ABSTRACT
BACKGROUND: The emergence and spread of antibiotic resistant micro-organisms is a global concern, which is largely attributable to inaccurate prescribing of antibiotics to patients presenting with non-bacterial infections. The use of 'omics' technologies for discovery of novel infection related biomarkers combined with novel treatment algorithms offers possibilities for rapidly distinguishing between bacterial and viral infections. This distinction can be particularly important for patients suffering from lower respiratory tract infections (LRTI) and/or sepsis as they represent a significant burden to healthcare systems. Here we present the study details of the TAILORED-Treatment study, an observational, prospective, multi-centre study aiming to generate a multi-parametric model, combining host and pathogen data, for distinguishing between bacterial and viral aetiologies in children and adults with LRTI and/or sepsis. METHODS: A total number of 1200 paediatric and adult patients aged 1 month and older with LRTI and/or sepsis or a non-infectious disease are recruited from Emergency Departments and hospital wards of seven Dutch and Israeli medical centres. A panel of three experienced physicians adjudicate a reference standard diagnosis for all patients (i.e., bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. Nasal swabs and blood samples are collected for multi-omics investigations including host RNA and protein biomarkers, nasal microbiota profiling, host genomic profiling and bacterial proteomics. Simplified data is entered into a custom-built database in order to develop a multi-parametric model and diagnostic tools for differentiating between bacterial and viral infections. The predictions from the model will be compared with the consensus diagnosis in order to determine its accuracy. DISCUSSION: The TAILORED-Treatment study will provide new insights into the interplay between the host and micro-organisms. New host- or pathogen-related biomarkers will be used to generate a multi-parametric model for distinguishing between bacterial and viral infections. This model will be helpful to better guide antimicrobial therapy for patients with LRTI and sepsis. This study has the potential to improve patient care, reduce unnecessary antibiotic prescribing and will contribute positively to institutional, national and international healthcare economics. TRIAL REGISTRATION: NCT02025699 . Registration Date: January, 1, 2014.
Subject(s)
Bacterial Infections/diagnosis , Respiratory Tract Infections/diagnosis , Sepsis/diagnosis , Virus Diseases/diagnosis , Adolescent , Adult , Anti-Bacterial Agents/therapeutic use , Antimicrobial Stewardship , Bacterial Infections/drug therapy , Biomarkers/analysis , Biomarkers/blood , Child , Child, Preschool , Diagnosis, Differential , Emergency Service, Hospital , Female , Hospitalization/statistics & numerical data , Host-Parasite Interactions , Humans , Infant , Male , Microbiota , Prospective Studies , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/virology , Risk Factors , Sepsis/drug therapy , Sepsis/microbiology , Sepsis/virology , Virus Diseases/drug therapy , Young AdultABSTRACT
Previously we have introduced two SPR-based assay principles (dual-binding assay and bridging assay), which allow the determination of two out of three possible interaction parameters for bispecific molecules within one assay setup: two individual interactions to both targets, and/or one simultaneous/overall interaction, which potentially reflects the inter-dependency of both individual binding events. However, activity and similarity are determined by comparing report points over a concentration range, which also mirrors the way data is generated by conventional ELISA-based methods So far, binding kinetics have not been specifically considered in generic approaches for activity assessment. Here, we introduce an improved slope-ratio model which, together with a sensorgram comparison based similarity assessment, allows the development of a detailed, USP-conformal ligand binding assay using only a single sample concentration. We compare this novel analysis method to the usual concentration-range approach for both SPR-based assay principles and discuss its impact on data quality and increased sample throughput.
Subject(s)
Chemistry, Pharmaceutical/methods , Models, Chemical , Surface Plasmon Resonance/methods , Angiopoietin-2/chemistry , Antibodies, Bispecific/chemistry , Enzyme-Linked Immunosorbent Assay , Ligands , Protein Binding , Vascular Endothelial Growth Factor A/chemistryABSTRACT
Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 × 10-57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 × 10-10 ; rs7568069: OR = 1.13, 95% CI: 1.07-1.18, p = 1.1 × 10-6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero.
Subject(s)
Body Height , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Adult , Body Height/genetics , Body Mass Index , Genotype , Humans , Male , Models, Statistical , Neoplasms, Germ Cell and Embryonal/genetics , Polymorphism, Single Nucleotide , Random Allocation , Risk Factors , Testicular Neoplasms/genetics , Waist-Hip RatioABSTRACT
The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (ß=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (ß=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (ß=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE É4 non-carriers (ß=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (ß=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (ß=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in É4-carriers (ß=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE É4-carriers might be at differential risk.
Subject(s)
Cognitive Dysfunction/genetics , Mendelian Randomization Analysis , Telomere/genetics , White People/genetics , Adult , Aged , Apolipoprotein E4/genetics , Cognitive Dysfunction/diagnosis , Cohort Studies , Female , Genetic Carrier Screening , Genotype , Humans , Male , Middle Aged , Neuropsychological Tests/statistics & numerical data , Psychometrics , Statistics as TopicABSTRACT
This corrects the article DOI: 10.1038/mp.2015.165.
ABSTRACT
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
Subject(s)
Bipolar Disorder/genetics , Carrier Proteins/genetics , Adult , Antimanic Agents/therapeutic use , Biomarkers, Pharmacological/blood , Bipolar Disorder/metabolism , Carrier Proteins/metabolism , Female , Genetic Predisposition to Disease/genetics , Genetic Variation , Genome-Wide Association Study/methods , Genotype , Humans , Lithium/metabolism , Lithium/therapeutic use , Lithium Compounds/therapeutic use , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors , Self Report , Sweden , United KingdomABSTRACT
BACKGROUND: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATP2A2 gene. Anecdotal reports suggest a relationship between Darier disease and intellectual disabilities, but these reports are based on small clinical samples and limited by absence of control populations. OBJECTIVES: To examine the risk of intellectual disability and subclinical impairments in cognitive ability in Darier disease. METHODS: We conducted a matched cohort study based on Swedish Population-, Patient- and Conscript Registers. The risk of being diagnosed with intellectual disability was estimated in 770 individuals with Darier disease, compared with matched comparison individuals without Darier disease. Associations were examined with risk ratios from conditional logistic regressions. In addition, we analysed test-based cognitive ability data (i.e. IQ data) from the Swedish conscript examination, for a subset of patients without diagnosed intellectual disability. RESULTS: Individuals with Darier disease had a sixfold increased risk of being diagnosed with intellectual disability (risk ratio 6.2, 95% confidence interval 3.1-12.4). For conscripted individuals with Darier disease but no diagnosed intellectual disability, mean cognitive ability scores were about half a standard deviation lower than for comparison subjects. CONCLUSIONS: Darier disease is associated with intellectual disability and subclinical impairments in cognitive ability. The Darier-causing mutations merit further attention in molecular genetic research on intellectual disability and cognitive ability.
Subject(s)
Cognition Disorders/etiology , Darier Disease/psychology , Intellectual Disability/etiology , Adolescent , Cognition Disorders/epidemiology , Darier Disease/epidemiology , Genetic Markers , Genotype , Humans , Intellectual Disability/epidemiology , Male , Risk Factors , Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics , Sweden/epidemiology , Young AdultABSTRACT
Mounting evidence has shown that the insulin-like growth factor-1 receptor (IGF-1R) has critical roles in cancer cell growth. This has prompted pharmacological companies to develop agents targeting the receptor. Surprisingly, clinical trials using specific IGF-1R antibodies have, however, revealed disappointing results. Further understanding of the role of IGF-1R in cancer cells is therefore necessary for development of efficient therapeutic strategies. Recently, we showed that IGF-1R is sumoylated and translocated into the cell nucleus where it activates gene transcription. Several other studies have confirmed our findings and it has been reported that nuclear IGF-1R (nIGF-1R) has prognostic and predictive impact in cancer. To increase the understanding of IGF-1R in cancer cells, we here present the first study that proposes a pathway by which IGF-1R translocates into the cell nucleus. We could demonstrate that IGF-1R first associates with the dynactin subunit p150(Glued), which transports the receptor to the nuclear pore complex, where it co-localizes with importin-ß followed by association with RanBP2. Sumoylation of IGF-1R seems to be required for interaction with RanBP2, which in turn may serve as the SUMO E3 ligase. In the context of sumoylation, we provided evidence that it may favor nIGF-1R accumulation by increasing the stability of the receptor. Taken together, topographic and functional interactions between dynactin, importin-ß and RanBP2 are involved in nuclear translocation of IGF-1R. Our results provide new understanding of IGF-1R in cancer, which in turn may contribute to development of new therapeutic strategies.
Subject(s)
Cell Nucleus/metabolism , Microtubule-Associated Proteins/metabolism , Molecular Chaperones/metabolism , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Nuclear Pore Complex Proteins/metabolism , Receptor, IGF Type 1/metabolism , beta Karyopherins/metabolism , Active Transport, Cell Nucleus/genetics , Cell Line, Tumor , Cell Nucleus/genetics , Cell Nucleus/pathology , Dynactin Complex , HEK293 Cells , Humans , Male , Microtubule-Associated Proteins/genetics , Molecular Chaperones/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Neoplasms/pathology , Nuclear Pore Complex Proteins/genetics , Receptor, IGF Type 1/genetics , Sumoylation/genetics , beta Karyopherins/geneticsABSTRACT
STUDY QUESTION: Is there an association between testicular germ cell tumor (TGCT) and genetic polymorphisms in AKT1, PTEN and the 8q24 locus? SUMMARY ANSWER: Our findings suggest that genetic variation in PTEN may influence the risk of TGCT. WHAT IS KNOWN ALREADY: There is strong evidence that genetic variation influences the risk of TGCT. The oncogene, AKT1, the tumor suppressor gene, PTEN and the chromosome 8q24 locus play important roles in cancer development in general. STUDY DESIGN, SIZE, DURATION: We have conducted a population-based Norwegian-Swedish case-parent study, based on cases diagnosed in 1990-2008, including 831 triads (TGCT case and both parents), 474 dyads (TGCT case and one parent) and 712 singletons (only the TGCT case). In addition we expanded the study to include 3922 unrelated male controls from the TwinGene project. PARTICIPANTS/MATERIALS, SETTING, METHODS: We genotyped 26 single nucleotide polymorphisms (SNPs) in AKT1, PTEN and the 8q24 locus. First, triads and dyads were included in a likelihood-based association test. To increase the statistical power, case singletons and controls from the TwinGene project were included in a single test for association. We examined if the allelic effect on TGCT risk differed by histological subgroup, country of origin or parent of origin. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated with Bonferroni correction (P bonf) for multiple testing. MAIN RESULTS AND THE ROLE OF CHANCE: In the case-parent analyses, none of the 26 SNPs were significantly associated with TGCT. Of the 23 SNPs investigated in the combined study, one SNP in PTEN (rs11202586) remained associated with TGCT risk after adjusting for multiple testing (OR = 1.16, 95% CI = 1.06-1.28, P bonf = 0.040). We found no difference in risk according to histological subgroup, parent of origin or between countries. LIMITATIONS, REASONS FOR CAUTION: Our study is strengthened by the population-based design and large sample size, which gives high power to detect risk alleles. The reported association was not highly significant, and although it was based on an a priori hypothesis of this tumor suppressor gene being implicated in the etiology of TGCT, replication studies, as well as functional studies of this polymorphism, are warranted. WIDER IMPLICATIONS OF THE FINDINGS: We report, to our knowledge, a novel association between TGCT and a marker in the tumor suppressor gene PTEN. Previous studies have linked PTEN to TGCT etiology, and there is also a link between PTEN and KITLG, which contains TGCT susceptibility loci revealed through recent genome-wide studies.
Subject(s)
Chromosomes, Human, Pair 8/genetics , Neoplasms, Germ Cell and Embryonal/genetics , PTEN Phosphohydrolase/genetics , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-akt/genetics , Testicular Neoplasms/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Norway , Odds Ratio , SwedenABSTRACT
BACKGROUND: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT. METHODS: We conducted a Norwegian-Swedish case-parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case-control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing. RESULTS: Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERß)] were statistically significantly associated with the risk of TGCT. In the case-parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592 SNPs were associated with an increased risk of TGCT (OR = 1.30, 1.30 and 1.21, respectively; all FDRs <5%). We found no statistically significant differences in allelic effect estimates between parental inherited genetic variation in the sex hormone pathways and TGCT risk in the offspring, and no evidence of heterogeneity between seminomas and non-seminomas, or between the Norwegian and the Swedish population, in any of the SNPs examined. CONCLUSIONS: Our findings provide support for ERß and aromatase being implicated in the aetiology of TGCT. Exploring the functional role of the TGCT risk-associated SNPs will further elucidate the biological mechanisms involved.
Subject(s)
Neoplasms, Germ Cell and Embryonal/genetics , Testicular Neoplasms/genetics , Adolescent , Adult , Aged , Aromatase/genetics , Case-Control Studies , Estrogen Receptor beta/genetics , Female , Genetic Markers , Genotype , Gonadal Steroid Hormones/genetics , Humans , Male , Middle Aged , Norway , Odds Ratio , Polymorphism, Single Nucleotide , Risk Assessment , SwedenABSTRACT
Rac1 has a role in proliferation and survival of tumor cells in vitro. The exact effects of Rac1 on growth, apoptosis and corresponding signaling pathways during tumorigenesis in vivo, however, have not been explored yet. Using mice with a keratinocyte-restricted deletion of the Rac1 gene, we found that Rac1 is essential for DMBA/TPA-induced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation at serine 298. Rac1 was furthermore required for Pak2-dependent hyperactivation of Akt, which under in vivo condition was restricted to the suprabasal cell layers corresponding to a suprabasal-specific expression of Pak2. It is surprising that none of these signaling pathways was altered in untreated Rac1-deficient skin, indicating a hyperproliferation-specific function of Rac1 in vivo. These data suggest that blocking of Rac1 function might allow tumor-specific growth repression, as Rac1 is not required for normal growth and growth signaling controlling pathways in skin in vivo.
Subject(s)
Extracellular Signal-Regulated MAP Kinases/physiology , Genes, ras , Mitogen-Activated Protein Kinase Kinases/physiology , Neuropeptides/physiology , Skin Neoplasms/etiology , p21-Activated Kinases/physiology , rac GTP-Binding Proteins/physiology , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Animals , Cell Proliferation , Cells, Cultured , Keratinocytes/pathology , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-akt/physiology , Tetradecanoylphorbol Acetate/toxicity , p38 Mitogen-Activated Protein Kinases/physiology , rac1 GTP-Binding ProteinABSTRACT
AIMS: To examine whether the addition of dorzolamide to timolol monotherapy influences oxygen saturation in the human retina. METHODS: Non-invasive spectrophotometric retinal oximetry was used to measure oxygen saturation in retinal vessels. Twenty patients with open-angle glaucoma (11) and ocular hypertension (9) were recruited. The patients were randomised into receiving timolol monotherapy or dorzolamide-timolol combination for an 8-month test period, followed by a second test period, before which the patients switched treatments. Oximetry measurements were performed at 2-month intervals during each period. Of the 20 patients, 13 followed the study protocol into the second test period, and 10 managed all study visits. RESULTS: The oxygen saturation in retinal vessels was stable within the test periods. The mean arteriolar saturation was 96 (2)% (mean (SD)) during timolol monotherapy and 97 (2)% during dorzolamide-timolol combination therapy (p = 0.17, all patients pooled, n = 13). Corresponding values in venules were 66 (5)% during timolol monotherapy and 65 (6)% during dorzolamide-timolol therapy (p = 0.13). Patients who started on dorzolamide-timolol combination showed a significant reduction in arteriolar (98 (2)% to 95 (2)%, p<0.01) and venular saturation (69 (5)% to 66 (6)%, p<0.05) when changing to timolol monotherapy. CONCLUSION: Adding dorzolamide to timolol monotherapy has a minimal effect, but going from dorzolamide-timolol combination to timolol alone lowered arteriolar and venular oxygen saturation. The retinal oxygen saturation measurements show a high degree of stability over an extended period of time. Previous studies have suggested increased retinal and optic nerve blood flow with dorzolamide. Unchanged oxygen saturation and increased blood flow would indicate increased oxygen delivery to the retina.
Subject(s)
Antihypertensive Agents/pharmacology , Ocular Hypertension/blood , Oxygen/blood , Retinal Vessels/metabolism , Sulfonamides/pharmacology , Thiophenes/pharmacology , Timolol/pharmacology , Adolescent , Adult , Aged , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Double-Blind Method , Drug Combinations , Female , Glaucoma, Open-Angle/blood , Glaucoma, Open-Angle/drug therapy , Humans , Intraocular Pressure/drug effects , Male , Middle Aged , Ocular Hypertension/drug therapy , Oximetry/methods , Sulfonamides/therapeutic use , Thiophenes/therapeutic use , Timolol/therapeutic use , Young AdultABSTRACT
Malignant tumor cells display uncontrolled proliferation, loss of epithelial cell polarity, altered interactions with neighboring cells and the surrounding extracellular matrix, and enhanced migratory properties. Proteins of the Rho GTPase family regulate all these processes in cell culture and, for that reason, Rho GTPases, their regulators, and their effectors have been suggested to control tumor formation and progression in humans. However, while the tumor-relevant functions of Rho GTPases are very well documented in vitro, we are only now beginning to assess their contribution to cancer in human patients and in animal models. This review will give a very brief overview of Rho GTPase function in general and then focus on in vivo evidence for a role of Rho GTPases in malignant tumors, both in human patients and in genetically modified mice.
Subject(s)
Neoplasms/etiology , rho GTP-Binding Proteins/physiology , Animals , Cell Cycle , Cell Movement , Cell Polarity , Cell Survival , Humans , Neovascularization, Pathologic/etiology , Signal Transduction , rhoA GTP-Binding Protein/physiology , rhoB GTP-Binding Protein/physiology , rhoC GTP-Binding ProteinABSTRACT
There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate x DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.
Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Receptors, AMPA/deficiency , Schizophrenia/genetics , Acclimatization , Animals , Crosses, Genetic , Disease Models, Animal , Female , Glutamic Acid/metabolism , Hyperkinesis/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/genetics , Receptors, AMPA/genetics , Social BehaviorABSTRACT
The aim of this paper is to develop an automatic method for the registration of multitemporal digital images of the fundus of the human retina. The images are acquired from the same patient at different times by a color fundus camera. The proposed approach is based on the application of global optimization techniques to previously extracted maps of curvilinear structures in the images to be registered (such structures being represented by the vessels in the human retina): in particular, a genetic algorithm is used, in order to estimate the optimum transformation between the input and the base image. The algorithm is tested on two different types of data, gray scale and color images, and for both types, images with small changes and with large changes are used. The comparison between the registered images using the implemented method and a manual one points out that the proposed algorithm provides an accurate registration. The convergence to a solution is not possible only when dealing with images taken from very different view-points.
Subject(s)
Artificial Intelligence , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Pattern Recognition, Automated/methods , Retinal Vessels/anatomy & histology , Retinoscopy/methods , Subtraction Technique , Algorithms , Colorimetry/methods , Humans , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Galanin is a 29 amino-acid (30 in humans) neuropeptide with a close functional relationship with neurotransmitter systems implicated in the pathophysiology and treatment of depression and anxiety disorders. In rodent models of depression-related behavior, treatment with galanin or compounds with agonist actions at galanin receptors has been shown to affect depression-related behaviors and the behavioral and neurochemical effects of antidepressants. Treatment with clinically efficacious antidepressants alters galanin and galanin receptor gene expression in rodents. Rodent anxiety-like behaviors appear to be modulated by galanin in a complex manner, with studies showing either increases, decreases and no effects of galanin treatments and galanin mutations on anxiety-like behavior in various tasks. One concept to emerge from this literature is that galanin recruitment during extreme behavioral and physiological provocations such as stress and opiate withdrawal may serve to attenuate negative emotional states caused by noradrenergic hyperactivation. The specific galanin receptor subtypes mediating the anxiety- and depression-related effects of galanin remains to be determined, with evidence supporting a possible contribution of GalR1, GalR2 and GalR3. While our understanding of the role of galanin as a modulator of emotion remains at an early stage, recent progress in this rapidly evolving field raise possibility of that galanin may represent a target for the development of novel antidepressant and anxiolytic drug treatments.
Subject(s)
Anxiety/metabolism , Anxiety/physiopathology , Depression/physiopathology , Galanin/physiology , Animals , Anti-Anxiety Agents/metabolism , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Depression/drug therapy , Galanin/administration & dosage , Humans , Receptors, Galanin/antagonists & inhibitors , Receptors, Galanin/metabolismABSTRACT
OBJECTIVES: To measure the coverage, gender distribution, and participants' prevalence of genital Chlamydia trachomatis infections using a new internet based self selective testing approach by means of home sampling in the general population in Sweden. To investigate factors associated with these measures. METHODS: Observational survey of people actively ordering coded testing packages, and checking their test results, from a known website. No personal invitations were sent out. All inhabitants (256 885 men and women) in a Swedish county were eligible to participate. A special interest was taken in coverage, gender distribution, participants' chlamydia prevalence, and determinants for infection. RESULTS: Testing was highest in the age group 20-24 years, where 298/9495 (3.1%) of all women and 171/9574 (1.8%) of all men in the population participated. The overall population participation (all ages) was 906/256 885 (0.4%). 40% (364/906) of the tests were from men and 60% (542/906) from women. The prevalence of Chlamydia trachomatis infection was 6.0% (95% CI: 3.6% to 8.4%) among male participants and 4.6% (95% CI: 2.8% to 6.4%) among female participants. Prevalence increased with decreasing age. Believing to be infected and having symptoms were the strongest determinants of infection. CONCLUSION: Simplifying and increasing the accessibility of chlamydia testing by means of internet and home sampling proved feasible. Self risk assessment improves the chance of finding people infected by Chlamydia trachomatis, especially among men, if an accessible testing method is offered. This new method can serve as a supplement to regular preventive methods and might encourage young people to be tested.
Subject(s)
Chlamydia Infections/epidemiology , Chlamydia trachomatis , Home Care Services/statistics & numerical data , Internet/statistics & numerical data , Adolescent , Adult , Aged , Female , Humans , Male , Mass Screening/methods , Middle Aged , Odds Ratio , Polymerase Chain Reaction , Prevalence , Specimen Handling , Surveys and Questionnaires , Sweden/epidemiologyABSTRACT
The progression of human immunodeficiency virus (HIV) disease and plasma levels of HIV may differ between racial groups. We compared HIV-specific T cell responses between vertically HIV-1-infected Hispanic and African American children. Subjects were matched for sex, age, viral load, and CD4(+) cell count in 18 pairs; T cell responses were measured by cytokine-enhanced interferon- gamma assay. Peripheral blood mononuclear cells were stimulated with HIV consensus peptides from Gag, Nef, and Tat. The influence of ethnicity, sex, age, viral load, and CD4(+) cell count on T cell responses was determined through linear regression analyses. After adjustment for CD4(+) count, age, and log(10) viral load, African American children demonstrated significantly higher Gag responses (average, 486 spot-forming cells higher; P=.01) than Hispanic children; this was significantly driven by robust responses in African American girls near the age of puberty, many of whom carried the human leukocyte antigen class I B*58 allele.
Subject(s)
Black People , HIV Infections/ethnology , HIV-1/immunology , Infectious Disease Transmission, Vertical , T-Lymphocytes/immunology , Adolescent , Black or African American , CD4 Lymphocyte Count , Child , Child, Preschool , Female , Gene Products, gag/immunology , HIV Infections/immunology , HIV Infections/transmission , HIV Infections/virology , HLA-B Antigens/metabolism , Hispanic or Latino , Humans , Infant , Lymphocyte Activation , Male , Sex Characteristics , Viral Load , White PeopleABSTRACT
We studied the transfer of information during coordinated care planning between a university hospital and a local health care centre/social welfare department about 35 km away. During a seven-month study period, 10 sessions were conducted by videoconferencing and seven sessions were conducted by face-to-face conferencing. Videoconferencing reduced the time required for each coordinated care-planning session from an average of 60 to 45 min. There was also an increase in the number of participating professional categories. Travel time for the staff in the face-to-face group was 60-180 min each. Use of a care-planning report during the sessions resulted in improved quality of documentation, which contributed to better care following discharge. The technical problems that occurred did not detract from the beneficial experience of participating. Interviews with next of kin showed that they had been able to influence the content of the care during the care-planning sessions. Videoconferencing proved useful in coordinated care planning. It resulted in time saved due to reduced travel time, participation by more staff categories and an enhancement of the documentation quality.