Analysis of mesenchymal cells (MSCs) from bone marrow, synovial fluid and mesenteric, neck and tail adipose tissue sources from equines.
Mesenchymal stem cells (MSCs) have been used in equines as an alternative therapy. A comparative study about the phenotype and in vitro performance of different MSCs tissue sources in adult equines was needed. This study might serve to provide the knowledge to select a valuable harvesting source of MSCs. Bone marrow, synovial and adipose (mesenteric, neck and tail fat) tissues were collected from adult equines. Cell surface markers expression (CD11α/CD18, CD45, CD79α, CD90, CD105 and MHC II) and in vitro differentiation assays were made. In vitro cell migration, cell growth and wound healing capacity tests helped to study their behavior and properties. MSCs phenotype was positively confirmed by the cell surfaces markers and a tri-lineage differentiation profile. Bone marrow cells showed the highest migration capacity, while synovial fluid cells displayed the highest cell growth. Bone marrow cells showed a better wound healing when compared with all the different MSCs. We conclude that bone marrow, synovial and adipose tissue derived from adult equines are a good source for cell therapy but they conserve different functional properties: bone marrow showed an interesting migration and wound healing capacity while synovial fluid cells and their highest cell growth suggest that these MSCs would yield higher cell numbers in a shorter time.


Treatment utilisation and trauma characteristics of child and adolescent inpatients with posttraumatic stress disorder.
Few empirical studies have addressed the impact of trauma exposure and posttraumatic stress disorder (PTSD) on treatment utilisation and outcome in South African youth. This study was undertaken to document demographic, clinical, and treatment characteristics of child and adolescent inpatients with PTSD. A retrospective chart study of all patients presenting to a child and adolescent inpatient unit was conducted between 1994-1996. For children and adolescents diagnosed with PTSD; demographic, diagnostic and treatment variables, including trauma type, family history, and delays in treatment seeking, were documented. Child and Adolescent Psychiatric Inpatient Unit, Tygerberg Hospital, Cape Town. Children and adolescents (2 to 18 years) presenting to an inpatient unit (n = 737). 10.3% (n = 76) met diagnostic criteria for PTSD. Gender differences were clearly evident: PTSD was six times more prevalent in girls (65 with PTSD were female and 11 were male); girls were most likely to have experienced rape or sexual abuse while boys were most likely to have witnessed a killing. Psychotherapy was the most common intervention for PTSD, followed by treatment with a tricyclic antidepressant. 97.4% of children and adolescents who were treated were improved at treatment endpoint. Delays in seeking treatment and problems with the primary support group were highly prevalent. PTSD is a common disorder that is responsive to treatment with psychotherapy and/or tricyclic antidepressants in child and adolescent inpatients. These findings underscore the importance of early identification and treatment of childhood PTSD in mental health settings, in particular tertiary service institutions.


Monopoly Airplane Lands in Esophagus Leading to Difficult Extraction: A Case Report on Anesthesia and Surgical Considerations.
A 2-year-old child presented with an airplane game piece from the board game Monopoly lodged in her esophagus. The airplane's wings, engines, and winglets acted like fish hooks that entered the esophageal mucosa easily but were difficult to extract. Chest radiographs were used to estimate the airplane wingspan dimensions, and a Foley catheter was used to dilate the esophagus to allow foreign body extraction via rigid esophagoscopy with optical forceps. Deliberate deep placement of the endotracheal tube facilitated surgical manipulation. This case report highlights the importance of teamwork, communication, and the involvement of multiple disciplines, each with their unique experience and expertise, to formulate a plan of action for patients during unique surgical emergencies.


A comparison of individual-based genetic distance metrics for landscape genetics.
A major aim of landscape genetics is to understand how landscapes resist gene flow and thereby influence population genetic structure. An empirical understanding of this process provides a wealth of information that can be used to guide conservation and management of species in fragmented landscapes and also to predict how landscape change may affect population viability. Statistical approaches to infer the true model among competing alternatives are based on the strength of the relationship between pairwise genetic distances and landscape distances among sampled individuals in a population. A variety of methods have been devised to quantify individual genetic distances, but no study has yet compared their relative performance when used for model selection in landscape genetics. In this study, we used population genetic simulations to assess the accuracy of 16 individual-based genetic distance metrics under varying sample sizes and degree of population genetic structure. We found most metrics performed well when sample size and genetic structure was high. However, it was much more challenging to infer the true model when sample size and genetic structure was low. Under these conditions, we found genetic distance metrics based on principal components analysis were the most accurate (although several other metrics performed similarly), but only when they were derived from multiple principal components axes (the optimal number varied depending on the degree of population genetic structure). Our results provide guidance for which genetic distance metrics maximize model selection accuracy and thereby better inform conservation and management decisions based upon landscape genetic analysis.


The role of GLP-1 receptor agonists during COVID-19 pandemia: a hypothetical molecular mechanism.
A number of anti-diabetic treatments have been favored during the continuing spread of the current SARS-CoV-2 pandemic. Glucagon like peptide-1 receptor agonists (GLP1-RAs) are a group of antidiabetic drugs, the glucose reducing effect of which is founded on augmenting glucose-dependent insulin secretion with concomitant reduction of glucagon secretion and delayed gastric emptying. Apart from their glucose lowering effects, GLP1-RAs also exert a plethora of pleiotropic activities in the form of anti-inflammatory, anti-thrombotic and anti-obesogenic properties, with beneficial cardiovascular and renal impact. All these make this class of drugs a preferred option for managing patients with type 2 diabetes (T2D), and potentially helpful in those with SARS-CoV2 infection. In the present article we propose a hypothetical molecular mechanism by which GLP1-RAs may interact with SARS-CoV-2 activity. The beneficial properties of GLP1-RAs may be of specific importance during COVID-19 infection for the most fragile patients with chronic comorbid conditions such as T2D, and those at higher cardiovascular and renal disease risk. Yet, further studies are needed to confirm our hypothesis and preliminary findings available in the literature.


Open(ing) Access: Top Health Publication Availability to Researchers in Low- and Middle-Income Countries.
Improving access to information for health professionals and researchers in low- and middle-income countries (LMICs) is under-prioritized. This study examines publication policies that affect authors and readers from LMICs. We used the SHERPA RoMEO database and publicly available publishing protocols to evaluate open access (OA) policies, article processing charges (APCs), subscription costs, and availability of health literature relevant to authors and readers in LMICs. Categorical variables were summarized using frequencies with percentages. Continuous variables were reported with median and interquartile range (IQR). Hypothesis testing procedures were performed using Wilcoxon rank sum tests, Wilcoxon rank sum exact tests, and Kruskal-Wallis test. A total of 55 journals were included; 6 (11%) were Gold OA (access to readers and large charge for authors), 2 (3.6%) were subscription (charge for readers and small/no charge for authors), 4 (7.3%) were delayed OA (reader access with no charge after embargo), and 43 (78%) were hybrid (author's choice). There was no significant difference between median APC for life sciences, medical, and surgical journals ($4,850 [$3,500-$8,900] vs. $4,592 [$3,500-$5,000] vs. $3,550 [$3,200-$3,860]; p = 0.054). The median US individual subscription costs (USD/Year) were significantly different for life sciences, medical, and surgical journals ($259 [$209-$282] vs. $365 [$212-$744] vs. $455 [$365-$573]; p = 0.038), and similar for international readers. A total of seventeen journals (42%) had a subscription price that was higher for international readers than for US readers. Most journals offer hybrid access services. Authors may be forced to choose between high cost with greater reach through OA and low cost with less reach publishing under the subscription model under current policies. International readers face higher costs. Such hindrances may be mitigated by a greater awareness and liberal utilization of OA policies.


Mitochondrial DNA in the bark weevils: size, structure and heteroplasmy.
Mitochondrial DNA of higher animals has been described as an example of extreme efficiency in genome structure and function. Where exceptionally large size molecules have been found (greater than 20 kb), most have occurred as rare variants within a species, suggesting that these variants arise infrequently and do not persist for long periods in evolutionary time. In contrast, all individuals of at least three species of bark weevil (Curculionidae: Pissodes) possess a mitochondrial genome of unusually large size (30-36 kb). The molecule owes its large size to a dramatically enlarged A + T-rich region (9-13 kb). Gene content and order outside of this region appear to be identical to that found in Drosophila. A series of 0.8-2.0-kb repeated sequences occur adjacent to the large A + T rich region and have perhaps played a role in the generation of the large size as well as an unprecedented frequency of size variant heteroplasmy. Every weevil sampled in all three species (n = 219) exhibits anywhere from two to five distinct size classes of mtDNA. The persistence of this large amount of size polymorphism through two speciation events combined with the abundant size variation within individuals suggests that these molecules may not be subject to strong selection for small overall size and efficiency of replication. This pattern of variation contrasts strongly with the conservation of gene content and arrangement in the coding region of the molecule.


Improved variant calling accuracy by merging replicates in whole-exome sequencing studies.
In large scale population-based whole-exome sequencing (WES) studies, there are some samples occasionally sequenced two or more times due to a variety of reasons. To investigate how to efficiently utilize these duplicated sequencing data, we conducted comprehensive evaluation of variant calling strategies. 92 samples subjected to WES twice were selected from a large population study. These 92 duplicated samples were divided into two groups: group H consisting of the higher sequencing depth for each subject and group L consisting of the lower depth for each subject. The merged samples for each subject were put in a third group M. Using the GATK multisample toolkit, we compared variant calling accuracy among three strategies. Hierarchical clustering analysis indicated that the two replicates for each subject showed high homogeneity. The comparative analyses on the basis of heterozygous-homozygous ratio (Hete/Homo), transition-transversion ratio (Ti/Tv), and overlapping rate with the 1000 Genomes Project consistently showed that the data quality of the SNPs detected from the M group was more accurate than that of SNPs detected from the H and L groups. These results suggested that merging homogeneous duplicated exomes instead of using one of them could improve variant calling accuracy.


Photoinactivation of virus infectivity by hypocrellin A.
We investigated the photoinactivation of virus infectivity by hypocrellin A and its mechanism. The titers of vesicular stomatitis virus (VSV) and human immunodeficiency virus type 1 (HIV-1), both of which are enveloped viruses, were reduced upon illumination with hypocrellin A in a concentration-dependent manner, whereas canine parvovirus, a nonenveloped virus, was not killed. The removal of oxygen or addition of sodium azide or beta-carotene both inhibited VSV inactivation. Mannitol and superoxide dismutase had no effect on VSV inactivation. These results indicate that singlet oxygen was involved in the process of VSV inactivation. Of the three major VSV membrane proteins, peripheral membrane protein M was most damaged by the hypocrellin A phototreatment.


Localization of the 18S, 5.8S and 28S rRNA genes and the 5S rRNA genes in the babirusa and the white-lipped peccary.
The locations of the genes encoding 18S, 5.8S and 28S rRNA and 5S rRNA were studied in two relatives of the domestic pig, the babirusa (Babyrousa babyrussa) and the white-lipped peccary (Tayassu pecari). In the babirusa, the 18S, 5.8S and 28S rDNA is located on chromosomes 6, 8 and 10. The genes on chromosomes 8 and 10 are actively transcribed, in contrast to those on chromosomes 6. In the white-lipped peccary, this rDNA was found to be located on chromosomes 4 and 8. The genes on both of these pairs of chromosomes are actively transcribed. The 5S rDNA was physically mapped to chromosome 16 in the babirusa, and to chromosome 11 in the white-lipped peccary. These data are compared to similar data obtained for the domestic pig, and confirm previously recognized chromosome homologies.


Osteosarcoma: a multidisciplinary approach to diagnosis and treatment.
The treatment of osteosarcoma requires a multidisciplinary approach involving the family physician, orthopedic oncologist, medical oncologist, radiologist and pathologist. Osteosarcoma is a mesenchymally derived, high-grade bone sarcoma. It is the third most common malignancy in children and adolescents. The most frequent sites of origin are the distal femur, proximal tibia and proximal humerus. Patients typically present with pain, swelling, localized enlargement of the extremity and, occasionally, pathologic fracture. Most patients present with localized disease. Radiographs commonly demonstrate a mixed sclerotic and lytic lesion arising in the metaphyseal region of the involved bone. Computed tomography and bone scanning are recommended to detect pulmonary and bone metastases, respectively. Before 1970, osteosarcomas were treated with amputation. Survival was poor: 80 percent of patients died from metastatic disease. With the development of induction and adjuvant chemotherapy protocols, advances in surgical techniques and improvements in radiologic staging studies, 90 to 95 percent of patients with osteosarcoma can now be treated with limb-sparing resection and reconstruction. Long-term survival and cure rates have increased to between 60 and 80 percent in patients with localized disease.


[Marginal notes on tobacco in medicine and history].
Some characteristics of the tobacco plant and its use by native peoples of the Caribbean islands and New Spain are described. The importance of the tobacco habit in Newspanish and Europe regions, that became one of the main revenues of the respective governments, is emphasized. The incipient preoccupations concerning medical and social aid for the workers in tobacco factories are also exposed. The first aspect is reflected in an entire chapter of Ramazzini's treatise, which was the basis of the medicine of work, published in 1700. The second aspect is manifested in the creation, in 1796, of nursery schools for the children of working women in the tobacco factories of New Spain. Impressions of European travelers who visited New Spain and Independent Mexico are reported also. In opposition to the predictions of some visitors during the last century, with the passage of time, the tobacco habit instead of decreasing, became progressively more accentuated in all social classes. As a conditional aggravation, in the present day the noxious effects of tobacco smoke are combined with those of environmental contamination.


Identification of rosmarinic acid and sulfated flavonoids as inhibitors of microfouling on the surface of eelgrass Zostera marina.
A bioassay-guided approach was used to identify defense compounds that are present on the surface of Zostera marina and which inhibit settlement of microfoulers at natural concentrations. Moderately polar eelgrass surface extracts inhibited the settlement of seven marine bacteria and one yeast that originated from non-living substrata. In contrast, five other bacterial strains that had been directly isolated from eelgrass surfaces were all insensitive, which suggested a selective effect of surface metabolites on the microbial communities present on eelgrass. Bioassay-guided isolation of active compounds from the extracts in combination with UPLC-MS and 1H-NMR spectroscopy resulted in the identification of rosmarinic acid, luteolin-7-sulfate and diosmetin-7-sulfate or its isomer chrysoeriol-7-sulfate. All three compounds are nontoxic repellents, as they did not inhibit bacterial growth, but prevented bacterial settlement in a dose-dependent manner. Between 15.6 and 106.8 μg ml-1 of rosmarinic acid were present on the eelgrass surface, enough for half maximal settlement inhibition of bacteria.


Cultural and religious determinants of HIV transmission: A qualitative study with people living with HIV in Belu and Yogyakarta, Indonesia.
As a part of a larger qualitative study to understand HIV-risk factors and impacts on people living with HIV (PLHIV) (52 women and 40 men) in Belu and Yogyakarta, Indonesia, this paper reports the influences of cultural practices and religious beliefs on sexual relationships and behaviours of participants as contributors for HIV transmission. This study was conducted from June to December 2020. Data collection was conducted using one-one-one in-depth interviews. Participants were recruited using the snowball sampling technique. Data analysis was guided by a qualitative data analysis framework. The findings showed that cultural practices in Belu related to the use of bride wealth, managing spousal disputes, marriage, and condom use, influenced spousal relationships and sexual behaviours or practices which contributed to HIV transmission. Javanese cultural practices and expectation of an 'ideal wife', Islamic religious beliefs about expected husband-wife relationships, forbidden premarital sex, and the participants' individual interpretation of their religious beliefs about condom use spousal sexual relations, also influenced spousal sexual relations and behaviours, which supported HIV transmission among the participants. The findings indicate the need for HIV education programs that address cultural practices and religious beliefs for community members and population groups to enhance their understanding about HIV, condom use, and how cultural practices and religious beliefs play a role in HIV transmission. The findings also indicate the need for involvement of religious leaders in HIV education programs to bring insights to people and help them interpret their religious beliefs in health promoting ways. Future studies that explore different aspects of culture and religion which may contribute to HIV transmission are recommended.


A simple method for construction of artificial microRNA vector in plant.
Artificial microRNA (amiRNA) is a powerful tool for silencing genes in many plant species. Here we provide an easy method to construct amiRNA vectors that reinvents the Golden Gate cloning approach and features a novel system called top speed amiRNA construction (TAC). This speedy approach accomplishes one restriction-ligation step in only 5 min, allowing easy and high-throughput vector construction. Three primers were annealed to be a specific adaptor, then digested and ligated on our novel vector pTAC. Importantly, this method allows the recombined amiRNA constructs to maintain the precursor of osa-miR528 with exception of the desired amiRNA/amiRNA* sequences. Using this method, our results showed the expected decrease of targeted genes in Nicotiana benthamiana and Oryza sativa.


System biology mediated assessment of molecular mechanism for sinapic acid against breast cancer: via network pharmacology and molecular dynamic simulation.
Sinapic acid is a hydroxycinnamic acid widespread in the plant kingdom, known to be a potent anti-oxidant used for the treatment of cancer, infections, oxidative stress, and inflammation. However, the mode of action for its chemotherapeutic properties has yet not been unleashed. Hence, we aimed to identify potential targets to propose a possible molecular mechanism for sinapic acid against breast cancer. We utilized multiple system biology tools and databases like DisGeNET, DIGEP-Pred, Cytoscape, STRING, AutoDock 4.2, AutoDock vina, Schrodinger, and gromacs to predict a probable molecular mechanism for sinapic acid against breast cancer. Targets for the disease breast cancer, were identified via DisGeNET database which were further matched with proteins predicted to be modulated by sinapic acid. In addition, KEGG pathway analysis was used to identify pathways; a protein-pathway network was constructed via Cytoscape. Molecular docking was performed using three different algorithms followed by molecular dynamic simulations and MMPBSA analysis. Moreover, cluster analysis and gene ontology (GO) analysis were performed. A total of 6776 targets were identified for breast cancer; 95.38% of genes predicted to be modulated by sinapic acid were common with genes of breast cancer. The 'Pathways in cancer' was predicted to be modulated by most umber of proteins. Further, PRKCA, CASP8, and CTNNB1 were predicted to be the top 3 hub genes. In addition, molecular docking studies revealed CYP3A4, CYP1A1, and SIRT1 to be the lead proteins identified from AutoDock 4.2, AutoDock Vina, and Schrodinger suite Glide respectively. Molecular dynamic simulation and MMPBSA were performed for the complex of sinapic acid with above mentioned proteins which revealed a stable complex throughout simulation. The predictions revealed that the mechanism of sinapic acid in breast cancer may be due to regulation of multiple proteins like CTNNB1, PRKCA, CASP8, SIRT1, and cytochrome enzymes (CYP1A1 & CYP3A4); the majorly regulated pathway was predicted to be 'Pathways in cancer'. This indicates the rationale for sinapic acid to be used in the treatment of breast cancer. However, these are predictions and need to be validated and looked upon in-depth to confirm the exact mechanism of sinapic acid in the treatment of breast cancer; this is future scope as well as a drawback of the current study.


International meeting: new diagnostic tests are urgently needed to treat patients with Chagas disease.
Trypanosoma cruzi infection is often not detected early on or actively diagnosed, partly because most infected individuals are either asymptomatic or oligosymptomatic. Moreover, in most places, neither blood banks nor healthcare units offer diagnostic confirmation or treatment access. By the time patients present clinical manifestations of advanced chronic Chagas disease, specific treatment with current drugs usually has limited effectiveness. Better-quality serological assays are urgently needed, especially rapid diagnostic tests for diagnosis patients in both acute and chronic phases, as well as for confirming that a parasitological cure has been achieved. Some new antigen combinations look promising and it is important to assess which ones are potentially the best, together with their requirements in terms of investigation and development. In August 2007, a group of specialized researchers and healthcare professionals met to discuss the state of Chagas infection diagnosis and to build a consensus for a plan of action to develop efficient, affordable, accessible and easy-to-use diagnostic tests for Chagas disease. This technical report presents the conclusions from that meeting.


Operative management of neuromatous knee pain: patient selection and outcome.
The management of intractable knee pain secondary to neuromata continues to be optimized. Forty-three patients with intractable knee pain were studied prospectively. Consideration for this procedure requires pain of at least a 1-year duration, failure of conservative management, pain localization at a Tinel's point, and at least a 5-point reduction of pain on a visual analog scale after nerve blockade with 1% lidocaine. Thirty patients met the criteria for the procedure and 25 patients underwent the procedure. Mean patient age was 50.3 years and mean duration of pain was 6.6 years. Pain etiology included total knee replacement in 10 patients and trauma in 15 patients. Mean number of prior operations on the knee was 5.1. Sixty-two nerves were excised in the 25 patients, including the infrapatellar branch of the saphenous nerve (N = 24), the tibiofibular branch of the peroneal nerve (N = 5), the medial retinacular nerve (N = 12), the lateral retinacular nerve (N = 8), the medial cutaneous nerve (N = 6), the anterior cutaneous nerve (N = 3), and the lateral femoral cutaneous nerve (N = 4). Complete pain relief was obtained in 11 patients (44%). Partial pain relief was reported in 10 patients (40%). No pain relief was reported in 4 patients (16%). Follow-up ranged from 1 to 4 years. Selective denervation for neuromatous knee pain is beneficial in select patients. Patient satisfaction was 84% (21 of 25 patients) after the procedure. No patient was made worse.


A gradient-descent-based approach for transparent linguistic interface generation in fuzzy models.
Linguistic interface is a group of linguistic terms or fuzzy descriptions that describe variables in a system utilizing corresponding membership functions. Its transparency completely or partly decides the interpretability of fuzzy models. This paper proposes a GRadiEnt-descEnt-based Transparent lInguistic iNterface Generation (GREETING) approach to overcome the disadvantage of traditional linguistic interface generation methods where the consideration of the interpretability aspects of linguistic interface is limited. In GREETING, the widely used interpretability criteria of linguistic interface are considered and optimized. The numeric experiments on the data sets from University of California, Irvine (UCI) machine learning databases demonstrate the feasibility and superiority of the proposed GREETING method. The GREETING method is also applied to fuzzy decision tree generation. It is shown that GREETING generates better transparent fuzzy decision trees in terms of better classification rates and comparable tree sizes.


Nodular Vasculitis in a Patient With Crohn's Disease on Vedolizumab.
Erythema induratum (EI), or nodular vasculitis (NV), is a type of panniculitis that is often associated with vasculitis affecting various-sized veins, venules, and arteries in reaction to various causative factors. Historically, EI was highly linked to tuberculosis, but in 1946, Montgomery first proposed the term NV to describe cases of EI not associated with tuberculosis. Only 2 reports of NV associated with inflammatory bowel disease have been reported in the literature. The authors report a 60-year-old woman with Crohn's disease presenting with exacerbation of NV in the setting of vedolizumab therapy.


Green Synthesis of Privileged Benzimidazole Scaffolds Using Active Deep Eutectic Solvent.
The exploitation and use of alternative synthetic methods, in the face of classical procedures that do not conform to the ethics of green chemistry, represent an ever-present problem in the pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus in synthetic organic chemistry, as they are building blocks of strong interest for the development of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of the already synthesized compounds have found very strong applications in medicine praxis. Here we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent, provides advantages in terms of yields as well as in the work up procedure of the reaction.


Generalizability of clinical trial efficacy results to a real-world population: An example in migraine prevention.
Health care decision makers are often concerned about the external validity of randomized controlled trials (RCTs), as their results may not apply to certain patients in the real world who intend to receive treatment. To demonstrate a methodology for assessing the generalizability of clinical trial results to a real-world population, before sufficient and appropriate real-world effectiveness data are available, using individual patient-level data from an RCT and aggregated baseline data from a real-world French registry in migraine. The analyses were conducted in 2 steps. First, individual patient-level baseline data from the multinational CONQUER RCT were weighted to match aggregated real-world InovPain registry patient characteristic data. Matched patient characteristics were sex, age, migraine type and duration, number of monthly migraine headache days, and number of monthly headache days at baseline. Second, the weighted CONQUER patient data were used to reanalyze the primary endpoint of CONQUER (least squares mean change from baseline in the number of monthly migraine headache days during the 3-month double-blind treatment phase) using predefined methodology. Sensitivity analyses were conducted to assess the robustness of findings. A total of 462 patients with migraine were randomized and treated with galcanezumab or placebo in CONQUER; aggregated InovPain data were available from 130 patients with migraine. We identified no important differences in baseline patient characteristics between the 2 prespecified populations, suggesting good external validity for CONQUER. Although this limited the extent of observed differences between the original and matched CONQUER populations, weighting of CONQUER data did help harmonize the 2 datasets and allow the results obtained in CONQUER to be generalized to patients more representative of the real-world French population with migraine. Results of weighted analyses suggested that galcanezumab would be superior to placebo for reducing monthly migraine headache days in a clinical trial in patients with episodic or chronic migraine who reflected the characteristics of patients eligible to receive the drug in France. Findings suggest that our methods may be helpful for assessing the generalizability of clinical trial results to a real-world population before the availability of substantial real-world clinical data.


[Guidelines for antifungal prophylaxis, diagnosis and therapy in pediatric hematology and oncology - a review of literature and expert recommendations].
Problems with importing non-registered medicines for treating rare life-threatening infectious diseases led to establishment of the Emergency Anti-Infective Drug Reserve (EAIDR) for the Czech Republic. Thirteen anti-infective drugs are included in the project: antisera against rabies virus, varicella-zoster virus, and botulinum toxin; antituberculosis drugs (intravenous rifampicin and isoniazid; capreomycin, cycloserine, and clofazimine); antiparasitics (intravenous quinine, primaquine, meglumine antimoniate, and praziquantel); and pentamidine. These drugs are imported according to the Czech drug legislation (specific drug availability programs). Realization: The project, approved by the Czech Ministry of Health in September 2013, was started in January 2014. The anti-infective drugs sufficient for 2-4 patients are permanently available in the Toxicological Information Center (TIC) in Prague. The medicines can be applied in any hospital throughout the Czech Republic within several hours. All but three drugs are available at present; the remaining ones will be imported after new batches of these drugs are released.


Novel MRI approaches to assess patients with multiple sclerosis.
This review summarizes novel MRI approaches for the investigation of lesion burden and understanding of the pathophysiology of multiple sclerosis (MS). Recent technical advances are improving our ability to detect and define the nature of focal lesions and 'diffuse' tissue damage in MS as well as the functional consequences of such structural abnormalities. New contrast agents allow to monitor the pluriformity of MS inflammation. Double inversion recovery sequences enable us to detect and monitor the evolution of MS lesions in the cortex. High and ultra-high field scanners are improving imaging of MS-related abnormalities at an unprecedented resolution. Furthermore, this new generation of scanners has the potential to ameliorate structural and functional MR studies of the disease. All of this has contributed, and is likely to continue to contribute, to the definition of the factors associated with the development of irreversible disability in MS. Finally, new analysis methods have allowed to track regional disease-related changes and are resulting in an increased correlation between MRI and clinical deficits. Novel MR approaches highlighted previously unrecognized or neglected aspects of MS pathophysiology, which are likely to improve our understanding of the heterogeneous clinical manifestations of this condition.


Transmission and plasmonic resonances on quasicrystal metasurfaces.
The control of light-matter interaction in metasurfaces offers an unexplored potential for the excitation and manipulation of light. Here, we combine experimental terahertz time-domain spectroscopy and near-field scanning terahertz microscopy to demonstrate the role of reciprocal vectors in the transmission and plasmonic resonances of quasicrystal metasurfaces. An investigation of two-dimensional metasurface structures with different rotationally symmetric quasicrystal arrangements demonstrates that the transmission minima resulting from Wood's anomaly are directly related to the surface plasmon resonances. We also find that the surface plasmon resonances of the quasicrystal metasurface were determined by the reciprocal vectors, which could be well explained by the coupling condition of the resonances, and the characteristic frequencies remain un-shifted under various slit sizes. Our findings demonstrate a new potential in developing novel plasmonic metasurfaces.


Dynamic renal scintigraphic estimation of deceased donor kidneys in a rat model.
At present a large number of the renal transplantations are being performed from the deceased donors. The success of these transplantations depends on the viability of the deceased donor kidneys. The aim of this study was to investigate the reliability of scintigraphic estimation of function of deceased donor kidneys by comparing the histopathologic and scintigraphic findings. Ten rats were included in the study (2-3 months old, 250-300 g, all male). Control scintigraphy was performed to all the rats by injection of 37 MBq Tc-99m DTPA from the tail vein in a dynamic manner. Brain death of the rats was achieved by inflation of a Fogartys catheter in the cranial cavity. Immediately, after brain death confirmation, dynamic renal scintigraphy was performed with the same parameters of control scintigraphy. In the comparison of scintigraphies obtained in the before and just after brain death period, there was impairment of tubular functions, concentration and excretion functions in the postbrain death period. In the immediate postbrain death period, there was a significant elevation in the glomerular filtration rate and time to maximum concentration values. In the histopathological evaluation of the kidney samples in the postbrain death period, there were definitive findings of tubular impairment. Dynamic renal scintigraphy also demonstrated definite impairment of tubular system and tubular functions in the deceased donor kidneys. This could explain the reason of the increased frequency of acute tubular necrosis seen among deceased donor kidneys.


[Comparison of detectability of liquid crystal displays (LCDs) and film using phantoms of small adenocarcinomas as abnormalities].
Following the trend of the digitalization of the modalities used for diagnostic imaging, the devices for such imaging have increasingly included monitors. The present study was undertaken to evaluate the usefulness of soft-copy (liquid crystal display; LCD) images of phantoms of small adenocarcinomas using receiver operating characteristic (ROC) analysis of two different display systems: LCD and hard copy (film). A two-tailed paired t-test and the jackknife method (parametric methods) were performed, and no significant differences were found in the area under the ROC curve (AUC) for the pulmonary fields, lungs, ribs, or mediastinum between the film and LCD display systems, and the detectability did not differ between the film and LCD monitors. A Mann-Whitney U test, which is a non-parametric method that applies to the analysis of a small sample, also showed no significant differences in the AUC. The results of this study suggest that LCDs can replace hard-copy film as a display system if the signals.


Probing the motional behavior of eumelanin and pheomelanin with solid-state NMR spectroscopy: new insights into the pigment properties.
Melanin is the most widespread pigment in the animal kingdom. Despite its importance, its detailed structure and overall molecular architecture remain elusive. Both eumelanin (black) and pheomelanin (red) occur in the human body. These two melanin compounds show very different responses to UV-radiation exposure, which could relate to their microscopic features. Herein, the structural properties and motional behavior of natural eu- and pheomelanin extracted from black and red human hair are investigated by means of solid-state NMR spectroscopy. Several 1D and 2D NMR spectroscopic techniques were combined to highlight the differences between the two forms of the pigment. The quantitative analysis of the (1) H NMR wide-line spectra extracted from 2D (1) H-(13) C LG-WISE experiments revealed the presence of two dynamically distinguishable components in both forms. Remarkably, the more mobile fraction of the pigment showed a higher mobility with respect to the proteinaceous components that coexist in the melanosome, which is particularly evident for the red pigment. An explanation of the observed effects takes into account the different architecture of the proteinaceous matrix that constitutes the physical substrate onto which melanin polymerizes within the eu- and pheomelanosomes. Further insight into the molecular structure of the more mobile fraction of pheomelanin was also obtained by means of the analysis of 2D (1) H-(13) C INEPT experiments. Our view is that not only structural features inherent in the pure pigment, but also the role of the matrix structure in defining the overall melanin supramolecular arrangement and the resulting dynamic behavior of the two melanin compounds should be taken into account to explain their functions. The reported results could pave a new way toward the explanation of the molecular origin of the differences in the photoprotection activity displayed by black and red melanin pigments.


Lens fiber cell differentiation and denucleation are disrupted through expression of the N-terminal nuclear receptor box of NCOA6 and result in p53-dependent and p53-independent apoptosis.
Nuclear receptor coactivator 6 (NCOA6) is a multifunctional protein implicated in embryonic development, cell survival, and homeostasis. An 81-amino acid fragment, dnNCOA6, containing the N-terminal nuclear receptor box (LXXLL motif) of NCOA6, acts as a dominant-negative (dn) inhibitor of NCOA6. Here, we expressed dnNCOA6 in postmitotic transgenic mouse lens fiber cells. The transgenic lenses showed reduced growth; a wide spectrum of lens fiber cell differentiation defects, including reduced expression of gamma-crystallins; and cataract formation. Those lens fiber cells entered an alternate proapoptotic pathway, and the denucleation (karyolysis) process was stalled. Activation of caspase-3 at embryonic day (E)13.5 was followed by double-strand breaks (DSBs) formation monitored via a biomarker, gamma-H2AX. Intense terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) signals were found at E16.5. Thus, a window of approximately 72 h between these events suggested prolonged though incomplete apoptosis in the lens fiber cell compartment that preserved nuclei in its cells. Genetic experiments showed that the apoptotic-like processes in the transgenic lens were both p53-dependent and p53-independent. Lens-specific deletion of Ncoa6 also resulted in disrupted lens fiber cell differentiation. Our data demonstrate a cell-autonomous role of Ncoa6 in lens fiber cell differentiation and suggest novel insights into the process of lens fiber cell denucleation and apoptosis.


Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study.
Streptococcal infection has been linked with the development of obsessive-compulsive disorder (OCD) and tic disorders, a concept termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). However, previous studies of this association have been small, and the results have been conflicting. To investigate the risk of mental disorders, specifically OCD and tic disorders, after a streptococcal throat infection. A population-based cohort study was conducted using data from the nationwide Danish registers from January 1, 1996, to December 31, 2013, with up to 17 years of follow-up. The Danish National Health Service Register provided information on individuals with the registration of a streptococcal test. Data analysis was conducted from January 1, 2016, to February 28, 2017. Individuals were followed up in the nationwide Psychiatric Central Register for a diagnosis of any mental disorder, OCD, or tic disorders. Incidence rate ratios (IRRs) were calculated by Poisson regression analysis. Of the 1 067 743 children (<18 years of age) included in the study (519 821 girls and 547 922 boys), 638 265 received a streptococcal test, 349 982 of whom had positive test results at least once. Individuals with a positive streptococcal test result had an increased risk of any mental disorder (n = 15 408; IRR, 1.18; 95% CI, 1.15-1.21; P < .001), particularly of OCD (n = 556; IRR, 1.51; 95% CI, 1.28-1.77; P < .001) and tic disorders (n = 993; IRR, 1.35; 95% CI, 1.21-1.50; P < .001), compared with individuals without a streptococcal test. Furthermore, the risk of any mental disorder and OCD was more elevated after a streptococcal throat infection than after a nonstreptococcal infection. Nonetheless, individuals with a nonstreptococcal throat infection also had an increased risk of any mental disorder (n = 11 315; IRR, 1.08; 95% CI, 1.06-1.11; P < .001), OCD (n = 316; IRR, 1.28; 95% CI, 1.07-1.53; P = .006), and tic disorders (n = 662; IRR, 1.25; 95% CI, 1.12-1.41; P < .001). This large-scale study investigating key aspects of the PANDAS hypothesis found that individuals with a streptococcal throat infection had elevated risks of mental disorders, particularly OCD and tic disorders. However, nonstreptococcal throat infection was also associated with increased risks, although less than streptococcal infections for OCD and any mental disorder, which could also support important elements of the diagnostic concept of pediatric acute-onset neuropsychiatric syndrome.


[Malaria in the Republic of Djibouti. Strategy for control using a biological antilarval campaign: indigenous larvivorous fishes (Aphanius dispar) and bacterial toxins].
The authors take stock of the present situation of malaria in the Republic of Djibouti which, after several decades of silence, seems to have been reintroduced at the beginning of the seventies. Actually it is hypo-endemic malaria with Plasmodium falciparum of which the only vector seems to be Anopheles arabiensis, gambiae complex. The specificity of the larvae nests allows a control strategy based on the only treatment of larvae sites by biological control: larvivorous fishes (Aphanius Dispar) and in addition the pin-point use of bacterial toxins as a complementary measure. The first results obtained in the rural zones around the capital are encouraging and permit to envisage the extensions of such a strategy to the whole of the territory of the Republic.


Intercellular relationships in the synthesis of macromolecules by organ cultures of corneas.
Sepharose CL-4B chromatography of guanidine hydrochloride and aqueous extracts of 3H-glucosamine labeled intact corneal tissue reveals four peaks representing proteoglycans and glycoproteins. To evaluate the universality of the 4th peak, hereafter designated as Sepharose CL-4B (IV), its presence was investigated in rabbit, bovine, cat, rhesus monkey, and human corneal preparations. Following incubation in isotopically labeled medium, corneas were extracted with aqueous and/or 4M guanidine hydrochloride and subjected to Sepharose CL-4B chromatography. Sepharose CL-4B (IV) was detected in all species studied; 3H-glucosamine and 14C-amino acids, but not 35SO4, were incorporated into this peak which eluted in the range consistent with an apparent molecular weight of approximately 30,000 D. To determine which layers were involved in the synthesis of Sepharose CL-4B (IV) the layers of the rabbit cornea were incubated separately (stroma scraped of endothelium and/or epithelium, epithelium only, endothelium only). A distinct Sepharose CL-4B (IV) peak was not identified in the chromatographs obtained from organ cultures of corneal epithelium, endothelium, or from corneal stroma scraped of epithelium and/or endothelium. This decrease in Sepharose CL-4B (IV) synthesis occurred even if the scraped cornea was not allowed to expand in volume by compressing it beneath a membrane porous to the incubation medium. Thus, Sepharose CL-4B (IV) synthesis was enhanced significantly by the stroma being in conjunction with other corneal cells as they exist in vivo.


Funduscopic abnormalities and electroretinography in cases of retinopathy in German Shepherd dogs.
To perform a clinical, ophthalmological, and electroretinographic assessment of retinopathic lesions in German Shepherd dogs. The study was conducted on 14 German Shepherds diagnosed with retinopathy during the course of an ophthalmological checkup. The animals were systemically healthy police dogs used for patrolling and tracking duties and which were, at times, exposed to considerable physical strain and stress. Periodic ophthalmological examinations using slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, and photography, as well as maze testing, were performed on all dogs. Electroretinography (ERG) was performed on 10 affected German Shepherds and eight control dogs. Ophthalmological examination revealed areas of tapetal hyper-reflectivity with pigmented centers, which were characteristic of inactive chorioretinitis. Most of the lesions were in proximity to blood vessels, and in a number of eyes, progression was observed during repeated examinations. Transition from active to inactive lesions, as well as onset in previously unaffected eyes, was also recorded. The ERG recordings showed impaired cone function, with significantly lower b-wave amplitudes and prolonged implicit times, in the mixed rod-cone, photopic, and flicker tests of affected dogs (P < 0.05). Retinopathy observed in German Shepherd dogs is characterized by areas of tapetal hyper-reflectivity with pigmented centers. The underlying causes of retinopathy in German Shepherd dogs remain unknown, although husbandry conditions and proximity of the lesions to blood vessels may suggest an association with physical exertion or circulatory disorders, respectively.


Maxillary sinus swelling in a child: clinical dilemma.
A 7-year-old girl had presented with right cheek swelling noted 3 months earlier. It was slowly progressive. Swelling was well defined, non-tender, smooth, firm in consistency and measured 4×4 cm. Intraoral examination revealed no missing teeth. Permanent teeth - central incisors (upper and lower), primary lateral incisor, canine and first and second molar were present. X-ray paranasal sinuses showed well-defined unilocular radiolucency with a thin sclerotic border enclosing permanent first molar, premolar and canine on the right side and first molar on the left side. The cyst was removed by enucleation procedure. Mucoperiosteal flap was elevated, and paper thin bone overlying the cyst was removed. The cyst was enclosing the permanent canine, premolar and molar teeth. Histopathological report was consistent with the dentigerous cyst. After 1-year follow-up, the patient has no obvious swelling over the cheek.


Lymphocytic mastitis preceding Sjögren's syndrome.
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and B cell hyperreactivity. Lacrimal and salivary glands are the most commonly involved causing keratoconjunctivitis sicca and xerostomia. A wide variety of other glandular and extraglandular manifestations can occur in SS. Lymphocytic mastitis is a rare presentation of several conditions including diabetes mellitus and autoimmune disorders. We report a case of a 43-year-old woman with a four-year history of arthralgias and positive antinuclear antibodies who developed a right painless breast mass. Biopsy revealed lymphocytic mastitis with predominant B cells. One year later she developed severe constitutional symptoms, sicca symptoms, lymphadenopathy, anemia, and interstitial lung disease. Serologies and minor salivary gland were consistent with the diagnosis of SS. This case further supports the association of lymphocytic mastitis with autoimmune diseases and demonstrates that it can even precede the clinical diagnosis of these entities.


Decreased local and systemic levels of sFRP3 protein in osteosarcoma patients.
Osteosarcoma is a malignant bone tumor that occurs mainly in children and adolescents. Because Wnt signaling has been implicated in the pathogenesis of osteosarcoma, we have investigated the circulating and local levels of the Wnt antagonist protein, Secreted Frizzled Related Protein (sFRP) 3, in osteosarcoma patients. Enzyme linked immunosorbent assay (ELISA) analysis of 67 osteosarcoma and age-matched non-diseased control sera showed that sFPR3 protein levels were significantly lower in osteosarcoma than in normal. Analysis of tumor and adjacent normal tissues (9 pairs) from osteosarcoma patients showed a decrease in sFRP3 expression in 5 out of 9 tumor samples compared to normal tissues. Furthermore, immunohistochemical analysis of tissue microarray revealed a significant decrease in sFRP3 levels in tumor compared to normal bone. RNA sequencing analysis in osteosarcoma cells shows suppression of sFRP3 and concomitant expression of multiple Wnt family members mediating canonical or non-canonical Wnt signaling. Taken together, our findings show that the systemic and local levels of sFRP3 protein are downregulated in osteosarcoma and sFRP3 levels could be explored further in the diagnosis and the care of osteosarcoma patients.


Tumescent liposuction.
The evolution of liposuction has been multidisciplinary. The tumescent variant was developed using dilute local lidocaine and epinephrine and was meant to specifically exclude additional intravenous sedation, regional or general anesthesia, and intravenous fluids. Clinical pharmacology, pathophysiology, and safety studies are reviewed in this article. Tumescent formulations for varied anatomic sites are discussed, as well as other indications for tumescent anesthesia.


Climate change and glacier retreat drive shifts in an Antarctic benthic ecosystem.
The Antarctic Peninsula (AP) is one of the three places on Earth that registered the most intense warming in the last 50 years, almost five times the global mean. This warming has strongly affected the cryosphere, causing the largest ice-shelf collapses ever observed and the retreat of 87% of glaciers. Ecosystem responses, although increasingly predicted, have been mainly reported for pelagic systems. However, and despite most Antarctic species being benthic, responses in the Antarctic benthos have been detected in only a few species, and major effects at assemblage level are unknown. This is probably due to the scarcity of baselines against which to assess change. We performed repeat surveys of coastal benthos in 1994, 1998, and 2010, analyzing community structure and environmental variables at King George Island, Antarctica. We report a marked shift in an Antarctic benthic community that can be linked to ongoing climate change. However, rather than temperature as the primary factor, we highlight the resulting increased sediment runoff, triggered by glacier retreat, as the potential causal factor. The sudden shift from a "filter feeders-ascidian domination" to a "mixed assemblage" suggests that thresholds (for example, of tolerable sedimentation) and alternative equilibrium states, depending on the reversibility of the changes, could be possible traits of this ecosystem. Sedimentation processes will be increasing under the current scenario of glacier retreat, and attention needs to be paid to its effects along the AP.


A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.
Sodium channels have four homologous domains (D1-D4) each with six putative transmembrane segments (S1-S6). The highly charged S4 segments in each domain are postulated voltage sensors for gating. We made 15 charge-neutralizing or -reversing substitutions in the first or third basic residues (arginine or lysine) by replacement with histidine, glutamine, or glutamate in S4 segments of each domain of the human heart Na+ channel. Nine of the mutations cause shifts in the conductance-voltage (G-V) midpoints, and all but two significantly decrease the voltage dependence of peak Na+ current, consistent with a role of S4 segments in activation. The decreases in voltage dependence of activation were equivalent to a decrease in apparent gating charge of 0.5-2.1 elementary charges (eo) per channel for single charge-neutralizing mutations. Three charge-reversing mutations gave decreases of 1.2-1.9 eo per channel in voltage dependence of activation. The steady-state inactivation (h infinity) curves were fit by single-component Boltzmann functions and show significant decreases in slope for 9 of the 15 mutants and shifts of midpoints in 9 mutants. The voltage dependence of inactivation time constants is markedly decreased by mutations only in S4D4, providing further evidence that this segment plays a unique role in activation-inactivation coupling.


Detection and characterization of influenza A virus PA-PB2 interaction through a bimolecular fluorescence complementation assay.
The influenza virus polymerase complex, consisting of the PA, PB1, and PB2 subunits, is required for the transcription and replication of the influenza A viral genome. Previous studies have shown that PB1 serves as a core subunit to incorporate PA and PB2 into the polymerase complex by directly interacting with PA and PB2. Despite numerous attempts, largely involving biochemical approaches, a specific interaction between PA and PB2 subunits has yet to be detected. In the current study, we developed and utilized bimolecular fluorescence complementation (BiFC) to study protein-protein interactions in the assembly of the influenza A virus polymerase complex. Proof-of-concept experiments demonstrated that BiFC can specifically detect PA-PB1 interactions in living cells. Strikingly, BiFC demonstrated an interaction between PA and PB2 that has not been reported previously. Deletion-based BiFC experiments indicated that the N-terminal 100 amino acid residues of PA are responsible for the PA-PB2 interaction observed in BiFC. Furthermore, a detailed analysis of subcellular localization patterns and temporal nuclear import of PA-PB2 binary complexes suggested that PA and PB2 subunits interacted in the cytoplasm initially and were subsequently transported as a dimer into the nucleus. Taken together, results of our studies reveal a previously unknown PA-PB2 interaction and provide a framework for further investigation of the biological relevance of the PA-PB2 interaction in the polymerase activity and viral replication of influenza A virus.


Tricuspid regurgitation in hypoplastic left heart syndrome: mechanistic insights from 3-dimensional echocardiography and relationship with outcomes.
Our purpose was to test the following hypotheses: (1) patients with hypoplastic left heart syndrome who develop significant tricuspid regurgitation (TR) or require tricuspid valve (TV) surgery in the medium term have detectable TV abnormalities by 3-dimensional echocardiography (3DE) prestage 1 palliation and (2) TR is associated with reduced survival and increased TV intervention. Infants were prospectively studied with 3DE and 2DE prestage 1 and followed up for the end points of TR, TV surgery, transplantation, or death. From prestage 1 3DE, spatial coordinates of TV annulus and leaflets were extracted; annulus size, leaflet area, prolapse volume, tethering volume, bending angle, and papillary muscle angle were measured. TR was assessed prestage 1 and at latest follow-up. Of 70 patients, 62 (88.6%) had mild or less TR and 8 (11.4%) had moderate or greater TR prestage 1. Prestage 1 tethering volume correlated to leaflet area (r=0.736; P<0.001), annulus area (r=0.651; P<0.001), right ventricular end-diastolic area (r=0.347; P=0.003), fractional area change (r=-0.387; P<0.001), and TR grade (r=0.447; P<0.001). At follow-up, 46 (65.7%) had mild or less TR (group A) and 24 (34.3%) had moderate or greater TR (group B). Prestage 1 3DE showed greater TV tethering volume and flatter annulus in group B. Survival was better in group A. Increased TV tethering volume and flatter bending angle prestage 1 palliation is associated with TV failure at medium-term follow-up. Increased prestage 1 tethering is related to having larger TV annulus, larger leaflet area, larger right ventricular size, and reduced systolic function. TR progression results in increased TV intervention and decreased survival.


Separation of superficial and cerebral hemodynamics using a single distance time-domain NIRS measurement.
In functional near-infrared spectroscopy (fNIRS) superficial hemodynamics can mask optical signals related to brain activity. We present a method to separate superficial and cerebral absorption changes based on the analysis of changes in moments of time-of-flight distributions and a two-layered model. The related sensitivity factors were calculated from individual optical properties. The method was validated on a two-layer liquid phantom. Absorption changes in the lower layer were retrieved with an accuracy better than 20%. The method was successfully applied to in vivo data and compared to the reconstruction of homogeneous absorption changes.


Endocrine effects of lifelong exposure to low-dose depleted uranium on testicular functions in adult rat.
Environmental toxicant exposure can induce disorders in sex steroidogenesis during fetal gonad development. Our previous study demonstrated that chronic adult exposure to a supra environmental concentration of depleted uranium (DU) does not impair testicular steroidogenesis in rats. In this study, we investigated the effects of lifelong exposure (embryo - adult) to low-dose DU (40 or 120mgL-1) on adult rat testicular steroidogenesis and spermatogenesis. A significant content of uranium was detected in testis and epididymis in the DU 120mgL-1 group and the assay in epididymal spermatozoa showed a significant content in both groups. No major defect was observed in testicular histology except a decrease in the number of basal vacuoles in the DU groups. Moreover, plasma Follicle-Stimuling Hormone [FSH] and Luteinizing Hormone [LH] levels were increased only in the DU 120mgL-1 group and intratesticular estradiol was decreased in both groups. Testosterone level was reduced in plasma and testis in the DU 40mgL-1 group. These modulations could be explained by an observed decrease in gene expression of luteinizing hormone receptor (LHR), and enzymes involved in steroid production and associated signal transduction (StAR, cyp11a1, cyp17a1, 3βhsd, 17βhsd, TGFβ1, AR). Several genes specific to germ cells and cell junctions of the blood-testis barrier were also modulated. In conclusion, these data show that fetal life is a critical window for chronic uranium exposure and that the endocrine activities of low-dose uranium could disrupt steroidogenesis through the hypothalamic-pituitary-testicular axis. Further investigation should be so useful in subsequent generations to improve risk assessment of uranium exposure.


Determination of the rate constant for ring opening of an alpha-cyclopropylvinyl radical.
The rate constant for ring opening of the 1-(trans-2-phenylcyclopropyl)ethen-1-yl radical, 4, generated by photolysis of the corresponding vinyl iodide 2, is reported. The value of the rate constant was determined by the tin hydride method and was found to be (1.6+/-0.2)x10(10) s-1, one order of magnitude smaller than the rate constant for rearrangement of the trans-2-phenylcyclopropylcarbinyl radical.


Where is the greatest impact of uncontrolled HIV infection on AIDS and non-AIDS events in HIV?
The extent to which controlled and uncontrolled HIV interact with ageing, European region of care and calendar year of follow-up is largely unknown. EuroSIDA participants were followed after 1 January 2001 and grouped according to current HIV progression risk; high risk (CD4 cell count ≤350/μl, viral load ≥10 000 copies/ml), low risk (CD4 cell count ≥500 cells/μl, viral load <50 copies/ml) and intermediate (other combinations). Poisson regression investigated interactions between HIV progression risk, age, European region of care and year of follow-up and incidence of AIDS or non-AIDS events. A total of 16 839 persons were included with 136 688 person-years of follow-up. In persons aged 30 years or less, those at high risk had a six-fold increased incidence of non-AIDS compared with those at low risk, compared with a two-to-three-fold increase in older persons (P = 0.0004, interaction). In Eastern Europe, those at highest risk of non-AIDS had a 12-fold increased incidence compared with a two-to-four-fold difference in all other regions (P = 0.0029, interaction). Those at high risk of non-AIDS during 2001-2004 had a two-fold increased incidence compared with those at low risk, increasing to a five-fold increase between 2013 and 2016 (P < 0.0001, interaction). Differences among high, intermediate and low risk of AIDS were similar across age groups, year of follow-up and Europe (P = 0.57, 0.060 and 0.090, respectively, interaction). Factors other than optimal control of HIV become increasingly important with ageing for predicting non-AIDS, whereas differences across Europe reflect differences in patient management as well as underlying socioeconomic circumstances. The differences between those at high, intermediate and low risk of non-AIDS between 2013 and 2016 likely reflects better quality of care.


Discrepancies between the electronic medical record, the prescriptions in the Swedish national prescription repository and the current medication reported by patients.
To study discrepancies between (i) the prescribed current treatment stated by patients with congestive heart failure (CHF) compared with patients with other chronic diseases, (ii) the data in the medication list (ML) in the electronic medical record and (iii) the data in the prescription list (PL) on the prescriptions stored in the national prescription repository in Sweden, to determine current, noncurrent, duplicate and missing prescriptions. At one healthcare centre, a random sample of patients 18 years and older with a diagnosis of CHF, diabetes mellitus (DM) or osteoarthritis (OA) provided written informed consent to participate. Participants were interviewed by telephone on the prescribed current treatment. Of 161 invited patients (61 CHF, 50 DM and 50 OA), 66 patients were included. More than 80% of the patients had at least one discrepancy, a noncurrent, a duplicate or a missing prescription, in the ML and PL. The overall congruence for unique prescriptions on current treatment between the ML and the PL was only 55%. Patients with CHF had overall more discrepancies and patients with DM fewer discrepancies in the ML. Prescriptions for noncurrent treatment, duplicates and missing prescriptions are common in both the ML in the electronic medical record and the list on prescriptions stored in the Swedish National Prescription Repository. Patients with CHF had more discrepancies in the ML. The risk for medication errors in primary care due to incorrect information on prescribed treatment may be substantial.


Small Nucleolar Noncoding RNA SNORA23, Up-Regulated in Human Pancreatic Ductal Adenocarcinoma, Regulates Expression of Spectrin Repeat-Containing Nuclear Envelope 2 to Promote Growth and Metastasis of Xenograft Tumors in Mice.
Small nucleolar noncoding RNAs (snoRNAs) regulate function of ribosomes, and specific snoRNAs are dysregulated in some cancer cells. We investigated dysregulation of snoRNAs in pancreatic ductal adenocarcinoma (PDAC) cells. We investigated snoRNA expression in PDAC cell lines by complementary DNA microarray and quantitative reverse transcription polymerase chain reaction. In PDAC (n = 133), intraductal papillary mucinous neoplasm (n = 16), mucinous cystic neoplasm-associated PDAC (n = 1), and non-tumor pancreas (n = 8) and liver (n = 3) tissues from subjects who underwent surgical resection, levels of snoRNA were measured by quantitative reverse transcription polymerase chain reaction and compared with clinicopathologic parameters and survival times determined by Kaplan-Meier analysis. To examine snoRNA function, PDAC cells were transfected with snoRNA-antisense oligonucleotides flanked with amido-bridged nucleic acids, or snoRNA-expression plasmids, and analyzed in proliferation, colony formation, spheroid formation, and invasion assays. To identify snoRNA-related factors, cells were analyzed by gene expression and proteomic profiling and immunoblot assays. Mice were given intrasplenic injections of MIA PaCa2- or Suit2-HLMC cells; tumor-bearing nude mice were then given 3 weekly injections of an antisense oligonucleotides against SNORA23, a H/ACA-box type snoRNA, and tumor growth and metastasis to liver, blood, and pancreas were analyzed. Levels of SNORA23 increased and accumulated at the nucleolus in highly metastatic MIA PaCa2- or Suit2-HLMC cells compared with their parental cells. We detected SNORA23 in human PDAC specimens but not in non-tumor pancreatic tissue. PDAC level of SNORA23 correlated with invasion grade and correlated inversely with disease-free survival time of patients. Expression of SNORA23 in PDAC cells increased their invasive activity and colony formation, and spheroid formation was inhibited by SNORA23 knockdown. In gene expression and proteomic profile analyses, we found SNORA23 to increase expression of spectrin repeat-containing nuclear envelope 2 (SYNE2) messenger RNA and protein. Knockdown of SYNE2 in PDAC cells reduced their invasive activities and anchor-independent survival. Administration of SNORA23 antisense oligonucleotides to mice slowed growth of xenograft tumors, tumor expression of SYNE2, tumor cell dissemination, and metastasis to liver. We found expression of the snoRNA SNORA23, which mediates sequence-specific pseudouridylation of ribosomal RNAs, to be increased in human PDAC tissues compared with non-tumor tissues, and levels to correlate with tumor invasion grade and patient survival time. SNORA23 increases expression of SYNE2, possibly through modulation of ribosome biogenesis, to promote PDAC cell survival and invasion, and growth and metastasis of xenograft tumors in mice.


Does computed tomographic scan affect diagnosis and management of patients with suspected renal colic?
Patients with renal colic commonly present to the emergency department (ED) and are usually treated with analgesics, antiemetics and hydration. Computed tomographic (CT) scan is commonly utilized in evaluating patients with suspected renal colic. We compared diagnosis and treatment plans before and after CT in patients with suspected renal colic with the aim to evaluate how often changes in diagnosis, treatment and disposition are made. In this prospective observational study, we enrolled a convenience sample of clinically Stable ED patients older than 17 with suspected renal colic for whom CT was planned. Exclusion criteria were: chronic kidney disease, urinary tract infection, recent CT and history of previous kidney stone. Pre-CT and Post-CT surveys were completed by the treating provider. The discharge diagnosis was renal colic in 62 of 93 enrolled patients (67%). Urinalysis showed blood in 52 of these patients (84%). CT confirmed obstructing kidney or bladder stone in 50 patients. There were five cases of alternative diagnoses noted on CT scan. After CT scan, 7 patients had changes in disposition. Sixteen providers felt that CT would not change management. In these cases, CT offered no alternative diagnosis and didn't change disposition. CT scan didn't change management when providers did not expect it would. This indicates that providers who are confident with the diagnosis of renal colic should consider forgoing a CT scan. CT scan did occasionally find important alternative diagnoses and should be utilized when providers are considering other concerning pathology.


Egg production in relation to the results of a long term serological survey of 73 flocks of fowl.
Seventy-three flocks of fowl were tested at regular intervals for the presence of precipitins to fowl adenovirus (AV) and infectious bronchitis virus (IBV), haemaggluinating inhibiting antibodies to BC in 14 virus, and of agglutinins to Mycoplasma gallisepticum (M.g.) and Mycoplasma synoviae (M.s.). In all the eight flocks affected with Egg Drop Syndrome (EDS '76), egg production problems were associated with increasing numbers of BC14 virus reactors and AV reactors. In flocks showing production problems other than EDS'73 without any apparent cause, the average percentage of AV reactors increased significantly after the rearing period; this was not true of IBV reactors. BC14 reactors were either absent or present only once, in small numbers and with low titres, during the test period. The average percentage of AV reactors did not increase after the rearing period either in normally producing flocks or in flocks with production problems for which other diseases or dietary errors plausibly accounted for these problems. All this suggests a pathogenic role of AV in production problems. One can conclude from the high percentage of reactors in all groups of flocks that subclinical IBV infections are common. The percentage of IBV reactors during the laying period of flocks with EDS'76 was significantly higher than that of normally producing flocks. It is therefore suggested that subclinical IBV infection could be among the factors causing stress, acting as a trigger for EDS'76. All M.g.-infected flocks showed production problems; M.s. infections could not be related to egg production disturbances.


Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis.
Alcoholic liver disease is associated with three histologically distinct processes: steatosis (parenchymal fat accumulation), alcoholic hepatitis (characterized by parenchymal infiltration by neutrophil polymorphs), and alcoholic cirrhosis (in which chronic inflammation and fibrosis dominate). Chemokines are cytokines that promote subset-specific leukoycte recruitment to tissues and could therefore play a crucial role in determining which leukocyte subsets are recruited to the liver in alcoholic liver disease. This paper reports that chemokine expression is increased in the liver of patients with alcoholic liver disease and, moreover, that distinct patterns of chemokine expression are associated with the different inflammatory responses to alcohol. Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were all detected in the parenchyma at sites of inflammation in alcoholic hepatitis, whereas in alcoholic cirrhosis, chemokines were restricted to inflammatory cells and endothelium in the fibrous septa and portal tracts. In alcoholic hepatitis, chemokine transcription was localized to sinusoidal cells, leukocytes, and fibroblasts in areas of parenchymal inflammation, but hepatocytes, despite staining strongly for chemokine protein, were negative. In alcoholic cirrhosis, chemokine mRNA was detected in portal tract endothelium, leukocytes, and fibroblasts. Thus, alcoholic hepatitis and alcoholic cirrhosis are associated with distinct patterns of chemokine expression that are likely to be important factors in determining whether a patient develops acute parenchymal inflammation and alcoholic hepatitis, or chronic septal inflammation and alcoholic cirrhosis.


Evaluation of a microtiter latex agglutination test for histoplasmosis.
Experiments were designed to evaluate a Microtiter latex agglutination (Micro-LA) test, as a serological aid in the diagnosis of histoplasmosis, and to compare this test with the conventional microtiter-complement fixation (CF) test for histoplasmosis. Sera tested were from cases of acute and chronic pulmonary and disseminated histoplasmosis, as well as from individuals not having histoplasmosis. Ninety-seven percent of the cases of acute pulmonary histoplasmosis had positive Micro-LA tests, whereas 91% had positive CF tests. Ninety-six percent of the patients having chronic pulmonary histoplasmosis showed positive Micro-LA tests and 91% had positive CF tests. In contrast, 64% of the cases of disseminated histoplasmosis had positive Micro-LA tests, whereas 82% had positive CF tests. None of these differences was statistically significant. Although there were no significant differences in complement fixing and agglutinating antibody cross-reactivity with Blastomyces antigens, more patients demonstrated CF titers than Micro-LA titers. Sera from patients with acute and chronic histoplasmosis showed higher Micro-LA titers than CF titers, whereas sera from cases of disseminated histoplasmosis showed higher CF titers. Histoplasmin skin testing has less of a boosting effect on agglutinating antibodies than on CF antibodies to histoplasmin. Anticomplementary sera can be used in the Micro-LA test. This test is simple to perform, and results can be obtained in 2 to 4 hr.


Transcriptional starts for cytadherence-related operons of Mycoplasma genitalium.
One mechanism of mycoplasma cytadherence possessed by several mycoplasmas, including Mycoplasma genitalium, necessitates coordination of multiple adhesins and adherence-associated proteins. The genes encoding these adherence-related proteins are located in three different regions of the M. genitalium genome and exhibit an operon-like organization with surrounding genes. To understand whether genes encoding adherence-related proteins in M. genitalium are regulated as operons, we performed transcriptional and reverse transcription-polymerase chain reaction (RT-PCR) analyses on the loci mg191 (encoding major cytadhesin P140 localized at the specialized tip organelle) and mg218 (encoding high molecular mass cytadherence-related protein MG218 required for tip-mediated adherence). Primer extension suggested that transcription of mg191 was under the control of two transcriptional starts, one immediately upstream of mg191 (Prm(MG191)) and the other upstream of mg190 (Prm(MG190)). In contrast, mg218 appeared to be transcribed by a single transcriptional start, located upstream of mg217. RT-PCR indicated that transcription was continuous from mg190 to mg192 and mg217 to mg219, suggesting that these loci constitute true operons. Additional data revealed heretofore undetected similarities between adherence-related operons of M. genitalium and Mycoplasma pneumoniae.


Metal Oxysulfides: From Bulk Compounds to Nanomaterials.
This review summarizes the syntheses and applications of metal oxysulfides. Bulk compounds of rare earth and transition metals are discussed in the section Introduction. After a presentation of their main properties and applications, their structures are presented and their syntheses are discussed. The section Bulk Materials and Their Main Applications is dedicated to the growing field of nanoscaled metal oxysulfides. Synthesis and applications of lanthanide-based nanoparticles are more mature and are discussed first. Then, works on transition-metal based nanoparticles are presented and discussed. Altogether, this review highlights the opportunities offered by metal oxysulfides for application in a range of technological fields, in relation with the most advanced synthetic routes and characterization techniques.


A putative blue-light receptor from Drosophila melanogaster.
A gene encoding a 62.5 kDa homolog of Drosophila melanogaster photolyase was isolated. Purified recombinant protein contained a flavin adenine dinucleotide chromophore. The recombinant protein did not show photolyase activity for either cyclobutane pyrimidine dimers or 6-4 photoproducts in vitro as well as in vivo in Escherichia coli host cells, suggesting that the protein is not a DNA repair enzyme but a blue-light photoreceptor. Reverse transcription polymerase chain reaction analysis showed that the gene is more expressed in head than in body and that it is more expressed in antennae than in legs, wings and mouth appendages. In a phylogenetic tree of the photolyase family, the Drosophila photolyase homolog is located in a cluster containing 6-4 photolyases and mammalian photolyase homologs, which is only distantly related to the clade of higher plant blue-light photoreceptors. The mammalian photolyase homologs are more closely related to Drosophila 6-4 photolyase than to the Drosophila photolyase homolog, suggesting different roles of the photolyase homologs.


Predominance of T cells in the lymphocytic infiltrates of synovial tissues in rheumatoid arthritis.
Synovial tissues from 5 patients with rheumatoid arthritis (RA) were examined immunofluorescence microscopy for the presence of lymphocytes with either bone marrow-derived (B) or thymus-derived (T) surface markers. Five synovial tissues with severe to mild lymphocytic infiltrations by bright field microscopy were examined in parallel with immunofluorescence. B cells were identified with a pepsin-digested fluoresceinated anti-F (ab')2 antiserum and T cells were detected with a specific rabbit and anti-T lymphocyte antiserum. By these techniques 75-90% of the lymphocytes in these frozen sections were identified as T cells. Cell suspensions were also prepared by collagenase digestion of two of the five synovial tissues. The lymphocytes in these cell suspensions were predominantly T lymphocytes (78-85%) as shown by their ability to form spontaneous rosettes with sheep erythrocytes (E rosettes).


Revision total knee arthroplasty for failed high tibial osteotomy and unicompartmental knee arthroplasty have similar patient-reported outcome measures in a two-year follow-up study.
Little is known about the relative outcomes of revision of unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) to total knee arthroplasty (TKA). The aim of this study is to compare the outcomes of revision surgery for the two procedures in terms of complications, re-revision and patient-reported outcome measures (PROMs) at a minimum of two years follow-up. This study was a retrospective review of data from an institutional arthroplasty registry for cases performed between 2001 and 2014. A total of 292 patients were identified, of which 217 had a revision of HTO to TKA, and 75 had revision of UKA to TKA. While mean follow-up was longer for the HTO group compared with the UKA group, patient demographics (age, body mass index and Charlson co-morbidity index) and PROMs (Short Form-36, Oxford Knee Score, Knee Society Score, both objective and functional) were similar in the two groups prior to revision surgery. Outcomes included the rate of complications and re-operation, PROMS and patient-reported satisfaction at six months and two years post-operatively. We also compared the duration of surgery and the need for revision implants in the two groups. At two-year follow-up, both groups of patients had made significant improvement in terms of PROMs compared with pre-operative scores. PROMs and satisfaction rates were similar in the two groups. Complications requiring re-operation were significantly more frequent in the HTO group whilst more revision implants were used in the UKA group, resulting in a longer operative duration. Revision of HTO and UKA achieve similar post-operative PROMs and satisfaction. Revision of UKA more frequently requires revision components with increased operation duration but fewer complications requiring re-operation compared with revision of HTO. Cite this article: Bone Joint J 2017;99-B:1329-34.


Population-Based Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease.
Pharmacokinetic (PK) data from 28 subjects who received 5-200-mg single ascending doses of ANAVEX3-71, formerly AF710B, were analyzed to characterize the PK of ANAVEX3-71 and its M8 metabolite. PK data from 12 subjects who received 160 mg ANAVEX3-71 under fed and fasted conditions were analyzed to characterize the effect of food on the PK of the drug and its M8 metabolite. PK was characterized using the standard 2-stage approach and the nonlinear mixed-effects modeling approach. Dose proportionality was determined using the power model. Two- and 3-compartment linear PK models were tested for the characterization of the PK of ANAVEX3-71 and its M8 metabolite. The PK of ANAVEX3-71 is linear, dose proportional, and time invariant. The drug is rapidly eliminated with a mean (standard deviation) apparent terminal elimination half-life of 3.56 (4.09) hours, while the M8 metabolite was eliminated with a mean (standard deviation) apparent terminal elimination half-life of 6.59 (1.64) hours. The population PK model was used to investigate the effects of covariates on the PK of ANAVEX3-71 and M8. Age, weight, and creatinine clearance were not explanatory of the variability in apparent clearance and apparent volume of the central compartment of ANAVEX3-71. Food had no effect on the PK of ANAVEX3-71 and its M8 metabolite.


Evidence for Elevated Levels of Arsenic in Public Wells of Bangladesh Due To Improper Installation.
One of the mainstays of mitigation to reduce the exposure of the rural population of Bangladesh to arsenic (As) from private, mostly <90-m deep wells over the past 15 years has been the installation of over 300,000 deeper community wells. A comprehensive testing campaign previously conducted across a 180 km2 of area of Bangladesh identified 9 out of total of 927 wells >90 m deep that contained >50 µg/L arsenic. We show here that for five of these nine wells, conductivity profiles obtained after spiking the well bore with salt indicate a shallow leak that could explain the high As in the well water. In two of the five leaky wells, the presence of additional screens at the depth of the leak was documented with a downhole camera. The downhole camera did not detect anomalies in the construction of the remaining three leaky wells or in the four wells that did not leak. The four wells that did not leak were all >150-m deep and located in two villages separated by less than 500 m. Excluding these two villages and a handful of leaky wells, the results indicate an aquifer that is consistently low in As over a sizeable area at depths >90 m. Isolated cases of public wells that are elevated in As that have been reported elsewhere in Bangladesh may therefore reflect improper installation rather than actual contamination of the deep aquifer.


SCH 48973: a potent, broad-spectrum, antienterovirus compound.
SCH 48973 is a novel molecule with potent, selective, antienterovirus activity. In assays of the cytopathic effect against five picornaviruses, SCH 48973 had antiviral activity (50% inhibitory concentrations [IC50s]) of 0.02 to 0.11 microg/ml, with no detectable cytotoxicity at 50 microg/ml. SCH 48973 inhibited 80% of 154 recent human enterovirus isolates at an IC50 of 0.9 microg/ml. The antiviral activity of SCH 48973 is derived from its specific interaction with viral capsid, as confirmed by competition binding studies. The affinity constant (Ki) for SCH 48973 binding to poliovirus was 8.85 x 10(-8) M. In kinetic studies, a maximum of approximately 44 molecules of SCH 48973 were bound to poliovirus capsid. SCH 48973 demonstrated efficacy in a murine poliovirus model of enterovirus disease. SCH 48973 increased the survival of infected mice when it was administered orally at dosages of 3 to 20 mg/kg of body weight/day. Oral administration of SCH 48973 also reduced viral titers in the brains of infected mice. On the basis of its in vitro and in vivo profiles, SCH 48973 represents a potential candidate for therapeutic intervention against enterovirus infections.


[Fever as a sign of inflammatory syndrome in a female patient with hepatic haemangioma].
A 41-year-old patient presented with fever, night sweats, general malaise, abdominal pain, and substantial weight loss. Laboratory analysis suggested an inflammatory process. Diagnostic imaging revealed a hepatic haemangioma with a diameter of 20 cm. Because such giant haemangiomas of the liver can lead to inflammatory syndrome, the tumour was surgically removed. Pathological analysis confirmed the clinical diagnosis and evidence of extensive thrombosis and other vascular defects was found. Following treatment, the symptoms resolved without further complications. In patients with a giant haemangioma in the liver who present with an inflammatory syndrome, the haemangioma should be considered as the causal factor. For these patients, resection is the treatment of choice.


Clinical relevance of terminal transferase and adenosine deaminase in leukemia.
Terminal Transferase (TdT), Adenosine Deaminase (ADA), immunological membrane markers, cytochemical reactivity and cytogenetics were analyzed in 226 patients with ALL, AUL and AML, in 70 patients with CML and in 3 cases of Ph' positive acute leukemia presenting as ALL. TdT was tested in peripheral blood and bone marrow with both the biochemical and immunofluorescence (IF) methods, and ADA was determined biochemically only in peripheral blood cells. By using conventional cytochemistry, cell surface markers determinations, TdT and ADA analysis, three distinct groups are recognized in ALL at presentation: T-ALL with TdT+ and very high ADA values; non-T, non-B ALL with TdT+ and intermediate levels of ADA; B-ALL with TdT absence and low levels of ADA. Clinical presentation and responses to therapy in adult and children ALL were correlated to TdT determinations. The median survivals in adults, calculated for TdT+ and TdT- groups, were 14.2 and 5.6 months, respectively. TdT and ADA were determined in ALL during remission. The wide fluctuation observed for TdT IF and ADA values prevented a reliable monitoring of remissions. At relapse, TdT and ADA values were similar to those found for ALL at presentation; TdT IF determinations were diagnostic in cases showing CNS involvement as the only localization. Forty per cent of AUL and 11% of AML cases were positive for TdT; the medians of ADA values of the TdT+ cases in both AML and AUL were several times higher than those obtained in the TdT- group. While TdT positivity and high ADA had a favorable prognostic value in AUL, similar conclusions can not be drawn at the moment for AML. In chronic phase of CML, TdT was strictly negative and ADA values were increased over the control line only in cases showing initial signs of transformation. In acute phase, the cases positive for TdT (32%) presented a significantly higher ADA activity than the TdT negative ones. The actuarial survival curves for the TdT+ and TdT- groups differ significantly, presenting median survivals from onset of phase of 11 and 4.8 months respectively. The three cases of Ph' positive ALL were all TdT+, presented high ADA values and entered chronic phase of CML after therapy.


Dose quantification in carbon ion therapy using in-beam positron emission tomography.
This work presents an iterative method for the estimation of the absolute dose distribution in patients undergoing carbon ion therapy, via analysis of the distribution of positron annihilations resulting from the decay of positron-emitting fragments created in the target volume. The proposed method relies on the decomposition of the total positron-annihilation distributions into profiles of the three principal positron-emitting fragment species - 11C, 10C and 15O. A library of basis functions is constructed by simulating a range of monoenergetic 12C ion irradiations of a homogeneous polymethyl methacrylate phantom and measuring the resulting one-dimensional positron-emitting fragment profiles and dose distributions. To estimate the dose delivered during an arbitrary polyenergetic irradiation, a linear combination of factors from the fragment profile library is iteratively fitted to the decomposed positron annihilation profile acquired during the irradiation, and the resulting weights combined with the corresponding monoenergetic dose profiles to estimate the total dose distribution. A total variation regularisation term is incorporated into the fitting process to suppress high-frequency noise. The method was evaluated with 14 different polyenergetic 12C dose profiles in a polymethyl methacrylate target: one which produces a flat biological dose, 10 with randomised energy weighting factors, and three with distinct dose maxima or minima within the spread-out Bragg peak region. The proposed method is able to calculate the dose profile with mean relative errors of 0.8%, 1.0% and 1.6% from the 11C, 10C, 15O fragment profiles, respectively, and estimate the position of the distal edge of the SOBP to within an average of 0.7 mm, 1.9 mm and 1.2 mm of its true location.


TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport.
The diffusion of materials from systemic circulation to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). Choroid plexus epithelial cells (CPECs) of the brain ventricles constitute the BCSFB and regulate the infiltration of plasma proteins as well as immune cells into the interstitium of the CNS. The barrier function is altered in pathologic conditions. However, the regulatory mechanism of BCSFB is not fully understood. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a polymodally gated divalent cation channel that is highly expressed in CPECs. TRPV4 was localized broadly on the apical membrane in swine CPECs, in contrast with an intense ciliary localization found on other cell types. Treatment with the TRPV4-specific agonist, GSK1016790A (GSK; EC₅₀ 34 nM), induced a robust calcium influx and an immediate serine/threonine protein phosphorylation. The agonist treatment induced a marked decrease in the amount of filamentous actin and disintegrated the cell junctions in 10-20 minutes. In contrast, inhibition of the basal TRPV4 activity with the TRPV4-specific antagonist, HC067047 (HC; IC₅₀ 74 nM), reduced the basolateral-to-apical transport of α-2-macroglobulin (A2M). Overall, this study demonstrated a novel physiologic function of TRPV4 in the regulation of BCSFB permeability.


Structured observations reveal slow HIV-1 CTL escape.
The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL escape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN-γ ELISpot and longitudinal HIV-1 gag, pol, and nef sequence data were used to study the timing and prevalence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero respectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two years.


The effect of sartorius transposition on wound morbidity following inguinal-femoral lymphadenectomy.
In spite of efforts to reduce complications associated with inguinal-femoral lymphadenectomy (IFL), morbidity continues to be substantial. We sought to assess the efficacy of sartorius transposition (ST) in reducing groin wound complications following IFL, in patients with vulvar malignancy. The records of 101 patients with vulvar cancer undergoing IFL through separate incisions between March 1975 and December 1994 were examined. Sixty-two patients undergoing ST (group 1) were compared to 38 who did not (group 2). The groups were similar with respect to age, weight, tobacco/alcohol use, prior abdominal/vulvar surgery, prevalence of diabetes, hypertension, or peripheral vascular disease, and previous exposure to irradiation or chemotherapy. Additionally, there was no significant difference with respect to extent of disease, incidence of macro-/microscopic groin metastases, use of groin drains, and use of perioperative antibiotics or deep venous thrombosis prophylaxis. Groin wound complications were less frequent in patients undergoing ST (group 1). The incidence of groin cellulitis was 30% in group 1 compared with an incidence of 58% in group 2 (P = 0.011). Significant groin wound morbidity, defined as either wound breakdown or cellulitis, was seen less frequently in group 1 (41% vs 66%; P = 0.029). Employing a multivariate analysis, only patient weight < 150 lbs and performance of ST were established as independently associated with a reduction in groin morbidity following IFL (P = 0.0281 and P = 0.0075, respectively). In conclusion, despite waning enthusiasm for its performance, ST appeared to significantly reduce the incidence of wound morbidity after IFL. Our data confirmed that separate incisions, and improved perioperative antibiotics, have not eliminated the value inherent in this surgical modification. We suggest a prospective trial to further establish the benefit of sartorius transposition during IFL.


Vernal keratopathy and its management.
The history of the recognition and characterization of the corneal manifestations of vernal disease is recounted. A revised classification of the 'remote' corneal signs is proposed. Forty cases of vernal plaque seen recently in London are analysed. Various parameters are discussed, and the usefulness of superficial keratectomy in the management of plaque is established. New histological findings in plaque are mentioned; these will be fully described in another paper.