Immunologic Aging in Adults with Congenital Heart Disease: Does Infant Sternotomy Matter?
Thymectomy is performed routinely in infants undergoing cardiothoracic surgery. Children post-sternotomy have decreased numbers of T lymphocytes, although the mechanisms involved and long-term consequences of this have not been defined. We hypothesized that lymphopenia in patients with adult congenital heart disease (ACHD) would be reflective of premature T cell maturation and exhaustion. Adults with ACHD who had sternotomy to repair congenital heart disease as infants (<1 year) and age-matched ACHD patients without prior sternotomy were studied using polychromatic flow cytometry interrogating markers of lymphocyte maturation, exhaustion and senescence. Group differences were analyzed using Mann-Whitney U and Fisher's exact tests. Eighteen ACHD patients aged 21-40 years participated: 10 cases and 8 controls. Median age at sternotomy for cases was 52 days. Cases and controls were matched for age (28.9 vs. 29.1 years; p = 0.83), gender (p = 0.15) and race (p = 0.62) and had similar case complexity. Cases had a lower mean percentage of cytotoxic CD8 lymphocytes compared to controls (26.8 vs. 33.9 %; p = 0.016), with fewer naive, undifferentiated CD8 T cells (31.0 vs. 53.6 %; p = 0.027). CD8 cells expressing PD1, a marker of immune exhaustion, trended higher in cases versus controls (25.6 vs. 19.0 %; p = 0.083). Mean percentage of CD4 cells was higher in cases versus controls (65.6 vs. 59.6 %; p = 0.027), without differences in CD4 T cell maturation subtype. In summary, ACHD patients who undergo sternotomy as infants exhibit differences in T lymphocyte composition compared to ACHD controls, suggesting accelerated immunologic exhaustion. Investigation is warranted to assess the progressive nature and clinical impact of this immune phenotypic change.


Grouping systems enhance outcomes analysis.
The production of outcomes data has often resulted in the collection of hundreds of additional data elements or review of massive numbers of charts. Tenet Healthcare Corporation (formerly National Medical Enterprises) developed an outcomes database using existing clinical-financial data elements with the help of two grouping systems provided by 3M Health Information Systems: all patient refined-diagnosis-related groups and ambulatory patient groups. These systems allow comparisons of outcomes within and across facilities, as is shown in specific examples in the article.


Low-level laser therapy reduces time to ambulation in dogs after hemilaminectomy: a preliminary study.
A prospective study to determine if low-level laser therapy and surgery for intervertebral disk herniation encourage ambulation faster than surgery alone. Thirty-six dogs with acute paraparesis/paraplegia due to acute intervertebral disk herniation were evaluated and given a modified Frankel score. Dogs with scores 0 to 3 were included in the study. Dogs were assigned to the control group (1) or the laser treatment group (2) based on alternating order of presentation. All dogs underwent surgery for their herniated disk. Dogs in group 2 were treated postoperatively with low-level laser therapy daily for five days, or until they achieved a modified Frankel score of 4. A 5 × 200-mW 810-nm cluster array was used to deliver 25 W/cm(2) to the skin. All dogs were scored daily by the investigators using the modified Frankel scoring system. The time to achieve a modified Frankel score of 4 was significantly lower (P=0.0016) in the low-level laser therapy group (median 3.5 days) than the control group (median 14 days). Low-level laser therapy in combination with surgery decreases the time to ambulation in dogs with T3-L3 myelopathy secondary to intervertebral disk herniation.


The HDAC Inhibitor TSA Ameliorates a Zebrafish Model of Duchenne Muscular Dystrophy.
Zebrafish are an excellent model for Duchenne muscular dystrophy. In particular, zebrafish provide a system for rapid, easy, and low-cost screening of small molecules that can ameliorate muscle damage in dystrophic larvae. Here we identify an optimal anti-sense morpholino cocktail that robustly knocks down zebrafish Dystrophin (dmd-MO). We use two approaches, muscle birefringence and muscle actin expression, to quantify muscle damage and show that the dmd-MO dystrophic phenotype closely resembles the zebrafish dmd mutant phenotype. We then show that the histone deacetylase (HDAC) inhibitor TSA, which has been shown to ameliorate the mdx mouse Duchenne model, can rescue muscle fiber damage in both dmd-MO and dmd mutant larvae. Our study identifies optimal morpholino and phenotypic scoring approaches for dystrophic zebrafish, further enhancing the zebrafish dmd model for rapid and cost-effective small molecule screening.


The risk of pet animals in spreading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and public health importance: An updated review.
Since the outbreak of SARS-CoV-2 was first identified in 2019, it has been reported that the virus could infect a variety of animals either naturally or experimentally. This review discusses the occurrence SARS-CoV-2 in dogs and cats and the role of these animals in transmitting coronavirus disease 2019 (COVID-19) to their owners. The data were collected from epidemiological studies and case reports that focused on studying the occurrence of SARS-CoV-2 in pet animals and their owners. Epidemiological studies and case reports indicate that dogs and cats are infected with SARS-CoV-2 either naturally or experimentally; however, the global number of naturally infected animals is far lower than the number of people who have COVID-19. These studies demonstrate that pet animals acquire the infection from direct contact with COVID-19-infected owners. Currently, there are no studies reporting that dogs and cats can transmit SARS-CoV-2 to other animals and humans, under natural conditions. The emergence of SARS-CoV-2 infection in companion animals (dogs and cats) in different countries worldwide raises concerns that pets are at higher risk for spreading and transmitting SARS-CoV-2 to humans and other animals, which poses a hazard to the public health. Therefore, investigating the role of dogs and cats in the transmission and epidemiology of SARS-CoV-2 will help us to design and implement appropriate preventive measures against the further transmission of SARS-CoV-2.


The physics of liquid impact, shock wave interactions with cavities, and the implications to shock wave lithotripsy.
This paper reviews research on the physics of liquid impact and the behaviour of cavities when a shock passes over them. It is shown that the problems are related since when a cavity collapses near a solid surface, or is collapsed by a shock wave, the collapse is asymmetric and a liquid jet is produced which can impact an adjacent solid. The implications of this research to shock wave lithotripsy are emphasized. Finally, the paper describes the development of a device, based on liquid jet impact, for fragmenting kidney stones.


Williams-Beuren syndrome critical region-5/non-T-cell activation linker: a novel target gene of AML1/ETO.
The chromosomal translocation t(8;21) fuses the AML1 (RUNX1) gene on chromosome 21 and the ETO gene on chromosome 8 in human acute myeloid leukemias (AMLs), resulting in expression of the chimeric transcription factor AML1/ETO. AML1/ETO-mediated dysregulation of target genes critical for hematopoietic differentiation and proliferation is thought to contribute to the leukemic phenotype. Several mechanisms, including recruitment of histone deacetylases (HDACs) to AML1 target genes, may be responsible for altered gene expression. We used an ecdysone-inducible expression system in the human monoblastic U-937 cell line to isolate genes that were differentially expressed upon induction of AML1/ETO expression. By representational difference analysis (cDNA-RDA), we identified 26 genes whose expression levels were significantly modulated following AML1/ETO induction for 48 h. None of these genes has previously been described as a target of AML1, ETO or AML1/ETO. One gene downregulated by AML1/ETO in vitro, Williams Beuren syndrome critical region 5 (WBSCR5), was expressed in primary t(8;21)-negative AML blasts but not in primary t(8;21)-positive AML blasts, strongly implying a role of this gene in the phenotype of t(8;21)-positive AML. Four upregulated and four downregulated genes were further studied with all-trans-retinoic acid (ATRA), an inducer of differentiation of U-937 cells, and Trichostatin A (TSA), an HDAC inhibitor. Three out of eight genes including WBSCR5 were regulated during ATRA-induced monocytic differentiation of U-937 cells, however, none of them antagonistically, upon both ATRA treatment and AML1/ETO induction. AML1/ETO-associated dysregulation of gene expression was not mediated by a TSA-sensitive mechanism. The identified genes provide a useful model to study the mechanism by which the AML1/ETO fusion protein exerts its function in transcriptional dysregulation in AML. The possible role of WBSCR5 in normal and malignant hematopoiesis warrants further study.


Color-Biased Dispersal Inferred by Fine-Scale Genetic Spatial Autocorrelation in a Color Polymorphic Salamander.
Behavioral traits can be influenced by predation rates of color morphs, potentially leading to reduced boldness or increased escape behaviors in one color morph. The red-backed salamander, Plethodon cinereus, is a small terrestrial salamander whose color morphs have different diets and select different microhabitats, but little is known about potential differences in dispersal behaviors. We used fine-scale genetic spatial autocorrelation to examine 122 P. cinereus in a color-polymorphic population at 10 microsatellite loci in order to generate estimates of spatial genetic structure for each color morph. Differences in spatial genetic structure have been used extensively to infer within-population sex-biased dispersal but have never been used to test for dispersal differences between other groups within populations such as color morphs. We found evidence for color-biased dispersal, but not sex-biased dispersal. Striped salamanders had significant positive genetic structure in the shortest distance classes indicating philopatry. In contrast, unstriped salamanders showed a lack of spatial genetic structure at shorter distances and higher than expected genetic similarity at further distances, as expected if they are dispersing from their natal site. These results show that genetic methods typically used for sex-biased dispersal can be used to investigate differences in dispersal between morphs that vary discretely in polymorphic populations, such as color morphs.


[Cystic renal adenocarcinoma].
Renal adenocarcinoma presenting as a cystic mass is uncommon and causes difficulty in making the differential diagnosis. Ultrasound and particularly CT are considered to be the most useful diagnostic methods. The usefulness of ultrasound or CT-guided punction-aspiration has yet to be established since the aspirate is often non-specific. The major difficulty encountered when making the differential diagnosis is that of distinguishing cystic renal adenocarcinoma from multilocular cystic nephroma. Multilocular renal carcinoma and multilocular cystic nephroma are the most common adult multilocular renal cystic masses. The latter is more common in the female, whereas cystic renal adenocarcinoma is more common in the male patient.


[The significance of parameters of the reservoir of bacillary patients with pulmonary tuberculosis in the assessment of tuberculosis epidemic situation].
The author analyzes the tuberculosis epidemic situation in Russia, by using the traditional scheme accepted in Russia and the procedure based on the follow-up of bacillary patients with pulmonary tuberculosis. The proposed procedure enabled the author to ascertain the reasons for the decreased rates of normalization of the tuberculosis situation and to make an objective proposal to implement tuberculosis-controlling measures. The performed study has led the author to recommend a new form of calculating the abacillation index and of establishing the standard for the proportion (75-85%) of bacterial isolation in patients with new-onset pulmonary tuberculosis.


Laparoscopic retroperitoneal adrenalectomy.
Laparoscopic adrenalectomy has largely replaced open adrenalectomy for resection of adrenal tumors, which are not adrenocortical cancer or malignant pheochromocytoma. Laparoscopic retroperitoneal adrenalectomy is a particularly useful technique in patients with tumors <7 cm and body mass index <45 kg/m2. When compared with laparoscopic transabdominal adrenalectomy, the laparoscopic retroperitoneal technique leads to reduced operating times, avoidance of intra-abdominal adhesions and irradiated fields, potentially less postoperative pain, and improved intraoperative hemostasis and visualization. The technique involves placement of 3 ports, dissecting the retroperitoneal space, identifying and ligating the adrenal vein, and removing the attachments to the adrenal gland. See the video, Supplemental Digital Content 1, http://links.lww.com/SLE/A38.


Osteolineage niche cells initiate hematopoietic stem cell mobilization.
Recent studies have implicated bone-lining osteoblasts as important regulators of hematopoietic stem cell (HSC) self-renewal and differentiation; however, because much of the evidence supporting this notion derives from indirect in vivo experiments, which are unavoidably complicated by the presence of other cell types within the complex bone marrow milieu, the sufficiency of osteoblasts in modulating HSC activity has remained controversial. To address this, we prospectively isolated mouse osteoblasts, using a novel flow cytometry-based approach, and directly tested their activity as HSC niche cells and their role in cyclophosphamide/granulocyte colony-stimulating factor (G-CSF)-induced HSC proliferation and mobilization. We found that osteoblasts expand rapidly after cyclophosphamide/G-CSF treatment and exhibit phenotypic and functional changes that directly influence HSC proliferation and maintenance of reconstituting potential. Effects of mobilization on osteoblast number and function depend on the function of ataxia telangiectasia mutated (ATM), the product of the Atm gene, demonstrating a new role for ATM in stem cell niche activity. These studies demonstrate that signals from osteoblasts can directly initiate and modulate HSC proliferation in the context of mobilization. This work also establishes that direct interaction with osteolineage niche cells, in the absence of additional environmental inputs, is sufficient to modulate stem cell activity.


Estrogen targets genes involved in protein processing, calcium homeostasis, and Wnt signaling in the mouse uterus independent of estrogen receptor-alpha and -beta.
Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17beta (E(2)) and its catechol metabolite 4-hydroxy-E(2) (4OHE(2)) can modulate uterine gene expression in ERalpha(-/-) mice. Whereas administration of E(2) or 4OHE(2) rapidly up-regulated (4-8-fold) the expression of immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and Sik similar protein (Sik-SP) genes in ovariectomized wild-type or ERalpha(-/-) mice, the expression of secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions. Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ERalpha, ERbeta, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ERalpha(-/-) uteri. Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.


Characterization of RAG1 and IgM (mu chain) marking development of the immune system in red-spotted grouper (Epinephelus akaara).
In vertebrates, lymphoid-specific recombinase protein encoded by recombination-activating genes (RAG1/2) plays a key role in V(D)J recombination of the T-cell receptor and B-cell receptor. In this study, both RAG1 and the immunoglobulin M (IgM) mu chain were cloned to characterize their potential role in the immune defense at developmental stages of red-spotted grouper, Epinephelus akaara. The open reading frame (ORF) of E. akaara RAG1 included 2778 nucleotide residues encoding a putative protein of 925 amino acids, while the ORF of the IgM mu chain had 1734 nucleotide residues encoding 578 amino acids including variable (VH) and constant (CH1-CH2-CH3-CH4) regions. E. akaara RAG1 was composed of a zinc-binding dimerization domain (ZDD) with a RING finger and zinc finger A (ZFA) in the non-core region and a nonamer-binding region (NBR), with a zinc finger B (ZFB), the central and C-terminal domains in the core region. Tridimensional models of the ZDD and NBR of E. akaara RAG1 were constructed for the first time in fishes, while a 3D model of the E. akaara IgM mu chain was also clarified. The RAG1 mRNA was only detected in the thymus and kidney of 4-month and 1.5-year old groupers using qPCR, and the RAG1 protein was confirmed using western blotting and immunohistochemistry. The IgM mu mRNA was examined in most tissues except the gonad. RAG1 and IgM mu gene expression were observed at 15 dph (days post-hatching) and 23 dph respectively, and increased to a higher level at 37 dph. In addition, this was the first time that the morphology of the E. akaara thymus was characterized. The oval-shaped thymus of 4-month old fish was clearly seen and there were amounts of T lymphocytes present. The results suggested that the immune action of E. akaara was likely to start to develop around 15 dph to 29 dph. The transcript level of the RAG1 gene and the number of lymphocytes in the thymus between 4-month and 1.5-year old groupers indicated that age-related thymic atrophy also occurs in fishes. The similar functional structures of RAG1 and IgM protein between fish and mammals indicated that teleost species share a similar mechanism of V(D)J recombination with higher vertebrates.


S100B and optic nerve sheath diameter correlation in head injury patients with contusions.
S100B is a biochemical marker of head injury and optic nerve sheath diameter (ONSD) is a non-invasive bedside technique to detect intracranial pressure. We aim to demonstrate whether ONSD correlates with S100B protein in head injury patients with contusions and also whether the grade of contusion correlates with S100B protein. This is a prospective study done on head injury patients aged between 18 and 75 years having isolated contusions admitted within 24 h of injury. Patients were assessed neurologically with Glasgow Coma Scale (GCS) and cranial computed tomography study on admission. Ocular sonography was done for ONSD recording, and S100B protein venous samples were collected at 24 h, 48 h, and at discharge. The outcome was evaluated with Glasgow Outcome Scale (GOS) at discharge and 3 months. Out of 42 patients, the mean age was 46.2 years and 27 were males. There were 12 patients with mild, 25 with moderate, and 5 patients with severe head injury. The mean GCS at 24 h was 12.35, the mean ONSD at 24 h was 3.9 mm, and the mean S100B at 24 h was 0.214 µg/L. There was a statistically significant correlation noted between mean S100B and contusion grade. A moderate positive correlation was noted between ONSD and S100B at 48 h in mild and moderate head injury groups. Favorable outcome (GOS 4,5) at 3 months can be predicted by GCS, contusion grade, and S100B values. Better GCS (14 and 15), focal contusion grade, and S100B values (<0.5 µg/L) predict good outcome. Although ONSD and S100B give important information in different scenarios, S100B gives better predictive information in patients with traumatic cerebral contusions. S100 B and ONSD are simple biochemical and radiological investigations that can be done in every neurosurgical setup and can be useful in the management of head injury patients.


Second line palliative endobronchial radiotherapy with HDR Ir 192 in recurrent lung carcinoma.
To observe the efficiency of reirradiation with high dose rate intraluminal brachytherapy in symptomatic palliation of recurrent endobronchial tumors. Between January 1994 and June 1998, 21 patients diagnosed with recurrent endobronchial tumors following external beam radiotherapy were treated palliatively with high dose rate intraluminal irradiation at Hacettepe University Oncology Institute. A single fraction of 10 Gy was prescribed to the specified area in 9 patients and 15 Gy to 12. Endobronchial treatment improved the performance and reduced symptomatology in 17 (81%) patients. Ten dyspneic patients (10/14, 71%) recovered clinically with an accompanying radiological downstaging. The median symptomatic palliation was 45 days (range, 0-9 months), and the overall median survival was 5.5 months (range, 4-12 months). The palliative intrabronchial brachytherapy was well tolerated, with the exception of in one patient with a fatal hemorrhage, and another with medically salvaged bronchospasm and intrabronchial edema. Recurrent patients with a history of previous thoracic external beam irradiation can be effectively palliated with high dose rate endobronchial reirradiation if the symptoms are directly related to the endobronchial tumor.


Aspergillosis of the frontal sinus.
Aspergillus is the most common fungal infection of the paranasal sinuses and usually appears as a chronic disease in an otherwise healthy person. Previously reported cases have involved the maxillary sinus alone in the majority of cases. To my knowledge, isolated frontal sinus aspergillosis has not been previously reported. A frontal osteoplastic flap approach was used to expose a fungus ball in the right frontal sinus of a healthy 69-year-old man. Histologic preparations and fungal cultures showed Aspergillus fumigatus. Follow-up substantiated prior experience that surgical removal of the fungal mass with drainage of the involved sinus is the treatment of choice in healthy patients with Aspergillus involving the paranasal sinuses.


Delta-centralization fails to control for population stratification in genetic association studies.
To investigate the validity of simulations and assumptions used to underpin the delta-centralization (DC) method for correcting for population stratification in genetic association studies; to assess the effectiveness of DC compared to genomic control (GC) under valid simulation conditions; and to highlight other studies employing similarly flawed simulations. DC and GC use data from unlinked null loci to correct the test statistic at the target locus, but differ in the way the correction is performed. We compare DC and GC under two simulation approaches: an invalid approach adopted by the originators of DC, which permits subpopulation allele frequency matching of null markers to the target locus; and a valid approach, based on the Balding-Nichols model, which does not allow subpopulation matching. DC works under invalid simulation conditions (subpopulation allele frequency matching), but not under our valid ones. We use theoretical arguments to assert that there are no valid conditions under which DC might work. We identify several studies which have adopted similarly invalid simulation approaches in this field. DC fails to control for population stratification and should not be used. Other results from studies which have used the same invalid simulation approach should be treated cautiously.


Vesicular release dynamics are altered by the interaction between the chemical cargo and vesicle membrane lipids.
The release of the cargo from soft vesicles, an essential process for chemical delivery, is mediated by multiple factors. Among them, the regulation by the interaction between the chemical cargo species and the vesicular membrane, widely existing in all vesicles, has not been investigated to date. Yet, these interactions hold the potential to complicate the release process. We used liposomes loaded with different monoamines, dopamine (DA) and serotonin (5-HT), to simulate vesicular release and to monitor the dynamics of chemical release from isolated vesicles during vesicle impact electrochemical cytometry (VIEC). The release of DA from liposomes presents a longer release time compared to 5-HT. Modelling the release time showed that DA filled vesicles had a higher percentage of events where the time for the peak fall was better fit to a double exponential (DblExp) decay function, suggesting multiple kinetic steps in the release. By fitting to a desorption-release model, where the transmitters adsorbed to the vesicle membrane, the dissociation rates of DA and 5-HT from the liposome membrane were estimated. DA has a lower desorption rate constant, which leads to slower DA release than that observed for 5-HT, whereas there is little difference in pore size. The alteration of vesicular release dynamics due to the interaction between the chemical cargo and vesicle membrane lipids provides an important mechanism to regulate vesicular release in chemical and physiological processes. It is highly possible that this introduces a fundamental chemical regulation difference between transmitters during exocytosis.


Intimate Partner Violence, Minority Stress, and Sexual Risk-Taking Among US MSM.
Abstract This paper examines the prevalence of intimate partner violence (IPV) among a national sample of internet-recruited U.S. MSM (n = 1,575), and examines associations between reporting of IPV, minority stress, and sexual risk-taking. Five outcomes are examined: experiences of physical and sexual violence, perpetration of physical and sexual violence, and unprotected anal intercourse (UAI) at last sexual encounter. MSM who reported experiencing more homophobic discrimination and internalized homophobia were more likely to report experiences of IPV. The results point to the need for prevention messages to address the external and internal stressors that influence both violence and sexual risk among MSM.


Lipoprotein(a) in cardiovascular diseases.
Lipoprotein(a) (Lp(a)) is an LDL-like molecule consisting of an apolipoprotein B-100 (apo(B-100)) particle attached by a disulphide bridge to apo(a). Many observations have pointed out that Lp(a) levels may be a risk factor for cardiovascular diseases. Lp(a) inhibits the activation of transforming growth factor (TGF) and contributes to the growth of arterial atherosclerotic lesions by promoting the proliferation of vascular smooth muscle cells and the migration of smooth muscle cells to endothelial cells. Moreover Lp(a) inhibits plasminogen binding to the surfaces of endothelial cells and decreases the activity of fibrin-dependent tissue-type plasminogen activator. Lp(a) may act as a proinflammatory mediator that augments the lesion formation in atherosclerotic plaques. Elevated serum Lp(a) is an independent predictor of coronary artery disease and myocardial infarction. Furthermore, Lp(a) levels should be a marker of restenosis after percutaneous transluminal coronary angioplasty, saphenous vein bypass graft atherosclerosis, and accelerated coronary atherosclerosis of cardiac transplantation. Finally, the possibility that Lp(a) may be a risk factor for ischemic stroke has been assessed in several studies. Recent findings suggest that Lp(a)-lowering therapy might be beneficial in patients with high Lp(a) levels. A future therapeutic approach could include apheresis in high-risk patients in order to reduce major coronary events.


The SA-dependent defense pathway is active against different pathogens in tomato and tobacco.
The importance of salicylic acid (SA) in plant defense against pathogen attack has been elaborately documented. Benzothiadiazole (BTH, BION), a chemical analogue of SA, also induces resistance through the SA-dependent pathway. We investigated the role of SA in both basal defense and induced resistance of tomato (Lycopersicon esculentum) and tobacco (Nicotiana tabacum) against Oidium neolycopersici (a biotrophic pathogen) and Botrytis cinerea (a necrotrophic pathogen). A comparison of NahG transgenic tomato and tobacco (unable to accumulate SA) to their respective wild types revealed that in both crops, SA was not involved in basal defense against O. neolycopersici. SA also played no role in the basal defense of tobacco against B. cinerea but NahG tomato plants were significantly more sensitive to B. cinerea than wild type plants. Activation of the SA-dependent defense pathway via BTH resulted in induced resistance against B. cinerea in tomato but not in tobacco. In contrast, BTH induced resistance against O. neolycopersci in tobacco but not in tomato. Microscopic analysis revealed that BTH treatment could prevent penetration of the odium germ tube through the epidermal cell wall of tobacco leaves whereas penetration was successful on tomato leaves, irrespective of BTH treatment. We conclude that even in two related plant species such as tomato and tobacco, the SA-dependent defense pathway does not trigger the same defense responses. It also means that the outcome of a BTH treatment cannot be predicted and has to be tested for each plant-pathogen combination.


Host-pathogen interaction profiling using self-assembling human protein arrays.
Host-pathogen protein interactions are fundamental to every microbial infection, yet their identification has remained challenging due to the lack of simple detection tools that avoid abundance biases while providing an open format for experimental modifications. Here, we applied the Nucleic Acid-Programmable Protein Array and a HaloTag-Halo ligand detection system to determine the interaction network of Legionella pneumophila effectors (SidM and LidA) with 10 000 unique human proteins. We identified known targets of these L. pneumophila proteins and potentially novel interaction candidates. In addition, we applied our Click chemistry-based NAPPA platform to identify the substrates for SidM, an effector with an adenylyl transferase domain that catalyzes AMPylation (adenylylation), the covalent addition of adenosine monophosphate (AMP). We confirmed a subset of the novel SidM and LidA targets in independent in vitro pull-down and in vivo cell-based assays, and provided further insight into how these effectors may discriminate between different host Rab GTPases. Our method circumvents the purification of thousands of human and pathogen proteins, and does not require antibodies against or prelabeling of query proteins. This system is amenable to high-throughput analysis of effectors from a wide variety of human pathogens that may bind to and/or post-translationally modify targets within the human proteome.


[The use of contrast media in magnetic resonance tomography of head and neck tumors].
The ranking of MRT was evaluated retrospectively in 37 patients with clinically confirmed malignant neoplasms of the head and neck. The results were compared with the clinical and endoscopic findings and with computed tomographic scans (CT). MR consistently showed superior soft tissue definition and extent of disease compared with CT. However, the sensitivity of both methods was comparably high. With the exception of tumours of the floor of the mouth and the anterior third of tongue the use of paramagnetic contrast material improved image quality compared with T2-sequences. MRT was superior to CT in imaging the post-treatment head and neck. Even here, contrast enhanced T1-images improved contrast between recurrent tumour and adjacent soft tissues, although in some cases false positive diagnosis was caused by postradiation oedema and inflammatory changes.


Discontinuous vs. in-continuity neck dissection in carcinoma of the oral cavity. Experience of two oncologic hospitals.
Many Authors have discussed the best indication and extension of neck dissection, but few have studied the surgical approach considering the continuity of neck dissection with the primary tumour. This retrospective study refers to patients submitted to major surgery between 1996 and 2001 for floor of mouth and oral tongue squamous cell carcinoma, at the Head and Neck Surgery Department of the Hospital "A.C. Camargo", São Paulo, Brazil and of the European Institute of Oncology, Milan, Italy. Patients were assigned to one of three groups: group I (in-continuity resection); group 2 (discontinuous resection) and group 3 (delayed discontinuous resection). Overall, 193 patients were studied. There were no differences in disease-free survival between the neck dissection groups. Furthermore, no statistical differences were found in disease specific survival between the groups. Discontinuous neck dissection seems not to change the disease-free survival or disease-specific survival when compared to in-continuity neck dissection, in this retrospective study. A prospective randomized trial is necessary to confirm these results.


Intrinsic network activity reflects the fluctuating experience of tonic pain.
Although we know sensation is continuous, research on long-lasting and continuously changing stimuli is scarce and the dynamic nature of ongoing cortical processing is largely neglected. In a longitudinal study, 38 participants across four sessions were asked to continuously rate the intensity of an applied tonic heat pain for 20 min. Using group-independent component analysis and dual regression, we extracted the subjects' time courses of intrinsic network activity. The relationship between the dynamic fluctuation of network activity with the varying time courses of three pain processing entities was computed: pain intensity, the direction of pain intensity changes, and temperature. We were able to dissociate the spatio-temporal patterns of objective (temperature) and subjective (pain intensity/changes of pain intensity) aspects of pain processing in the human brain. We found two somatosensory networks with distinct functions: one network that encodes the small fluctuations in temperature and consists mainly of bilateral primary somatosensory cortex (SI), and a second right-lateralized network that encodes the intensity of the subjective experience of pain consisting of SI, secondary somatosensory cortex, the posterior cingulate cortex, and the thalamus. We revealed the somatosensory dynamics that build up toward a current subjective percept of pain. The timing suggests a cascade of subsequent processing steps toward the current pain percept.


Neural mechanisms of scene segmentation: recordings from the visual cortex suggest basic circuits for linking field models.
Synchronization of neural activity has been proposed to code feature linking. This was supported by the discovery of synchronized neural activities in cat and monkey visual cortex which occurred stimulus dependent either oscillatory (30-100 Hz) or nonrhythmical, internally generated or stimulus dominated. The area in visual space covered by receptive fields of an actually synchronized assembly of neurons was termed the "linking field." The present paper aims at relating signals of stimulus dependent synchronization and desynchronization, observed by us in the visual cortex of monkeys, with models of basic neural circuits explaining the measured signals and extending our former linking field model. The circuits include: 1) a model neuron with the capability of fast mutual spike linking and decoupling which does not degrade the receptive field properties; 2) linking connections for fast synchronization in neighboring assemblies driven by the same stimulus; 3) feedback inhibition in local assemblies via a common interneuron subserving synchronization, desynchronization, and suppression of uncorrelated signals; and 4) common-input connectivity among members of local and distant assemblies supporting zero-delay phase difference in distributed assemblies. Other recently observed cortical effects that potentially support scene segmentation are shortly reviewed to stimulate further ideas for models. Finally, the linking field hypothesis is critically discussed, including contradictory psychophysical work and new supportive neurophysiological evidence.


ERCC1 expression does not predict survival and treatment response in advanced stage non-small cell lung cancer cases treated with platinum based chemotherapy.
ERCC1 is considered as a promising molecular marker that may predict platinum based chemotherapy response in non small cell lung cancer patients. We therefore investigated whether its expression is indeed associated with clinical outcomes in advanced stage NSCLC patients. Pretreatment tumor biopsy samples of 83 stage 3B and 4 non-small cell lung cancer patients treated with platinum based chemotherapy were retrospectively analyzed for immunohistochemical ERCC1 expression. None of the patients received curative surgery or radiotherapy. By calculating H- scores regarding the extent and intensity of immunohistochemical staining of tumor biopsy samples, ERCC1 expression was found to be positive in 50 patients (60.2%). ERCC1 positive and negative groups had no statistically significant differences regarding treatment response, progression free survival and overall survival (respectively p=0.161; p=0.412; p=0.823). In our study we found no association between ERCC1 expression and survival or treatment response. The study has some limitations, such as small sample size and retrospective analysis method. There is need of more knowledge for use of ERCC1 guided chemotherapy regimens in advanced stage NSCLC.


Pulpitis induction in baboon primary teeth using carious dentine or Streptococcus mutans.
The objective of this equivalency study was to see if a colony of Streptococcus mutans placed into cavities in primary molar teeth produced pulpitis similar to an established pulpitis induction method using carious dentine. In two juvenile baboons (Papio ursinus), occlusal cavities were cut in all 16 primary molar teeth, followed by making a small pulpal exposure after which the cavity was swabbed with 37 per cent phosphoric acid. In one half of the teeth, fresh soft human carious dentine was placed over the pulpal exposure; in the remaining teeth the exposure was covered with a colony of Streptococcus mutans in agar. All the cavities were restored with unlined light-cured composite resin. After 14 days specimens were harvested and examined under the light microscope with the examiner blind to the induction method. In both groups of teeth there was recognisable pulp, hyperaemia, micro-abscesses in the pulp and peri-apical abscesses. Reactions to soft caries were more severe than to Streptococcus mutans. The results show that Streptococcus mutans placed in a cavity with an exposure produces comparable pulpitis to fresh soft human carious dentine in the same type of cavity and that both methods produce pulpitis suitable for testing pulpotomy or pulpectomy treatments.


Local Alignment of DNA Sequence Based on Deep Reinforcement Learning.
Goal: Over the decades, there have been improvements in the sequence alignment algorithm, with significant advances in various aspects such as complexity and accuracy. However, human-defined algorithms have an explicit limitation in view of developmental completeness. This paper introduces a novel local alignment method to obtain optimal sequence alignment based on reinforcement learning. Methods: There is a DQNalign algorithm that learns and performs sequence alignment through deep reinforcement learning. This paper proposes a DQN x-drop algorithm that performs local alignment without human intervention by combining the x-drop algorithm with this DQNalign algorithm. The proposed algorithm performs local alignment by repeatedly observing the subsequences and selecting the next alignment direction until the x-drop algorithm terminates the DQNalign algorithm. This proposed algorithm has an advantage in view of linear computational complexity compared to conventional local alignment algorithms. Results: This paper compares alignment performance (coverage and identity) and complexity for a fair comparison between the proposed DQN x-drop algorithm and the conventional greedy x-drop algorithm. Firstly, we prove the proposed algorithm's superiority by comparing the two algorithms' computational complexity through numerical analysis. After that, we tested the alignment performance actual HEV and E.coli sequence datasets. The proposed method shows the comparable identity and coverage performance to the conventional alignment method while having linear complexity for the [Formula: see text] parameter. Conclusions: Through this study, it was possible to confirm the possibility of a new local alignment algorithm that minimizes computational complexity without human intervention.


Synthesis and applications of stereospecifically (3)H-labeled arachidonic acids as mechanistic probes for lipoxygenase and cyclooxygenase catalysis.
Stereospecifically (3)H-labeled substrates are useful tools in studying the mechanism of hydrogen abstractions involved in the oxygenation of polyunsaturated fatty acids. Here, we describe modified methods for the synthesis of arachidonic acids labeled with a single chiral tritium on the methylene groups at carbons 10 or 13. The appropriate starting material is a ketooctadecanoic acid which is prepared from an unsaturated C18 fatty acid precursor or by total synthesis. The (3)H label is introduced by NaB(3)H(4) reduction and the resulting tritiated hydroxy fatty acid then is tosylated, separated into the enantiomers by chiral phase HPLC, and subsequently transformed into stearic acids. A variety of stereospecifically labeled unsaturated fatty acids are obtained using literature methods of microbial transformation with the fungus Saprolegnia parasitica. Two applications are described: (i) In incubations of [10S-(3)H]- and [10R-(3)H]arachidonic acids in human psoriatic scales we show that a 12R-lipoxygenase accounts not only for synthesis of the major product 12R-HETE, but it contributes also, through subsequent isomerization, to the minor amounts of 12S-HETE. (ii) The [10R-(3)H]- and [10S-(3)H]arachidonic acids were also used to demonstrate that prostaglandin ring formation by cyclooxygenases does not involve carbocation formation at C-10 of arachidonic acid as was hypothesized recently.


Is spinal stenosis better treated surgically or nonsurgically?
For patients with clinical and radiographic lumbar spinal stenosis, is surgery or continued nonsurgical treatment a better option for improvements in baseline disability scores; and what proportion of patients treated surgically and nonsurgically get better, worse, or remain the same with time? We prospectively evaluated 125 consecutive patients for this non-randomized cohort study. Of the patients choosing surgery, 54 underwent decompression only and 42 had decompression and fusion for preexisting spondylolisthesis; twenty-nine patients declined surgery. At 2 years followup, the average improvements in Roland-Morris questionnaire score in the decompression only, decompression with fusion, and nonsurgical groups were 6.9, 6.1, and 1.2, respectively. The percentages of patients who were better, worse, or the same were similar for those who had decompression only (63.3%, 4.1%, and 32.7%, respectively) and decompression with fusion (61.5%, 2.6%, and 35.9%, respectively) but different from those treated without surgery (25.0%, 12.5%, and 62.5%, respectively). We observed no occurrences of cauda equina syndrome or severe neurologic dysfunction in any of the groups after 2 years. A majority of patients declining surgery had persistent symptoms. The majority of patients who choose surgery will be improved but will have residual symptoms and therefore should be counseled about realistic expectations.


Incorporation of integrative medicine education into undergraduate medical education: a longitudinal study.
Integrative medicine (IM) combines complementary medical approaches into conventional medicine and considers the whole person. We implemented a longitudinal IM short-course curriculum into our medical school education. This study aimed to evaluate the feasibility and effectiveness of the curriculum via knowledge and attitude surveys regarding IM among students. A mandatory short IM curriculum across all years of medical school was created and taught by IM professionals and physician faculty members with expertise in integrative therapies. Graduating classes of 2015 and 2016 completed the same survey in their first and third years of medical school. Paired data analysis was done, and only students who completed surveys at both time points were included in final analyses. Of 52 students in each class, 17 (33%) in the class of 2015 and 22 (42%) in the class of 2016 completed both surveys. After the IM curriculum, students' knowledge of and comfort with several IM therapies-biofeedback, mindfulness, and the use of St. John's wort-improved significantly. Students' personal health practices also improved, including better sleep, exercise, and stress management for the class of 2015. Students graduating in 2016 reported decreased alcohol use in their third year compared with their first year. It is feasible to incorporate IM education into undergraduate medical education, and this is associated with improvement in students' knowledge of IM and personal health practices.


The Effect of Parkinson Drug Timing on Cardiovascular Response during Treadmill Exercise in a Person with Parkinson Disease and Freezing of Gait.
To examine the response of cerebral oxygenation during treadmill walking in a person with Parkinson disease (PD) who experiences freezing of gait (FOG) and to determine whether the oxygen response was related to the timing of his PD medication. Client Description: A 61-year-old man with PD performed two bouts of treadmill testing on the same day, during the on- and off-phases of his PD medication. Measures and Outcome: The client experienced two FOG episodes during the first testing session (on-phase with hypokinetic movement session). Cerebral oxygen response (measured by near-infrared spectroscopy) was stable until the FOG episodes occurred, at which point it decreased until the FOG episode was over. No electrocardiogram (ECG) changes or lightheadedness were noted; blood pressure (BP) remained stable. During the second exercise testing session (off-phase with dyskinetic movement session), the client did not experience any FOG episodes, and his cerebral oxygen response remained stable. Toward the end of the second testing session, he experienced lightheadedness and a drop in BP of approximately 30 mmHg, along with significant ST segment depression on his ECG. Haemodynamic and cerebral oxygen changes occurred that were specific to the timing of the client's PD medication and to his FOG episodes. This case study shows a person with PD demonstrating decreased cerebral oxygenation during FOG, which may be based on his variable response to levodopa medication or may be attributable to as yet unidentified physiologic mechanisms.


Effect of organic matter amendment, arsenic amendment and water management regime on rice grain arsenic species.
Arsenic accumulation in rice grain has been identified as a major problem in some regions of Asia. A study was conducted to investigate the effect of increased organic matter in the soil on the release of arsenic into soil pore water and accumulation of arsenic species within rice grain. It was observed that high concentrations of soil arsenic and organic matter caused a reduction in plant growth and delayed flowering time. Total grain arsenic accumulation was higher in the plants grown in high soil arsenic in combination with high organic matter, with an increase in the percentage of organic arsenic species observed. The results indicate that the application of organic matter should be done with caution in paddy soils which have high soil arsenic, as this may lead to an increase in accumulation of arsenic within rice grains. Results also confirm that flooding conditions substantially increase grain arsenic.


Outcome of early stage Merkel carcinoma treated by exclusive radiation: a study of 53 patients.
Early stage Merkel cell carcinoma (MCC) is a rare and aggressive primary skin cancer. The standard of care for MCC is broad excision and adjuvant external beam radiation therapy (EBRT). However, for some patients, anesthesia is contraindicated, while others run the risk of serious aesthetic sequelae. In such cases, exclusive radiotherapy is an interesting alternative to surgery. Though limited data is available, this study evaluates exclusive radiotherapy for MCC, using data from the largest retrospective study to date. All patients who were followed in our center between 1989 and 2019 for histologically proven early stage MCC were included in the study. They were treated either by surgery with a 2-cm clear margin followed by adjuvant radiotherapy (RT) or by exclusive RT. Survival rates with adjuvant and exclusive EBRT were analyzed using Cox model and Fine and Gray model depending on the type of survival. p value < 0.05 was considered significant. Eighty-four patients treated for MCC were included. Fifty-three of them (63.1%) were treated by exclusive RT, and 31 (36.9%) had surgical excision followed by adjuvant RT. Local relapse rate was 13.7% (95% CI 8.0-43.7) in the RT monotherapy group (group A) and 25.8% (95% CI 10.3-56.2) in the surgery + RT group (group B) (p = 0.42). No statistical difference was found for nodal relapse (p = 0.81), metastatic relapse (p = 0.10), disease free survival (p = 0.83) or overall survival (p = 0.98). Our study suggests that exclusive radiotherapy for early Merkel cell carcinoma leads to a similar oncological outcome as combined treatment, with fewer aesthetic sequelae. The approach is interesting for elderly patients with comorbidities or patients for whom surgery would cause significant functional or aesthetic sequelae.


Drugs inhibiting the renin - angiotensin system.
There are several approaches for interfering with the renin-angiotensin system. Antibodies against renin angiotensins I and II (AI and AII) have not been consistently successful in the past, probably because of nonspecific effects; however, recent purification of renin now makes this approach more promising. Renin inhibitors include pepstatin and analogs, lipids and phospholipids, and renin-substrate analogs. Pepstatin and analogs are the most potent and specific but they are not orally active. The phospholipids are the most effective in vivo but their specificity is yet to be established. No renin-substrate analogs have been developed that have biologically significant effects. Some of the most potent and specific agents available for interfering with the renin-angiotensin system are the AII-receptor antagonists. While these compounds effectively prevent the actions of AII, they suffer from several severe deficiencies: partial agonist activity, short duration of action, and lack of oral activity. The recent development of angiotensin-converting enzyme ACE) inhibitors that are orally active has provided the greatest degree of clinical success for inhibitors of the renin-angiotensin system and, consequently, the impetus to develop still better compounds. Captopril (SQ 14,225) is the prototype ACE inhibitor, being highly potent and specific with no other demonstrated pharmacological activity. Captopril is effective in all forms of human and animal models of hypertension except mineralocorticoid hypertension, which requires concomitant diuretic therapy. Because ACE is the same enzyme as kininase II, the enzyme that degrades kinins, the possibility exists that kinins are involved in the cardiovascular action of captopril, although this prospect is unlikely.


Intracranial Volume Measurement: A Systematic Review and Comparison of Different Techniques.
The ability to calculate intracranial volume (ICV) from 3-dimensional imaging is a useful tool in a craniofacial team's armamentarium. Intracranial volume uses range from decision making to assessment. Various methods to calculate ICV exist including fully manual, semiautomatic, and fully automatic techniques and they are used with varying frequency in craniofacial centres globally.This study aimed to systematically analyze and compare ICV calculations across the 3 methods and provide information to allow the reader to utilize these processes in practice.Twenty-six computed tomography scans from Apert patients were used to compare ICV measurements calculated using the following techniques: fully manual segmentation with OsiriX (taken as the gold standard); semiautomatic segmentation using Simpleware ScanIP; and fully automatic segmentation using FSL neuroimaging software. In addition, to assess the effect that a reducing CT scan slice number had on ICV measurement, 13 scans were remeasured using half, quarter, and an eighth of the slices of the full scan.The manual and semiautomatic techniques had intraclass correlation coefficients of 0.997, and 0.993 respectively. Intracranial volume measurements using the semi- and fully automatic techniques showed high linear correlation with manual techniques (R = 0.993 and R = 0.995). The coefficients of determination for full scan versus half, quarter, and eighth scan were R = 0.98, 0.96, and 0.94 respectively.Similar ICV results can be obtained using manual, semiautomatic, or automatic techniques with decreasing amount of time required to perform each method. Command line code for the fully automatic method is provided.


Characterization of the organic hydroperoxide resistance system of Brucella abortus 2308.
The organic hydroperoxide resistance protein Ohr has been identified in numerous bacteria where it functions in the detoxification of organic hydroperoxides, and expression of ohr is often regulated by a MarR-type regulator called OhrR. The genes annotated as BAB2_0350 and BAB2_0351 in the Brucella abortus 2308 genome sequence are predicted to encode OhrR and Ohr orthologs, respectively. Using isogenic ohr and ohrR mutants and lacZ promoter fusions, it was determined that Ohr contributes to resistance to organic hydroperoxide, but not hydrogen peroxide, in B. abortus 2308 and that OhrR represses the transcription of both ohr and ohrR in this strain. Moreover, electrophoretic mobility shift assays and DNase I footprinting revealed that OhrR binds directly to a specific region in the intergenic region between ohr and ohrR that shares extensive nucleotide sequence similarity with so-called "OhrR boxes" described in other bacteria. While Ohr plays a prominent role in protecting B. abortus 2308 from organic hydroperoxide stress in in vitro assays, this protein is not required for the wild-type virulence of this strain in cultured murine macrophages or experimentally infected mice.


Effects of Sachet Water Consumption on Exposure to Microbe-Contaminated Drinking Water: Household Survey Evidence from Ghana.
There remain few nationally representative studies of drinking water quality at the point of consumption in developing countries. This study aimed to examine factors associated with E. coli contamination in Ghana. It drew on a nationally representative household survey, the 2012-2013 Living Standards Survey 6, which incorporated a novel water quality module. E. coli contamination in 3096 point-of-consumption samples was examined using multinomial regression. Surface water use was the strongest risk factor for high E. coli contamination (relative risk ratio (RRR) = 32.3, p < 0.001), whilst packaged (sachet or bottled) water use had the greatest protective effect (RRR = 0.06, p < 0.001), compared to water piped to premises. E. coli contamination followed plausible patterns with digit preference (tendency to report values ending in zero) in bacteria counts. The analysis suggests packaged drinking water use provides some protection against point-of-consumption E. coli contamination and may therefore benefit public health. It also suggests viable water quality data can be collected alongside household surveys, but field protocols require further revision.


Milk thistle extract and silymarin inhibit lipopolysaccharide induced lamellar separation of hoof explants in vitro.
The pathogenesis of laminitis is not completely identified and the role of endotoxins (lipopolysaccharides, LPS) in this process remains unclear. Phytogenic substances, like milk thistle (MT) and silymarin, are known for their anti-inflammatory and antioxidant properties and might therefore have the potential to counteract endotoxin induced effects on the hoof lamellar tissue. The aim of our study was to investigate the influence of endotoxins on lamellar tissue integrity and to test if MT and silymarin are capable of inhibiting LPS-induced effects in an in vitro/ex vivo model. In preliminary tests, LPS neutralization efficiency of these phytogenics was determined in an in vitro neutralization assay. Furthermore, tissue explants gained from hooves of slaughter horses were tested for lamellar separation after incubation with different concentrations of LPS. By combined incubation of explants with LPS and either Polymyxin B (PMB; positive control), MT or silymarin, the influence of these substances on LPS-induced effects was assessed. In the in vitro neutralization assay, MT and silymarin reduced LPS concentrations by 64% and 75%, respectively, in comparison PMB reduced 98% of the LPS concentration. In hoof explants, LPS led to a concentration dependent separation. Accordantly, separation force was significantly decreased by 10 µg/mL LPS. PMB, MT and silymarin could significantly improve tissue integrity of explants incubated with 10 µg/mL LPS. This study showed that LPS had a negative influence on the structure of hoof explants in vitro. MT and silymarin reduced endotoxin activity and inhibited LPS-induced effects on the lamellar tissue. Hence, MT and silymarin might be used to support the prevention of laminitis and should be further evaluated for this application.


Fucoidan exerts protective effects against diabetic nephropathy related to spontaneous diabetes through the NF-κB signaling pathway in vivo and in vitro.
Fucoidan, an extract of the seaweed, Fucus vesiculosus, has been widely investigated for its antioxidant effects. However, to date and to the best of our knowledge, pathological studies on the effects of fucoidan against diabetic nephropathy (DN) related to spontaneous diabetes have not been carried out. DN is one of the most serious microvascular complications of diabetes. Therefore, in the present study, the effects of fucoidan against DN related to spontaneous diabetes were investigated in vitro and in vivo. Goto-Kakizaki (GK) rats were allowed free access to standard rat food with or without fucoidan for 13 weeks, and Wistar rats were used as controls. Fucoidan did not show any cytotoxicity on glomerular mesangial cells (GMCs) which were separated from rat kidneys. Fasting blood glucose levels were measured using a blood glucose meter, blood urea nitrogen (BUN) and serum creatinine (Cr) levels were measured using an automatic biochemistry analyzer and urine protein levels were measured using an ELISA kit. Collagen Ⅳ levels in the renal cortex were measured using an ELISA kit, and the expression levels of transforming growth factor-β1 (TGF-β1) and fibronectin (FN) in the renal cortex and GMCs, and nuclear factor-κB (NF-κB) in GMCs were determined by western blot analysis. Fasting blood glucose, BUN, serum Cr, urine protein and collagen Ⅳ levels, and the expression of TGF-β1 and FN, as well as NF-κB p65 nuclear translocation all significantly increased in the GK rats compared with the control Wistar rats. The increase in the fasting blood glucose, BUN, serum Cr, urine protein and collagen Ⅳ levels in the renal cortex was reversed in the GK rats which were orally administered fucoidan. The oral administration of fucoidan also decreased the expression of TGF-β1 and FN in the renal cortex and GMCs, as well as the nuclear translocation of NF-κB p65 in the GMCs. Taken together, the data from our in vitro and in vivo experiments indicate that fucoidan attenuates hyperglycemia and prevents or impedes the development of DN related to spontaneous diabetes by attenuating the activation of the NF-κB signaling pathway.


Investigation of the heparin-thrombin interaction by dynamic force spectroscopy.
The interaction between heparin and thrombin is a vital step in the blood (anti)coagulation process. Unraveling the molecular basis of the interactions is therefore extremely important in understanding the mechanisms of this complex biological process. In this study, we use a combination of an efficient thiolation chemistry of heparin, a self-assembled monolayer-based single molecule platform, and a dynamic force spectroscopy to provide new insights into the heparin-thrombin interaction from an energy viewpoint at the molecular scale. Well-separated single molecules of heparin covalently attached to mixed self-assembled monolayers are demonstrated, whereby interaction forces with thrombin can be measured via atomic force microscopy-based spectroscopy. Further these interactions are studied at different loading rates and salt concentrations to directly obtain kinetic parameters. An increase in the loading rate shows a higher interaction force between the heparin and thrombin, which can be directly linked to the kinetic dissociation rate constant (koff). The stability of the heparin/thrombin complex decreased with increasing NaCl concentration such that the off-rate was found to be driven primarily by non-ionic forces. These results contribute to understanding the role of specific and nonspecific forces that drive heparin-thrombin interactions under applied force or flow conditions.


Evolution of Rh blood group genes have experienced gene conversions and positive selection.
There are two tightly linked loci (D and CE) for the human Rh blood group. Their gene products are membrane proteins having 12 transmembrane domains and form a complex with Rh50 glycoprotein on erythrocytes. We constructed phylogenetic networks of human and nonhuman primate Rh genes, and the network patterns suggested the occurrences of gene conversions. We therefore used a modified site-by-site reconstruction method by using two assumed gene trees and detected 9 or 11 converted regions. After eliminating the effect of gene conversions, we estimated numbers of nonsynonymous and synonymous substitutions for each branch of both trees. Whichever gene tree we selected the branch connecting hominoids and Old World monkeys showed significantly higher nonsynonymous than synonymous substitutions, an indication of positive selection. Many other branches also showed higher nonsynonymous than synonymous substitutions; this suggests that the Rh genes have experienced some kind of positive selection.


MRI: how to understand it.
MRI is a staple of the neurologist's armoury when facing diagnostic challenges. At times, it can reveal or confirm the diagnosis with clarity, at others it brings us no further forwards, or even muddies the water. We rely on the expertise of neuroradiology colleagues to interpret MR images, but the choice of protocol for MR acquisition and its interpretation hinge crucially on the clinical information we provide. Having a degree of understanding about how MRI works, its limitations and pitfalls, can help to optimise what we learn from a scan.


[Rational (injection) of calcitonin for stimulation of the mandibular reparative regeneration].
This investigation permit to detect, that first resorption stage of the mandible reparative regeneration terminats after fracture 5 days later. Calcitonine injection during 5 days after fracture i.e. in paratiroid hormone dependent stage distorts normal reparative process. Rats with traumatic osteomielitis become 1.5 times more and rats with normal regeneration become 3 times less. Injection calcitonine in KT-dependent stage, i.e. in 6-11 days after fracture increases quantity of rats with normal regeneration in 7 times and decreases quantity animals with traumatic osteomielitis on 50%. There's recommendation to inject KT from 6 days after trauma.


Death and dying abroad: the Canadian experience.
The objective was to examine the characteristics of international travelers from Canada, who have died while abroad, and to review the health protection and promotion strategies for prevention of adverse health outcomes associated with travel, which may have prevented these deaths. An EpiInfo 6 program was created to analyse all of the Consular reports received in 1995 via the Secure Integrated Global Network, which provides communications and computerization services to the Department of Foreign Affairs and International Trade, Canada. The Consular Management and Operations System was designed to support the delivery of consular services by the Department, and to link Headquarters in Ottawa with missions in other countries, through case management files, including a "Death Abroad" file. The type of data collected included personal demographics (age, gender), date, country, and cause of death. In 1995, consular services received 309 reports of Canadians dying abroad. Two hundred and twenty deaths were males (71.2%), and 69 were females (22.3%). The average age (56 years) and median age (43 years) were similar for males and females (age range 0.3-86 years). Recorded causes of death were: natural (62.1%), accidents (24.9%), murder (7.8%), and suicide (5.2%). Cardiovascular disease and trauma were the two most commonly specified causes of death. At least 36% of the deaths occurring in Canadian travelers would be considered preventable. Pretravel medical interventions for travelers with known preexisting medical problems, may have prevented many more deaths. International travelers need to be aware of the health risks associated with travel. Access to appropriate health risk assessment, prior to exposure, in many cases, would have prevented death abroad.


LogD: lipophilicity for ionisable compounds.
The octanol/water partition coefficient (Kow) for organic compounds is widely used in predictive environmental studies. A significant proportion of contaminants of surface and ground water are ionisable (e.g. many pesticides, pharmaceuticals, metabolites). Such compounds may be partially ionised dependent on the pH. Since the neutral and ionic species exhibit different polarities, the Kow value of ionisable pesticides is pH dependent. It is therefore essential to determine Kow values over the full range of pH that occurs in the environment in order to get appropriate predictors. Numerous methods are available to measure lipophilicity but only a few are appropriate for ionisable pesticides (e.g. pH metric and filter probe methods). Parameters such as pH and ionic strength need to be carefully controlled when working with ionisable compounds. Variation of these factors probably explains why literature can yield Kow values that differ by more than one order of magnitude for some compounds. In this article, Kow values obtained for six acidic pesticides with three different methods are compared as well (data from the literature, measured by pH metric method and calculated with five computer programs). The values used in predictive regression equations needs to be either measured with a suitable method or selected from the literature with great care.


Ultrasound Measurement of Lateral Patellar Displacement: A Cadaveric Validation Study.
Patellofemoral pain syndrome (PFPS) is one of the most common musculoskeletal complaints seen in outpatient settings. It has been suggested that hip adduction creates loads on the iliotibial band and causes lateral displacement of the patella (patellar tilt), which can lead to uneven patellofemoral joint loading, and hence, cause patellofemoral pain. In previous studies in the literature, ultrasound has been used to measure lateral patellar displacement. However, the method lacks validity data. The aim of this study was to validate the use of ultrasound to measure lateral displacement of the patella, by comparing the position of the patella as measured first by ultrasound, and then by direct measurement. Descriptive Laboratory Study. Nine soft-fixed cadavers were used in this study. The cadavers had been donated for anatomical examination and research under the Human Tissue Act (2004). The distance between the lateral femoral condyle and the lateral edge of the patella were measured by B-mode real-time ultrasound, and then by direct measurement, in two positions, neutral and at 20° hip adduction. The mean difference in the patella-to-lateral femoral condyle distance in the neutral position and at 20° adduction was 0.27 cm (ultrasound), and 0.34 cm (direct measurement), respectively. There were no significant differences between the measurements obtained by US and by direct measurement (Pearson correlation= 0.97, p=0.83). Ultrasound is a valid and reliable method for measuring patellar position relative to the femoral condyle, and the validity data reported here suggest that it can be used with confidence in clinic to assess lateral patellar displacement. 3.


An educational intervention for district nurses: use of electronic records in leg ulcer management.
To evaluate district nurses' management of leg ulcer patients and the effects of an in-service education programme led by district nurses as local educators at primary health-care centres. Data were collected from electronic patient records (EPRs), both before and after the educational intervention. Nineteen district nurses undertook a one-day course focusing on four themes: Doppler assessment and measurement of ankle brachial pressure index; compression treatment; patient education; nursing documentation. Fourteen acted as in-service educators; 12 educators completed the intervention. The EPRs were scrutinised with an audit tool. The documentation on the selected key areas for the management of patients with leg ulcers was generally sparse, although the educational intervention resulted in statistically significant effects on documentation in three areas. Further improvements in care are necessary, as are qualitative and quantitative studies to explore the large discrepancies between guidelines and everyday clinical practice in this field.


Granulocyte-macrophage colony-stimulating factor enhances selective effector functions of tissue-derived macrophages.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by a variety of cells at sites of exposure to antigens. GM-CSF has a stimulatory effect on a number of neutrophil functions, but the effect on macrophage function is less clear. We investigated the effect of purified murine recombinant GM-CSF on murine peritoneal macrophage oxidative metabolism, Fc-dependent phagocytosis, anti-Toxoplasma activity, and expression of class II major histocompatibility antigen (Iad). GM-CSF significantly increased phorbol myristate acetate- and zymosan-elicited H2O2 release by resident and thioglycollate-elicited macrophages after 48 hours in vitro. The effect of recombinant GM-CSF was blocked by polyclonal anti-GM-CSF antibody and was not altered by lipopolysaccharide (0.01 to 1.0 microgram/mL). GM-CSF also stimulated Fc-dependent phagocytosis by peritoneal macrophages, although the stimulation of resident macrophages (1.4-fold) was less dramatic than that of thioglycollate-elicited cells (2.1-fold). GM-CSF (at doses up to 100 U/mL) had no effect on macrophage anti-Toxoplasma activity or on expression of Iad. In addition to stimulating macrophage growth, GM-CSF selectively promotes the functional capacity of tissue-derived macrophages.


The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit.
According to the telomere hypothesis of senescence, the progressive shortening of telomeres that occurs upon division of normal somatic cells eventually leads to cellular senescence. The immortalisation of human cells is associated with the acquisition of a telomere maintenance mechanism which is usually dependent upon expression of the enzyme telomerase. About one third of in vitro immortalised human cell lines, however, have no detectable telomerase but contain telomeres that are abnormally long. The nature of the alternative telomere maintenance mechanism (referred to as ALT, for Alternative Lengthening of Telomeres) that must exist in these telomerase-negative cells has not been elucidated. It has previously been shown that abnormal lengthening of yeast telomeres may occur due to mutations in the yeast telomerase RNA gene. That this is not the mechanism of the abnormally long telomeres in ALT cell lines was demonstrated by the finding that seven of seven ALT lines have wild-type human telomerase RNA (hTR) sequence, including a novel polymorphism that is present in 30% of normal individuals. We found that two ALT cell lines have no detectable expression of the hTR gene. This shows that the ALT mechanism in these cell lines is not dependent on hTR. Expression of exogenous hTR via infection of these cells with a recombinant hTR-adenovirus vector did not result in telomerase activity, indicating that their lack of telomerase activity is not due to absence of hTR expression. We conclude that the ALT mechanism is not dependent on the expression of hTR, and does not involve mutations in the hTR sequence.


Short communication: Genomic selection for hoof lesions in first-parity US Holsteins.
Hoof lesions contributing to lameness are crucial economic factors that hinder the profitability of dairy enterprises. Producer-recorded hoof lesions data of US Holsteins were categorized into infectious (abscess, digital and interdigital dermatitis, heel erosion, and foot rot) and noninfectious (korn, corkscrew, sole and toe ulcer, sole hemorrhage, white line separation, fissures, thin soles, and upper leg lesions) categories of hoof lesions. Pedigree- and genomic-based univariate analyses were conducted to estimate the variance components and heritability of infectious and noninfectious hoof lesions. A threshold sire model was used with fixed effects of year-seasons and random effects of herd and sire. For genomic-based analysis, a single-step procedure was conducted, incorporating H matrix to estimate genomic variance components and heritability for hoof lesions. The pedigree-based analysis produced heritability estimates of 0.11 (±0.05) for infectious hoof lesions and 0.08 (±0.05) for noninfectious hoof lesions. The single-step genomic analysis produced heritability estimates of 0.14 (±0.06) for infectious hoof lesions and 0.12 (±0.08) for noninfectious hoof lesions. Approximated genetic correlations between hoof lesion traits and hoof type traits along with productive life and net merit were all low and ranged between -0.25 and 0.14. Sire reliabilities increased, on average, by 0.24 and 0.18 for infectious and noninfectious hoof lesions, respectively, with incorporation of genomic data.


Lack of production of electron-shuttling compounds or solubilization of Fe(III) during reduction of insoluble Fe(III) oxide by Geobacter metallireducens.
Studies with the dissimilatory Fe(III)-reducing microorganism Geobacter metallireducens demonstrated that the common technique of separating Fe(III)-reducing microorganisms and Fe(III) oxides with semipermeable membranes in order to determine whether the Fe(III) reducers release electron-shuttling compounds and/or Fe(III) chelators is invalid. This raised doubts about the mechanisms for Fe(III) oxide reduction by this organism. However, several experimental approaches indicated that G. metallireducens does not release electron-shuttling compounds and does not significantly solubilize Fe(III) during Fe(III) oxide reduction. These results suggest that G. metallireducens directly reduces insoluble Fe(III) oxide.


Glassy carbon microelectrode arrays enable voltage-peak separated simultaneous detection of dopamine and serotonin using fast scan cyclic voltammetry.
Progress in real-time, simultaneous in vivo detection of multiple neurotransmitters will help accelerate advances in neuroscience research. The need for development of probes capable of stable electrochemical detection of rapid neurotransmitter fluctuations with high sensitivity and selectivity and sub-second temporal resolution has, therefore, become compelling. Additionally, a higher spatial resolution multi-channel capability is required to capture the complex neurotransmission dynamics across different brain regions. These research needs have inspired the introduction of glassy carbon (GC) microelectrode arrays on flexible polymer substrates through carbon MEMS (C-MEMS) microfabrication process followed by a novel pattern transfer technique. These implantable GC microelectrodes provide unique advantages in electrochemical detection of electroactive neurotransmitters through the presence of active carboxyl, carbonyl, and hydroxyl functional groups. In addition, they offer fast electron transfer kinetics, capacitive electrochemical behavior, and wide electrochemical window. Here, we combine the use of these GC microelectrodes with the fast scan cyclic voltammetry (FSCV) technique to optimize the co-detection of dopamine (DA) and serotonin (5-HT) in vitro and in vivo. We demonstrate that using optimized FSCV triangular waveform at scan rates ≤700 V s-1 and holding and switching at potentials of 0.4 and 1 V respectively, it is possible to discriminate voltage reduction and oxidation peaks of DA and 5-HT, with 5-HT contributing distinct multiple oxidation peaks. Taken together, our results present a compelling case for a carbon-based MEA platform rich with active functional groups that allows for repeatable and stable detection of electroactive multiple neurotransmitters at concentrations as low as 1.1 nM.


Trans-scaphoid dislocation of the proximal row: a case report.
This report is of a 32 year old man who presented with complains of pain, swelling and deformity of right wrist of four weeks duration. He gave history of road traffic accident four weeks back leading to injury to right wrist; Preoperative radiographs and C.T. scan images were suggestive of trans-scaphoid dislocation of the proximal row of wrist. A volar and dorsal approach were used to reduce this complex dislocation but was not successful. Wrist arthodesis was performed after doing proximal row carpectomy. One year follow-up of the patient showed fair result with grip strength of 85% to contralateral side and modified Mayo wrist score of 65 at one year.


[Precision and comparison of CT-, MRI- and DL-controlled interventions exemplified by lumbar facet infiltration--an experimental study].
We evaluated the accuracy of the needle tip representation by different imaging techniques for the guidance of facet infiltrations. For visualisation of the lumbar facet joints we used a high-field magnetic resonance tomograph (MRT) with a 2.0 Tesla field and 3.5 mm slice thickness, an open low-field magnetic resonance tomography (MRT) with an 0.064 Tesla field and 9 mm slice thickness, and IMATRON electron beam computed tomograph (EBCT) with a slice thickness of 6 mm, and a mobile C-arm fluoroscope. The study was performed on 4 human cadaveric lumber spine preparations, each of which had 8 facet joints. Under imaging control, special injection needles were placed as close as possible to the facet joint space. Following placement of he needle, all specimens were scanned with the electron beam tomograph using a slice thickness of 1.5 mm. The thin-slice study served as the gold standard. The distance between the tip of the needle and the facet joint was measured in all the images. Comparison of the different modalities with the gold standard revealed the following results: 1) median values of the absolute differences were 1.25 mm for high-field MRI, 1.35 mm for 6 mm EBCT, 2.05 mm for low-field MRI, and 2.30 mm for X-ray fluoroscopy. 2) While there was no statistically significant difference in the accuracy of tip localization between high-field MRI and 6" EBCT (p = 0.293), both systems were more precise than low-field MRI (p = 0.04) and X-ray fluoroscopy (p = 0.009). When choosing the best imaging technique, such additional factors as radiation, costs and time, must also be considered. Provided necessary radiological precautions are taken, and assuming careful pre-interventional planning, CT. EBCT and X-ray fluoroscopy are currently more effective than the expensive, time-consuming and costly magnetic resonance tomography.


Potential role of novel nucleoside analogs in the treatment of acute myeloid leukemia.
Nucleoside analogs remain a cornerstone in acute myeloid leukemia therapy. As many new nucleosides are being investigated in clinical trials, this review aims to update the current state of experience with these new compounds and where they may fit into treatment strategies for acute myeloid leukemia. Many new nucleoside analogs are emerging with novel metabolic properties and mechanisms of action. Some have entered clinical trials and are actively investigated in the context of acute myeloid leukemia therapy. Clofarabine is the most-developed compound, and single-agent experience and combinations with other active agents in acute myeloid leukemia are being explored. Troxacitabine and sapacitabine are still in single-agent phases of their development and clinical experience is accumulating quickly. Nucleosides remain the most important class of drugs in acute myeloid leukemia and the interest in new compounds is strong. The plethora of new analogs continues to provide ample opportunity to expand the effectiveness of these drugs in acute myeloid leukemia therapy. Furthermore, their unique mechanisms of action provide possibilities for mechanism-based combinations.


Acute brain injury increases pulmonary capillary permeability via sympathetic activation-mediated high fluid shear stress and destruction of the endothelial glycocalyx layer.
Neurogenic pulmonary edema secondary to acute brain injury (ABI) is a common and fatal disease condition. However, the pathophysiology of brain-lung interactions is incompletely understood. This study aims to investigate whether sympathetic activation-mediated high fluid shear stress after ABI would damage pulmonary endothelial glycocalyx thus leading to increased pulmonary capillary permeability. The tricuspid annular plane systolic excursion (TAPSE) was detected in a rat model of controlled cortical impact (CCI) and CCI + transection of the cervical sympathetic trunk (TCST). Changes in pulmonary capillary permeability were assessed by analyzing the Evans blue, measuring the dry/wet weight ratio of the lungs and altering protein levels in the bronchoalveolar lavage fluid (BALF). The parallel-plate flow chamber system was used to simulate the fluid shear stress in vitro. Western blotting and immunofluorescence staining were used to determine the expression levels of hyaluronan-binding protein (CEMIP), syndecan-1 and tight junction proteins (TJPs, including claudin-5 and occludin). TCST could restrain cardiac overdrive and sympathetic activation in a rat model of CCI. Compared to the CCI group, the CCI + TCST group showed a reduction of CEMPI (which degrades hyaluronic acid), along with an increase of syndecan-1 and TJPs. CCI + TCST group presented decreasing pulmonary capillary permeability. In vitro, high shear stress (HSS) increased the expression of CEMIP and reduced syndecan-1 and TJPs, which was coordinated with the results in vivo. Our findings show that sympathetic activation-mediated high fluid shear stress after ABI would damage pulmonary endothelial glycocalyx thus leading to increased pulmonary capillary permeability.


Regional variations in breast cancer incidence among California women, 1988-1997.
Internationally, California has some of the highest breast cancer rates; these rates also show substantial regional variations within the state. This study describes geographic breast cancer incidence patterns within California and evaluates the degree to which socioeconomic status (SES) and urbanization explain the regional variability. Invasive breast cancer cases in women > or =20 year of age were identified from the California Cancer Registry, for 1988-1997, then assigned to one of three regions (San Francisco Bay Area, Southern Coastal Area and the rest of California), based on residence at diagnosis. Neighborhood SES and urbanization were derived from U.S. Census data. Rate ratios (RR) and 95% confidence intervals (CI) were computed using Poisson regression. Analyses were conducted for all invasive breast cancer cases (n=176,302) and by selected histologic subtypes: ductal (n=121,619); lobular (n=13,410); mixed ductal and lobular (n=9744). Compared to block groups with the lowest quartile of SES, rates were highest in block groups with high SES. Rates also were higher in suburban and city areas than in small town/rural areas. Compared to the rest of California, age- and race-adjusted rates for all breast cancer were approximately 20% higher in the San Francisco Bay Area and 10% higher in the Southern Coastal Area. After adjusting for SES and urbanization the rate ratios were reduced to near unity (RR=1.06, 95% CI: 1.03-1.09 for San Francisco Bay Area; RR=1.02, 95% CI: 0.99-1.04 for Southern Coastal Area). Rates ratios for ductal carcinomas mirrored those for all cases. For lobular cases, rate ratios remained elevated after adjustment for age, race/ethnicity, neighborhood SES and urbanization (RR=1.18, 95% CI: 1.11-1.27 for San Francisco Bay Area; RR=1.10, 95% CI: 1.04-1.17 for Southern Coastal Area). For the subset of cases with mixed ductal and lobular histologies, the rate ratio for the San Francisco Bay Area was no longer elevated after adjusting for age, race/ethnicity, SES and urbanization (RR=0.92, 95% CI: 0.84-1.01); the adjusted rate ratio for the Southern Coastal Area, however, remained elevated (RR=1.22, 95% CI: 1.12-1.32). Regional differences in neighborhood SES and urbanization appear to largely explain regional rate differences in California for all breast cancers and ductal carcinomas but do not fully explain geographic patterns of breast cancer with a lobular component.


SEQUENTIAL FORMATION AND ACCUMULATION OF PRIMARY AND SECONDARY SHUNT METABOLIC PRODUCTS IN CLAVICEPS PURPUREA.
The fungus Claviceps purpurea was grown on a rich and a limited nutrient medium such that alkaloid was produced after 8 days on the former medium and after 3 days on the latter medium. Cultures grown on both were assayed for the primary shunt metabolic products, polyols, trehalose, lipids, ribonucleic acid, and polyphosphate, and the secondary metabolic product, ergot alkaloid. Although differing considerably in composition, the two media nevertheless allowed formation of both primary and secondary shunt products. In both instances, however, the secondary product, ergot alkaloid, did not form until formation and accumulation of the primary products had ceased and the mycelial content of these products was actually decreasing. In both instances, alkaloid formation took place after the total dry weight of the mycelium had begun to decrease but while the dry weight of the residual, or structural portion of the mycelium, was either constant or increasing. The dilution of labeling in mannitol isolated from mycelia grown on rich medium containing 1,6-C(14)-labeled mannitol was 2.2. Thus, about half of the mycelial mannitol was actually mannitol which had been taken up directly from the medium.


Extreme variation in migration strategies between and within wandering albatross populations during their sabbatical year, and their fitness consequences.
Migratory behavior, routes and zones used during the non-breeding season are assumed to have been selected to maximize fitness, and can lead to genetic differentiation. Yet, here we show that migration strategies differ markedly between and within two genetically similar populations of wandering albatross Diomedea exulans from the Crozet and Kerguelen archipelagos in the Indian Ocean. Wandering albatrosses usually breed biennially if successful, and during the sabbatical year, all birds from Kerguelen migrate to the Pacific Ocean, whereas most from Crozet are sedentary. Instead of taking the shortest routes, which would involve a return against headwinds, migratory birds fly with the westerly winds, requiring detours of 10,000 s km. In total, migrants circumnavigate Antarctica 2 to 3 times, covering more than 120,000 km in a single sabbatical year. Our results indicate strong links between migratory behavior and fitness; all birds from Kerguelen breed biennially, whereas a significant proportion of those from Crozet, especially females, are sedentary and breed in consecutive calendar years. To breed annually, these females temporarily change mate, but return to their original partner in the following year. This extreme variation in migratory behavior has important consequences in term of life history evolution and susceptibility to climate change and fisheries.


Enhanced transcription of pancreatic peptide YY by 1α-hydroxyvitamin D3 administration in streptozotocin-induced diabetic mice.
Peptide YY (PYY) is a peptide hormone secreted from L cells in the intestine in response to food intake that regulates appetite and gastrointestinal function. PYY is also produced in the pancreatic islets. The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D3 that regulates numerous physiological processes. VDR is expressed in the pancreatic islets and pharmacological VDR activation increases PYY expression in mouse peripheral islet cells. Although VDR is present in insulin-producing β cells as well as non-β cells, the role of β cell VDR in Pyy transcription remains unknown. We treated mice with streptozotocin to ablate β cells in the pancreas. Pancreatic Vdr mRNA expression was decreased in streptozotocin-induced diabetic mice. Interestingly, streptozotocin-treated mice exhibited increased basal Pyy expression and 1α-hydroxyvitamin D3 treatment further increased expression. Moreover, 1α-hydroxyvitamin D3 increased mRNA expression of pancreatic polypeptide and decreased that of neuropeptide Y in streptozotocin-induced diabetic mice but not in control mice. 1α-Hydroxyvitamin D3 slightly increased mRNA expression of insulin but transcript levels were nearly undetectable in the pancreas of streptozotocin-treated mice. Thus, VDR in non-β islet cells is involved in Pyy expression in the mouse pancreas. The findings from this β cell ablation study suggest a hormone transcription regulatory network composed of β cells and non-β cells.


Morphometric analysis of embryonic rat trigeminal neurons treated with different neurotrophins.
In whole-mount explant cultures of the trigeminal ganglion (TG) with intact peripheral and brainstem targets, exogenous application of nerve growth factor (NGF) and neurotrophin-3 (NT-3) leads to elongation and precocious arborization of embryonic trigeminal axons, respectively. In addition, neurotrophins play a major role in survival and differentiation of distinct classes of TG neurons. In the present study, we conducted morphometric analyses of trigeminal neurons exposed to exogenous NGF or NT-3 in whole-mount explant cultures. Explants dissected from embryonic day (E) 13 and E15 rats were cultured in the presence of serum-free medium (SFM) or in SFM supplemented with NGF or NT-3 for 3 days. TG neurons were then retrogradely labeled with lipophilic tracer DiI and their soma size distributions were compared following different treatments. The mean diameters of E13 and E15 trigeminal neurons grown in the presence of NT-3 were similar to those grown in SFM. On the other hand, in cultures supplemented with NGF, the mean diameters of neurons were larger at E13, but smaller at E15. Double immunolabeling with TrkA and TrkC antibodies confirmed the presence of large-diameter TrkA-positive neurons in E13 TG, but not in E15 TG. At both ages, other large-diameter neurons expressed only TrkC. These results show that exposure to NGF leads to phenotypic changes in TrkA-expressing trigeminal neurons at early embryonic development, but selective survival of small diameter neurons at later ages.


Gambling for Gatorade: risk-sensitive decision making for fluid rewards in humans.
Determining how both humans and animals make decisions in risky situations is a central problem in economics, experimental psychology, behavioral economics, and neurobiology. Typically, humans are risk seeking for gains and risk averse for losses, while animals may display a variety of preferences under risk depending on, amongst other factors, internal state. Such differences in behavior may reflect major cognitive and cultural differences or they may reflect differences in the way risk sensitivity is probed in humans and animals. Notably, in most studies humans make one or a few choices amongst hypothetical or real monetary options, while animals make dozens of repeated choices amongst options offering primary rewards like food or drink. To address this issue, we probed risk-sensitive decision making in human participants using a paradigm modeled on animal studies, in which rewards were either small squirts of Gatorade or small amounts of real money. Possible outcomes and their probabilities were not made explicit in either case. We found that individual patterns of decision making were strikingly similar for both juice and for money, both in overall risk preferences and in trial-to-trial effects of reward outcome on choice. Comparison with decisions made by monkeys for juice in a similar task revealed highly similar gambling styles. These results unite known patterns of risk-sensitive decision making in human and nonhuman primates and suggest that factors such as the way a decision is framed or internal state may underlie observed variation in risk preferences between and within species.


Synthesis of Heterostructured Metallic Films with Precisely Defined Multimodal Microstructures.
Heterostructured materials (e.g., metals with multimodal microstructures) offer the promise of unprecedented functionality and performance by avoiding trade-offs between competing properties such as strength and ductility. However, methods to reproducibly synthesize heterostructured materials with explicit microstructural control are still elusive, and therefore optimizing their mechanical and functional properties via microstructural engineering is presently infeasible. Here, we describe a broadly applicable method to synthesize metallic films with precisely defined multimodal microstructures. This method enables explicit control of the size, volume fraction, and spatial connectivity of fine and coarse grains by exploiting two distinct forms of film growth (epitaxial and Volmer-Weber) simultaneously. We fabricated Cu and Fe films with bimodal and multimodal microstructures using this method and investigated their mechanical properties, which reveals a hitherto unknown breakdown in the strength-ductility synergy produced by such microstructures at small sample dimensions. Our approach enables systematic design of multimodal microstructures to tailor the mechanical properties of metallic materials and provides a platform to create functional thin films and 2D materials with prescribed phase morphologies and microstructures.


Explicit and implicit learning of event sequences: evidence from event-related brain potentials.
Event-related brain potentials (ERPs) were recorded during a serial reaction time (RT) task, where single deviant items seldom (Experiment 1) or frequently (Experiment 2) replaced 1 item of a repeatedly presented 10-item standard sequence. Acquisition of sequence knowledge was reflected in faster RTs for standard as compared with deviant items and in an enhanced negativity (N2 component) of the ERP for deviant items. Effects were larger for participants showing explicit knowledge in their verbal reports and in a recognition test. The lateralized readiness potential indicated that correct responses were activated with shorter latencies after training. For deviant items, participants with explicit knowledge showed an initial activation of the incorrect but expected response. These findings suggest that the acquisition of explicit and implicit knowledge is reflected in different electrophysiological correlates and that sequence learning may involve the anticipatory preparation of responses.


An Efficient Synthesis of Bis-indolylindane-1,3-diones, Indan-1,3-diones, and Indene-1,3(2H)-denies Using [Hbim]BF 4 Ionic Medium.
We prepared a brand new molecule in one step for the synthesis of bis-indolylindane-1,3-dione and indan-1,3-diones from the reaction of ninhydrin and 3 substituted/unsubstituted indoles using [Hbim]BF4 ionic liquid in excellent yields. The method was also used for the synthesis of novel indene-1,3(2H)-denies derivatives.


Effect of increased calcium concentration in sea water on calcification and photosynthesis in the scleractinian coral Galaxea fascicularis.
The relationship between calcification and photosynthesis in coral was investigated using standard sea water with enhanced calcium concentration. In standard sea water at 23 degrees C with the calcium concentration increased by 2.5 mmol l(-1), incorporation of calcium into the skeleton increased by 30-61 %, depending on the method of data normalisation, and photosynthesis, measured as (14)C incorporation into the tissues, also increased by 87 %. At 29 degrees C, calcium incorporation into the skeleton increased by 54-84 % and (14)C incorporation increased by 32 % when sea water calcium concentration was increased by 5 mmol l(-1). However, photosynthesis measured as net photosynthetic oxygen production did not increase. Similarly there was no change in respiration rate when coral polyps were incubated in high-calcium sea water. It is conjectured that an increase in photorespiration may be responsible for the latter observations. Bisphosphonate has been considered to inhibit calcification but not photosynthesis in corals. We show that bisphosphonate may not inhibit formation of amorphous calcium carbonate and that the inhibition of calcification is possibly illusory. The data are consistent with the trans-calcification model, which suggests that calcification is a source of CO(2) for photosynthesis in corals.