The outcomes of auto-transplanted premolars in the anterior maxilla following traumatic dental injuries.

BACKGROUND/AIMS: Tooth auto-transplantation is a treatment option, which is often not considered to replace anterior maxillary incisors in children and adolescents. There are multiple prognostic factors that may influence the outcomes of premolar auto-transplantation, but there is limited evidence from human studies. The aim of this study was to report the outcomes of auto-transplanted premolars in the anterior maxilla following traumatic dental injuries (TDIs) and to identify their prognostic factors. MATERIALS AND METHODS: The clinical records of patients who had premolars transplanted in the anterior maxilla following TDI, with appropriate radiographs and a minimal of 1-year follow-up, were reviewed retrospectively. A specific data extraction form was developed, tested and used to collect information for the prognostic factors and outcomes. RESULTS: The cohort included 120 patients with 144 auto-transplanted premolars. The mean age was 12.2 years (±2.0), and the mean observation period was 3.7 years (±1.8). The success rate was 80%, and the survival rate was 93%. Unfavourable outcomes included external replacement resorption in 12.5%, uncontrolled external inflammatory resorption in 2.7%, and both resorption types in 4.9% of teeth. Periodontal healing was significantly associated with donor tooth root maturity, graft handling at the time of surgery including ease of donor tooth extraction and placement at the recipient sites, recipient site alveolar bone status, and post-operative transplant mobility. Seventy-four teeth (53.4%) were immature at the time of transplantation where pulp revascularisation was anticipated, and 52 (70%) of those had radiographic and clinical signs of pulp healing. Pulp healing was significantly related to donor tooth eruption stage, ease of extraction of donor tooth, and ease of placement in the recipient site. CONCLUSIONS: Good outcomes were observed for premolar teeth auto-transplanted in the anterior maxilla. The main prognostic factors were ease of extraction of donor tooth and ease of placement in the recipient sites and donor tooth root maturity.

An exploration of the use of photobiomodulation for management of oral mucositis in children and young people undergoing cancer treatment in the UK.

PURPOSE: Oral mucositis affects up to 80% of children and young people (CYP) receiving chemotherapy. This can result in pain, reduced oral intake and, in severe cases, hospitalisation for parental nutrition and pain relief. Photobiomodulation is recommended by multiple bodies for mucositis management for those undergoing cancer treatments. The current use of photobiomodulation within the UK, and the barriers and facilitators to implementation is unknown. METHOD: An online mixed-methods survey was administered to representatives from the Children's Cancer and Leukaemia Group (CCLG) between October 2021 and March 2022. This explored: use of photobiomodulation, planned future use, barriers and facilitators to implementation and dental assessment. Quantitative data underwent descriptive statistics. Barriers and facilitators to the implementation of photobiomodulation were analysed using the Theoretical Domains Framework (TDF). RESULTS: All UK CCLG centres responded (n = 20, a response rate of 100%). Two units in Scotland were delivering photobiomodulation. A further four units were planning to implement a service. Most units, 65% (n = 13) utilised specialist Paediatric Dentistry services for dental assessment. In the TDF analysis, five domains were most frequently populated: knowledge, skills, environmental context and resources, social influences, and social/professional role and identity. CONCLUSION: Photobiomodulation was only available in Scotland in two children's cancer units. Lack of knowledge and skills, and insufficient environmental resources were identified as barriers. Collaboration with paediatric dental services was identified as a facilitator. The establishment of a national network of Paediatric Dentists and Oncologists would promote collaboration to standardise protocols and to address the identified barriers to wider implementation of photobiomodulation.

Outcomes and prognostic factors that influence the success of tooth autotransplantation in children and adolescents.

BACKGROUND/AIM: Tooth autotransplantation has been advocated for replacement of missing teeth or teeth that are unsuitable for restoration. The aim of this study was to investigate the outcomes and prognostic factors that influenced the success of tooth transplantation in a paediatric population. MATERIALS AND METHODS: Data were extracted from the records of 75 patients (89 teeth). Demographic and prognostic factors were recorded and analysed for the clinical and radiographic outcomes for periodontal ligament (PDL) and pulp healing of transplanted teeth. RESULTS: The mean age at transplant was 13.2 years, and the mean follow-up observation period was 2.6±1.8 years with a range of 12.0 months to 9.9 years. The main reason for transplantation was to replace upper central incisors lost or missing due to dental trauma, hypodontia and dilaceration. Of the 45 teeth that were monitored for pulp revascularization, 75.6% showed clinical and radiographic signs of pulp healing and 24.4% showed signs of pulp necrosis and infection. Pulp healing was significantly related to the stage of root development of the transplant. Favourable PDL healing was observed in 87.6% of the transplants, while 13.5% showed signs of replacement resorption. PDL healing was significantly related to the stage of root formation of the transplanted tooth at the time of the surgery, the ease of handling and placement of the tooth, and the status of the alveolar bone at the recipient site at the time of the surgery. Overall success of tooth transplantation was 87.6%, and the survival rate was 94.4%. CONCLUSIONS: Tooth transplantation carried out in children and adolescents demonstrated high success and survival, with the stage of root development influencing both the pulp and PDL healing of the transplanted teeth.

Coordination Chemistry of 2,2'-Bipyridyl- and 2,2':6',2″-Terpyridyl-Substituted BEDT-TTFs: Formation of a Supramolecular Capsule Motif by the Iron(II) Tris Complex of 2,2'-Bipyridine-4-thiomethyl-BEDT-TTF.

Molecules of tris(2,2'-bipyridine-4-thiomethyl-BEDT-TTF)iron(II) (BEDT-TTF = bis(ethylenedithio)tetrathiafulvalene) assemble in pairs to form a novel supramolecular capsular structure in the solid state. Three BEDT-TTF residues from one complex lie in the three grooves between coordinated bipyridines of the other complex, and vice versa, to form a capsule with 3-fold rotational symmetry and an internal volume of ca. 160 Å(3). Further aspects of the coordination chemistry of this ligand, its 6-substituted isomer, and the 2,2':6'2″-terpyridyl-4'-thiomethyl-BEDT-TTF analogue are described.

Analysis of the giant genomes of Fritillaria (Liliaceae) indicates that a lack of DNA removal characterizes extreme expansions in genome size.

Plants exhibit an extraordinary range of genome sizes, varying by > 2000-fold between the smallest and largest recorded values. In the absence of polyploidy, changes in the amount of repetitive DNA (transposable elements and tandem repeats) are primarily responsible for genome size differences between species. However, there is ongoing debate regarding the relative importance of amplification of repetitive DNA versus its deletion in governing genome size. Using data from 454 sequencing, we analysed the most repetitive fraction of some of the largest known genomes for diploid plant species, from members of Fritillaria. We revealed that genomic expansion has not resulted from the recent massive amplification of just a handful of repeat families, as shown in species with smaller genomes. Instead, the bulk of these immense genomes is composed of highly heterogeneous, relatively low-abundance repeat-derived DNA, supporting a scenario where amplified repeats continually accumulate due to infrequent DNA removal. Our results indicate that a lack of deletion and low turnover of repetitive DNA are major contributors to the evolution of extremely large genomes and show that their size cannot simply be accounted for by the activity of a small number of high-abundance repeat families.

The dental health of children subject to a child protection plan.

BACKGROUND: In the United Kingdom, child maltreatment is an area of increased awareness and concern. AIM: To compare the dental health of children subject to child protection plans with controls. DESIGN: Children had to be aged between two and 11 years, medically healthy, and subject either to a child protection plan or attending the paediatric outpatient orthopaedic or general surgery clinics (control group). All children had a standardized oral examination. RESULTS: Seventy-nine children were examined in each group. Children with child protection plans had statistically higher levels of primary tooth decay than controls (mean dmft 3.82 and 2.03, Mann-Whitney U test P = 0.002). After adjusting for socioeconomic status, the incidence rate ratios for the occurrence of dental caries in the primary dentition in children with a child protection plan was 1.76 (95% CI: 1.44-2.15) relative to the controls. There was no statistical difference in the levels of permanent tooth decay between the study and control groups (mean DMFT 0.71 and 0.30, respectively). The care index was significantly lower (P = 0.008, Mann-Whitney U test) in the study group (1.69%) compared to the control group (6.02%). CONCLUSIONS: Children subject to child protection plans had significantly higher levels of dental caries in the primary dentition.

Evolutionary relationships in the medicinally important genus Fritillaria L. (Liliaceae).

Fritillaria (Liliaceae) is a genus of approximately 140 species of bulbous perennial plants that includes taxa of both horticultural and medicinal importance. As well as being commercially valuable, Fritillaria species have attracted attention because of their exceptionally large genome sizes, with all values recorded to date in excess of 30Gb. Despite such interest in the genus, phylogenetic relationships between the majority of species have remained untested. Here we present the first phylogenetic reconstruction of relationships to encompass most of the currently recognised species diversity in the genus. Three regions of the plastid genome were sequenced in 117 individuals of Fritillaria, representing 92 species (c. 66% of the genus) and in representatives of nine other genera of Liliaceae. Eleven low-copy nuclear gene regions were also screened in selected species for their potential utility. Phylogenetic analysis of a combined plastid dataset using maximum parsimony and Bayesian inference provided support for the monophyly of the majority of currently recognised subgenera. However, subgenus Fritillaria, which is by far the largest of the subgenera and includes the most important species used in traditional Chinese medicine, is found to be polyphyletic. Moreover, several taxa that were represented by multiple individuals show evidence of species non-monophyly. The Japanese endemic subgenus Japonica, which contains the species with the largest recorded genome size for any diploid plant, is resolved as sister to the predominantly Middle Eastern and Central Asian subgenus Rhinopetalum. Whilst relationships between most of the major Fritillaria lineages can now be resolved, our results also highlight the need for data from additional independently evolving loci; an endeavour that may be particularly challenging in light of the huge nuclear genomes found in these plants.

ß1-adrenergic receptor antagonists signal via PDE4 translocation.

It is generally assumed that antagonists of Gs-coupled receptors do not activate cAMP signalling, because they do not stimulate cAMP production via Gs-protein/adenylyl cyclase activation. Here, we report a new signalling pathway whereby antagonists of ß1-adrenergic receptors (ß1ARs) increase cAMP levels locally without stimulating cAMP production directly. Binding of antagonists causes dissociation of a preformed complex between ß1ARs and Type-4 cyclic nucleotide phosphodiesterases (PDE4s). This reduces the local concentration of cAMP-hydrolytic activity, thereby increasing submembrane cAMP and PKA activity. Our study identifies receptor/PDE4 complex dissociation as a novel mechanism of antagonist action that contributes to the pharmacological properties of ß1AR antagonists and might be shared by other receptor subtypes.

Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations.

PURPOSE: Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations. METHODS: Adducts were quantified in all postdose blood samples using a validated high-performance liquid chromatography electrochemical detection (HPLC-EC) assay. RESULTS: Comparison of pharmacokinetic parameters for adducts did not reveal significant differences between ER and IR formulations, with one exception. Formation rates for adducts were faster for IR than the ER formulation (0.420 ± 0.157 vs. 0.203 ± 0.080 1/h), respectively. Maximum plasma concentrations (Cmax) of adducts for IR and ER were 0.108 (±0.020) and 0.100 (±0.028) nmol/ml serum, respectively, and were two orders of magnitude lower than adduct levels previously reported in adults with acute liver failure secondary to APAP. CONCLUSIONS: APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure.

Variant Carvajal syndrome with additional dental anomalies.

BACKGROUND: This paper aims to review the case of a girl who presented with a number of dental anomalies, in addition to unusual skin, nail and hair conditions. Tragically an undiagnosed cardiomyopathy caused unexpected sudden death. The case is discussed with reference to a number of dermatological and oral conditions which were considered as possible diagnoses. CASE REPORT: AW had been under long term dental care for prepubertal periodontitis, premature root resorption of primary teeth, soft tissue and dental anomalies, and angular cheilitis. Separately she had also been seen by several dermatologists with respect to palmar plantar keratosis, striae keratoderma, wiry hair and abnormal finger nails. Tragically the patient suffered a sudden unexpected death and the subsequent post mortem identified an undiagnosed dilated cardiomyopathy. CONCLUSION: The most likely diagnosis is that this case is a variant of Carvajal Syndrome with additional dental anomalies. To date we have been unable to identify mutations in the desoplakin gene. We aim to emphasise the importance of recognising these dental and dermatological signs when they present together as a potential risk factor for cardiac abnormalities.

The comparative pharmacokinetics of modified-release and immediate-release paracetamol in a simulated overdose model.

BACKGROUND: Panadol Extend (PEx) is an over-the-counter, modified-release formulation of paracetamol. Each 665 mg tablet contains 69% slow-release and 31% immediate-release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area-under-the-curve (AUC) than comparable doses of immediate-release paracetamol (APAP-IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption. OBJECTIVE: Do differences in pharmacokinetics (PK) between PEx and APAP-IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol? METHODS: Cross-over study of 80 mg/kg of PEx or APAP-IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24 h. Peak plasma concentration (Cmax), AUC((0-∞),) time to peak concentration (Tmax) and elimination half-life (t(1/2) ) were compared. RESULTS: PEx exhibited significantly lower paracetamol Cmax (252.33 µmol/L vs 565.56 µmol/L, P= 0.0421), AUC((0-∞)) (2133 µmol/h/L vs 2637 µmol/h/L, P= 0.0004) and delayed Tmax (2.889 h vs 1.389 h, P= 0.0189) than APAP-IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP-IR, showed similar AUC((0-∞)) (1369 µmol/h/L vs 1089 µmol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 µmol/L vs 95.889 µmol/L) and t(1/2) (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 µmol/L vs 335.22 µmol/L, P= 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected. CONCLUSION: There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx.

The association between green space and cause-specific mortality in urban New Zealand: an ecological analysis of green space utility.

BACKGROUND: There is mounting international evidence that exposure to green environments is associated with health benefits, including lower mortality rates. Consequently, it has been suggested that the uneven distribution of such environments may contribute to health inequalities. Possible causative mechanisms behind the green space and health relationship include the provision of physical activity opportunities, facilitation of social contact and the restorative effects of nature. In the New Zealand context we investigated whether there was a socioeconomic gradient in green space exposure and whether green space exposure was associated with cause-specific mortality (cardiovascular disease and lung cancer). We subsequently asked what is the mechanism(s) by which green space availability may influence mortality outcomes, by contrasting health associations for different types of green space. METHODS: This was an observational study on a population of 1,546,405 living in 1009 small urban areas in New Zealand. A neighbourhood-level classification was developed to distinguish between usable (i.e., visitable) and non-usable green space (i.e., visible but not visitable) in the urban areas. Negative binomial regression models were fitted to examine the association between quartiles of area-level green space availability and risk of mortality from cardiovascular disease (n = 9,484; 1996 - 2005) and from lung cancer (n = 2,603; 1996 - 2005), after control for age, sex, socio-economic deprivation, smoking, air pollution and population density. RESULTS: Deprived neighbourhoods were relatively disadvantaged in total green space availability (11% less total green space for a one standard deviation increase in NZDep2001 deprivation score, p < 0.001), but had marginally more usable green space (2% more for a one standard deviation increase in deprivation score, p = 0.002). No significant associations between usable or total green space and mortality were observed after adjustment for confounders. CONCLUSION: Contrary to expectations we found no evidence that green space influenced cardiovascular disease mortality in New Zealand, suggesting that green space and health relationships may vary according to national, societal or environmental context. Hence we were unable to infer the mechanism in the relationship. Our inability to adjust for individual-level factors with a significant influence on cardiovascular disease and lung cancer mortality risk (e.g., diet and alcohol consumption) will have limited the ability of the analyses to detect green space effects, if present. Additionally, green space variation may have lesser relevance for health in New Zealand because green space is generally more abundant and there is less social and spatial variation in its availability than found in other contexts.

Dental trauma: an overview of its influence on the management of orthodontic treatment. Part 1.

This is the first of two papers discussing the implications of dental trauma for patients requiring orthodontic treatment. This paper will focus on the factors the orthodontic specialist should consider when contemplating movement of traumatized teeth. The prevalence of dental trauma and the recognition and prevention of traumatic injuries are discussed. The evidence available in the literature relating to orthodontic tooth movement in vital and endodontically treated traumatized teeth is explored. The interdisciplinary management of root fractured and intruded teeth receive special attention. The second paper will look at the role of the specialist team in the management of failing anterior teeth and will outline possible treatment options for children and adolescents encountering such situations. Avulsion injuries and tooth transplantation are considered in particular detail.

Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4.

Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that beta1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a beta2AR/beta-arrestin/PDE complex reported previously. The beta1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the beta2AR is a prerequisite for the recruitment of a complex consisting of beta-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of beta1- and beta2-adrenoceptor signaling.

Systematic review of the effectiveness of population screening for colorectal cancer.

AIM: To estimate the effectiveness of colorectal cancer screening with faecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), and combinations of FOBT and FS in preventing colorectal cancer (CRC) deaths. METHOD: A systematic review was conducted examining randomised controlled trials (RCTs) published between 1997 and 2004 inclusive. A systematic search of Medline, Embase, Current Contents, and the Cochrane Library was undertaken. Studies that evaluated screening with FOBT, FS or combinations of FOBT and FS, were appraised. A meta-analysis of population-based trials of FOBT was conducted. RESULTS: Four RCTs were identified that examined FOBT screening. The three trials that investigated guaiac-based FOBT found CRC mortality was reduced in the screening group. In the two population-based trials, the pooled relative risk was 0.86 (95%CI 0.79-0.93). A fourth RCT was identified, with shorter term follow-up, which considered FOBT screening combined with FS compared with FOBT alone. No significant reduction in CRC mortality was reported in this trial. CONCLUSION: There is high-quality evidence showing that guaiac-based FOBT screening reduces mortality from CRC. No such evidence exists for screening with FS either alone, or in combination with FOBT, but this should be re-evaluated once data become available from four large ongoing trials.

Characterization of the GRK2 binding site of Galphaq.

Heterotrimeric guanine nucleotide-binding proteins (G proteins) transmit signals from membrane bound G protein-coupled receptors (GPCRs) to intracellular effector proteins. The G(q) subfamily of Galpha subunits couples GPCR activation to the enzymatic activity of phospholipase C-beta (PLC-beta). Regulators of G protein signaling (RGS) proteins bind to activated Galpha subunits, including Galpha(q), and regulate Galpha signaling by acting as GTPase activating proteins (GAPs), increasing the rate of the intrinsic GTPase activity, or by acting as effector antagonists for Galpha subunits. GPCR kinases (GRKs) phosphorylate agonist-bound receptors in the first step of receptor desensitization. The amino termini of all GRKs contain an RGS homology (RH) domain, and binding of the GRK2 RH domain to Galpha(q) attenuates PLC-beta activity. The RH domain of GRK2 interacts with Galpha(q/11) through a novel Galpha binding surface termed the "C" site. Here, molecular modeling of the Galpha(q).GRK2 complex and site-directed mutagenesis of Galpha(q) were used to identify residues in Galpha(q) that interact with GRK2. The model identifies Pro(185) in Switch I of Galpha(q) as being at the crux of the interface, and mutation of this residue to lysine disrupts Galpha(q) binding to the GRK2-RH domain. Switch III also appears to play a role in GRK2 binding because the mutations Galpha(q)-V240A, Galpha(q)-D243A, both residues within Switch III, and Galpha(q)-Q152A, a residue that structurally supports Switch III, are defective in binding GRK2. Furthermore, GRK2-mediated inhibition of Galpha(q)-Q152A-R183C-stimulated inositol phosphate release is reduced in comparison to Galpha(q)-R183C. Interestingly, the model also predicts that residues in the helical domain of Galpha(q) interact with GRK2. In fact, the mutants Galpha(q)-K77A, Galpha(q)-L78D, Galpha(q)-Q81A, and Galpha(q)-R92A have reduced binding to the GRK2-RH domain. Finally, although the mutant Galpha(q)-T187K has greatly reduced binding to RGS2 and RGS4, it has little to no effect on binding to GRK2. Thus the RH domain A and C sites for Galpha(q) interaction rely on contacts with distinct regions and different Switch I residues in Galpha(q).

Splenectomy in severe haemophilia.

The management of any surgical condition in a haemophilia patient is a challenging problem for the surgeon. It is particularly difficult if the patient presents in extremis, with no apparent cause for their collapse. We report a case of successful management of spontaneous splenic rupture in a severe haemophiliac, and review the literature associated with this unusual condition.

Differential interaction of GRK2 with members of the G alpha q family.

Regulators of G protein signaling (RGS) proteins bind to active G alpha subunits and accelerate the rate of GTP hydrolysis and/or block interaction with effector molecules, thereby decreasing signal duration and strength. RGS proteins are defined by the presence of a conserved 120-residue region termed the RGS domain. Recently, it was shown that the G protein-coupled receptor kinase 2 (GRK2) contains an RGS domain that binds to the active form of G alpha(q). Here, the ability of GRK2 to interact with other members of the G alpha(q) family, G alpha(11), G alpha(14), and G alpha(16), was tested. The signaling of all members of the G alpha(q) family, with the exception of G alpha(16), was inhibited by GRK2. Immunoprecipitation of full-length GRK2 or pull down of GST-GRK2-(45-178) resulted in the detection of G alpha(q), but not G alpha(16), in an activation-dependent manner. Moreover, activated G alpha(16) failed to promote plasma membrane (PM) recruitment of a GRK2-(45-178)-GFP fusion protein. Assays with chimeric G alpha(q)(-)(16) subunits indicated that the C-terminus of G alpha(q) mediates binding to GRK2. Despite showing no interaction with GRK2, G alpha(16) does interact with RGS2, in both inositol phosphate and PM recruitment assays. Thus, GRK2 is the first identified RGS protein that discriminates between members of the G alpha(q) family, while another RGS protein, RGS2, binds to both G alpha(q) and G alpha(16).

G protein-coupled receptor Kinase 2/G alpha q/11 interaction. A novel surface on a regulator of G protein signaling homology domain for binding G alpha subunits.

G protein-coupled receptors (GPCRs) transduce cellular signals from hormones, neurotransmitters, light, and odorants by activating heterotrimeric guanine nucleotide-binding (G) proteins. For many GPCRs, short term regulation is initiated by agonist-dependent phosphorylation by GPCR kinases (GRKs), such as GRK2, resulting in G protein/receptor uncoupling. GRK2 also regulates signaling by binding G alpha(q/ll) and inhibiting G alpha(q) stimulation of the effector phospholipase C beta. The binding site for G alpha(q/ll) resides within the amino-terminal domain of GRK2, which is homologous to the regulator of G protein signaling (RGS) family of proteins. To map the Galpha(q/ll) binding site on GRK2, we carried out site-directed mutagenesis of the RGS homology (RH) domain and identified eight residues, which when mutated, alter binding to G alpha(q/ll). These mutations do not alter the ability of full-length GRK2 to phosphorylate rhodopsin, an activity that also requires the amino-terminal domain. Mutations causing G alpha(q/ll) binding defects impair recruitment to the plasma membrane by activated G alpha(q) and regulation of G alpha(q)-stimulated phospholipase C beta activity when introduced into full-length GRK2. Two different protein interaction sites have previously been identified on RH domains. The G alpha binding sites on RGS4 and RGS9, called the "A" site, is localized to the loops between helices alpha 3 and alpha 4, alpha 5 and alpha 6, and alpha 7 and alpha 8. The adenomatous polyposis coli (APC) binding site of axin involves residues on alpha helices 3, 4, and 5 (the "B" site) of its RH domain. We demonstrate that the G alpha(q/ll) binding site on the GRK2 RH domain is distinct from the "A" and "B" sites and maps primarily to the COOH terminus of its alpha 5 helix. We suggest that this novel protein interaction site on an RH domain be designated the "C" site.

Paediatric dentistry in the new millennium: 6. Dental anomalies in children.

Developmental defects of the human dentition are not uncommon and can adversely affect the physical and psychological health of children. This paper reviews briefly the most common dental defects that can occur during childhood and discusses in more detail defects of enamel and dentine. Guidelines are provided for clinicians to identify children who deviate from normal dental development in order to provide appropriate interventions or make appropriate referrals.