Electrical and SERS detection of disulfide-mediated dimerization in single-molecule benzene-1,4-dithiol junctions.
We applied a combination of mechanically controllable break junction (MCBJ) and in situ surface enhanced Raman spectroscopy (SERS) methods to investigate the long-standing single-molecule conductance discrepancy of prototypical benzene-1,4-dithiol (BDT) junctions. Single-molecule conductance characterization, together with configuration analysis of the molecular junction, suggested that disulfide-mediated dimerization of BDT contributed to the low conductance feature, which was further verified by the detection of S-S bond formation through in situ SERS characterization. Control experiments demonstrated that the disulfide-mediated dimerization could be tuned via the chemical inhibitor. Our findings suggest that a combined electrical and SERS method is capable of probing chemical reactions at the single-molecule level.


The time is now: formation of true transplant centers.
With the advances in the complexity of medical care there is a need to change the way we are organized in order to deliver that care in the most patient-friendly, efficient manner. This need is perhaps most compellingly manifest in the field of whole organ transplantation. Yet we are trying to deliver medical care with an organizational structure that was developed over 100 years ago when medical practice was considerably different. We argue for the development of a vertically integrated organizational structure in academic health centers for certain disciplines like transplantation. While this new arrangement for medical practice could be applied to many areas of medicine, transplantation is one of the best fields to begin making these changes. True transplant centers would bring avoid fragmentation of care and resources, thus bringing together the medical school and hospital into an integrated organization that would be responsible for all aspects of transplantation such as patient care, research, education and fiscal issues.


Microtubule-associated proteins and in vitro astrocyte differentiation.
Primary cultures of mouse brain astrocytes have been used to identify the microtubule-associated proteins (MAPs) present in this cell type at different stages of in vitro differentiation. The MAPs of the astrocyte have been identified by polyacrylamide gel electrophoresis and immunological detection. Two antisera were raised against two brain MAPs, tau and MAP-2. These antisera were also used to label the microtubular network in the intact astrocytes at different stages of the culture. The mature astrocyte contains a variety of MAP-like proteins. Anti-MAP-2 serum detected several proteins of high molecular weight (380,000, 260,000, 205,000 and 165,000 mol wt) and one microheterogeneous peak of 83,000 mol wt. Anti-tau also detected high molecular weight components (380,000 to approximately 200,000 mol wt) but not the 165,000-mol-wt peak; in addition two microheterogeneous peaks of 83,000 and 62,000 mol wt were detected by the anti-tau serum. The 62,000-mol-wt peak was therefore detected only by the anti-tau serum whereas the 83,000-mol-wt component cross-reacted with both antisera. At early stages of the culture the immature cell contained about two times less immunoreactive material than at mature stages. Qualitative changes of the high molecular weight components were also observed. In the intact cell both antisera revealed a dense fibrous network. At early stages of the culture the astroblasts were stained by the antisera but the reaction was very diffuse in the cytoplasm; few fibrous cells were intensively stained. Morphological differentiation, which began after serum deprivation and which was accelerated by forskolin (a drug that induces cyclic AMP accumulation), led to high labeling of both the cell body and the cellular processes. In the presence of colchicine the staining regressed, the processes shortened, and the cell returned to a less-apparently differentiated state.


Factors influencing the age at onset in familial frontotemporal lobar dementia: Important weight of genetics.
To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations. We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models. A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e-4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e-5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families. Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.


Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial.
Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.


[Arthroscopic debridement of full-thickness tears of the rotator cuff: a retrospective multicenter study of 283 cases with 3-year follow-up].
The purpose of this study was to assess clinical and radiological course of full-thickness rotator cuff tears treated by arthroscopic debridement and to discuss surgical indications according to patient demands and anatomical lesions. This retrospective and multicentric study included patients with a minimal 3 years follow-up. The coronal extent of the supraspinatus tear was described as distal, intermediate or retracted. The sagittal extent to the infraspinatus and/or subscapularis and rotator interval was detailed. All patients were evaluated pre and post-operatively using Constant score and radiological A-P view for sub-acromial space measurement. In order to assess the influence of age, anatomical extent of the tear and follow-up, results were analyzed for 4 groups of patients according to their age: group I (19 cases less than 50 years), group II (88 cases from 51 to 60 years), group III (58 cases from 61 to 65 years) and group IV (118 cases over 65 years). Results were finally evaluated according the arthroscopic procedure (isolated acromioplasty and biceps tenotomy, or association of both). 283 patients, aged 63.1 years (range 32 to 82) entered this study. A complete antero-posterior tear of the supra-spinatus tendon was noticed in 93.2 p. 100 of cases. The tear extended to the infraspinatus tendon in 57.3 p. 100, and to the subscapularis tendon in 29 p. 100 of cases. The long head of the biceps was involved in 73 p. 100 of cases. 218 acromioplasties and 116 biceps tenotomies were performed. The 2 procedures were combined in nearly 25 p. 100 of cases. At final revision (mean follow-up of 4.7 years), 98 patients (34.6 p. 100) were very satisfied, 122 (43.1 p. 100) satisfied, 43 (15.2 p. 100) moderatly satisfied and 20 (7.1 p. 100) were disappointed. The average Constant score increased from 42.4 to 67.6 points. The radiological study showed a 1 mm narrowing of the sub-acromial space. Objective results were surprisingly good for group I at a 5.4 years follow-up but dropped from group II to group IV, mainly in relation with the extent of the tear. A deleterious effect of the isolated biceps tenotomy was demonstrated in case of subacromial space superior to 7 mm. Inversely after this procedure patients with a narrowed space improved. Even if traditional bias of retrospective and mullticentric study could not be avoided, the large number of patients and long follow-up of this study are superior to most of the published papers. The extent of the supraspinatus tear seems to progress during the 50-60 years decade. Objective results appeared to be much more related to the anatomical lesions than to the arthroscopic procedure. This series did not demonstrate a secondary clinical or radiological deterioration after an endoscopic treatment without repair of full-tickness rotator cuff tears. Subacromial decompression and/or biceps tenotomy indications depend on age and extension of the tear.


Plant health emergencies demand open science: Tackling a cereal killer on the run.
Outbreaks of emerging plant diseases and insect pests are increasing at an alarming rate threatening the food security needs of a booming world population. The role of plant pathologists in addressing these threats to plant health is critical. Here, we share our personal experience with the appearance in Bangladesh of a destructive new fungal disease called wheat blast and stress the importance of open-science platforms and crowdsourced community responses in tackling emerging plant diseases. Benefits of the open-science approach include recruitment of multidisciplinary experts, application of cutting-edge methods, and timely replication of data analyses to increase the robustness of the findings. Based on our experiences, we provide some general recommendations and practical guidance for responding to emerging plant diseases.


Langerhans Cell Histiocytosis With Clinical and Histologic Features of Hidradenitis Suppurativa: Brief Report and Review.
Langerhans cell histiocytosis (LCH) is an uncommon histiocytic disorder in adults. Clinically, this rare entity can mimic other dermatologic conditions, including hidradenitis suppurativa. A case of LCH is reported with clinical and histologic features of hidradenitis suppurativa, along with a review of these unusual findings. Clinical dermatologists and dermatopathologists benefit from awareness of this unique presentation, which may prompt earlier identification and diagnosis of adult patients with LCH.


Factors associated with continuity and changes in disruptive behavior patterns between childhood and adolescence.
The relationships between disruptive behaviors in middle childhood (7 to 9 years) and conduct disorder in adolescence (14 to 16 years) were studied in a birth cohort of New Zealand children. Latent class analysis suggested strong behavioral continuity, with children showing early disruptive behaviors having odds of adolescent conduct disorder that were over 16 times higher than children who did not display early disruptive behavior. Nonetheless, in the region of 12% of children showed a discontinuous history, with 5% of children showing an early onset of conduct problems and later remission while 7% showed later onset conduct problems. Children showing discontinuous histories of behavior problems came from backgrounds in which levels of risk were intermediate between those of children who showed a persistent pattern of conduct problems and those who were consistently nonproblem children. Peer factors played an influential role in behavioral change in adolescence, with individuals showing late onset of conduct problems having high rates of affiliation with delinquent peers but those showing remission of problem behaviors in adolescence having relatively low rates of such affiliations.


AMPATH: living proof that no one has to die from HIV.
The HIV/AIDS epidemic in sub-Saharan Africa is decimating populations, deteriorating economies, deepening poverty, and destabilizing traditional social orders. The advent of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) made significant supplemental resources available to sub-Saharan national programs for the prevention and treatment of HIV/AIDS, but few programs have demonstrated the capacity to use these resources to increase rapidly in size. In this context, AMPATH, a collaboration of Indiana University School of Medicine, the Moi University School of Medicine, and the Moi Teaching and Referral Hospital in Eldoret, Kenya, is a stunning exception. This report summarizes findings from an assessment of AMPATH staff perceptions of how and why this has happened. PARTICIPANTS AND APPROACH: Semistructured, in-depth, individual interviews of 26 AMPATH workers were conducted and recorded. Field notes from these interviews were generated by independent reviewers and subjected to close-reading qualitative analysis for themes. The themes identified were as follows: creating effectively, connecting with others, making a difference, serving those in great need, providing comprehensive care to restore healthy lives, and growing as a person and a professional. Inspired personnel are among the critical assets of an effective program. Among the reasons for success of this HIV/AIDS program are a set of work values and motivations that would be helpful in any setting, but perhaps nowhere more critical than in the grueling work of making a complex program work spectacularly well in the challenging setting of a resource-poor country. Sometimes, even in the face of long odds, the human spirit prevails.


2D group-VA fluorinated antimonene: synthesis and saturable absorption.
A new derivative of antimonene named fluorinated antimonene was synthesized using the method of ionic liquid-assisted electrochemical exfoliation and synchronous fluorination. Passive Q-switched pulses were produced from a Nd:LuAG laser with fluorinated antimonene, having a pulse width of 326.7 ns and a repetition rate of 733.1 kHz demonstrating its potential application as a saturable absorber. Density functional theory calculations revealed that compared with pure antimonene with an indirect bandgap, fluorinated antimonene exhibits a direct bandgap modulated by the fluorination degree showing that fluorinated antimonene would be applied as optical devices beyond its application as a saturable absorber.


Differences in antibiotic resistance patterns of Enterococcus faecalis and Enterococcus faecium strains isolated from farm and pet animals.
The prevalence of acquired resistance in 146 Enterococcus faecium and 166 Enterococcus faecalis strains from farm and pet animals, isolated in 1998 and 1999 in Belgium, against antibiotics used for growth promotion and for therapy was determined. Acquired resistance against flavomycin and monensin, two antibiotics used solely for growth promotion, was not detected. Avoparcin (glycopeptide) resistance was found sporadically in E. faecium only. Avilamycin resistance was almost exclusively seen in strains from farm animals. Resistance rates were higher in E. faecium strains from broiler chickens than in strains from other animal groups with tylosin and virginiamycin and in E. faecalis as well as in E. faecium strains with narasin and bacitracin. Resistance against ampicillin was mainly found among E. faecium strains from pets and was absent in E. faecalis. Tetracycline resistance occurred most often in strains from farm animals, while enrofloxacin resistance, only found in E. faecalis, occurred equally among strains from all origins. Resistance against gentamicin was very rare in broiler strains, whereas resistance rates were high in strains from other origins. It can be concluded that resistance against antibiotics used solely for growth promotion was more prevalent in E. faecium strains than in E. faecalis strains. With few exceptions, resistance against the different categories of antibiotics was more prevalent in strains from farm animals than in those from pets.


Sport, how people choose it: A network analysis approach.
In order to investigate the behaviour of athletes in choosing sports, we analyse data from part of the We-Sport database, a vertical social network that links athletes through sports. In particular, we explore connections between people sharing common sports and the role of age and gender by applying "network science" approaches and methods. The results show a disassortative tendency of athletes in choosing sports, a negative correlation between age and number of chosen sports and a positive correlation between age of connected athletes. Some interesting patterns of connection between age classes are depicted. In addition, we propose a method to classify sports, based on the analyses of the behaviour of people practising them. Thanks to this brand new classifications, we highlight the links of class of sports and their unexpected features. We emphasise some gender dependency affinity in choosing sport classes.


Caudolateral areas of medulla-mediating release of ACTH in cats.
The effect of electrical stimulation of the caudolateral brain stem on plasma adrenocorticotropin (ACTH) was assessed in cats anesthetized with alpha-chloralose-urethan. To examine the influence of stimulus pattern on ACTH release, an equal number of pulses was presented in a continuous pattern and in a burst pattern at each electrode site. Stimulation of the magnocellular portion (layers 4-6) of trigeminal nucleus caudalis evoked a significant (P less than 0.01) and equal peak change in plasma ACTH after continuous pattern (+121 +/- 32 pg/ml) and after burst pattern stimuli (+126 +/- 30 pg/ml, n = 21). In contrast, stimulation of more ventromedial portions (layers 7-8) of nucleus caudalis had no significant effect on plasma ACTH. Stimulation of the trigeminal lateral cervical region the caudal extent of the A1 noradrenergic cell group, or the lateral reticular nucleus evoked significant peak increases in plasma ACTH regardless of stimulus pattern. Transient changes in arterial pressure accompanied brain stem stimulation and were not correlated with the changes in ACTH. The results indicate that stimulation of trigeminal subnucleus caudalis, a brain stem region that processes nociceptor afferent information, evokes a prompt increase in plasma ACTH. Stimulation of brain stem regions that process autonomic and cardiovascular afferent information (A1 region, lateral reticular nucleus) also facilitate ACTH release. No significant influence of stimulus pattern on brain stem-evoked ACTH release was seen. The results support the hypothesis that the influence of the central nervous system on ACTH release may be processed by parallel pathways at the caudal brain stem level.


A novel respiratory model of infection with monkeypox virus in cynomolgus macaques.
Variola, the causative agent of smallpox, and the related monkeypox virus are both select agents that, if purposefully released, would cause public panic and social disruption. For this reason research continues in the areas of animal model and therapeutic development. Orthopoxviruses show a widely varying degree of host specificity, making development of accurate animal models difficult. In this paper, we demonstrate a novel respiratory infection technique that resulted in "classic" orthopox disease in nonhuman primates and takes the field of research one step closer to a better animal model.


Heterogeneity of iron bioavailability on plants assessed with a whole-cell GFP-based bacterial biosensor.
Ferric iron is an essential element for microbial growth but its water solubility in aerobic environments is considered to be low. Thus it is a limiting resource for which microbes must compete in natural habitats. Since competition for iron occurs at the level of individual cells, knowledge of the variability in iron bioavailability to such individuals is required to assess the nature of the competition in these habitats. Ferric iron availability to cells of Pseudomonas syringae was assessed by quantifying the fluorescence intensity of single cells harbouring a plasmid-borne transcriptional fusion of an iron-regulated promoter from a locus encoding a membrane receptor for a pyoverdine siderophore with a reporter gene encoding green fluorescent protein (GFP) following fluorescence microscopy. Cells of this iron biosensor exhibited iron-dependent GFP fluorescence that was inversely proportional to the amount of iron added to the media, and which differed by over 20-fold in iron-replete compared to iron-deplete culture media. Cells cultured in a medium of a given iron content exhibited a very narrow range of fluorescence intensities. In contrast, the fluorescence intensity of cells of the biosensor strain recovered from the rhizosphere or phylloplane of inoculated bean plants varied greatly. The distribution of fluorescence intensities was strongly right-hand skewed, with about 10% of the cells exhibiting substantially higher GFP fluorescence than that of the median cell. Cells of a positive control strain, harbouring a fusion of the constitutive nptII promoter with the gfp reporter gene, exhibited uniform GFP fluorescence both in culture media and on plants. These results indicate that there is substantial heterogeneity of iron biovailability to cells of P. syringae on plants, with only a small subset of cells experiencing low iron availability. Such heterogeneity places constraints on models of interactions of bacteria in natural habitats that are based on competition for limited iron.


Omega-6 and omega-3 oxylipins are implicated in soybean oil-induced obesity in mice.
Soybean oil consumption is increasing worldwide and parallels a rise in obesity. Rich in unsaturated fats, especially linoleic acid, soybean oil is assumed to be healthy, and yet it induces obesity, diabetes, insulin resistance, and fatty liver in mice. Here, we show that the genetically modified soybean oil Plenish, which came on the U.S. market in 2014 and is low in linoleic acid, induces less obesity than conventional soybean oil in C57BL/6 male mice. Proteomic analysis of the liver reveals global differences in hepatic proteins when comparing diets rich in the two soybean oils, coconut oil, and a low-fat diet. Metabolomic analysis of the liver and plasma shows a positive correlation between obesity and hepatic C18 oxylipin metabolites of omega-6 (ω6) and omega-3 (ω3) fatty acids (linoleic and α-linolenic acid, respectively) in the cytochrome P450/soluble epoxide hydrolase pathway. While Plenish induced less insulin resistance than conventional soybean oil, it resulted in hepatomegaly and liver dysfunction as did olive oil, which has a similar fatty acid composition. These results implicate a new class of compounds in diet-induced obesity-C18 epoxide and diol oxylipins.


Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations.
Cardiac hypertrophy represents one of the most important cardiovascular problems yet the mechanisms responsible for hypertrophic remodeling of the heart are poorly understood. In this report we aimed to explore the molecular pathways leading to two different phenotypes of cardiac hypertrophy in transgenic mice carrying mutations in the human ventricular myosin essential light chain (ELC). Mutation-induced alterations in the heart structure and function were studied in two transgenic (Tg) mouse models carrying the A57G (alanine to glycine) substitution or lacking the N-terminal 43 amino acid residues (Δ43) from the ELC sequence. The first model represents an HCM disease as the A57G mutation was shown to cause malignant HCM outcomes in humans. The second mouse model is lacking the region of the ELC that was shown to be important for a direct interaction between the ELC and actin during muscle contraction. Our earlier studies demonstrated that >7 month old Tg-Δ43 mice developed substantial cardiac hypertrophy with no signs of histopathology or fibrosis. Tg mice did not show abnormal cardiac function compared to Tg-WT expressing the full length human ventricular ELC. Previously reported pathological morphology in Tg-A57G mice included extensive disorganization of myocytes and interstitial fibrosis with no abnormal increase in heart mass observed in >6 month-old animals. In this report we show that strenuous exercise can trigger hypertrophy and pathologic cardiac remodeling in Tg-A57G mice as early as 3 months of age. In contrast, no exercise-induced changes were noted for Tg-Δ43 hearts and the mice maintained a non-pathological cardiac phenotype. Based on our results, we suggest that exercise-elicited heart remodeling in Tg-A57G mice follows the pathological pathway leading to HCM, while it induces no abnormal response in Tg-Δ43 mice.


Coxiella burnetii (Q fever) infection in dairy cattle and associated risk factors in Latvia.
The purpose of this study was to describe prevalence and spatial distribution of Coxiella burnetii infections in dairy cow sheds in Latvia and to investigate risk factors contributing to C. burnetii infections. Blood serum samples from abortion cases from 1010 sheds have been tested by ELISA for the presence of C. burnetii antibodies and bulk tank milk (BTM) samples from 252 sheds have been tested by real time polymerase chain reaction and ELISA for the presence of C. burnetii DNA and antibodies. Prevalence of C. burnetii antibody-positive sheds in cases of abortion was 13·4%. A total of 10·7% and 13·2% of dairy cow sheds tested positive for the presence of C. burnetii DNA and antibodies in BTM, respectively. Two distinct areas of clustering of test-positive dairy cattle sheds were identified by spatial scan statistics of abortion cases and randomly sampled BTM samples. Three factors were identified as significantly contributing to the risk of C. burnetii DNA presence in BTM - number of cattle in shed (>200 animals/shed) (OR 3·93), location of the shed within risk area in Northern Latvia (OR 8·29) and for the first time, purchasing cattle from abroad has been shown to significantly increase risk (OR 2·68) of C. burnetii infection in dairy cows in Latvia.


Proteins at the polypeptide tunnel exit of the yeast mitochondrial ribosome.
Oxidative phosphorylation in mitochondria requires the synthesis of proteins encoded in the mitochondrial DNA. The mitochondrial translation machinery differs significantly from that of the bacterial ancestor of the organelle. This is especially evident from many mitochondria-specific ribosomal proteins. An important site of the ribosome is the polypeptide tunnel exit. Here, nascent chains are exposed to an aqueous environment for the first time. Many biogenesis factors interact with the tunnel exit of pro- and eukaryotic ribosomes to help the newly synthesized proteins to mature. To date, nothing is known about the organization of the tunnel exit of mitochondrial ribosomes. We therefore undertook a comprehensive approach to determine the composition of the yeast mitochondrial ribosomal tunnel exit. Mitochondria contain homologues of the ribosomal proteins located at this site in bacterial ribosomes. Here, we identified proteins located in their proximity by chemical cross-linking and mass spectrometry. Our analysis revealed a complex network of interacting proteins including proteins and protein domains specific to mitochondrial ribosomes. This network includes Mba1, the membrane-bound ribosome receptor of the inner membrane, as well as Mrpl3, Mrpl13, and Mrpl27, which constitute ribosomal proteins exclusively found in mitochondria. This unique architecture of the tunnel exit is presumably an adaptation of the translation system to the specific requirements of the organelle.


Liver only metastatic disease in patients with metastatic colorectal cancer: impact of surgery and chemotherapy.
Metastatectomy in colorectal cancer (CRC) is now a standard of care with improved survival reported. Conversion chemotherapy has increased the population who are suitable for surgery. Here we assess patterns of care and treatment outcome in liver only metastases in South Australia using the clinical registry for advanced CRC. We analysed the outcomes for patients with liver only metastatic involvement from the SA Metastatic CRC Database with the aim to investigate the role of chemotherapy on liver resection and outcome in comparison to liver resection only and chemotherapy without liver resection. Patients who had no therapy or non-surgical liver interventions were excluded for this analysis. One thousand nine hundred and eight patients were available for analysis, 687 (36%) had liver only metastatic disease and 455 (24%) had active therapy as defined. In total 54.2% (247/455) had chemotherapy alone, 19.1% (87/455) had liver resection alone, and 26.6% (121/455) had combined treatment. The three-year survival for chemotherapy, resection and combined treatment subgroups is 19.5%, 73.8% and 73.7%, respectively. The addition of chemotherapy to surgery did not improve survival. Switching chemotherapy was associated with a poorer outcome; three-year overall survival for chemotherapy switch was 62.5%, compared with same regimen pre- and post-74%, and chemo post-resection 80%. Liver only metastatic disease is common in CRC and patients undergoing liver resection have improved long-term survival. Survival for a combined approach of chemotherapy and hepatic resection is similar to surgery alone. Patients not suitable for surgery with liver only disease have a poorer prognosis highlighting the need for improved liver-directed therapies and attempts to covert non-resectable to resectable disease if possible.


[The surgical aspects of the lessons of the war in Afghanistan].
There were no two identical wars in human history. From the medical point of view, the civil war, which is still going on in Afghanistan, also has its own face. The structure of sanitary losses, the character, gravity, and peculiarities of gunshot pathology give the possibility to call it as a mine war, because of its massive and, above all, effective mine warfare. The war in Afghanistan conclusively proves the predominance of blast injuries over other sanitary losses in the structure of combat surgical pathology, that may be considered as a common feature for the wars of century XX. The mine blast trauma must be regarded as a combat heavy concomitant trauma or gunshot blast polytrauma. This statement is the basic one for the rest of medical lessons gained from the war in Afghanistan. Using the comparative analysis of the different functions of medical service of two armies, the article shows the priority of organizational aspects for care and treatment of the wounded in war.


Cultured epithelial autografts for coverage of large burn wounds in eighty-eight patients: the Indiana University experience.
Since 1990, the authors have used a new technique for coverage of large burns, which begins with early tangential excision and coverage with cadaver allograft (A), followed by placement of cultured epithelial autograft (CEA) onto an allodermis base (CEA/A). They present their 18-year experience (1990-present) using CEA in 88 patients (20 children and 68 adults) with age range of 6 months to 73 years. A review of prospectively collected data was conducted on adult and pediatric patients grafted with CEA at the Indiana University Medical Center for definitive wound coverage (TBSA 28-98%). These patients were followed up for 3 to 90 months. Complications, take rates, and outpatient follow-ups were noted. The mean final take rate of CEA/A was 72.7%, and the overall patient survival rate was 91% (80 of 88 patients). Complications were classified as early and late, they included: (early) blistering and shearing (31%), pruritus and itching (4.7%), (late) CEA loss (2 patients, 2.3%), and wound contractures (66%). Contracture releases were performed on 32 patients (36%); of which, 18 were children (56%). Cultured keratinocytes provide an excellent alternative or adjunct to conventional split-thickness skin grafting in treating large burn wounds. A dedicated team of physicians, nurses, and therapists well rehearsed in CEA care are vital for success in keratinocyte grafting. The final graft take of 72.7% with a 91% overall survival rate gives much optimism for continuing to use CEA in critically burned patients.


Sublethal effects of imidacloprid on the performance of the bird cherry-oat aphid Rhopalosiphum padi.
The bird cherry-oat aphid, Rhopalosiphum padi (L.), is a major insect pest of cereal crops in many countries. Imidacloprid has been widely used for controlling piercing-sucking insect pests worldwide, but its sublethal effects on R. padi have not been well addressed. In this study, we investigated the sublethal effects of imidacloprid on biological parameters and five enzyme activities of R. padi. The LC10, LC20, and LC25 of imidacloprid to adult aphids were 0.0053, 0.0329 and 0.0659 mg L-1, respectively. These concentrations significantly decreased pre-adult survival rate, but prolonged the development duration of 1st instar nymphs, pre-oviposition period, and adult longevity. Adult oviposition period was also extended by LC20. The intrinsic rate of increase (r), net reproductive rate (R0), and finite rate (λ) decreased at all three concentrations, whereas mean generation time (T) increased. Moreover, LC20 and LC25 significantly inhibited superoxide dismutase (SOD) activity, but increased catalase (CAT) activity. Acetylcholinesterase (AChE) activity also increased at LC20. However, cytochrome P450 enzyme and peroxidase (POD) activity did not differ between imidacloprid treatments and the control. In conclusion, the imidacloprid concentrations tested here have negative impacts on the performance of R. padi by reducing its nymphal survival, extending the development duration of some stages, decreasing the rate of population growth, and altering enzyme activities.


General practitioners' needs and perceptions in rural mental health care.
The objective of this needs analysis was to explore the 'upskilling' needs of rural general practitioners in specified areas of mental health. Their perceptions of the difficulties in managing special groups of patients and in referring to the mental health services were reported. Fifty-six per cent of general practitioners servicing four rural areas in the south-west of Western Australia participated in completing a structured questionnaire. The unmet educational needs consisted of five types of counselling: crisis individual, family, marital and parenting. Groups that the GPs perceived as being difficult to manage were adolescents and youth, and Aboriginals and migrants. The shortage of referral services and the poor communication with mental health specialists were of concern to the GPs in this study. Proposed strategies to overcome these barriers were discussed.


Functional Magnetic Resonance Imaging of the Spinal Cord: Current Status and Future Developments.
Although functional magnetic resonance imaging has become popular for brain imaging, it is still difficult to apply this technique to the spinal cord because of complex issues related to the physiology of the spinal cord and technical challenges related to magnetic resonance imaging hardware, pulse sequences, and image processing techniques. In this article, we examine these key aspects and discuss their present status, unresolved issues, and future directions.


BSN vs. non-BSN students and success in graduate study.
In this study, the entry and progression characteristics of graduate students (nurses) with baccalaureate degrees in fields other than nursing (non-BSN) were compared to characteristics of students whose baccalaureate degrees were in nursing (BSN). Subjects were students enrolled in the Graduate School at the University of Minnesota majoring in Nursing. Analyses showed that BSN and non-BSN students did not differ with respect to the entry or progression measures used. All non-BSN students who have been admitted have been successful in graduate study. The results of this study suggest the feasibility of serving the non-BSN population at the graduate level under certain circumstances.


Transfusion-associated AIDS: serologic evidence of human T-cell leukemia virus infection of donors.
An assay for antibodies to membrane antigens of cells infected by human T-cell leukemia virus was used to examine serum from persons who donated blood to 12 patients with acquired immunodeficiency syndrome (AIDS) associated with blood transfusions. The occurrence of positive results in the assay was significantly greater among donors to the AIDS patients (9 of 117; 7.7 percent) than among random donors (1 of 298; 0.3 percent). Of 12 sets of donors examined, 9 sets included a donor whose serum gave positive results for the presence of the antibodies. In six of these nine sets, the seropositive donor was an individual who was also identified as a possible source of AIDS transmission when epidemiologic and immunologic criteria were used.


Sequential Rocket-Mode Bioactivating Ticagrelor Prodrug Nanoplatform Combining Light-Switchable Diphtherin Transgene System for Breast Cancer Metastasis Inhibition.
The increased risk of breast cancer metastasis is closely linked to the effects of platelets. Our previously light-switchable diphtheria toxin A fragment (DTA) gene system, known as the LightOn system, has demonstrated significant therapeutic potential; it lacks antimetastatic capabilities. In this study, we devised an innovative system by combining cell membrane fusion liposomes (CML) loaded with the light-switchable transgene DTA (pDTA) and a ticagrelor (Tig) prodrug. This innovative system, named the sequential rocket-mode bioactivating drug delivery system (pDTA-Tig@CML), aims to achieve targeted pDTA delivery while concurrently inhibiting platelet activity through the sequential release of Tig triggered by reactive oxygen species with the tumor microenvironment. In vitro investigations have indicated that pDTA-Tig@CML, with its ability to sequentially release Tig and pDTA, effectively suppresses platelet activity, resulting in improved therapeutic outcomes and the mitigation of platelet driven metastasis in breast cancer. Furthermore, pDTA-Tig@CML exhibits enhanced tumor aggregation and successfully restrains tumor growth and metastasis. It also reduces the levels of ADP, ATP, TGF-β, and P-selectin both in vitro and in vivo, underscoring the advantages of combining the bioactivating Tig prodrug nanoplatform with the LightOn system. Consequently, pDTA-Tig@CML emerges as a promising light-switchable DTA transgene system, offering a novel bioactivating prodrug platform for breast cancer treatment.


Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGFβ signaling to specify V2b interneurons in the spinal cord.
During development of the ventral spinal cord, the V2 interneurons emerge from p2 progenitors and diversify into two major subtypes, V2a and V2b, that play key roles in locomotor coordination. Dll4-mediated Notch activation in a subset of p2 precursors constitutes the crucial first step towards generating neuronal diversity in this domain. The mechanism behind the asymmetric Notch activation and downstream signaling events are, however, unknown at present. We show here that the Ascl1 and Neurog basic helix-loop-helix (bHLH) proneural factors are expressed in a mosaic pattern in p2 progenitors and that Foxn4 is required for setting and maintaining this expression mosaic. By binding directly to a conserved Dll4 enhancer, Foxn4 and Ascl1 activate Dll4 expression, whereas Neurog proteins prevent this effect, thereby resulting in asymmetric activation of Dll4 expression in V2 precursors expressing different combinations of proneural and Foxn4 transcription factors. Lineage tracing using the Cre-LoxP system reveals selective expression of Dll4 in V2a precursors, whereas Dll4 expression is initially excluded from V2b precursors. We provide evidence that BMP/TGFβ signaling is activated in V2b precursors and that Dll4-mediated Notch signaling is responsible for this activation. Using a gain-of-function approach and by inhibiting BMP/TGFβ signal transduction with pathway antagonists and RNAi knockdown, we further demonstrate that BMP/TGFβ signaling is both necessary and sufficient for V2b fate specification. Our data together thus suggest that the mosaic expression of Foxn4 and proneural factors may serve as the trigger to initiate asymmetric Dll4-Notch and subsequent BMP/TGFβ signaling events required for neuronal diversity in the V2 domain.


Filter Plate-Based Screening of MIP SPE Materials for Capture of the Biomarker Pro-Gastrin-Releasing Peptide.
Affinity-based solid-phase extraction (SPE) is an attractive low-cost sample preparation strategy for biomarker analysis. Molecularly imprinted polymers (MIPs) as affinity sorbents offer unique opportunities for affinity SPE, due to their low manufacturing cost and high robustness. A limitation is the prediction of their affinity; therefore, screening of analyte recovery and specificity within a large range of SPE conditions is important in order to ensure high-sensitivity detection and assay reproducibility. Here, a µ-SPE method for screening of the MIP-SPE materials using a commercial 384-well filter plate is presented. The method allows for rapid and automated screening using 10-30 µL of packed SPE sorbent per well and sample volumes in the range of 10-70 µL. This enables screening of many different SPE sorbents while simultaneously identifying optimal SPE conditions. In addition, the 384-well format also facilitates detection with a multitude of analytical platforms. Performance of the µ-MIP-SPE method was investigated using a series of MIPs designed to capture pro-gastrin-releasing peptide (ProGRP). Fractions coming from sample load, cartridge wash, and elution were collected and analyzed using mass spectrometry (MS). The top-performing MIPs were identified, together with proper SPE conditions.


Clinical consideration for techniques to detect and quantify blood flow through intrapulmonary arteriovenous anastomoses: lessons from physiological studies.
Intrapulmonary arteriovenous anastomoses (IPAVA) are large diameter (>50 μm) vascular conduits, present in >95% of healthy humans. Because IPAVA are large diameter pathways that allow blood flow to bypass the pulmonary capillary network, blood flow through IPAVA (QIPAVA) can permit the transpulmonary passage of particles larger than pulmonary capillaries. IPAVA have been known to exist for over 50 years, but their physiological and clinical significance are still being established; although, currently suggested roles for QIPAVA include allowing emboli to reach the systemic circulation and providing a source of shunt. Studying QIPAVA is an important area of research and as the suggested roles become better established, detecting and quantifying QIPAVA may become significantly more important in the clinic. Several techniques that can be used to quantify and/or detect QIPAVA in animals, ex vivo human/animal lungs, and intact healthy humans; microspheres, radiolabeled macroaggregated albumin particles, and saline contrast echocardiography, are reviewed with limitations and advantages to each. The current body of literature using these techniques to study QIPAVA in animals, ex vivo lungs, and healthy humans has established conditions when QIPAVA is present, such as during exercise or with arterial hypoxemia and conditions when QIPAVA is absent, such as at rest or during exercise breathing 100% O2 . Many of these physiological studies have direct application to patient populations and we discuss each of these findings in the context of their potential to influence the clinical utility, and interpretation, of the results from these techniques highlighted in this review.


Venus volcanism: initial analysis from magellan data.
Magellan images confirm that volcanism is widespread and has been fimdamentally important in the formation and evolution of the crust of Venus. High-resolution imaging data reveal evidence for intrusion (dike formation and cryptodomes) and extrusion (a wide range of lava flows). Also observed are thousands of small shield volcanoes, larger edifices up to several hundred kilometers in diameter, massive outpourings of lavas, and local pyroclastic deposits. Although most features are consistent with basaltic compositions, a number of large pancake-like domes are morphologically similar to rhyolite-dacite domes on Earth. Flows and sinuous channels with lengths of many hundreds of kilometers suggest that extremely high effusion rates or very fluid magmas (perhaps komatiites) may be present. Volcanism is evident in various tectonic settings (coronae, linear extensional and compressional zones, mountain belts, upland rises, highland plateaus, and tesserae). Volcanic resurfacing rates appear to be low (less than 2 Km(3)/yr) but the significance of dike formation and intrusions, and the mode of crustal formation and loss remain to be established.


Vitamin E improves the uptake of unsaturated soya lecithin liposomes by human fibroblasts in vitro.
Liposomes may exert certain toxic effects on human cells depending on their composition and concentration when used as drug carriers. In this study, the behaviour of human fibroblasts in the presence of soya phosphatidylcholine (soya-PC) liposomes and the effect of the incorporation of vitamin E into the membrane of such liposomes, was investigated. Human fibroblasts were incubated for 72 h with low (50 microM) and high (200 microM) concentrations of large, unilamellar (LUV) soya-PC liposomes in the presence and absence of vitamin E (soya-PC:vitamin E; 10:0.5). The resulting cultures were studied by scanning and transmission electron microscopy, fluorescence microscopy and labelling with rhodamine B. The large unilamellar soya-PC liposomes obtained were of mean diameter 86.4 nm (soya-PC) and 78.3 nm (soya-PC: vitamin E). No significant changes in cell viability were observed between untreated fibroblasts and those incubated with 50 microM soya-PC liposomes. In contrast, a marked loss of cells was apparent at a concentration of 200 microM soya-PC liposomes which was reversible by the addition of vitamin E. Morphological changes including the production of microvilli or 'bubbling' of the cell membrane, were incurred by some of the fibroblasts on addition of soya-PC liposomes. The addition of vitamin E did not affect the changes produced at the lower liposome concentrations but was able to reduce the cytotoxic effects occurring at higher concentrations, possibly by inhibiting the formation of liposome aggregates. The use of PC-soya liposomes containing vitamin E at high concentrations is proposed as a means of delivering high doses of drugs.


Effects of depression, metabolic syndrome, and cardiorespiratory fitness on mortality: results from the Cooper Center Longitudinal Study.
Depression and metabolic syndrome (MetS) are frequently comorbid disorders that are independently associated with premature mortality. Conversely, cardiorespiratory fitness (CRF) is associated with reduced mortality risk. These factors may interact to impact mortality; however, their effects have not been assessed concurrently. This analysis assessed the mortality risk of comorbid depression/MetS and the effect of CRF on mortality in those with depression/MetS. Prospective study of 47 702 adults in the Cooper Center Longitudinal Study. Mortality status was attained from the National Death Index. History of depression was determined by patient response (yes or no) to a standardized medical history questionnaire. MetS was categorized using the American Heart Association/National Heart, Lung, and Blood Institute criteria. CRF was estimated from the final speed/grade of a treadmill graded exercise test. 13.9% reported a history of depression, 21.4% met criteria for MetS, and 3.0% met criteria for both MetS and history of depression. History of depression (HR = 1.24, p = 0.003) and MetS (HR = 1.28, p < 0.001) were independently associated with an increased mortality risk, with the greatest mortality risk among individuals with both a history of depression and MetS (HR = 1.59, p < 0.001). Higher CRF was associated with a significantly lower risk of mortality (p < 0.001) in all individuals, including those with MetS and/or a history of depression. Those with higher levels CRF had reduced mortality risk in the context of depression/MetS. Interventions that improve CRF could have substantial impact on the health of persons with depression/MetS.


Loss of SETDB1 decompacts the inactive X chromosome in part through reactivation of an enhancer in the IL1RAPL1 gene.
The product of dosage compensation in female mammals is the inactive X chromosome (Xi). Xi facultative heterochromatin is organized into two different types, one of which is defined by histone H3 trimethylated at lysine 9 (H3K9me3). The rationale for this study was to assess SET domain bifurcated 1 (SETDB1) as a candidate for maintaining this repressive modification at the human Xi. Here, we show that loss of SETDB1 does not result in large-scale H3K9me3 changes at the Xi, but unexpectedly we observed striking decompaction of the Xi territory. Close examination revealed a 0.5 Mb region of the Xi that transitioned from H3K9me3 heterochromatin to euchromatin within the 3' end of the IL1RAPL1 gene that is part of a common chromosome fragile site that is frequently deleted or rearranged in patients afflicted with intellectual disability and other neurological ailments. Centrally located within this interval is a powerful enhancer adjacent to an ERVL-MaLR element. In the absence of SETDB1, the enhancer is reactivated on the Xi coupled with bidirectional transcription from the ERVL-MaLR element. Xa deletion of the enhancer/ERVL-MaLR resulted in loss of full-length IL1RAPL1 transcript in cis, coupled with trans decompaction of the Xi chromosome territory, whereas Xi deletion increased detection of full-length IL1RAPL1 transcript in trans, but did not impact Xi compaction. These data support a critical role for SETDB1 in maintaining the ERVL-MaLR element and adjacent enhancer in the 3' end of the IL1RAPL1 gene in a silent state to facilitate Xi compaction.


CPK12 and Ca2+-mediated hypoxia signaling.
Hypoxia triggers reactive oxygen species (ROS)-induced elevation in cytoplasmic calcium (Ca2+) in the plant cells. Calcium-dependent protein kinase 12 (CPK12) acts as a sensor to recognize the Ca2+ signature and is activated by autophosphorylation. Then, the CPK12 moves into the nucleus with the help of phosphatidic acid (PA) and phosphorylates ERF-VII family proteins that activate hypoxia signaling and response. The study provides a novel mechanism of hypoxia signaling in plants. Moreover, the mechanism of hypoxia-specific Ca2+ signature generation remains elusive.


Cell differentiation in the preimplantation human embryo.
This brief paper analyses current knowledge on gene expression in individual blastomeres of preimplantation mammalian embryos. Initially, current knowledge on axes and cleavage planes in mammalian eggs and embryo blastomeres is described, together with gene and system homologies with flies and nematodes, and their influence on differentiation. Stress is placed on the need to study individual blastomeres, and even specific components within blastomeres. Examples of published work concentrate on the possible allocation of a single founder blastomere for trophectoderm, which contains large amounts of maternal leptin, STAT3 and other proteins positioned at the animal pole. The recent discovery that single human blastomeres in cleaving embryos contain high levels of HCGbeta mRNA and LHbeta mRNA suggests these are also trophectoderm foundation cells. It is now essential to discover if the maternal proteins leptin/STAT3 and maternal/embryonic HCGbeta transcripts locate to the same blastomere. Problems in jointly identifying maternal proteins and embryonic and maternal transcripts for specific proteins within one cell, and the nature of early cell allocation in mouse and human embryo, are discussed.


Immunophenotyping of hematopoietic progenitor cells: Comparison between cord blood and adult mobilized blood grafts.
To study the immunophenotype of hematopoietic progenitor cells from cord blood (CB) grafts (n = 39) in comparison with adult apheresis grafts (AG, n = 229) and pre-apheresis peripheral blood (PAPB) samples (n = 908) using flow cytometry analysis. First, we performed a qualitative analysis of CD34+ cell sub-populations in both CB and PAPB grafts using the standardized ISHAGE protocol and a wide panel of 20 monoclonal antibodies. Next, we studied some parameters, such as the age of mothers and the weight of newborns, which can influence the quality and the quantity of CD34+ cells from CB. We found that the percentage of apoptotic cells was high in CB in comparison to PAPB (PAPB: 4.6% ± 2.6% vs CB: 53.4% ± 5.2%, P < 0.001). In CB, the weight of newborn and the age of the mother have the influence on CD34+ cells. The follow-up of Ag CD133 in the ISHAGE double platform protocol in association with CD45, CD34 and the 7'AAD shows an equal rate between the two cell populations CD133+CD45+CD34+ high and CD34+CD45+ high with a higher percentage. So, is the inclusion of Ac CD133 necessary in the present panel included in the ISHAGE method? Last part, we showed a significant presence of interferon γ in CB in comparison to PAPB, the annexin showing the high number of apoptotic cells in CB. This study demonstrates that many different obstetric factors must be taken into account when processing and cryo-banking umbilical CB units for transplantation.


Cytokine networks in the pathogenesis of bronchial asthma: implications for therapy.
Bronchial asthma is characterised by a multicellular inflammatory process in the airways. The bronchial inflammation is orchestrated by a network of cytokines and growth factors which includes those encoded by the GM-CSF/IL-4/IL-5 gene cluster on chromosome 5. Their cellular origins are diverse and include both inflammatory and structural cells in the airways. The efficacy of glucocorticoids in the therapy of bronchial asthma may include the ability to disrupt these cytokine networks. The failure of glucocorticoids to provide benefit in some asthmatic patients may be caused by an excess of pro-inflammatory transcription factors which sequester the glucocorticoid receptor (GR), thereby preventing it from exerting its anti-inflammatory effects. Progress is being made in the elucidation of the molecular regulation of the transcription of TH2 cytokine genes. These novel insights may provide future strategies for therapeutic intervention in asthma.


Four years of problem-based learning: a student's perspective.
After four years as a student in a medical school using problem-based learning I still find it an excellent way to learn. Group work has developed my personal skills and abilities. Learning how to obtain knowledge on my own has given me independence and confidence. Motivation to study has been encouraged by early clinical experience. Training in critical thinking has been further enhanced by in-depth studies. Medical education at the University of Linkoping has developed over the years and a contributing factor has been students' involvement in designing the medical training. There are benefits and disadvantages with problem-based learning, but on the whole it is an enjoyable and fruitful experience.


The role of alcohol in the Russian mortality crisis.
Alcohol is believed to be an important factor behind the sharp rise in mortality during the period 1990-94 in Russia. However, the rise in the standard alcohol consumption proxy does not seem to be sufficient to explain all the increase in mortality. This study adopts a novel approach to exploring the role of the alcohol factor in the increased mortality by investigating whether the mismatch between trends in mortality and recorded alcohol consumption is due to an underestimation of the consumption increase. First, the alcohol effect on the male accident rate was estimated using data for the period 1959-89. Next, the estimated alcohol effect and the observed accident mortality rate for the period 1990-98 were used to backcast alcohol consumption during that period. Thirdly, the backcasted alcohol series was used to predict trajectories in alcohol poisoning mortality, the homicide rate and all-cause mortality during the period 1990-98. There was a markedly stronger increase in the backcasted consumption proxy than in the standard alcohol consumption proxy during the period 1990-98. There was a substantial gap between the observed mortality rates and the rates predicted from the standard alcohol consumption proxy, whereas the predictions from the backcasted alcohol proxy were much closer to the target. Much of the rise in Russian mortality in 1990-94 appears to have been due to the increase in population drinking, but this increase is grossly underestimated by the commonly used consumption proxy combining alcohol sales, estimation of illicit alcohol production and proportion of alcohol-positive violent deaths.


A water quality modeling study of non-point sources at recreational marine beaches.
A model study was conducted to understand the influence of non-point sources including bather shedding, animal fecal sources, and near shore sand, as well as the impact of the environmental conditions, on the fate and transport of the indicator microbe, enterococci, at a subtropical recreational marine beach in South Florida. The model was based on an existing finite element hydrodynamic and transport model, with the addition of a first order microbe deactivation function due to solar radiation. Results showed that dog fecal events had a major transient impact (hundreds of Colony Forming Units/100 ml [CFU/100 ml]) on the enterococci concentration in a limited area within several hours, and could partially explain the high concentrations observed at the study beach. Enterococci released from beach sand during high tide caused mildly elevated concentration for a short period of time (ten to twenty of CFU/100 ml initially, reduced to 2 CFU/100 ml within 4 h during sunny weather) similar to the average baseline numbers observed at the beach. Bather shedding resulted in minimal impacts (less than 1 CFU/100 ml), even during crowded holiday weekends. In addition, weak current velocity near the beach shoreline was found to cause longer dwelling times for the elevated concentrations of enterococci, while solar deactivation was found to be a strong factor in reducing these microbial concentrations.


Molecular identification and characterisation of Mannheimia haemolytica.
Mannheimia haemolytica is known as one of the major bacterial contributors to Bovine Respiratory Disease (BRD) syndrome. This study sought to establish a novel species-specific PCR to aid in identification of this key pathogen. As well, an existing multiplex PCR was used to determine the prevalence of serovars 1, 2 or 6 in Australia. Most of the 65 studied isolates originated from cattle with a total of 11 isolates from small ruminants. All problematic field isolates in the identification or serotyping PCRs were subjected to whole genome sequencing and bioinformatic analysis. The field isolates were also subjected to rep-PCR fingerprinting. A total of 59 out of the 65 tested isolates were conformed as M. haemolytica by the new species-specific PCR which is based on the rpoB gene. The confirmed M. haemolytica field isolates were assigned to serovars 1 (24 isolates), 2 (seven isolates) and 6 (26 isolates) while two of the isolates were negative in the serotyping PCR. The two non-typeable isolates were assigned to serovar 7 and 14 following whole genome sequencing and bioinformatic analysis. The rep-PCR typing resulted in five major clusters with serovars 1 and 6 often within the same cluster. The M. haemolytica-specific PCR developed in this work was species specific and should be a valuable support for frontline diagnostic laboratories. The serotyping results support the relative importance of serovars 1 and 6 in bovine respiratory disease.


Cost-effectiveness of treatment with etanercept for psoriasis in Sweden.
To estimate the cost-effectiveness, from a Swedish societal perspective, of intermittent use of etanercept (Enbrel) with interruptions of use after 24 weeks compared to continuous use of adalimumab (Humira) as well as non-systemic standard of care in patients with moderate to severe psoriasis. A Markov decision-tree model was constructed from clinical trials results. Patients starting etanercept, adalimumab, or non-systemic therapy moved through the model's 10-years horizon. Model input parameters included clinical response rates. Outcome measures included direct and indirect costs and quality-adjusted life-years (QALYs). The incremental total (direct and indirect) costs per QALY were 1,559,939 kr (<euro>165,354) for adalimumab 40 mg every other week, compared with intermittent once-weekly Enbrel 50 mg, and 93,629 kr (<euro>9,925) for once-weekly intermittent etanercept 50 mg compared with non-systemic standard of care. This analysis showed that, with a 470,000 kr (<euro>50,000) per QALY willingness-to-pay threshold, once-weekly etanercept 50 mg, used intermittently, is a cost-effective treatment for moderate to severe psoriasis compared with adalimumab and non-systemic standard of care.


Unraveling transcriptional regulatory programs by integrative analysis of microarray and transcription factor binding data.
Unraveling the transcriptional regulatory program mediated by transcription factors (TFs) is a fundamental objective of computational biology, yet still remains a challenge. Here, we present a new methodology that integrates microarray and TF binding data for unraveling transcriptional regulatory networks. The algorithm is based on a two-stage constrained matrix decomposition model. The model takes into account the non-linear structure in gene expression data, particularly in the TF-target gene interactions and the combinatorial nature of gene regulation by TFs. The gene expression profile is modeled as a linear weighted combination of the activity profiles of a set of TFs. The TF activity profiles are deduced from the expression levels of TF target genes, instead directly from TFs themselves. The TF-target gene relationships are derived from ChIP-chip and other TF binding data. The proposed algorithm can not only identify transcriptional modules, but also reveal regulatory programs of which TFs control which target genes in which specific ways (either activating or inhibiting). In comparison with other methods, our algorithm identifies biologically more meaningful transcriptional modules relating to specific TFs. We applied the new algorithm on yeast cell cycle and stress response data. While known transcriptional regulations were confirmed, novel TF-gene interactions were predicted and provide new insights into the regulatory mechanisms of the cell.


Hysteretic characteristics of 1/λ⁴ scattering of light during adsorption and desorption of water in porous Vycor glass with nanopores.
Porous Vycor glass with nanopores is transparent in the visible region and is often used in colorimetric chemical sensing when impregnated with selectively reacting reagents. However, it has some disadvantages in sensing, since changes in the humidity of ambient air strongly affect its transmission. In this work, by combining a humidity-controlled thermostatic chamber and an ultraviolet-visible and near-infrared spectrophotometer through fiber optics, we analyzed the effect of increasing and decreasing humidity in the ambient air on the transparency change of the nanoporous glass. The transparency response in the visible region to changes in humidity is analyzed to correlate the turbidity response of the glass with the amount of water in it. The turbidity is found to be dependent on the inverse fourth power of the wavelength (1/λ⁴), which implies that Rayleigh-type scattering takes place for both adsorption and desorption of water. We show that measures of the extent of the optical inhomogeneity that causes the scattering, such as the effective radius of scatterers and their number density, exhibit a pronounced hysteretic characteristic for the imbibition and drainage of water, while the absorption inherent to imbibed water also shows another type of hysteresis that is quite similar to the sorption isotherms of water. On the basis of the above observations, we show that the transitory white turbidity of nanoporous glasses during changes in humidity can be consistently interpreted and quantitatively analyzed by a simple Rayleigh scattering mechanism.


[Psychophysiological mechanisms of formation and development of functional states].
The modern approaches to the problem of formation and development of human functional states was presented. Described grounded theoretical results of experimental studies of the concept of "pattern of functional state" as a description of the functional state in terms of the characteristics of the activity of functional systems to ensure its formation and development in accordance with the dominant. Presented the characteristics of patterns of functional states, determining the reliability of human activities in extreme conditions.


Evolved polygenic herbicide resistance in Lolium rigidum by low-dose herbicide selection within standing genetic variation.
The interaction between environment and genetic traits under selection is the basis of evolution. In this study, we have investigated the genetic basis of herbicide resistance in a highly characterized initially herbicide-susceptible Lolium rigidum population recurrently selected with low (below recommended label) doses of the herbicide diclofop-methyl. We report the variability in herbicide resistance levels observed in F1 families and the segregation of resistance observed in F2 and back-cross (BC) families. The selected herbicide resistance phenotypic trait(s) appear to be under complex polygenic control. The estimation of the effective minimum number of genes (N E), depending on the herbicide dose used, reveals at least three resistance genes had been enriched. A joint scaling test indicates that an additive-dominance model best explains gene interactions in parental, F1, F2 and BC families. The Mendelian study of six F2 and two BC segregating families confirmed involvement of more than one resistance gene. Cross-pollinated L. rigidum under selection at low herbicide dose can rapidly evolve polygenic broad-spectrum herbicide resistance by quantitative accumulation of additive genes of small effect. This can be minimized by using herbicides at the recommended dose which causes high mortality acting outside the normal range of phenotypic variation for herbicide susceptibility.


Blind-velocity SAR/ISAR imaging of a moving target in a stationary background.
A synthetic aperture radio/inverse synthetic aperture radar (SAR/ISAR) coherent system model and inversion to image a target moving with an unknown constant velocity in a stationary background are presented. The approach is based on a recently developed system modelling and inversion principle for SAR/ISAR imaging that utilizes the spatial Fourier decomposition of SAR data in the synthetic aperture domain to convert the SAR system model's nonlinear phase functions into linear phase functions suitable for a computationally manageable inversion. It is shown that SAR/ISAR imaging of a moving target can be converted into imaging the target in a stationary squint-mode SAR problem where the parameters of the squint-mode geometry depend on the target's velocity. A method for estimating the moving target's velocity that utilizes a spatial Doppler analysis of the SAR data within overlapping subapertures is presented. The spatial Doppler technique does not require the radar signal to be narrowband, so the reconstructed image's resolution is not sacrificed to improve the target's velocity estimator.


Devices and dressings to secure peripheral venous catheters to prevent complications.
A peripheral venous catheter (PVC) is typically used for short-term delivery of intravascular fluids and medications. It is an essential element of modern medicine and the most frequent invasive procedure performed in hospitals. However, PVCs often fail before intravenous treatment is completed: this can occur because the device is not adequately attached to the skin, allowing the PVC to fall out, leading to complications such as phlebitis (irritation or inflammation to the vein wall), infiltration (fluid leaking into surrounding tissues) or occlusion (blockage). An inadequately secured PVC also increases the risk of catheter-related bloodstream infection (CRBSI), as the pistoning action (moving back and forth in the vein) of the catheter can allow migration of organisms along the catheter and into the bloodstream. Despite the many dressings and securement devices available, the impact of different securement techniques for increasing PVC dwell time is still unclear; there is a need to provide guidance for clinicians by reviewing current studies systematically. To assess the effects of PVC dressings and securement devices on the incidence of PVC failure. We searched the following electronic databases to identify reports of relevant randomised controlled trials (RCTs): the Cochrane Wounds Group Register (searched 08 April 2015): The Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), Ovid MEDLINE (1946 to March 7 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, March 7 2015); Ovid EMBASE (1974 to March 7 2015); and EBSCO CINAHL (1982 to March 8 2015). RCTs or cluster RCTs comparing different dressings or securement devices for the stabilisation of PVCs. Cross-over trials were ineligible for inclusion, unless data for the first treatment period could be obtained. Two review authors independently selected studies, assessed trial quality and extracted data. We contacted study authors for missing information. We used standard methodological procedures expected by Cochrane. We included six RCTs (1539 participants) in this review. Trial sizes ranged from 50 to 703 participants. These six trials made four comparisons, namely: transparent dressings versus gauze; bordered transparent dressings versus a securement device; bordered transparent dressings versus tape; and transparent dressing versus sticking plaster. There is very low quality evidence of fewer catheter dislodgements or accidental removals with transparent dressings compared with gauze (two studies, 278 participants, RR 0.40; 95% CI 0.17 to 0.92, P = 0.03%). The relative effects of transparent dressings and gauze on phlebitis (RR 0.89; 95% CI 0.47 to 1.68) and infiltration (RR 0.80; 95% CI 0.48 to 1.33) are unclear. The relative effects on PVC failure of a bordered transparent dressing and a securement device have been assessed in only one small study and these were unclear. There was very low quality evidence from the same single study of less frequent dislodgement or accidental catheter removal with bordered transparent dressings than securement devices (RR 0.14, 95% CI 0.03 to 0.63) but more phlebitis with bordered dressings (RR 8.11, 95% CI 1.03 to 64.02) (very low quality evidence). A small single study compared bordered transparent dressings with tape and found very low quality evidence of more PVC failure with the bordered dressing (RR 1.84, 95% CI 1.08 to 3.11) but the relative effects on dislodgement were not clear (very low quality evidence). The relative effects of transparent dressings and a sticking plaster have only been compared in one small study and are unclear. More high quality RCTs are required to determine the relative effects of alternative PVC dressings and securement devices. It is not clear if any one dressing or securement device is better than any other in securing peripheral venous catheters. There is a need for further, independent high quality trials to evaluate the many traditional as well as the newer, high use products. Given the large cost differences between some different dressings and securement devices, future trials should include a robust cost-effectiveness analysis.


Ouabain-induced changes in electrophysiologic properties of neonatal, young and adult canine cardiac Purkinje Fibers.
Young patients frequently require higher concentrations of digitalis per kilogram of body weight or per square meter of surface area than adults to induce digitalis effect or toxicity. In order to investigate the electrophysiologic basis for this observation, we used standard microelectrode techniques to study the effects of ouabain on action potential characteristics of cardiac Purkinje fibers of neonatal (1-7 day), 4 to 7 week and adult dogs. Purkinje fibers were stimulated at a 500-msec cycle length. Action potentials were recorded during control Tyrode's perfusion and 23.5 minutes after onset of superfusion with ouabain, 2 X 10(-7) M (10% ouabain-3H). The Purkinje fibers were then assayed for ouabain uptake. Ouabain accelerated repolarization and decreased action potential amplitude, resting membrane potential and maximum upstroke velocity of phase O. Changes were greatest in the adults, least in the neonates. Ouabain increased the slope of phase 4 depolarization in 10 to 12 adults, 7 of 16- 4 to 7-week puppies and 0 of 12 neonates. Hence, ouabain induced lesser changes in the action potentials of Purkinje fibers taken from young animals. These results suggest that Purkinje fiber sensitivity to ouabain effects increases with age.


Interaction of L-threo and L-erythro isomers of 3-fluoroglutamate with glutamate decarboxylase from Escherichia coli.
L-threo-3-Fluoroglutamate and L-erythro-3-fluoroglutamate were tested with glutamate decarboxylase from Escherichia coli. Both isomers were substrates: the threo isomer was decarboxylated into optically active 4-amino-3-fluorobutyrate, whereas the erythro isomer lost the fluorine atom during the reaction, yielding succinic semialdehyde after hydrolysis of the unstable intermediate enamine. The difference between the two isomers demonstrates that the glutamic acid-pyridoxal phosphate Schiff base is present at the active site under a rigid conformation. Furthermore, although the erythro isomer lost the fluorine atom, yielding a reactive aminoacrylic acid in the active site, no irreversible inactivation of E. coli glutamate decarboxylase was observed.


Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury.
After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.


Who Suffers From Pharmaceutical Poverty and What Are Their Needs? Evidence From a Spanish Region.
Background: Pharmaceutical poverty occurs when a patient cannot afford the cost of prescribed medication and/or medical products. Nonprofit organizations are covering the cost of medication to those patients in some contexts. The aim of the study was to describe the population of beneficiaries of the PB, a nongovernmental organization based on the primary healthcare system, which provides free-of-charge access to medicines and their utilization pattern of medicines and healthcare products. Methods: This was an observational study using PB beneficiary data collected between November 2017 and December 2018 in Catalonia. The Catalan Health Service provided information from the general population. A descriptive analysis of the beneficiaries' characteristics was conducted and compared to the general population. Results: The beneficiaries (N = 1,206) were mainly adults with a low level of education, unemployed, with functional disability, and with ≥1 child. Compared with the general population, the beneficiaries were older, had a lower level of education, showed a higher prevalence of functional disability, were less likely to be Spanish, and were more likely to be divorced and unemployed. The beneficiaries were polymedicated, and most were using medication related to the nervous (79%), musculoskeletal (68%), and cardiovascular system (56%) and alimentary tract and metabolism (68%). Almost 19% of beneficiaries used healthcare products. Female beneficiaries were older and more likely to be divorced or widowed, employed, and with children. Compared to men, women were more likely to use medicines for pain and mental disorders. The pediatric group used medications for severe, chronic conditions (heart diseases, autoimmune diseases, conduct disorders, and attention deficit hyperactivity disorder). Conclusion: Patients with severe, chronic, and disabling conditions are affected by pharmaceutical poverty. While the system of copayment remains unchanged, family physicians and pediatricians should explore economic barriers to treatment and direct their patients to resources that help to cover the cost of treatment.


The Ratio of Key Metabolic Transcripts Is a Predictive Biomarker of Breast Cancer Metastasis to the Lung.
Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to compare metabolic fluxes used by parental breast cancer cells and their brain- and lung-homing derivatives. Divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This strong Warburg effect was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, which correlated with lung metastasis in patients with breast cancer. Although feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of metastasis to the lung but not to other organs, independent of other transcriptomic signatures. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in patients with breast cancer. Lung-homing metastatic breast cancer cells express an elevated ratio of lactate dehydrogenase to pyruvate dehydrogenase, indicating that ratios of specific metabolic gene transcripts have potential as metabolic biomarkers for predicting organ-specific metastasis.


Minimal access is not maximal safety: pelviureteric necrosis following percutaneous chemical lumbar sympathectomy.
Lumbar sympathectomy remains popular in the treatment of a variety of painful and circulatory conditions of the lower extremities. Although percutaneous chemical lumbar sympathectomy (PCLS) under radiographic guidance is minimally invasive and has decreased the need for open surgical sympathectomy, inadvertent damage to neighbouring structures is a matter for concern. We report the case of a 38-year-old man with thromboangiitis obliterans who had PCLS under radiographic guidance for relief of ischaemic rest pain that was complicated by necrotic disruption of the left pelviureteric region. The kidney was salvaged with an ureterocalycostomy and he remains well 4 years later. Such complications point to imprecise and unpredictable spread of the injected chemical too far beyond the needle tip. It is possible that such complications are often under reported and, therefore, not taken into consideration during informed consent. Precise neurolysis with laser and radiofrequency may be a safer alternative.


A ruthenium complex as a single-component redox shuttle for electrochemical photovoltaics.
A primitive version of a ruthenium complex [Ru(bpy)3(2+)] was employed for the first time as a new conceptual "single-component redox shuttle" for dye-sensitized solar cells. This single shuttle led to a large enhancement of the open-circuit photovoltage (VOC) to ∼940 mV relative to that of conventional iodine-based shuttle and greatly increased the efficiency of the solar-to-electric energy conversion at lower illumination levels by a factor of ca. 5.6.


Chronic progressive cervical myelopathy with HTLV-I infection: Variant form of HAM/TSP?
To investigate the role of human T-lymphotrophic virus type I (HTLV-I) infection in four patients who developed slowly progressive myelopathy with abnormal MRI lesions in the cervical cord levels. Clinical and neuroradiologic examinations were performed, and the odds that an HTLV-I-infected individual of specified genotype, age, and provirus load had HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were calculated. Anti-HTLV-I antibodies were positive in both the serum and the CSF in all of the patients. Biopsied sample from spinal cord lesions showed inflammatory changes in Patient 1. Patient 2 had a demyelinating type of sensorimotor polyneuropathy. Two of the three patients examined showed high risk of developing HAM/TSP in virologic and immunologic aspects. These four cases may belong to a variant form of HAM/TSP, predominantly involving the cervical cord levels.


Evaluation of jaw function, oral health-related quality of life, and nutritional status during oral rehabilitation procedures - a pilot study.
To evaluate limitations in jaw function, oral health-related quality of life (OHRQoL), and nutritional status during extensive oral rehabilitation procedures. Fourteen participants (mean age ± SD: 70 ± 3.8) undergoing major oral rehabilitation involving the restoration of a minimum of eight teeth were recruited in the study. Jaw function limitations scores (JFLS), oral health-impact profile (OHIP), and nutritional status were measured at different time points during, six months, and one year after the rehabilitation procedures. Nutritional status was evaluated by measuring the body weight and arm and calf muscle circumference. The effect of time points on the measured variables was evaluated with Friedman's test. Trends in nutritional status were evaluated with linear regression analysis. The results of the analysis showed significant main effects of time points on the JLFS (p < .001) and OHIP scores (p = .005). However, there was no effect of time points on the body weight (p = .917) and calf muscle circumference (p = .424), but a significant effect on arm circumference (p = .038). Further, there was a decreasing trend for body weight (64.3%), arm (71.4%), and calf circumference (64.3%) in the majority of the patients. The results of the preliminary study suggest that people undergoing extensive oral rehabilitation procedures show improvement in jaw function and an increase in OHRQoL after the rehabilitation procedure. Despite no major changes in the nutritional indicators, most patients showed a negative trend in their body weight, arm circumference, and calf circumference, suggesting that they may be susceptible to nutritional changes.


Neural mechanisms of cognitive reappraisal in remitted major depressive disorder.
Down-regulation of negative emotions by cognitive strategies relies on prefrontal cortical modulation of limbic brain regions, and impaired frontolimbic functioning during cognitive reappraisal has been observed in affective disorders. However, no study to date has examined cognitive reappraisal in unmedicated euthymic individuals with a history of major depressive disorder relative to symptom-matched controls. Given that a history of depression is a critical risk factor for future depressive episodes, investigating the neural mechanisms of emotion regulation in remitted major depressive disorder (rMDD) may yield novel insights into depression risk. We assessed 37 individuals (18 rMDD, 19 controls) with functional magnetic resonance imaging (fMRI) during a task requiring cognitive reappraisal of sad images. Both groups demonstrated decreased self-reported negative affect after cognitive reappraisal and no group differences in the effects of cognitive reappraisal on mood were evident. Functional MRI results indicated greater paracingulate gyrus (rostral anterior cingulate cortex, Brodmann area 32) activation and decreased right midfrontal gyrus (Brodmann area 6) activation during the reappraisal of sad images. Trial-by-trial ratings of pre-regulation affect were not collected, limiting the interpretation of post-regulation negative affect scores. Results suggest that activation of rostral anterior cingulate cortex, a region linked to the prediction of antidepressant treatment response, and of the right midfrontal gyrus, a region involved in cognitive control in the context of cognitive reappraisal, may represent endophenotypic markers of future depression risk. Future prospective studies will be needed to validate the predictive utility of these neural markers.


Autonomic and cortical response of soldiers in different combat scenarios.
The study of chronic and acute responses when exposed to extreme, aggressive and stressful environments, such as in combat environments, is becoming increasingly popular as such information leads to better optimisation of soldiers' physical and psychological performance, as well as mission effectiveness and efficiency. Due to internal complexity, uncertainty and variability of real combat scenarios, a specific approach to all possible types of military combat scenarios is necessary. Modifications in the autonomic modulation and cortical arousal before and after asymmetrical, symmetrical and close quarter combat simulations were analysed in 31 male professional veteran soldiers (age: 34.5±4.2 years) with between seven and 18 years of experience in their respective units, as well as experience in international missions in current conflict areas such as Lebanon, Afghanistan, Bosnia, Kosovo and Iraq. The three combat situations produced a non-significant decrease in cortical arousal after combat simulations, presenting a trivial effect size in symmetrical and close quarter combat situations and a small effect size in asymmetrical situations. HR increased significantly in the three combat situations, and close quarter combat produced the highest sympathetic modulation of the three situations analysed. Symmetrical, asymmetrical and close quarter combat situations produced an increase in sympathetic modulation, being highest in the close quarter combat situation, where actions are performed at a close distance and in closed spaces.


A regularized point process generalized linear model for assessing the functional connectivity in the cat motor cortex.
Identification of multiple simultaneously recorded neural spike train recordings is an important task in understanding neuronal dependency, functional connectivity, and temporal causality in neural systems. An assessment of the functional connectivity in a group of ensemble cells was performed using a regularized point process generalized linear model (GLM) that incorporates temporal smoothness or contiguity of the solution. An efficient convex optimization algorithm was then developed for the regularized solution. The point process model was applied to an ensemble of neurons recorded from the cat motor cortex during a skilled reaching task. The implications of this analysis to the coding of skilled movement in primary motor cortex is discussed.


Positive association of a women's continuing medical education conference on career advancement and promotion.
Women physicians are underrepresented in leadership positions across medical specialties. Understanding factors that improve women's promotion metrics may lead to career and leadership advancement. This study examined if a woman-centered Continuing Medical Education (CME) conference is associated with differences in productivity metrics toward career advancement. The authors conducted a cross-sectional survey study of women physicians attending a national woman-centered CME conference for professional growth, wellness and networking in September 2019. The survey measured promotion metrics achieved in the year prior to the conference and compared them with previous attendees. Of 425 women attendees of the conference, 389 (91.5%) respondents completed the survey. Respondents were divided into two groups for analysis: first time (FT) attendees, and those that attended the conference previously (PV). In the year preceding the survey, PV attendees were more likely to have published a manuscript as first-author or co-author in a peer-reviewed journal (17.5% vs. 9.7%, p = 0.029), given a talk in their area of practice (48.3% vs. 27.9%, p < 0.001) and to have mentored at least one peer (40.8% vs. 27.5%, p = 0.009) and to have asked for a promotion (15.8% vs. 8.6%, p = 0.033) than FT. As compared to first-time conference attendees, women physicians who previously attended a woman-centered CME conference were more likely to achieve career performance metrics including publications and speaking engagements in the preceding year. This study demonstrated a positive association of Women-centered CME conferences in career advancement metrics for women in medicine and suggests further studies on this and other women-centered CME conferences.


Prolonged release biodegradable vesicular carriers for rifampicin--formulation and kinetics of release.
An attempt has been made to design suitable liposome and niosome-encapsulated drug delivery system for rifampicin and evaluated the same in vitro and in vivo. A modified lipid layer hydration method was employed to prepare these vesicular carriers. The formulated systems were characterized in vitro for size distribution analysis, drug entrapment, drug release profiles and vesicular stability at different conditions of storage. In vivo drug kinetics was evaluated in normal, healthy albino rats for niosomal formulation upon subcutaneous injection and various pharmacokinetic parameters were determined. Niosomes and liposomes exhibited mean diameter of 9.73 and 11.87 microns with entrapment efficiencies of 30.5 and 34.2% respectively. Both the products exhibited sustained release characteristics in vitro with zero order drug release kinetics up to initial 10 hr. Stability evaluation indicated that both formulations were not significantly leaky over a period of one month. Niosomal formulation elevated plasma elimination half life and decreased elimination rate constants for rifampicin in vivo suggested that encapsulation retarded the removal of the drug from circulation compared to free drug due to slow drug release into systemic circulation. A five-fold increase in the area under plasma rifampicin concentration-time curve for niosomal rifampicin as compared to free drug indicated better bioavailability of encapsulated drug. It is evident from this study that niosomes and liposomes could be promising delivery systems for rifampicin with prolonged drug release profiles and reasonably good stability characteristics.


HIV Point-of-Care Testing in Canadian Settings: A Scoping Review.
HIV point-of-care testing (POCT) was approved for use in Canada in 2005 and provides important public health benefits by providing rapid screening results rather than sending a blood sample to a laboratory and waiting on test results. Access to test results soon after testing (or during the same visit) is believed to increase the likelihood that individuals will receive their results and improve access to confirmatory testing and linkages to care. This paper reviews the literature on the utilization of HIV POCT across Canadian provinces. We searched OVID Medline, Embase, EBM Reviews, PsycINFO, CINAHL, and 20 electronic grey literature databases. All empirical studies investigating HIV POCT programs in Canada published in French or English were included. Searches of academic databases identified a total of 6,091 records. After removing duplicates and screening for eligibility, 27 records were included. Ten studies are peer-reviewed articles, and 17 are grey literature reports. HIV POCT in Canada is both feasible and accepted by Canadians. It is preferred to conventional HIV testing (ranging from 81.1 to 97%), and users are highly satisfied with the testing process (ranging between 96 and 100%). The majority of studies demonstrate that HIV POCT is feasible, preferred, and accepted by diverse populations in Canada. Losses to follow-up and linkage rates are also good. However, more research is needed to understand how best to scale up HIV POCT in contexts that currently have very limited or no access to testing.


Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism.
Trypanosomatid genomes encode for numerous proteins containing an RNA recognition motif (RRM), but the function of most of these proteins in mRNA metabolism is currently unknown. Here, we report the function of two such proteins that we have named PTB1 and PTB2, which resemble the mammalian polypyrimidine tract binding proteins (PTB). RNAi silencing of these factors indicates that both are essential for life. PTB1 and PTB2 reside mostly in the nucleus, but are found in the cytoplasm, as well. Microarray analysis performed on PTB1 and PTB2 RNAi silenced cells indicates that each of these factors differentially affects the transcriptome, thus regulating a different subset of mRNAs. PTB1 and PTB2 substrates were categorized bioinformatically, based on the presence of PTB binding sites in their 5' and 3' flanking sequences. Both proteins were shown to regulate mRNA stability. Interestingly, PTB proteins are essential for trans-splicing of genes containing C-rich polypyrimidine tracts. PTB1, but not PTB2, also affects cis-splicing. The specificity of binding of PTB1 was established in vivo and in vitro using a model substrate. This study demonstrates for the first time that trans-splicing of only certain substrates requires specific factors such as PTB proteins for their splicing. The trypanosome PTB proteins, like their mammalian homologs, represent multivalent RNA binding proteins that regulate mRNAs from their synthesis to degradation.


Autophagy in frog visual cells in vitro.
Isolated frog retinas were incubated in a medium free of serum and amino acids under dim white incandescent light of 20 lux/m2. After 1, 2, 6, and 9 hr of incubation, six retinas at each time point were fixed for electron microscopic investigation. Histochemical staining of acid phosphatase was performed in control and experimental tissues. Autophagic vacuoles in visual cell inner segments were counted and compared with the incidence of vacuoles in control tissues. The ratio of newly formed: old autophagic vacuoles was assessed in incubated retinas, and the number of autophagic vacuoles per rod cell and per cone cell was evaluated. The results indicated that the number of autophagic vacuoles was significantly increased from 1 to 9 hr of incubation, the ratio of newly formed: old autophagic vacuoles was constant over this period, and the amount of autophagy occurring in rods and cones was similar. In a second group of experiments, retinas were incubated under the same conditions but at two different levels of illumination. One series of retinas was incubated in dim red incandescent light of 5 lux/m2, the other series was incubated at bright white fluorescent light of 300 lux/m2. The total numbers of autophagic vacuoles showed a consistent elevation of 20% in bright white light material as compared wot dim red light material. Autophagic vacuoles per cone were significantly higher in retinas incubated in white light than in retinas incubated in red light. Autophagic vacuoles per rod were about equal in both groups. Our observations indicated that visual cells contain an intracellular mechanism of degradation, which is increased under changed metabolic conditions and modified as a function of different levels of illumination.