Functional neuroanatomy of tachykinins in brainstem autonomic regulation

Little is known about the role that tachykinins, such as substance P and its receptor, the neurokinin-1 receptor, play in the generation of sympathetic nerve activity and the integration within the ventrolateral medulla (VLM) of many vital autonomic reflexes such as the baroreflex, chemoreflex, somato-sympathetic reflex, and the regulation of cerebral blood flow. The studies described in this thesis investigate these autonomic functions and the role of tachykinins through physiological (response to hypercapnoea, chapter 3), anatomical (neurokinin-1 receptor immunohistochemistry, chapter 4) and microinjection (neurokinin-1 receptor activation and blockade, chapters 5 and 6) experiments. In the first series of experiments (chapter 3) the effects of chemoreceptor activation with hyperoxic hypercapnoea (5%, 10% or 15% CO2 in O2) on splanchnic sympathetic nerve activity and sympathetic reflexes such as the baroreflex and somato-sympathetic reflex were examined in anaesthetized rats. Hypercapnoea resulted in sympatho-excitation in all groups and a small increase in arterial blood pressure in the 10 % CO2 group. Phrenic nerve amplitude and phrenic frequency were also increased, with the frequency adapting back to baseline during the CO2 exposure. Hypercapnoea selectively attenuated (5% CO2) or abolished (10% and 15% CO2) the somato-sympathetic reflex while leaving the baroreflex unaffected. This selective inhibition of the somato-sympathetic reflex while leaving the baroreflex unaffected was also seen following neurokinin-1 receptor activation in the rostral ventrolateral medulla (RVLM) (see below). Microinjection of substance P analogues into the RVLM results in a pressor response, however the anatomical basis for this response is unknown. In the second series of experiments (chapter 4), the distribution of the neurokinin-1 receptor in the RVLM was investigated in relation to catecholaminergic (putative sympatho-excitatory “C1”) and bulbospinal neurons. The neurokinin-1 receptor was demonstrated on a small percentage (5.3%) of C1 neurons, and a small percentage (4.7%) of RVLM C1 neurons also receive close appositions from neurokinin-1 receptor immunoreactive terminals. This provides a mechanism for the pressor response seen with RVLM microinjection of substance P analogues. Neurokinin-1 receptor immunoreactivity was also seen a region overlapping the preBötzinger complex (the putative respiratory rhythm generation region), however at this level a large percentage of these neurons are bulbospinal, contradicting previous work suggesting that the neurokinin-1 receptor is an exclusive anatomical marker for the propriobulbar rhythm generating neurons of the preBötzinger complex. The third series of experiments (chapter 5) investigated the effects of neurokinin-1 receptor activation and blockade in the RVLM on splanchnic sympathetic nerve activity, arterial blood pressure, and autonomic reflexes such as the baroreflex, somato-sympathetic reflex, and sympathetic chemoreflex. Activation of RVLM neurokinin-1 receptors resulted in sympatho-excitation, a pressor response, and abolition of phrenic nerve activity, all of which were blocked by RVLM pre-treatment with a neurokinin-1 receptor antagonist. As seen with hypercapnoea, RVLM neurokinin-1 receptor activation significantly attenuated the somato-sympathetic reflex but did not affect the sympathetic baroreflex. Further, blockade of RVLM neurokinin-1 receptors significantly attenuated the sympathetic chemoreflex, suggesting a role for RVLM substance P release in this pathway. The fourth series of experiments (chapter 6) investigated the role of neurokinin-1 receptors in the RVLM, caudal ventrolateral medulla (CVLM), and nucleus tractus solitarius (NTS) on regional cerebral blood flow (rCBF) and tail blood flow (TBF). Activation of RVLM neurokinin-1 receptors increased rCBF associated with a decrease in cerebral vascular resistance (CVR). Activation of CVLM neurokinin-1 receptors decreased rCBF, however no change in CVR was seen. In the NTS, activation of neurokinin-1 receptors resulted in a biphasic response in both arterial blood pressure and rCBF, but no significant change in CVR. These findings suggest that in the RVLM substance P and the neurokinin-1 receptor play a role in the regulation of cerebral blood flow, and that changes in rCBF evoked in the CVLM and NTS are most likely secondary to changes in arterial blood pressure. Substance P and neurokinin-1 receptors in the RVLM, CVLM and NTS do not appear to play a role in the brainstem regulation of tail blood flow. In the final chapter (chapter 7), a model is proposed for the role of tachykinins in the brainstem integration of the sympathetic baroreflex, sympathetic chemoreflex, cerebral vascular tone, and the sympatho-excitation seen following hypercapnoea. A further model for the somato-sympathetic reflex is proposed, providing a mechanism for the selective inhibition of this reflex seen with hypercapnoea (chapter 3) and RVLM neurokinin-1 receptor activation (chapter 5). In summary, the ventral medulla is essential for the generation of basal sympathetic tone and the integration of many vital autonomic reflexes such as the baroreflex, chemoreflex, somato-sympathetic reflex, and the regulation of cerebral blood flow. The tachykinin substance P, and its receptor, the neurokinin-1 receptor, have a role to play in many of these vital autonomic functions. This role is predominantly neuromodulatory

Lipid-protein and protein-protein interactions in the mechanisms of photosynthetic reaction centre and the Na+,K+-ATPase

Lipid-protein and protein-protein interactions are likely to play important roles in the function and regulation of charge-transporting membrane proteins. This thesis focuses on two different membrane proteins, the photosynthetic reaction centre (RC) from purple bacteria and the Na+,K+-ATPase. The influence of the lipid surroundings and cholesterol derivatives on the kinetics of electron transfer of the RC were investigated by reconstituting the protein in phosphatidylcholine vesicles containing cholesterol and derivatives known to modulate the membrane dipole potential. The experiments performed on the Na+,K+-ATPase were designed to contribute to a better understanding of the role that oligomeric protein-protein interactions have in the enzyme’s mechanism. Our results show that the cholesterol derivatives significantly modify the electron transfer kinetics within the RCs and their multiphasic behavior. These effects seem to be associated with the extent of the dipole potential change experienced by the RC within the phospholipid membrane. Indeed, the largest effects on the rates are observed when 6-ketocholestanol and cholesterol are present, consistent by with their previously demonstrated significant increase of the dipole potential. We interpret this data as indicating an increased free energy barrier for protons to enter the protein. The consequences of the increased dipole potential seem to be experienced across the entire protein, since the rates of the P+QA- charge recombination in the presence of AQ- acting as QA are also modified by the same effectors. Also interesting is the effect of the dipole potential on the two conformational states of the RCs (previously reported) as revealed by the biphasic decays of the electron transfer kinetics. In particular, we report for the first time a biphasicity of the P+QA- charge recombination in the WT RCs. This non exponential behaviour, absent in the phospholipid membrane or isolated RCs, is induced by the presence of the cholesterol derivatives, suggesting that the equilibration time between the two RC conformations is slowed down significantly by these molecules. According to this work, the dipole potential seems to be an important parameter that has to be taken into account for a fine understanding of the charge transfer function of the RCs. Reported literature values of the dissociation constant, Kd, of ATP with the E1 conformation of the Na+,K+-ATPase based on equilibrium titrations and kinetic methods disagree. Using isothermal titration calorimetry (ITC) and simulations of the expected equilibrium behaviour for different binding models, this thesis presents an explanation for this apparent discrepancy based on protein-protein interactions. Because of the importance of Mg2+ in ATP hydrolysis, kinetic studies of Mg2+ binding to the protein were also carried out. These studies showed that ATP alone is responsible for Mg2+ complexation, with no significant contribution from the enzyme environment

Dental Status and Associated Factors in a Dentate Adult Population in Bulgaria: A Cross-Sectional Survey

This study aimed to determine variations in the dental status of a dentate adult population in terms of “decayed,” “missing,” and “filled” teeth in relation to several sociodemographic and behavioral factors. Quota sampling was used to draw 2531 subjects aged 20 years and over. Data were collected by means of a questionnaire and an oral examination. Multiple logistic regression analyses were performed to observe associations between “decayed,” “missing,” and “filled” teeth and the factors of interest. The mean numbers of “decayed,” “missing,” and “filled” teeth were 2.2, 6.7, and 4.9, respectively. Molar teeth were significantly more often “missing” than premolar and anterior teeth. Age, gender, education, and tooth brushing revealed most noticeable associations. Increasing age was associated with a lower chance of having “decayed” and “filled” teeth, but with a higher chance of having “missing” teeth. Females were more likely to have “missing” and “filled” teeth. Higher education was associated with a lower chance of having “missing” teeth. More frequent tooth brushing was associated with a lower chance of having “decayed” and “missing” teeth, but with a higher chance of having “filled” teeth. These risk indicators should be considered in prevention program planning if reduction of tooth loss is to be achieved

Dental Laboratory Production of Prosthetic Restorations in a Population in Sofia, Bulgaria: A Descriptive Study

Objective. To describe prosthodontic production related to mutilated dentitions in Sofia, Bulgaria. Methods. Prosthodontic production from 5 dental laboratories was recorded during a 14-day period. Production was related to dentitions as noted from casts. Dentitions were classified as edentulous, interrupted/reduced, slightly interrupted, shortened, and complete. The representativeness of the laboratory sample was verified trough comparison with a Sofia population sample using proportions of crowned or replaced teeth per dental region. Results. The total production consisted of 243 crowns, 16 post and cores, 82 fixed dental prostheses, and 41 removable dentures. Proportions of crowned teeth were significantly different between the samples; proportions of replaced teeth were not. Of the 58 incomplete dentitions analyzed, 19 were restored to the level of completeness, 15 resulted in slightly interrupted, and 24 in shortened dentitions. Conclusions. Predominantly fixed restorations were provided to restore mutilated dentitions to a functional level and not necessarily to complete dentitions

Large scale analysis of expressed genes in common wheat

To assess associations between occlusal tooth wear and shortened dental arches (SDA) in Chinese 40 years and older subjects. From a sample of 1462 urban and rural adults, those presenting with SDA (n = 150) were compared with a control group of 65 randomly selected subjects with complete dentitions (CDA). Occlusal wear was assessed using a modified Smith and Knight index - the occlusal tooth wear index (OWTI) - and analysed using multivariate (logistic) regression. There was no significant effect from SDA on severe occlusal wear (OTWI score 3 or 4: OR = 2.016; 95% CI = 0.960-4.231; P = 0.064). Higher age was associated with severe occlusal wear (P values </=0.007) and with higher mean OTWI scores; urban had less often severe occlusal wear than rural residents (OR = 0.519; P = 0.008). Higher mean OTWI scores were associated with rural residents, except for anterior teeth. Females had lower mean OTWI score for anterior teeth (effect = -0.153; P = 0.030). Premolars in SDA had higher mean OTWI scores compared with those in CDA (effect = +0.213; P = 0.006). In SDA, more posterior occluding pairs (POPs) were associated with lower mean OTWI sores for anterior teeth (effect: -0.158; P = 0.008) and higher scores for molars (effect: +0.249, P = 0.003). Subjects with SDA or CDA presented comparable occlusal wear, but premolars in SDA tend to have higher probability for having occlusal wear. Fewer numbers of POPs were associated with more wear in anterior teeth

Tooth loss and oral health-related quality of life: a systematic review and meta-analysis

Contains fulltext : 87677.pdf (publisher's version ) (Open Access)BACKGROUND: It is increasingly recognized that the impact of disease on quality of life should be taken into account when assessing health status. It is likely that tooth loss, in most cases being a consequence of oral diseases, affects Oral Health-Related Quality of Life (OHRQoL). The aim of the present study is to systematically review the literature and to analyse the relationship between the number and location of missing teeth and oral health-related quality of life (OHRQoL). It was hypothesized that tooth loss is associated with an impairment of OHRQoL. Secondly, it was hypothesized that location and distribution of remaining teeth play an important role in this. METHODS: Relevant databases were searched for papers in English, published from 1990 to July 2009 following a broad search strategy. Relevant papers were selected by two independent readers using predefined exclusion criteria, firstly on the basis of abstracts, secondly by assessing full-text papers. Selected studies were grouped on the basis of OHRQoL instruments used and assessed for feasibility for quantitative synthesis. Comparable outcomes were subjected to meta-analysis; remaining outcomes were subjected to a qualitative synthesis only. RESULTS: From a total of 924 references, 35 were eligible for synthesis (inter-reader agreement abstracts kappa = 0.84 +/- 0.03; full-texts: kappa = 0.68 +/- 0.06). Meta-analysis was feasible for 10 studies reporting on 13 different samples, resulting in 6 separate analyses. All studies showed that tooth loss is associated with unfavourable OHRQoL scores, independent of study location and OHRQoL instrument used. Qualitative synthesis showed that all 9 studies investigating a possible relationship between number of occluding pairs of teeth present and OHRQoL reported significant positive correlations. Five studies presented separate data regarding OHRQoL and location of tooth loss (anterior tooth loss vs. posterior tooth loss). Four of these reported highest impact for anterior tooth loss; one study indicated a similar impact for both locations of tooth loss. CONCLUSIONS: This study provides fairly strong evidence that tooth loss is associated with impairment of OHRQoL and location and distribution of tooth loss affect the severity of the impairment. This association seems to be independent from the OHRQoL instrument used and context of the included samples

'Just Little Things': Nurses' perceptions of quality of life for people with severe multiple impairments.

ABSTRACT Notions of quality of life dictate philosophies and policies for services for people with developmental disabilities. There is an abundance of research on quality of life, much of which has influenced the significant amount of study of quality of life for people with developmental disabilities. According to specialist developmental disability nurses, however, this research has little meaning for one group of people with developmental disabilities with whom they work - people with severe multiple impairments. Nevertheless, judgements and decisions about the lives of this group continue to be driven by the idea of quality of life. While the literature review found that researchers are urged to seek the perceptions of people regarding their own quality of life by asking them, some authors have noted the difficulty in pursuing such a method with people, such as people with severe multiple impairments, who are unable to communicate in the usual ways. Given, then, that it is difficult to directly determine the views of people with severe multiple impairments, this study sought the perceptions of nurses about the quality of life of the people with whom they work. In order to discover and conceptualise nurses' views, a symbolic interaction perspective was chosen to guide this study and data were analysed using the grounded theory approach. The study was conducted in two stages. Stage One consisted of semi-structured indepth interviews with expert nurses to explore their perceptions of quality of life for the people with whom they worked. A significant finding in these interviews was that perceptions of quality of life are mediated by interaction. Consequently, Stage Two involved a participant observation study in which the interactions of nurses and people with severe multiple impairments were examined. Specialist developmental disability nurses have a unique view of quality of life for people with severe multiple impairments. They refer to it as 'just little things', a phrase which masks complex nursing knowledge and skills, and which can be described by four interrelated categories which emerged from the data: humans being, supporting, becoming intimate, and situated belonging. As nurses become more intimate with individuals, they perceive that people with severe multiple impairments are humans being as they wish, and that quality resides in supporting their everyday lives in a context of situated belonging. This thesis represents a new conceptualisation of quality of life for people with severe multiple impairments, a conceptualisation which may have significance for other groups and, indeed, for the whole quality of life enterprise. This conceptualisation draws on knowledge not usually related to quality of life, that is, knowledge of the body, of the emotions, of identity and of humanness. Such findings demonstrate the power of an interpretive approach in explicating the meanings nurses have regarding quality of life. Further, these findings have implications for how the question of quality of life is approached, for how different ways of thinking about people impact on quality of life, and for the importance of the life in quality of life

Occlusion and Temporomandibular Function among Subjects with Mandibular Distal Extension Removable Partial Dentures

Objective. To quantify effects on occlusion and temporomandibular function of mandibular distal extension removable partial dentures in shortened dental arches. Methods. Subjects wearing mandibular extension removable partial dentures (n = 25) were compared with subjects with shortened dental arches without extension (n = 74) and with subjects who had worn a mandibular extension removable partial denture in the past (n = 19). Subjects with complete dentitions (n = 72) were controls. Data were collected at baseline and at 3-, 6-, and 9-year observations. Results. Occlusal activity in terms of reported awareness of bruxism and occlusal tooth wear of lower anterior teeth did not differ significantly between the groups. In contrast, occlusal tooth wear of premolars in shortened dental arches with or without extension dentures was significantly higher than in the controls. Differences amongst groups with respect to signs and symptoms related to temporomandibular disorders were not found. Occlusal support of the dentures did not influence anterior spatial relationship. Occlusal contacts of the denture teeth decreased from 70% for second premolars via 50% for first molars, to 30% for second molars. Conclusions. Mandibular distal extension removable partial dentures in moderate shortened dental arches had no effects on occlusion and temporomandibular function

Q-Curves with Complex Multiplication

The Hecke character of an abelian variety A/F is an isogeny invariant and the Galois action is such that A is isogenous to its Galois conjugate A^σ if and only if the corresponding Hecke character is fixed by σ. The quadratic twist of A by an extension L/F corresponds to multiplication of the associated Hecke characters. This leads us to investigate the Galois groups of families of quadratic extensions L/F with restricted ramification which are normal over a given subfield k of F. Our most detailed results are given for the case where k is the field of rational numbers and F is a field of definition for an elliptic curve with complex multiplication by K. In this case the groups which occur as Gal(L/K) are closely related to the 4-torsion of the class group of K. We analyze the structure of the local unit groups of quadratic fields to find conditions for the existence of curves with good reduction everywhere. After discussing the question of finding models for curves of a given Hecke character, we use twists by 3-torsion points to give an algorithm for constructing models of curves with known Hecke character and good reduction outside 3. The endomorphism algebra of the Weil restriction of an abelian variety A may be determined from the Grössencharacter of A. We describe the computation of these algebras and give examples in which A has dimension 1 or 2 and its Weil restriction has simple abelian subvarieties of dimension ranging between 2 and 24