Finding your first job as an associate in general dental practice.

The landscape of dentistry is changing at a rapid rate and nowhere is this more apparent than in the job market. Finding work as an associate GDP is more competitive and seems increasingly driven by large corporate practices and faceless recruitment agencies. There is a massive emphasis in vocational training (VT) and dental school on clinical training, and rightly so, however, practical advice on how to obtain an associate position and what to avoid when looking for work was a little thin on the ground as I finished my degree in 2011. In this article I have attempted to give some basic tips on how to find an associate general dental practice job, what to look for in a practice and basic pitfalls to avoid. I should know--within three years of graduating I had already worked in a variety of NHS and private settings in five different practices.

Evaluation of waist-mounted tri-axial accelerometer based fall-detection algorithms during scripted and continuous unscripted activities.

It is estimated that by 2050 more than one in five people will be aged 65 or over. In this age group, falls are one of the most serious life-threatening events that can occur. Their automatic detection would help reduce the time of arrival of medical attention, thus reducing the mortality rate and in turn promoting independent living. This study evaluated a variety of existing and novel fall-detection algorithms for a waist-mounted accelerometer based system. In total, 21 algorithms of varying degrees of complexity were tested against a comprehensive data-set recorded from 10 young healthy volunteers performing 240 falls and 120 activities of daily living (ADL) and 10 elderly healthy volunteers performing 240 scripted ADL and 52.4 waking hours of continuous unscripted normal ADL. Results show that using an algorithm that employs thresholds in velocity, impact and posture (velocity+impact+posture) achieves 100% specificity and sensitivity with a false-positive rate of less than 1 false-positive (0.6 false-positives) per day of waking hours. This algorithm is the most suitable method of fall-detection, when tested using continuous unscripted activities performed by elderly healthy volunteers, which is the target environment for a fall-detection device.

Relationship of vitamin A deficiency, iron deficiency, and inflammation to anemia among preschool children in the Republic of the Marshall Islands.

INTRODUCTION: Although vitamin A deficiency, iron deficiency, and inflammation may contribute to anemia, their relative contribution to anemia has not been well characterized in preschool children in developing countries. OBJECTIVE: To characterize the contributions of vitamin A and iron deficiencies and inflammation to anemia among preschool children in the Republic of the Marshall Islands. SUBJECTS AND METHODS: A community-based survey, the Republic of the Marshall Islands Vitamin A Deficiency Study, was conducted among 919 preschool children. The relationship of vitamin A and iron status and markers of inflammation, tumor necrosis factor-alpha, alpha1-acid glycoprotein, and interleukin-10, to anemia were studied in a subsample of 367 children. RESULTS: Among the 367 children, the prevalence of anemia was 42.5%. The prevalence of severe vitamin A deficiency (serum vitamin A < 0.35 micromol/l) and iron deficiency (serum ferritin < 12 microg/dl) were 10.9 and 51.7%, respectively. The respective prevalence of iron deficiency anemia (hemoglobin < 110 g/l and iron deficiency), anemia with inflammation (anemia with TNF-alpha > 2 pg/ml and/or AGP > 1000 mg/l), and severe vitamin A deficiency combined with anemia was 26.7, 35.6, and 7.6%. In multivariate linear regression models that adjusted for age, sex, and inflammation, both iron deficiency (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.08-2.83, P = 0.023) and severe vitamin A deficiency (OR 4.85, 95% CI 2.14-10.9, P < 0.0001) were significantly associated with anemia. CONCLUSIONS: Both iron and vitamin A deficiencies were independent risk factors for anemia, but inflammation was not a significant risk factor for anemia among these preschool children.

Assessment of vitamin A status of preschool children in Indonesia using plasma retinol-binding protein.

Although plasma retinol-binding protein (RBP) has been proposed as an indicator of vitamin A status of populations in less technologically developed settings, potential factors which could influence this indicator include inflammation and protein energy status. Plasma RBP, retinol, alpha1-acid glycoprotein (AGP), C-reactive protein (CRP), and albumin were measured in a study of 236 preschool children in Bandung, Indonesia. Spearman correlation coefficient between plasma RBP and retinol concentrations was 0.55 (p < 0.0001). By linear regression, 0.70 pmol/l retinol was equivalent to 0.69 micromol/l RBP. With these cut-off points for defining vitamin A deficiency and plasma retinol as the standard for comparison, RBP had a sensitivity and specificity of 75.0 per cent and 63.2 per cent, respectively. The correlation between RBP and retinol was not affected by plasma AGP, CRP, or albumin concentration. Measurement of plasma RBP by radial immunodiffusion is simple and inexpensive, and this test can be used as a simple surrogate measure for vitamin A concentrations in large field studies.

Retinol binding protein as a surrogate measure for serum retinol: studies in vitamin A-deficient children from the Republic of the Marshall Islands.

BACKGROUND: Serum retinol is transported by retinol binding protein (RBP), which has one high-affinity binding site for retinol; consequently, the molar ratio of retinol to RBP in the circulation is approximately 1 to 1. In vitamin A deficiency (VAD), both serum retinol and RBP decline. However, the retinol-RBP relation has not been well studied in populations with a high incidence of severe VAD. OBJECTIVE: The purpose of this study was to determine whether RBP is a good surrogate for serum retinol at the very low retinol concentrations encountered in VAD. DESIGN: The stoichiometric relation between retinol and RBP was studied in 239 Marshallese children: 65 with severe VAD (< or = 0.35 micromol retinol/L), 94 with moderate VAD (0.36-0.70 micromol retinol/L), and 80 with vitamin A sufficiency (> 0.70 micromol retinol/L). RESULTS: Excellent correlation between retinol and RBP (r = 0.94) was observed across all retinol concentrations. Severe VAD was predicted with 96% sensitivity and 91% specificity on the basis of an RBP cutoff of < or = 0.48 micromol/L, whereas moderate VAD was predicted with 87% sensitivity and 98% specificity on the basis of an RBP cutoff of < or = 0.70 micromol/L. CONCLUSIONS: The use of RBP results in the classification of essentially the same children with VAD as does retinol, and RBP is an excellent surrogate for serum retinol. Considering the relative ease of measuring RBP with immunodiagnostic kits compared with that of serum retinol by HPLC, the use of RBP concentrations to assess VAD may be particularly advantageous in field settings. Consequently, measuring RBP concentrations may be a practical alternative to measuring serum retinol in population surveys assessing the prevalence of VAD.

Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice.

Transthyretin (TTR) acts physiologically in the transport of retinol in the circulation. We previously reported the generation and partial characterization of TTR-deficient (TTR(-)) mice. TTR(-) mice have very low circulating levels of retinol and its specific transport protein, retinol-binding protein (RBP). We have examined the biochemical basis for the low plasma retinol-RBP levels. Cultured primary hepatocytes isolated from wild type (WT) and TTR(-) mice accumulated RBP in their media to an identical degree, suggesting that RBP was being secreted from the hepatocytes at the same rate. In vivo experiments support this conclusion. For the first 11 h after complete nephrectomy, the levels retinol and RBP rose in the circulations of WT and TTR(-) mice at nearly identical rates. However, human retinol-RBP injected intravenously was more rapidly cleared from the circulation (t(12) = 0.5 h for TTR(-) versus t(12) >6 h for WT) and accumulated faster in the kidneys of TTR(-) compared with WT mice. The rate of infiltration of the retinol-RBP complex from the circulation to tissue interstitial fluids was identical in both strains. Taken together, these data indicate that low circulating retinol-RBP levels in TTR(-) mice arise from increased renal filtration of the retinol-RBP complex.

A debriefing approach to dealing with the stress of CPR attempts.

Nurses may suffer physiological and psychological stress following a cardiopulmonary resuscitation attempt. Implementation of debriefing sessions following the care of a patient experiencing a cardiac arrest can reduce staff stress. Using a debriefing process enables learning opportunities to be identified and acted on by resuscitation teams.

Use of the retinol-binding protein: transthyretin ratio for assessment of vitamin A status during the acute-phase response.

The ratio plasma retinol-binding protein (RBP):transthyretin (TTR) has been proposed as a means to improve the assessment of vitamin A status of individuals with concurrent infection or inflammation. We have measured RBP and TTR in stored sera from South African children who had accidentally ingested kerosene. Samples were collected from these children in hospital when suffering acute inflammation and respiratory distress, and from them and neighbourhood control children 3 months later. Vitamin A status was defined by modified relative dose response (MRDR) tests of liver retinol stores at 3 months and by serum retinol concentration both when children were ill and when they were well. Illness was defined as either being in hospital or, at follow-up, as having a raised plasma alpha 1-acid glycoprotein (AGP) level. The RBP:TTR value was significantly decreased by both illness and low liver retinol stores. When the effects on RBP:TTR of illness and vitamin A stores were considered together for the 3-month follow-up samples, only vitamin A status significantly decreased the value. We calculated sensitivity and specificity of the RBP:TTR ratio against established measures of vitamin A status using a cut-off value of 0.3 for RBP:TTR and standard cut-off values for MRDR (0.06) and plasma retinol (0.7 mumol/l). Compared with MRDR, RBP:TTR had sensitivities of 76% and 43% and specificities of 22% and 81% to detect vitamin A deficiency in hospitalized and well children respectively. Compared with plasma retinol, sensitivities were 88% and 44% and specificities were 55% and 64% in hospitalized and well children respectively. Only for the case of clinically well children with biochemical evidence of subclinical inflammation did sensitivity (62% and 100% against MRDR and plasma retinol respectively) and specificity (100% and 60% against MRDR and retinol) approach useful levels for an assessment tool. Overall, although a trend supporting the theory behind the use of the RBP:TTR for assessment of vitamin A status in infection was observed in the current study, the ratio did not provide adequate sensitivity and specificity to be a useful assessment tool.

Retinol and retinol-binding protein: gut integrity and circulating immunoglobulins.

Vitamin A (retinol) is required to maintain immunity and epithelial turnover and is a key micronutrient needed for combating infection. Vitamin A actions on the immune system are diverse and cannot be accounted for by a single effect or mechanism. The actions of retinol in maintaining gut integrity in humans and immunoglobulin levels in mice was investigated. For 30 children, performance on the lactulose/mannitol test, a test commonly used to assess intestinal barrier function, was inversely correlated (P=.012) with serum retinol concentrations. Thus, children with lower serum retinol, and presumably poorer vitamin A nutritional status, are more likely to have impaired intestinal integrity. Knockout mice that have impairments in plasma retinol transport have circulating immunoglobulin levels that are half those observed in matched wild type mice. No differences were observed in B and T cell populations present in spleen, thymus, and bone marrow.

The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes.

Transcriptional activation requires both access to DNA assembled as chromatin and functional contact with components of the basal transcription machinery. Using the hormone-bound vitamin D(3) receptor (VDR) ligand binding domain (LBD) as an affinity matrix, we previously identified a novel multisubunit coactivator complex, DRIP (VDR-interacting proteins), required for transcriptional activation by nuclear receptors and several other transcription factors. In this report, we characterize the nuclear receptor binding features of DRIP205, a key subunit of the DRIP complex, that interacts directly with VDR and thyroid hormone receptor in response to ligand and anchors the other DRIP subunits to the nuclear receptor LBD. In common with other nuclear receptor coactivators, DRIP205 interaction occurs through one of two LXXLL motifs and requires the receptor's AF-2 subdomain. Although the second motif of DRIP205 is required only for VDR binding in vitro, both motifs are used in the context of an retinoid X receptor-VDR heterodimer on DNA and in transactivation in vivo. We demonstrate that both endogenous p160 coactivators and DRIP complexes bind to the VDR LBD from nuclear extracts through similar sequence requirements, but they do so as distinct complexes. Moreover, in contrast to the p160 family of coactivators, the DRIP complex is devoid of any histone acetyltransferase activity. The results demonstrate that different coactivator complexes with distinct functions bind to the same transactivation region of nuclear receptors, suggesting that they are both required for transcription activation by nuclear receptors.

Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group.

OBJECTIVE: The purpose of this study was to further define the therapeutic value of penciclovir cream in the treatment of sunlight-induced herpes labialis by comparing its efficacy and tolerability with those of an inactive control (purified water). METHODS: In this randomized, double-blind, placebo-controlled, parallel-group clinical trial, lesions were induced by exposure to sunlight. Treatment was self-initiated within 1 hour of development of the signs or symptoms of a recurrence. RESULTS: Healthy male and female patients (mean age, 38.3 years; range, 18 to 81 years) who had a history of sunlight-induced herpes labialis (mean of 6 recurrences in previous 12 months) applied either penciclovir cream (n = 266) or purified water (n = 275). Penciclovir cream significantly decreased the time to lesion healing (P < 0.001), with a reduction in median time of up to 2 days. The efficacy of penciclovir cream was further supported by a significant reduction in maximum lesion area (P = 0.008), a faster loss of lesion-associated symptoms (P = 0.026), and significant reductions in daily assessments of pain (P < or = 0.040), itching (P < or = 0.032), burning (P < or = 0.028), and tenderness (P < or = 0.026) as moderate or severe. These effects were reinforced by the results of the daily self-assessment of lesion attributes, with significantly fewer severe/extreme assessments of lesion size (P < or = 0.003), noticeability (P < or = 0.003), amount of scab/crust (P < or = 0.003), raised/ swollen area (P < or = 0.040), soreness/tenderness (P < or = 0.043), and overall severity (P < or = 0.001) throughout the study period. CONCLUSIONS: Penciclovir cream has demonstrated efficacy for a broad range of clinically important outcomes. Significant effects on lesion area, lesion symptoms, and other lesion attributes extend the clinical efficacy of penciclovir cream beyond lesion healing.

Substrate specificities and 13-cis-retinoic acid inhibition of human, mouse and bovine cis-retinol dehydrogenases.

Recent studies of the human, mouse and bovine genes for 11-cis-retinol dehydrogenase (11cRDH) and human and mouse 9-cis-retinol dehydrogenase (9cRDH) suggest that they are homologs of the same enzyme. This conclusion is inconsistent with earlier literature indicating that 11cRDH is expressed solely in the eye and does not utilize 9-cis-retinol as a substrate. We have compared directly the kinetic properties of recombinant human and mouse 9cRDH with those of bovine 11cRDH for 9-cis- and 11-cis-retinol and investigated the inhibitory properties of 13-cis-retinoic acid on each of these enzymes. Human and mouse 9cRDH and bovine 11cRDH have very similar kinetic properties towards 9-cis- and 11-cis-retinol oxidation and they respond identically to 13-cis-retinoic acid inhibition. Our biochemical data are consistent with the conclusion that 9cRDH and 11cRDH are the same enzyme.

Biochemical properties, tissue expression, and gene structure of a short chain dehydrogenase/ reductase able to catalyze cis-retinol oxidation.

We have identified a retinol dehydrogenase (cRDH) that catalyzes the oxidation of 9-cis- but not all-trans-retinol and proposed that this enzyme plays an important role in synthesis of the transcriptionally active retinoid, 9-cis-retinoic acid. There is little information regarding either the biochemical properties of cRDH or how its 9-cis-retinol substrate is formed. We now report studies of the properties and expression of human and mouse cRDH and of the characteristics and location of the murine cRDH gene. Additionally, we report mouse hepatic 9-cis-retinol concentrations and demonstrate that 9-cis-retinol is formed in a time- and protein-dependent manner upon incubation of all-trans -retinol with cell homogenate. Human and mouse cRDH display similar substrate specificities for cis-isomers of retinol and retinaldehyde. Moreover, human and mouse cRDH show marked sensitivity to inhibition by 13-cis-retinoic acid, with both being inhibited by approximately 50% by 0.15 microm 13-cis-retinoic acid (for substrate concentrations of 10 microm). Lesser inhibition is seen for 9-cis- or all-trans-retinoic acids. Immunoblot analysis using antiserum directed against human cRDH demonstrates cRDH expression in several tissues from first trimester human fetuses, indicating that cRDH is expressed early in embryogenesis. Adult mouse brain, liver, kidney, and to a lesser extent small intestine and placenta express cRDH. The murine cRDH gene consists of at least 5 exons and spans approximately 6 kb of genomic DNA. Backcross analysis mapped the mouse cRDH gene to the most distal region of chromosome 10. Taken together, these data extend our understanding of the properties of cRDH and provide additional support for our hypothesis that cRDH may play an important role in 9-cis-retinoic acid formation.

Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex.

Nuclear receptors modulate the transcription of genes in direct response to small lipophilic ligands. Binding to ligands induces conformational changes in the nuclear receptors that enable the receptors to interact with several types of cofactor that are critical for transcription activation (transactivation). We previously described a distinct set of ligand-dependent proteins called DRIPs, which interact with the vitamin D receptor (VDR); together, these proteins constitute a new cofactor complex. DRIPs bind to several nuclear receptors and mediate ligand-dependent enhancement of transcription by VDR and the thyroid-hormone receptor in cell-free transcription assays. Here we report the identities of thirteen DRIPs that constitute this complex, and show that the complex has a central function in hormone-dependent transactivation by VDR on chromatin templates. The DRIPs are almost indistinguishable from components of another new cofactor complex called ARC, which is recruited by other types of transcription activators to mediate transactivation on chromatin-assembled templates. Several DRIP/ARC subunits are also components of other potentially related cofactors, such as CRSP, NAT, SMCC and the mouse Mediator, indicating that unique classes of activators may share common sets or subsets of cofactors. The role of nuclear-receptor ligands may, in part, be to recruit such a cofactor complex to the receptor and, in doing so, to enhance transcription of target genes.

Plasma delivery of retinoic acid to tissues in the rat.

All-trans-retinoic acid (RA) activates ligand-dependent transcription factors that regulate retinoid-responsive gene expression. It is assumed that all-trans-RA is formed within cells through in situ oxidation of retinol derived from the circulation. However, the circulation contains low levels of all-trans-RA (approximately 0.2-0.7% of that of plasma retinol). Our studies investigated the extent to which plasma all-trans-RA contributes to tissue pools of this retinoid and explored factors responsible for regulating its uptake by tissues and cells. Rats were continuously infused, to steady state, with all-trans-[3H]RA. From measures of specific activities of all-trans-[3H]RA at steady state, we determined that the preponderance of all-trans-RA in brain and liver was derived from the circulation. For six other tissues, approximately 10-30% of the retinoid was derived from the circulation, but pancreas and testis derived very little from the circulating pool. In other studies, we showed that retinoid nutritional status influences clearance of a bolus dose of all-trans-RA and that neither the rate of cellular all-trans-RA uptake nor its intracellular half-life is influenced by cellular lipid levels. Taken together, our data indicate that plasma all-trans-RA contributes to tissue pools of this retinoid and that specific and physiologically responsive cellular processes mediate its uptake.

A positive, individually ventilated caging system: a local barrier system to protect both animals and personnel.

Most local barrier systems are designed primarily either to protect animals from airborne contamination (exclusion) or to ensure the safety of personnel (hazard containment). Few, other than isolators, are able to cope with the often conflicting demands to do both. The Positive Individually Ventilated system (PIV), which provides pressure adjustable, individual supply and exhaust ventilation to each cage has been tested with this in mind as well as the need to ensure that environmental conditions comply with the requirements of the Home Office Code of Practice (CoP). The results indicate that when compared with traditional open racking the system can reduce both the risk of animals becoming contaminated by airborne infection from the room and the risk of aeroallergens escaping from the cages into the room air. At the same time, environmental conditions within the cages are both less variable and less stressful to the occupants. Conditions of air temperature, relative humidity, ventilation rates, light intensity and (with appropriate air handling) sound levels, all comply with or are better than those required by the CoP. Even with the room air change rate set at only 8/h (8 ac/h) the air distribution system results in draught-free cage ventilation rates of around 50-120 ac/h. This means that with at least the PIV exhaust(s) linked directly into the air conditioning system of the building, the size of the latter and its associated running costs can be reduced by around 50%; this energy saving concept has been approved in principle by the Home Office. Additional benefits include the fact that bedding is kept much drier allowing further cost savings in bedding and associated labour costs. The system is thus beneficial to the animals in protecting them from airborne infection and other stresses. By providing a less variable environment it also helps to minimise the sort of interference with experiments which can arise from that source. Similarly, in accordance with the aims of 'The Control of Substances Hazardous to Health Regulations' (COSHH 1988) and the Health & Safety Executive (HSE 1990), by reducing dust levels in the room air, including allergens, it is also beneficial to the personnel working in the animal rooms.

The role of iconicity in sign language learning by hearing adults.

The feature of transparency has been identified as facilitating the learning of manual signs as word surrogates. The recognition and retention of transparent and nontransparent signs by 50 sign-naive hearing college freshmen was investigated in three tasks: (1) a transparency task; (2) after a training period, a short-term memory task; and (3) a long-term memory task. Results indicated that both transparent and nontransparent signs were retained over a short and a long period of time; however, there was a significant decrease in the number of nontransparent signs retained as the period of time after training increased. Implications for sign language training are discussed.

Regulation of carnitine palmitoyltransferase by insulin results in decreased activity and decreased apparent Ki values for malonyl-CoA.

Administration to normal rats of 100 mg of streptozotocin/kg body weight produced ketotic diabetic rats in which the affinity of carnitine palmitoyltransferase for malonyl-CoA was decreased by 10-fold and its activity was increased by 30%, but the injection of insulin brought the affinity and the activity back to normal within 4 h. Administration of 60 mg of streptozotocin/kg produced non-ketotic diabetic rats and caused a less substantial change in the affinity of carnitine palmitoyltransferase for malonyl-CoA. In the BB Wistar diabetic rat, the onset of diabetes also increased the activity of carnitine palmitoyltransferase and decreased its affinity for malonyl-CoA. Injection of insulin brought both of these values back to normal within 2 h. The total activity of mitochondrial carnitine palmitoyltransferase (outer + inner activities) was 40% greater in the BB Wistar diabetic rat, but treatment with insulin did not decrease the total activity to normal values within 2 h. The elevated activity and decreased affinity for malonyl-CoA found in fasting rats did not respond to short-term insulin treatment. The evaluation of a previous report that cycloheximide blocks the effects of starvation indicated that cycloheximide did not act by inhibiting protein synthesis, but produced its effect by preventing gastric emptying. Current data suggest that diabetes increases the activity of carnitine palmitoyltransferase and greatly diminishes the affinity of the enzyme for malonyl-CoA and that the severity of diabetes is associated with differences in the affinity of the enzyme for its inhibitor. Insulin acts on the outer carnitine palmitoyltransferase to reverse these effects very rapidly, but diabetes produces some change in the total activity that is not reversed by short-term treatment with insulin.