Serotonin and attention

The serotonergic system along with other brain neurotransmitter systems has been implicated in the modulation of cognitive function. Dysregulation or pathology in neurotransmitter systems is thought to underlie the cognitive impairments associated with normal ageing, a number of disease states and chronic drug abuse. Research into the influence of serotonergic systems on cognition has focussed on the modulation of other neurotransmitter systems by serotonergic input and the importance of serotonergic receptor subtypes for learning and memory. There is evidence supporting an action of serotonin to inhibit attentional processes, perhaps primarily through inhibition of dopaminergic function, but also via other neurotransmitter systems critical to attentional function such as the noradrenergic and cholinergic systems. Studies indicate that the serotonin selective reuptake inhibitors may impair aspects of attention, whilst acute tryptophan depletion to reduce serotonin synthesis and release, may enhance aspects of attention. These data have resulted in several researchers proposing general theories of serotonergic inhibition, particularly in respect to attention/arousal. However, differential effects may be seen from studies of the various serotonergic receptor subtypes, which have so far been targeted, indicating a general theory may not be sufficient to explain the data. The evidence presented in this thesis demonstrates that some of the paradigms used thus far to support general theories of serotonergic inhibition of attention/arousal may be flawed. Specifically, monoamine depletion studies may not be able to separate serotonergic and dopaminergic influences on cognition, whilst studies of selective serotonin reuptake inhibitors and chronic ecstasy use have not controlled well for influences of sleep on cognition. Furthermore, evidence from studies of the serotonin receptor subtypes may indicate effects specific to neuropsychological processes underlying measures of attention/arousal or differential effects on aspects of cognition, which may contradict a general theory of inhibition. In conclusion, general theories of inhibition are still sufficient to account for the majority of data. However, in further academic and clinical research, thorough investigation of cognition will be critical to the development of more detailed theory and the development of effective drug treatments for cognitive disorders. Furthermore, the consideration of confounding factors in research such as the influence of sleep on cognition and the competition between monoamines for transport, is critical to the understanding and interpretation of the scientific literature to date.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effects of diabetes and hypertension on glomerular transforming growth factor-β receptor expression

Effects of diabetes and hypertension on glomerular transforming growth factor-β receptor expression.BackgroundSeveral studies have suggested that transforming growth factor-β1 (TGF-β1) is an important determinant of diabetic glomerular injury. TGF-β1 forms a heteromeric complex with two cellular receptor subtypes, designated TGF-β RII and TGF-β RI, but the effects of diabetes mellitus on glomerular TGF-β receptor expression have not been completely elucidated. We first compared the effect of experimental type I diabetes mellitus and uninephrectomy on glomerular TGF-β receptor expression in spontaneously hypertensive rats (SHRs), and then sought to determine whether changes in TGF-β receptor expression were strain specific by studying normotensive Wistar-Kyoto (WKY) rats.MethodsFive groups of male SHRs were studied. The first group received streptozotocin (60 mg/kg IV) and was studied after one week. The second group received streptozotocin and was studied after two weeks. The third group received streptozotocin (60 mg/kg IV) but received insulin to maintain euglycemia. The fourth group of age-matched SHRs served as the control group, while a fifth group of SHRs underwent uninephrectomy. Four groups of male WKY rats were also studied. The first group of WKY rats served as the age-matched control group. The second group of WKY rats received streptozotocin, while a third group of WKY rats underwent uninephrectomy. The fourth group underwent uninephrectomy and received streptozotocin. At each time point, glomeruli were isolated for protein extraction, and the protein was subjected to Western blot analysis of TGF-β RII and TGF-β RI expression.ResultsBasal expression of both TGF-β receptors per microgram of glomerular protein was similar in normotensive WKY rats and hypertensive SHRs. Hyperglycemia (blood glucose level, 17.8 ± 2.9 mmol/L) led to an early twofold increase in TGF-β RII protein expression and a fourfold increase in TGF-β RI protein expression in the glomeruli of hypertensive diabetic SHRs compared with euglycemic SHRs (blood glucose level, 5.8 ± 0.8 mmol/L), which was sustained after two weeks. Insulin treatment (blood glucose level, 5.2 ± 0.9 mmol/L) normalized both TGF-β RII and TGF-β RI expression in the glomeruli of SHRs that received streptozotocin. Glomerular capillary hypertension in the uninephrectomized SHRs led to a twofold increase in glomerular TGF-β RII protein expression, but did not reproduce the effect of diabetes mellitus on TGF-β RI expression. In contrast to the findings in SHRs, neither hyperglycemia (blood glucose level, 15.5 ± 2.1 mmol/L), uninephrectomy, nor hyperglycemia (blood glucose level, 16.8 ± 3.0 mmol/L) and uninephrectomy altered TGF-β receptor expression in the glomeruli of normotensive WKY rats.ConclusionThese studies support the hypothesis that hemodynamic factors and metabolic factors influence glomerular TGF-β receptor in vivo in the SHRs

A discrete cluster of urinary biomarkers discriminates between active systemic lupus erythematosus patients with and without glomerulonephritis.

BackgroundManagement of lupus nephritis (LN) would be greatly aided by the discovery of biomarkers that accurately reflect changes in disease activity. Here, we used a proteomics approach to identify potential urinary biomarkers associated with LN.MethodsUrine was obtained from 60 LN patients with paired renal biopsies, 25 active non-LN SLE patients, and 24 healthy controls. Using Luminex, 128 analytes were quantified and normalized to urinary creatinine levels. Data were analyzed by linear modeling and non-parametric statistics, with corrections for multiple comparisons. A second cohort of 33 active LN, 16 active non-LN, and 30 remission LN SLE patients was used to validate the results.ResultsForty-four analytes were identified that were significantly increased in active LN as compared to active non-LN. This included a number of unique proteins (e.g., TIMP-1, PAI-1, PF4, vWF, and IL-15) as well as known candidate LN biomarkers (e.g., adiponectin, sVCAM-1, and IL-6), that differed markedly (>4-fold) between active LN and non-LN, all of which were confirmed in the validation cohort and normalized in remission LN patients. These proteins demonstrated an enhanced ability to discriminate between active LN and non-LN patients over several previously reported biomarkers. Ten proteins were found to significantly correlate with the activity score on renal biopsy, eight of which strongly discriminated between active proliferative and non-proliferative/chronic renal lesions.ConclusionsA number of promising urinary biomarkers that correlate with the presence of active renal disease and/or renal biopsy changes were identified and appear to outperform many of the existing proposed biomarkers

Activation of mesangial cell MAPK in responseto homocysteine

Activation of mesangial cell MAPK in response to homocysteine.BackgroundAlteration in mesangial cell function is central to the progression of glomerular disease in numerous models of chronic renal failure (CRF). Animal models of chronic glomerular disease are characterized by mesangial cell proliferation and elaboration of extracellular matrix protein (ECM), resulting in glomerulosclerosis. Elevated plasma levels of homocysteine (Hcy) are seen in both animal models and humans with CRF, and have been proposed to contribute to the high prevalence of vascular disease in this group. Some of the pathogenetic effects of Hcy are thought to be mediated via the induction of endoplasmic reticulum stress. Thus, Hcy effects on mesangial cells could contribute to the progression of CRF. Previous work has shown Hcy- mediated induction of Erk mitogen-activated protein kinase (MAPK) in vascular smooth muscle cells (VSMCs). Erk induces increases in activator protein-1 (AP-1) transcription factor activity which may augment mesangial cell proliferation and ECM protein production. Consequently, we studied the effect of Hcy on mesangial cell Erk signaling.MethodsMesangial cells were exposed to Hcy after 24 hours of serum starvation and Erk activity assessed. Nuclear translocation of phospho-Erk was visualized by confocal microscopy. AP-1 nuclear protein binding was measured in response to Hcy by mobility shift assay. Hcy-induced mesangial cell calcium flux was measured in Fura-2 loaded cells. Mesangial cell DNA synthesis in response to Hcy was assessed by [3H]-thymidine incorporation and proliferation by Western blotting for proliferating cell nuclear antigen (PCNA). Expression of endoplasmic reticulum stress response genes were determined by Northern and Western analysis.ResultsHcy led to an increase in Erk activity that was maximal at 50 μmol/L and 20 minutes of treatment. Subsequent experiments used this concentration and time point. Erk activity in response to Hcy was insensitive to n-acetylcysteine and catalase, indicating oxidative stress did not play a role. However, Hcy50 μmol/L induced a brief increase in intracellular mesangial cell calcium within 5 minutes, and the calcium ionophores A23187 and ionomycin increased Erk activity while chelation of intracellular calcium with BAPTA-AM abrogated the Erk response to Hcy. Confocal microscopy of activated Erk nuclear translocation mirrored these results as did mesangial cell nuclear protein binding to AP-1 consensus sequences. Hcy- induced increases in thymidine incorporation and PCNA expression at 24 hours were Erk dependent. The expression of endoplasmic reticulum stress response genes was significantly elevated by Hcy in an Erk-dependent manner.ConclusionHcy increases Erk activity in mesangial cells via a calcium-dependent mechanism, resulting in increased AP-1 nuclear protein binding, cell DNA synthesis and proliferation and induction of endoplasmic reticulum stress. These observations suggest potential mechanisms by which Hcy may contribute to progressive glomerular injury

Functional modulation of IFT kinesins extends the sensory repertoire of ciliated neurons in Caenorhabditis elegans

The diversity of sensory cilia on Caenorhabditis elegans neurons allows the animal to detect a variety of sensory stimuli. Sensory cilia are assembled by intraflagellar transport (IFT) kinesins, which transport ciliary precursors, bound to IFT particles, along the ciliary axoneme for incorporation into ciliary structures. Using fluorescence microscopy of living animals and serial section electron microscopy of high pressure–frozen, freeze-substituted IFT motor mutants, we found that two IFT kinesins, homodimeric OSM-3 kinesin and heterotrimeric kinesin II, function in a partially redundant manner to build full-length amphid channel cilia but are completely redundant for building full-length amphid wing (AWC) cilia. This difference reflects cilia-specific differences in OSM-3 activity, which serves to extend distal singlets in channel cilia but not in AWC cilia, which lack such singlets. Moreover, AWC-specific chemotaxis assays reveal novel sensory functions for kinesin II in these wing cilia. We propose that kinesin II is a “canonical” IFT motor, whereas OSM-3 is an “accessory” IFT motor, and that subtle changes in the deployment or actions of these IFT kinesins can contribute to differences in cilia morphology, cilia function, and sensory perception

Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes.

OBJECTIVE: To examine the relationship between the social determinants of health and markers of early renal injury in adolescent patients with type 1 diabetes (T1D). STUDY DESIGN: Renal outcomes included estimated glomerular filtration rate (eGFR) and albumin-creatinine excretion ratio (ACR). Differences in urinary and serum inflammatory markers also were assessed in relation to social determinants of health. Regression analysis was used to evaluate the association between the Ontario Marginalization Index (ON-Marg) as a measure of the social determinants of health, patient characteristics, ACR, eGFR, and renal filtration status (hyperfiltration vs normofiltration). RESULTS: Participants with T1D (n = 199) with a mean age of 14.4 ± 1.7 years and diabetes duration of 7.2 ± 3.1 years were studied. Mean eGFR was 122.0 ± 19.4 mL/min/1.73 m2. Increasing marginalization was positively associated with eGFR (P < .0001) but not with ACR (P = .605). Greater marginalization was associated with greater median levels of urinary interleukin (IL)-2, IL-12 (p40), macrophage-derived chemokine, monocyte chemoattractant protein-3, and tumor necrosis factor-β and serum IL-2. ON-Marg was significantly associated with eGFR after we controlled for age, sex, body mass index z score, ethnicity, serum glucose, and hemoglobin A1c in linear regression. A similar association between hyperfiltration and ON-Marg score was observed in multivariable logistic regression. CONCLUSION: Increasing marginalization is significantly associated with both eGFR and hyperfiltration in adolescents with T1D and is associated with significant changes in urinary inflammatory biomarkers. These findings highlight a potentially important interaction between social and biological determinants of health in adolescents with T1D