fruit juice were observed for intakes of both apple juice and grape juice. The associations between high fruit juice intakes and obesity were observed with apple juice intakes only. Because most of the fruit juice mixtures were classified as single fruit juices, the findings, especially those with grape juice, need to be cautiously interpreted. High intakes of fruit juice, however, appear to be associated with growth extremes in young children. Thus, it would seem prudent for parents and caretakers to moderate the fruit juice intakes of their young children.


Modelling the effect of prosthetic feet and shoes on the heel-ground contact force in amputee gait.
Gait laboratory measurements have been widely used to explore footwear and prosthetic effects on intact and amputee gait in spite of the confounding effects of adaptation, acclimation and inherent variability of human subjects. To facilitate understanding of the variables that affect impact forces that arise from heel-ground contact during amputee walking, a lumped parameter model is proposed to simulate the movement of the human body, prosthetic components and footwear during the period immediately following initial contact. Non-linear viscoelastic properties of prosthetic feet have a proportional relationship to both the magnitude of the impact peak and the rate of increase in the ground reaction force (GRF) immediately following initial contact. Footwear, in spite of a larger capacity to dissipate impact energy than a prosthetic foot alone, can actually amplify the magnitude of the impact peak. These results suggest limitations in the ability of conventional prosthetic feet and footwear to attenuate transmission of potential tissue-damaging forces.


Nutrient intake of horses in thoroughbred and standardbred stables.
Twenty-five Thoroughbred (TB) and 25 Standardbred (SB) stables were visited to determine their feeding practices. The ingredients of the main feed of the day for a mature gelding of average size in full training were weighted at each stable. Nutrient content of diets was calculated using published data for the individual ingredients. Results are expressed as mean +/- sd. The estimated body weight of TB horses was 493 +/- 34 kg and 437 +/- 32 kg for SB horses. There was considerable variation in diet composition and nutrient intake between stables. The TB trainers fed 11.0 +/- 2.4 kg and SB trainers 11.8 +/- 2.5 kg per day. The concentrate component of the diet weighed 7.8 +/- 1.6 and 7.7 +/- 2.3 kg for TB and SB stables, respectively, and the roughage component for TB horses 3.3 +/- 1.4 and SB horses 4.1 +/- 1.4 kg per day. The digestible energy intake of horses at TB stables was 129 +/- 29 MJ per day and at SB stables 132 +/- 31 MJ per day. Crude protein intake of TB horses was 1452 +/- 363 g and SB horses 1442 +/- 338 g per day. There were differences in some feeding practices at TB and SB stables. Standardbred trainers fed more roughage than TB trainers. Standardbred trainers fed chaffed lucerne (alfalfa) and cereal hays as the major roughage, whereas TB trainers fed more hay. The major hay type fed by TB trainers was lucerne, whereas many SB trainers preferred clover hay. Both trainers fed oats as the major grain, but TB trainers fed slightly more maize (corn) than SB trainers.(ABSTRACT TRUNCATED AT 250 WORDS)


[Experimental studies on ectopic osteogenesis by seeding human mesenchymal stem cell on human natural bone derived scaffold materials].
To investigate the ectopic osteogenesis potential of human natural bone derived material combined with human bone marrow mesenchymal stem cells (MSCs). Cell-scaffold complexes were implanted subcutaneously into the left back of the nude mice, and human natural bone derived material were implanted into the right back as control group. The mice were killed respectively on the postoperative 2 weeks, 4 weeks and 8 weeks. The macroscopic, histopathological, alkaline phosphatase (ALP) activity assay methods were performed to assess the ectopic osteogenesis potential. The cartilaginous osteogenesis were observed in both deproteinated bone and decalcified bone, and the more new bone tissue formed gradually as the time went by after implantation. ALP activity become stronger followed with the time (P < 0.05), and compared with the decalcified bone, deproteinated bone displayed stronger ALP activity (P < 0.05). The MSCs and human natural bone derived material can be used as good seed cells and scaffold materials respectively to construct tissue-engineered bone, and as the scaffold material, deproteinated bone has better osteogenesis ability than decalcifed bone.


Bioconversion of alpha-[14C]zearalenol and beta-[14C]zearalenol into [14C]zearalenone by Fusarium roseum 'Gibbosum'.
Cultures of Fusarium roseium 'Gibbosum' on rice were treated with [14C]zearalenone, alpha[14C]zearalenol, or beta-[14C]zearalenol to determine whether a precursor-product relationship exists among these closely related fungal metabolites. Culture extracts were purified by silica gel column chromatography and fractionated by high-pressure liquid chromatography, and the level of radioactivity was determined. Within 7 days, the beta-[14C]zearalenol was converted to zearalenone, and no residual beta-[14C]zearalenol was detectable. Most of the alpha-[14C]zearalenol added was also converted into zearalenone with 14 days. In cultures treated with [14C]zearalenone, no radioactivity was noted in any other components.


Mechanistic studies on metabolic interactions between gemfibrozil and statins.
A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (approximately 4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of [(14)C]SVA to dogs, GFZ treatment significantly reduced (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8- and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.


Tumor Cells Growth and Survival Time with the Ketogenic Diet in Animal Models: A Systematic Review.
Recently, interest in targeted cancer therapies via metabolic pathways has been renewed with the discovery that many tumors become dependent on glucose uptake during anaerobic glycolysis. Also the inability of ketone bodies metabolization due to various deficiencies in mitochondrial enzymes is the major metabolic changes discovered in malignant cells. Therefore, administration of a ketogenic diet (KD) which is based on high in fat and low in carbohydrates might inhibit tumor growth and provide a rationale for therapeutic strategies. So, we conducted this systematic review to assess the effects of KD on the tumor cells growth and survival time in animal studies. All databases were searched from inception to November 2015. We systematically searched the PubMed, Scopus, Google Scholars, Science Direct and Cochrane Library according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. To assess the quality of included studies we used SYRCLE's RoB tool. 268 articles were obtained from databases by primary search. Only 13 studies were eligible according to inclusion criteria. From included studies, 9 articles indicate that KD had a beneficial effect on tumor growth and survival time. Tumor types were included pancreatic, prostate, gastric, colon, brain, neuroblastoma and lung cancers. In conclusions, although studies in this field are rare and inconsistence, recent findings have demonstrated that KD can potentially inhibit the malignant cell growth and increase the survival time. Because of differences physiology between animals and humans, future studies in cancer patients treated with a KD are needed.


'Have you seen what is on Facebook?' The use of social networking software by healthcare professions students.
The use of social networking software has become ubiquitous in our society. The aim of this study was to explore the attitudes and experiences of healthcare professional students using Facebook at our school, to determine if there is a need for development of policy to assist students in this area. A mixed-methods approach was employed, using semistructured interviews to identify themes which were explored using an online survey. A combination of descriptive statistics and thematic analysis was used for analysis. Healthcare professions education programmes at a large Canadian university. Students of medicine, nursing, pharmacy, speech and language pathology, occupational therapy, physical therapy, dentistry, dental hygiene and medical laboratory Science were invited to participate. 14 participants were interviewed, and 682 participants responded to an online survey; the female:male balance was 3 : 1. 14 interviews were analysed in-depth, and 682 students responded to the survey (17% response rate). 93% reported current Facebook use. Themes identified included patterns of use and attitudes to friendship, attitudes to online privacy, breaches of professional behaviour on Facebook and attitudes to guidelines relating to Facebook use. A majority considered posting of the following material unprofessional: use of alcohol/drugs, crime, obscenity/nudity/sexual content, patient/client information, criticism of others. 44% reported seeing such material posted by a colleague, and 27% reported posting such material themselves. A majority of participants agreed that guidelines for Facebook use would be beneficial. Social networking software use, specifically Facebook use, was widespread among healthcare students at our school who responded to our survey. Our results highlight some of the challenges which can accompany the use of this new technology and offer potential insights to help understand the pedagogy and practices of Facebook use in this population, and to help students navigate the dilemmas associated with becoming 21st century healthcare professionals.


Computerized morphometric analysis of pathological prion protein deposition in scrapie-infected hamster brain.
Transmissible spongiform encephalopathies (TSEs or prion diseases) are characterized by a constellation of typical though variable pathological changes in the brain. Deposition of disease-associated abnormal prion protein (PrP(Sc)) is the pathological feature of TSEs most consistent and accessible for quantification. However, the evaluation of PrP(Sc) deposits detected by immunohistochemical techniques has been traditionally based on arbitrarily assigned semiquantitative scores. This approach is limited by its subjectivity and bias, yielding considerable variability. In this study, we used MetaMorph 6.1 image analysis software for quantitative analysis of immunostained PrP(Sc) deposits in the CNS of hamsters infected with the 263K strain of scrapie agent. Computerized morphometric analysis (CMA) allowed unambiguous detection of even minimal amounts of immunostained PrP(Sc). CMA values for intensity of staining and area stained correlated well with semiquantitative scores, providing reproducible quantitative data and objective criteria for analyzing PrP(Sc) deposition. CMA provides a simple and reliable method for improved and consistent diagnosis of TSEs that may also be used to quantify other immunostained biomarkers.


Metalloenzyme inhibitors for the treatment of Gram-negative bacterial infections: a patent review (2009-2012).
Bacteria were divided into two main classes in consideration of their ability to retain Gram staining. Gram-positive bacteria are able to retain the blue/violet staining, whereas Gram-negative bacteria are not, as they possess a thinner peptidoglycan wall, which is surrounded by an additional outer lipopolysaccharide membrane. This constitutes a serious hurdle for antibiotics to pass through, thereby representing a mechanism of bacterial defence and drug resistance. Targeting bacterial metalloenzymes represents an attractive approach for the development of new anti-infective drugs. In particular, small molecules able to inhibit metalloenzymes are of interest for their use alone or in association with known antibiotics with the aim to reduce mutations and various drug resistance mechanisms. The article deals with a selection of patents claiming the use of small molecules as inhibitors of gram-negative bacterial metalloenzymes and therefore useful for the treatment of infections caused or propagated by such pathogens. Inhibition of bacterial metalloenzymes from Gram-negative bacteria, such as histidinol dehydrogenase, UDP-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase, peptide deformylase, bacterial extracellular metalloprotease, and carbonic anhydrases, was reported in the scientific and patent literature. Such metalloenzyme inhibitors, amenable to the development of conceptually novel antibiotics, represent a promising approach for the development of novel anti-infectives.


Intraoperative Pulmonary Embolism Diagnosed by Rescue Transesophageal Echocardiography in a Morbidly Obese Patient Undergoing Orthopedic Surgery following Motor Vehicle Crash.
A case of intraoperative pulmonary embolism diagnosed by rescue transesophageal echocardiography in a morbidly obese patient undergoing orthopedic surgery following motor vehicle crash, who developed acute and persistent tachycardia, hypotension, and reduction of end-tidal CO2 during general and regional anesthesia, is described.


Ahmed Versus Baerveldt Glaucoma Drainage Device in Uveitic Glaucoma: A Retrospective Comparative Study.
Baerveldt glaucoma drainage device demonstrated a greater reduction in intraocular pressure (IOP) than Ahmed in patients with uveitic glaucoma. The most common cause of failure was uncontrolled IOP in Ahmed and hypotony in the Baerveldt group. To compare the efficacy and safety of Ahmed and Baerveldt glaucoma drainage devices in uveitic glaucoma. The retrospective comparative study included patients with uveitic glaucoma who underwent Ahmed or Baerveldt glaucoma drainage device implantation with a minimum follow-up of 3 months. Success was defined as IOP ≥6 and ≤21 mm Hg and >20% reduction on 2 consecutive visits after the third month with (qualified success) or without (complete success) medications and no further glaucoma surgery or loss of vision. IOP, number of medications, visual acuity, complications, and interventions were compared between groups. In total, 137 eyes of 122 patients (67 Ahmed, 70 Baerveldt) were included. The preoperative IOP and number of medications in the Ahmed group (32.7±10.3 mm Hg; 4.1±1.3) were similar to Baerveldt (32.1±10.2 mm Hg; 4.3±1.3; P=0.73, 0.35). These at the last follow-up were (18.1±9.8 mm Hg; 2.1±1) in Ahmed and (12.7±6.9 mm Hg; 1.3±1.3) in Baerveldt groups (P=0.04, 0.01). The Baerveldt had greater IOP reduction (60.3% vs. 44.5%) and complete success rate (30% vs. 9%) with higher complication rate (51.4% vs. 20.9%) (all P≤0.05). The de novo glaucoma reoperation rate was 19% in the Ahmed group and 4% in the Baerveldt group (P=0.006). Hypotony resulted in failure in 7 eyes (10%) in the Baerveldt group and none in the Ahmed group (P=0.013). Higher complete success rate and significantly greater reduction in mean IOP and number of medications were observed in the Baerveldt group, but with a higher rate of complications including hypotony.


Nitric oxide-sensitive guanylyl cyclase signaling affects CO2-dependent but not pressure-dependent regulation of cerebral blood flow.
Cerebrovascular CO2 reactivity is affected by nitric oxide (NO). We tested the hypothesis that sildenafil selectively potentiates NO-cGMP signaling, which affects CO2 reactivity. Fourteen healthy males (34 ± 2 yr) were enrolled in the study. Blood pressure (BP), ECG, velocity of cerebral blood flow (CBF; measured by transcranial Doppler), and end-tidal CO2 (EtCO2) were assessed at baseline (CO2 ~39 mmHg), during hyperventilation (CO2 ~24 mmHg), during hypercapnia (CO2 ~46 mmHg), during boluses of phenylephrine (25-200 µg), and during graded head-up tilting (HUT). Measurements were repeated 1 h after 100 mg sildenafil were taken. Results showed that sildenafil did not affect resting BP, heart rate, CBF peak and mean velocities, estimated regional cerebrovascular resistance (eCVR; mean BP/mean CBF), breath/min, and EtCO2: 117 ± 2/67 ± 3 mmHg, 69 ± 3 beats/min, 84 ± 5 and 57 ± 4 cm/s, 1.56 ± 0.1 mmHg·cm-1·s-1, 14 ± 0.5 breaths/min, and 39 ± 0.9 mmHg, respectively. Sildenafil increased and decreased the hypercapnia induced in CBF and eCVR, respectively. Sildenafil also attenuated the decrease in peak velocity of CBF, 25 ± 2 vs. 20 ± 2% (P < 0.05) and increased the eCVR, 2.5 ± 0.2 vs. 2 ± 0.2% (P < 0.03) during hyperventilation. Sildenafil did not affect CBF despite significant increases in the eCVRs that were elicited by phenylephrine and HUT. This investigation suggests that sildenafil, which potentiates the NO-cGMP signaling, seems to affect the cerebrovascular CO2 reactivity without affecting the static and dynamic pressure-dependent mechanisms of cerebrovascular autoregulation.


Attenuation of cell migration and induction of cell death by aged garlic extract in rat sarcoma cells.
Previous studies have shown that aged garlic extract suppresses cancer growth and enhances immune system against cancer, and yet little is known about inhibition of the cancer cell migration. In this study we investigated whether the aged garlic extract inhibits growth and migration of rat sarcoma tumor cells. The suppression of tumor cell growth was demonstrated by counting the cell number in three groups (control, cultured with 10 mg/ml, 20 mg/ml of aged garlic extracts) after culturing for 3 days and 5 days. The results showed that aged garlic extract inhibited the growth of rat sarcoma cancer cells in a dose-dependent manner, compared to the numbers of the cells grown in control group. The inhibition of tumor cell migration was examined by measuring the distance of trails left behind by the tumor cells when they passed through the polybeads overnight in four groups (control, 5 mg/ml, 10 mg/ml, 20 mg/ml aged garlic extracts). The average distance of trails in control group was 7.44 mm, whereas the average distance of cell movement is only 2.48 mm when treated with the highest concentration (20 mg/ml) of the aged garlic extract. The results also showed that the inhibitory effect of aged garlic extracts on tumor cell migration was dose-dependent. This is the first report to show that the aged garlic extract inhibits rat sarcoma cell migration, a critical feature of tumor cell metastasis. It can be thus envisioned that if tumor cell metastasis could be attenuated if not completely stopped, it would be possible to stabilize the tumor in the local area for surgical removal. The results suggest that garlic, as a natural plant, unlike other cancer treatment methods, may play a role in fighting cancer without significant side effects.


Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer.
To evaluate the quality of life (QOL) of breast cancer patients who survived 2 to 5 years following initiation of adjuvant cytotoxic and/or hormonal therapy and to characterize relationships between QOL and patient physical symptoms, sexual function, and preferences regarding adjuvant treatment. Eighty-six patients who had completed systemic adjuvant therapy for early-stage breast cancer between 1988 and 1991 were surveyed by written questionnaire and telephone interview. Sociodemographic information was obtained for each patient, and patients were asked to complete the Functional Living Index-Cancer (FLIC), the Symptom Distress Scale (SDS), the Medical Outcomes Study (MOS) Short Form 36 (SF-36), a series of questions regarding sexual function, and a survey about preferences for adjuvant therapy in relation to possible benefit. The mean FLIC score among all patients was 138.3 (+/- 12.2), which suggests a high level of QOL. The reported frequency of moderate to severe symptoms was generally low (ie, < 15%), with fatigue (31.4%), insomnia (23.3%), and local numbness at the site of surgery (22.1%) occurring with greatest frequency. Patients reported a wide range of sexual difficulties. Preference assessment showed that more than 65% of patients were willing to undergo 6 months of chemotherapy for a 5% increase in likelihood of cancer cure. Self-rated QOL in breast cancer patients 2 to 5 years following adjuvant therapy was generally favorable. Less than one third of patients reported moderate to severe symptoms. Selected aspects of sexual function appeared to be compromised. The majority of patients indicated a willingness to accept 6 months of chemotherapy for small to modest potential benefit.


An 'in-cell trial' to assess the efficacy of a monovalent anti-MET antibody as monotherapy and in association with standard cytotoxics.
In clinical practice, targeted therapies are usually administered together with chemotherapeutics. However, little is known whether conventional cytotoxic agents enhance the efficacy of targeted compounds, and whether a possible synergy would be dictated by drug-sensitizing genetic alterations. To explore these issues, we leveraged the design of clinical studies in humans to conduct a multi-arm trial in an 'in-cell' format. Using the MET oncogene as a model target and a panel of genetically characterized cell lines as a reference population, we found that two different chemotherapeutic regimens - cisplatin and 5-fluorouracil - exerted widespread cytotoxic activity that was not further enhanced by MET inhibition with a monovalent anti-MET antibody. From a complementary perspective, targeted MET inhibition was successful in a selected complement of cells harboring MET genomic lesions. In this latter setting, addition of chemotherapy did not provide a therapeutic advantage. Mechanistically, chemotherapeutics did not influence the basal activity of MET in cells with normal MET genomic status nor did they contribute to neutralize MET signals in cells with MET amplification. These data suggest that tumors displaying MET aberrations achieve plateau responses by MET monotherapy and do not receive further benefit by addition of cytotoxic treatments.


Stress in farmers.
This study aims to document the nature and extent of occupational stress in farming. A postal survey of farmers in the South West of England, was undertaken and results indicate high levels of occupational stress in farming families. 35% of respondents scored positively on the General Health Questionnaire (GHQ) with female respondents showing significantly higher scores than males. A significant proportion of respondents also showed elevated levels of anxiety and depression as measured by the Hospital Anxiety and Depression Scale (HAD). Indices of psychological distress were correlated with ill health and family problems though the most common sources of perceived stress were coping with new legislation, the amount of paper work and media criticism. People who reported a greater number of stressors scored higher on all 3 measure of psychological distress.


Therapeutic Effect of Microcurrent Therapy in Children With In-toeing Gait Caused by Increased Femoral Anteversion: A Pilot Study.
To investigate the efficacy of portable microcurrent therapy device (PMTD) of the hip internal rotators in the treatment of in-toeing gait caused by increased femoral anteversion in children over 8 years of age. Eleven children (22 legs; 4 boys and 7 girls; mean age, 10.4±1.6 years) with in-toeing gait caused by increased femoral anteversion were included in the present study. All children received 60 minutes of PMTD (intensity, 25 µA; frequency, 8 Hz) applied to the hip internal rotators daily for 4 weeks. Hip internal rotation (IR) angle, external rotation (ER) angle, and midmalleolar-second toe angle (MSTA) measurement during stance phase at transverse plane and Family Satisfaction Questionnaire, frequency of tripping and fatigue like pains about the PMTD were performed before treatment and at 4 weeks after initial PMTD treatment. Paired t-test and Fisher exact test were used for statistical analysis. Hip IR/ER/MSTA was 70.3°±5.4°/20.1°±5.5°/-11.4°±2.7°, and 55.7°±7.8°/33.6°±8.2°/-2.6°±3.8° before treatment and at 4 weeks after initial PMTD treatment, respectively (p<0.01). Ten of 11 (91%) children's family stated that they were generally satisfied with the PMTD treatment. The frequency of tripping and fatigue like pains was significantly lower at 4 weeks after PMTD treatment (p<0.05). Excellent inter-rater and intra-rater reliability was observed for repeated MSTA measurements between the examiners (k=0.91-0.96 and k=0.93-0.99), respectively. PMTD of the hip internal rotators can be effective in improving the gait pattern of children with in-toeing gait caused by increased femoral anteversion.


Constant expression of hexose-6-phosphate dehydrogenase during differentiation of human adipose-derived mesenchymal stem cells.
The reductase activity of 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) plays an important role in the growth and differentiation of adipose tissue via the prereceptorial activation of glucocorticoids. This enzyme colocalizes with hexose-6-phosphate dehydrogenase (H6PD) at the luminal surface of the endoplasmic reticulum membrane, and the latter enzyme provides NADPH to the former, which can thus act as an 11beta-reductase. It was suggested that, during adipogenesis, the increased expression of H6PD causes a dehydrogenase-to-reductase switch in the activity of HSD11B1. However, only the expression of the HSD11B1 has been extensively studied, and little is known about the expression of H6PD. Here, we investigated the expression and the activity of H6PD in the course of the differentiation of human adipose-derived mesenchymal stem cells (ADMSCs) and murine 3T3-L1 cells. It was found that H6PD is already present in adipose-derived stem cells and in 3T3-L1 fibroblasts even before the induction of adipogenesis. Moreover, mRNA and protein levels, as well as the microsomal H6PD activities remained unchanged during the differentiation. At the same time a great induction of HSD11B1 was observed in both cell types. The observed constant expression of H6PD suggests that HSD11B1 acts as a reductase throughout the adipogenesis process in human ADMSCs and murine 3T3-L1 cells.


Strategies for neonatal developmental care and family-centered neonatal care.
To evaluate neonatal developmental care and family-centered care in a neonatal unit. Participatory action research with a purposive sample of health personnel and parents of hospitalized newborn in a Neonatal Unit in Valle del Cauca, Colombia. Five focal groups were conducted with seven mothers and 40 professionals of the unit team, and additionally, 24 non-participant observations were conducted about neonatal developmental care and family-centered care. Three strategies for promotion were implemented for both approaches and subsequently, results were evaluated in terms of practices that take place during neonatal care, after the intervention. A quantitative analysis with descriptive statistics and a qualitative content analysis were done to process the data. Three strategies were implemented: continuing education for professionals, allocation of materials for the positioning of the babies and an informative video for the parents about how the unit operates. The focus groups and the initial observation showed the necessity to enhance knowledge and practices of the personnel regarding neonatal developmental care and family-centered care. The promotion of neonatal developmental care and family-centered care generated positive changes in care practices of the professionals in the neonatal unit, through the use of education strategies, communication and the provision of positioning materials.


[Study of the enzymatic activity of the blood leukocytes in experimental nephrotoxic nephritis in rats].
The enzymatic activity of blood leukocytes was studied in rats with Masugi nephritis by means of the quantitative cytochemical method. Nephrotoxin injection during first hours and days did not produce specific changes in the enzymatic activity. Maximum changes were observed on the 8-th day when the elevation of the activity of dehydrogenase lymphocytes and neutrophils acid phosphatase was observed at the same time with most pronounced histological changes in the kidneys, the decrease of the complement titer and the presence of nephrotoxin and autoglobulin in the renal glomeruli. Later the histological changes became less pronounced, and the enzymatic activity decreased. In rats with proteinuria the activity of the neutrophil leukocytes acid phosphatase was higher than in animals without proteinuria.


DEP-induced fra-1 expression correlates with a distinct activation of AP-1-dependent gene transcription in the lung.
Recent studies indicate a potential role for Fra-1, a heterodimeric partner of activator protein (AP)-1, in toxicant-induced epithelial injury, repair, and cellular transformation. Here we have investigated the effects of diesel exhaust particles (DEP) on fra-1 expression in C10 cells, a murine lung epithelial cell line. DEP markedly upregulated fra-1, but not fra-2, expression. The increase in fra-1 mRNA expression correlated well with its protein- and DNA-binding activity. DNA-binding assays also revealed a predominant presence of Jun-B and Jun-D in the AP-1 complex. Interestingly, DEP did not alter Jun-B and Jun-D protein levels. Transcriptional analysis revealed that fra-1 induction is regulated in part at the transcriptional level. The -379 to +32 bp 5'-flanking region mediated this induction. Furthermore, inhibitors of ERK1/2, JNK1, and p38 mitogen-activated protein kinases (MAPKs) significantly suppressed DEP-stimulated fra-1 transcription, suggesting their involvement in the induction process. Consistent with this finding, DEP stimulated phosphorylation of ERK1/2, JNK1, and p38 MAPKs with a distinct activation pattern. Overexpression of Fra-1 downregulated c-Jun and Nrf2 enhanced AP-1- and ARE-mediated reporter gene expression, respectively. In contrast, Fra-1 had the opposite effect on matrix metalloproteinase (MMP)-9 promoter activity. In particular, it bound to the functional AP-1 site of the MMP-9 promoter after DEP stimulation. Consistent with this result, DEP also markedly upregulated MMP-9 promoter activity. Collectively, these findings suggest that fra-1 induction by DEP may play a role in selectively regulating gene expression involved in alveolar epithelial cell injury and repair.


Monitoring Membrane Hydration with 2-(Dimethylamino)-6-Acylnaphtalenes Fluorescent Probes.
A family of polarity sensitive fluorescent probes (2-(dimethylamino)-6-acylnaphtalenes, i.e. LAURDAN, PRODAN, ACDAN) was introduced by Gregorio Weber in 1979, with the aim to monitor solvent relaxation phenomena on protein matrices. In the following years, however, PRODAN and particularly LAURDAN, were used to study membrane lateral structure and associated dynamics. Once incorporated into membranes, the (nanosecond) fluorescent decay of these probes is strongly affected by changes in the local polarity and relaxation dynamics of restricted water molecules existing at the membrane/water interface. For instance, when glycerophospholipid containing membranes undertake a solid ordered (gel) to liquid disordered phase transition the fluorescence emission maximum of these probes shift ~ 50 nm with a significant change in their fluorescence lifetime. Furthermore, the fluorescence parameters of LAURDAN and PRODAN are exquisitely sensitive to cholesterol effects, allowing interpretations that correlate changes in membrane packing with membrane hydration. Different membrane model systems as well as innate biological membranes have been studied with this family of probes allowing interesting comparative studies. This chapter presents a short historical overview about these fluorescent reporters, discusses on different models proposed to explain their sensitivity to membrane hydration, and includes relevant examples from experiments performed in artificial and biological membranes.


Diet and migraine: what is proven?
The purpose of this review is to present the latest research findings about diet and migraine, what can be used in the clinic now, and what needs further investigation. Recent findings highlight that dietary triggers exist for migraine, for example, coffee and alcohol, according to a new systematic review. Elimination diets must be personalized to delineate a balanced diet with acceptable quality and pattern. A piece of average-quality evidence shows that the ketogenic diet (KD) and the Dietary Approaches to Stop Hypertension (DASH) are effective in reducing the frequency, duration, and severity of migraine headaches in adult patients. The gut microbiome is altered in patients with migraine, and further research will identify the benefits of pre and probiotic use for migraine. Advanced digital technology in continuous monitoring can provide educational content based on patients' needs, help patients adhere to dietary plans, and strengthen personalized care. The complex interaction of lifestyle factors, the influence of age and sex, and patients' needs in various life phases are essential in formulating dietary plans. The diet-migraine interaction is a dynamic bidirectional phenomenon that requires careful monitoring, review, and justification of dietary choices to yield the optimal outcome while minimizing potential risks.


Lung injury related to consuming Sauropus androgynus vegetable.
Taking Sauropus androgynus, a Malaysian food, to reduce weight began as a fad in Taiwan in 1994. Some advocates of this fad developed pulmonary dysfunction. The aim of this study is to report the lung injury in patients taking Sauropus androgynus. From July 1995 to November 1995, we investigated 104 nonsmoking patients (one male and 103 females) with chest roentgenography, pulmonary function, test, and Technetium 99m-labeled diethylene triamine penta-acetate (Tc-99m DTPA) radioaerosol inhalation lung scintigraphy. Among the 90 patients receiving Tc-99m DTPA inhalation lung scan, 46 (51.1%) patients had increased clearance of Tc-99m DTPA from lung and 20 (22.2%) patients had inhomogeneous deposition of the submicronic radioaerosol. Eighteen (18/100) patients had obstructive ventilatory impairment in pulmonary function test. Analyzing the results, we found that the patients with respiratory symptoms (n = 42) took more vegetables (p = 0.016), had increased clearance of Tc-99m DTPA (p = 0.010) and had lower FEV1 (p = 0.001), FEV1/FVC (p < 0.001), FEF25-75 (p = 0.001), VC (p = 0.002) and DLCO (p = 0.009) than the patients without respiratory symptoms (n = 62). FEV1 and FEV1/FVC were significantly reduced in patients with severe impairment of alveolar permeability. The cumulative dosage and duration of exposure were significantly associated with the reduction of FEV1 and FEV1/FVC. The lung injury after taking Sauropus androgynus involves alveoli and/or small airways and is manifest as obstructive ventilatory impairment with inhomogeneous aerosol distribution and increased lung epithelial permeability.


Innovative alcohol- and drug-user treatment of inmates in New Zealand prisons.
The Kowhai Alcohol and Drug Treatment Unit at Rolleston Prison offers an innovative treatment approach for New Zealand inmates. The development of the program has involved local staff from Public Prisons, Psychological Services, and the Community Probation Service (CPS). This presentation outlines the author's impression of this bold innovation. The primary aim of the program is to reduce recidivism. This is achieved by assisting inmates to recognize the thoughts, emotions, and behaviours that are present in the period preceding and/or during the commission of criminal activity--particularly those that are precipitated and/or maintained by alcohol and drug use. This insight, coupled with the learning of specific coping skills and intensive lifestyle and reintegration planning, leads naturally to the follow-up phase that is conducted in the community. The functional relationship between offending and substance use is far more explicitly addressed in this new program compared with past programs that focused more on substance use.


Errors in the assessment of pocket depth in vitro.
The inaccuracy of the calibration of two Merritt-B probes, old and new style, was investigated. It appeared that the calibration of the Merritt-B "new style" probe was better than the calibration of the old one. The influence of the mode of calibration and the reading of the calibration on pocket depth assessment with a Merritt-B "old style" probe was studied in an in vitro model. The model consisted of 32 aluminium cubes each with a hole in the centre. The holes were 1 mm in cross-section and the depth varied from 0.25 mm to 8 mm in 0.25-mm increments. Results show that pocket depths of 1 mm to 8 mm +/- 0.25 mm generally were read correctly about 90% of the time. This was not true for the 4- and 6-mm areas. When a probe was used where the 4- and 6-mm marks were omitted, pocket depth in that area were read correctly only in about 60% of instances. This difference disappeared when the 4- and 6-mm marks were added. Results of measuring the half millimeter values showed that generally 80% were recorded as the lower whole millimeter.


The bioactive effects of casein proteins on enteroendocrine cell health, proliferation and incretin hormone secretion.
Previous studies suggest that casein exerts various anti-diabetic effects. However, it is not known which casein proteins are bioactive, nor their effects on enteroendocrine cells. This study evaluated the effects of intact whole casein, intact individual proteins (alpha, beta and kappa casein) and hydrolysates on an enteroendocrine cell line. High content analysis accurately monitored changes in cell health and intracellular glucagon-like peptide-1 (GLP-1) content. Cheese ripening duration and GLP-1 secretory responses were also considered. Beta casein significantly stimulated enteroendocrine cell proliferation and all caseins were potent GLP-1 secretagogues (except kappa casein). Interestingly the GLP-1 secretory activity was almost always lost or significantly reduced upon hydrolysis with proteolytic enzymes. Only pepsin-derived beta casein hydrolysates had significantly increased potency compared with the intact protein, but this was diminished with prolonged hydrolysis. In conclusion casein proteins are not detrimental to enteroendocrine cells, and alpha and beta casein are particularly beneficial stimulating proliferation and GLP-1 secretion.


Some Multidimensional Unintended Consequences of Telehealth Utilization: A Multi-Project Evaluation Synthesis.
Telehealth initiatives have bloomed around the globe, but their integration and diffusion remain challenging because of the complex issues they raise. Available evidence around telehealth usually deals with its expected effects and benefits, but its unintended consequences (UCs) and influencing factors are little documented. This study aims to explore, describe and analyze multidimensional UCs that have been associated with the use of telehealth. We performed a secondary analysis of the evaluations of 10 telehealth projects conducted over a 22-year period in the province of Quebec (Canada). All material was subjected to a qualitative thematic-pragmatic content analysis with triangulation of methodologies and data sources. We used the conceptual model of the UCs of health information technologies proposed by Bloomrosen et al to structure our analysis. Four major findings emerged from our analysis. First, telehealth utilization requires many adjustments, changes and negotiations often underestimated in the planning and initial phases of the projects. Second, telehealth may result in the emergence of new services corridors that disturb existing ones and involve several adjustments for organizations, such as additional investments and resources, but also the risk of fragmentation of services and the need to balance between standardization of practices and local innovation. Third, telehealth may accentuate power relations between stakeholders. Fourth, it may lead to significant changes in the responsibilities of each actor in the supply chain of services. Finally, current legislative and regulatory frameworks appear ill-adapted to many of the new realities brought by telehealth. This study provides a first attempt for an overview of the UCs associated with the use of telehealth. Future research-evaluation studies should be more sensitive to the multidimensional and interdependent factors that influence telehealth implementation and utilization as well as its impacts, intended or unintended, at all levels. Thus, a consideration of potential UCs should inform telehealth projects, from their planning until their scaling-up.


Elimination of double strand nuclease activity from S1 nuclease prepared from crude alpha amylase.
Single strand-specific s1 nuclease prepared as previously described from crude alpha amylase by DEAE-cellulose chromatography also contains nuclease which degrades double strand nucleic acid. The double strand activity can be removed by repeating the DEAE-cellulose chromatography procedure at least two additional times. S1 nuclease prepared by this procedure does not degrade double strand sheared DNA as measured by Sephadex chromatography. Under the same conditions single strand DNA is completely degraded. Thus, S1 nuclease prepared by this procedure is suitable for use in removing single strand regions in DNA/DNA duplexes and DNA/RNA hybrids.


Enhancing Butanol Production under the Stress Environments of Co-Culturing Clostridium acetobutylicum/Saccharomyces cerevisiae Integrated with Exogenous Butyrate Addition.
In this study, an efficient acetone-butanol-ethanol (ABE) fermentation strategy integrating Clostridium acetobutylicum/Saccharomyces cerevisiae co-culturing system with exogenous butyrate addition, was proposed and experimentally conducted. In solventogenic phase, by adding 0.2 g-DCW/L-broth viable S. cerevisiae cells and 4.0 g/L-broth concentrated butyrate solution into C. acetobutylicum culture broth, final butanol concentration and butanol/acetone ratio in a 7 L anaerobic fermentor reached the highest levels of 15.74 g/L and 2.83 respectively, with the increments of 35% and 43% as compared with those of control. Theoretical and experimental analysis revealed that, the proposed strategy could, 1) extensively induce secretion of amino acids particularly lysine, which are favorable for both C. acetobutylicum survival and butanol synthesis under high butanol concentration environment; 2) enhance the utilization ability of C. acetobutylicum on glucose and over-produce intracellular NADH for butanol synthesis in C. acetobutylicum metabolism simultaneously; 3) direct most of extra consumed glucose into butanol synthesis route. The synergetic actions of effective amino acids assimilation, high rates of substrate consumption and NADH regeneration yielded highest butanol concentration and butanol ratio in C. acetobutylicum under this stress environment. The proposed method supplies an alternative way to improve ABE fermentation performance by traditional fermentation technology.


Failures in Phase III: Causes and Consequences.
Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.


Towards Plant Synthetic Genomics.
Rapid advances in DNA synthesis techniques have allowed the assembly and engineering of viral and microbial genomes. Multicellular eukaryotic organisms, with their larger genomes, abundant transposons, and prevalent epigenetic regulation, present a new frontier to synthetic genomics. Plant synthetic genomics have long been proposed, and exciting progress has been made using the top-down approach. In this perspective, we propose applying bottom-up genome synthesis in multicellular plants, starting from the model moss Physcomitrium patens, in which homologous recombination, DNA delivery, and regeneration are possible, although further optimizations are necessary. We then discuss technical barriers, including genome assembly and plant transformation, associated with synthetic genomics in seed plants.


Perspectives on cancer therapy: cell cycle blockers and perturbators.
Over the past few decades, remarkable advances have been achieved in cancer therapy, including chemotherapeutic agents, their mode of application and more broader therapeutic strategies. Promising new therapeutic targets have emerged in the past ten years as a result of recent advances in our understanding of the pathobiology of malignant cells, in particular, regarding functions of suppressor oncogene products. Among them, the agents that alter the cell cycle have recently been of particular interest, since cell cycle regulation is basic mechanism underlying cell fate, i.e., proliferation, differentiation or death. Furthermore, the human genome project has made possible the future development of so-called "tailor-made medicine", i.e. the design of appropriate drugs for specific genetic profiles and application of drugs that are tailored to each tumor and patient. In this article, we will introduce and discuss recent progress in the development of agents that influence the cell cycle and their future potential in cancer therapy from three standpoints with our own experimental works; i) the inhibition of cell proliferation and/or induction of differentiation by cyclin-dependent kinase (cdk)-inhibitor, e.g. olomoucin, butyrolactone-I, ii) induction of apoptosis by directing "abortive cell cycle", or the transient upregulation of cdk activity, e.g. flavopiridol, and iii) countering the development of drug resistance by adjunctive administration of cdk-inhibitors with conventional anti-cancer drug, e.g., p21-gene transfer with cisplatin. Conclusively none of these three approaches by itself is satisfactory, and that the effective cancer therapies will require the administration of several agents and/or methods under the design of their synergistic effects.


An approximation to the vibrational coupled-cluster method for CH-stretching of large molecules: application to naphthalene and anthracene.
We propose an approximation to the vibrational coupled-cluster method (VCCM) to describe the CH-stretching region of the vibrational spectrum of large molecules. The vibrational modes of a molecule are divided into two sets: the target set and the bath set. The target set includes the CH stretches and the modes that are strongly coupled with the CH stretches and/or involve strong Fermi resonances with a CH stretch fundamental. The rest of the modes are in the bath set. First, the effective harmonic oscillator (EHO) approximation is invoked for the whole system to obtain the zeroth-order frequencies and modified potentials. The effects of interaction between the bath set and the target sets are included in the modified potential from the EHO calculation. The VCCM equations are constructed with the modified potential from the EHO calculations and for the target set only. The transition energies and intensities are calculated using such a truncated VCCM approximation. The proposed method is applied to calculate the IR spectra of naphthalene and anthracene. The results with three different criteria for selecting the modes in the target set are compared with the experimental IR spectra.


The prediction of a pathogenesis-related secretome of Puccinia helianthi through high-throughput transcriptome analysis.
Many plant pathogen secretory proteins are known to be elicitors or pathogenic factors,which play an important role in the host-pathogen interaction process. Bioinformatics approaches make possible the large scale prediction and analysis of secretory proteins from the Puccinia helianthi transcriptome. The internet-based software SignalP v4.1, TargetP v1.01, Big-PI predictor, TMHMM v2.0 and ProtComp v9.0 were utilized to predict the signal peptides and the signal peptide-dependent secreted proteins among the 35,286 ORFs of the P. helianthi transcriptome. 908 ORFs (accounting for 2.6% of the total proteins) were identified as putative secretory proteins containing signal peptides. The length of the majority of proteins ranged from 51 to 300 amino acids (aa), while the signal peptides were from 18 to 20 aa long. Signal peptidase I (SpI) cleavage sites were found in 463 of these putative secretory signal peptides. 55 proteins contained the lipoprotein signal peptide recognition site of signal peptidase II (SpII). Out of 908 secretory proteins, 581 (63.8%) have functions related to signal recognition and transduction, metabolism, transport and catabolism. Additionally, 143 putative secretory proteins were categorized into 27 functional groups based on Gene Ontology terms, including 14 groups in biological process, seven in cellular component, and six in molecular function. Gene ontology analysis of the secretory proteins revealed an enrichment of hydrolase activity. Pathway associations were established for 82 (9.0%) secretory proteins. A number of cell wall degrading enzymes and three homologous proteins specific to Phytophthora sojae effectors were also identified, which may be involved in the pathogenicity of the sunflower rust pathogen. This investigation proposes a new approach for identifying elicitors and pathogenic factors. The eventual identification and characterization of 908 extracellularly secreted proteins will advance our understanding of the molecular mechanisms of interactions between sunflower and rust pathogen and will enhance our ability to intervene in disease states.