Facilitators for increasing dental attendance of people from vulnerable groups: a rapid review of evidence relevant to the UK.

Objective To rapidly review facilitators of access for vulnerable groups and to evaluate their effectiveness.Methods Data sources: MEDLINE via Ovid. Publications in English from 2000. DATA SELECTION: Research involving 'vulnerable groups' relevant to UK health systems, with a primary outcome of increasing attendance. DATA EXTRACTION: One author extracted and tabulated data. These were audited by a second author. DATA SYNTHESIS: A narrative synthesis was produced.Results Data from 31 studies were available for ten vulnerable groups: people with learning, physical or sensory disabilities (n = 8); people experiencing homelessness (n = 6); prisoners (n = 4); asylum-seekers and refugees (n = 3); people living in socioeconomically deprived areas (n = 3); people with severe mental health conditions (n = 2); vulnerable children (n = 2); dependent older people (n = 1); Gypsy, Roma or Traveller groups (n = 1); and people with drug dependency (n = 1). Many facilitators involved organisational reform and more integration of health, social and other services. Other facilitators included: modification of premises; team development and skill-mix use; and awareness of needs and flexible services to meet them. Few studies evaluated effectiveness.Conclusion Although facilitators for access for vulnerable groups have been proposed, there is little evidence to support or refute their effectiveness. Efforts are needed to promote access for vulnerable groups in the UK with evaluation plans embedded.

Awake minimally invasive parafascicular approach to a language eloquent brain tumour-surgical video.

Deep-seated brain tumours are surgically challenging to access. When planning approaches to these lesions, it is important to take into account eloquent cortical areas, grey matter nuclei, and subcortical white matter tracts. Traditionally, access to deep-seated lesions would require brain retraction; however, this is associated with secondary brain damage, which may impair neurological function. A trans-sulcal minimally invasive parafascicular approach allows gentle splitting of brain fibres and is thought to splay rather than sever white matter tracts. This is particularly important when approaching medially located, language-eloquent tumours, which lack brain surface expression. This video describes a minimally invasive approach to a deep-seated, language-eloquent brain tumour. We utilized preoperative cortical and subcortical planning to define a safe surgical corridor. We then demonstrate using intraoperative neuro-monitoring and mapping of the motor and language functions to define the boundaries of surgical resection. We find trans-sulcal minimally invasive parafascicular approach to be a safe and effective technique when approaching language-eloquent lesions medial to the main language subcortical networks.

Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

Background: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes. Methods: People with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety. Findings: Between 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms. Interpretation: Favipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection. Funding: The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

Delayed brain metastasis after 17-years from papillary thyroid cancer without local recurrence: case report and literature review.

Papillary thyroid carcinoma (PTC) is the most common malignancy originating from the thyroid, with a good overall prognosis. However, distant metastasis of such lesions is very rare, with the brain being an incredibly uncommon site for secondary spread. The authors report a case of PTC brain metastasis 17-years after successful treatment of the primary malignancy, with no local or locoregional recurrence. Initial diagnostic uncertainty necessitated the involvement of a multidisciplinary team, and eventually the patient underwent image-guided gross surgical resection with intraoperative neuromonitoring (IOMN).

A landscape review of controlled release urea products: Patent objective, formulation and technology.

Fertiliser has been a vital part of agriculture due to it boosting crop productivity and preventing starvation throughout the world. Despite this huge contribution, the application of nitrogen (N) fertilisers results in N leaching and the formation of greenhouse gases, which threaten the environment and human health. To minimise the impacts, slow/controlled release fertilisers (S/CRFs) have been being developed since the beginning of the 20th century. Despite the efforts made over a century, the basic terminological and classification information of these fertilisers remains vague. The scientific knowledge published in S/CRF patents has also been overlooked since the beginning. This review focused on the information gaps, clarified the definitions, differentiation and classification methods that have been randomly used in previous literature. The objectives, formulations and technologies of 109 controlled release urea patents involving sulphur coated urea, polymer coated urea and urea matrix fertilisers published in the years since these products emerged were also reviewed to 1) highlight the overlooked scientific knowledge in the patents; 2) understand the evolutionary processes and current research states of the products; 3) clarify research preferences and challenges to date; 4) identify remaining gaps for the future direction. It is expected that the organised basic information and the patent knowledge highlighted in this paper can be new resources and foster the development of S/CRFs in the future.

Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells.

BACKGROUND: Impaired mineral ion metabolism is a hallmark of CKD-metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR. METHODS: To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox ). RESULTS: Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D3), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice. CONCLUSIONS: These results suggest that, in addition to CaSR's established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.

Electrospun Membranes as a Porous Barrier for Molecular Transport: Membrane Characterization and Release Assessment.

Electrospun nanofibers have been extensively studied for encapsulated drugs releasing from the inside of the fiber matrix, but have been barely looked at for their potential to control release as a semi-permeable membrane. This study investigated molecular transport behaviors across nanofiber membranes with different micro-structure sizes and compositions. Four types of membranes were made by 5% and 10% poly (ε-caprolactone) (PCL) solutions electro-spun with or without 50 nm calcium carbonate (CaCO3) nanoparticles. The membranes were tested for thickness, fiber diameter, pore size, porosity, tensile strength and elongation, contact angle of water and their impacts on molecular transport behaviors. The presence of the CaCO3 nanoparticles made the 5% membranes stronger and stiffer but the 10% membranes weaker and less stiff due to the different (covering or embedded) locations of the nanoparticles with the corresponding fibers. Solute transport studies using caffeine as the model drug found the 5% membranes further retarded release from the 10% membranes, regardless of only half the amount of material being used for synthesis. The addition of CaCO3 nanoparticles aided the water permeation process and accelerated initial transports. The difference in release profiles between 5% and 10% membranes suggests different release mechanisms, with membrane-permeability dominated release for 5% PCL membranes and solute-concentration-gradient dominated release for 10% PCL membranes.

Metastatic Colon Cancer in the Pituitary: A Case Report with Review of Literature.

We report a rare case of metastatic colonic adenocarcinoma to the pituitary gland in a 58-year-old who presented with visual decline and panhypopituitarism. He underwent urgent transsphenoidal endoscopic surgery with significant improvement of his vision, followed by adjuvant fractionated radiotherapy to the resection cavity. He made a satisfactory recovery, but regrettably died from COVID-19 9 weeks after completion of radiotherapy. A multidisciplinary approach is essential for optimal management of this condition due to its rarity and complexity.

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats.

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.

Children's toothache is becoming everybody's business: where do parents go when their children have oral pain in London, England? A cross-sectional analysis.

OBJECTIVES: To assess the number of parents who visited community pharmacies in London seeking pain medications for their children's pain and specifically for oral pain, to identify which health services parents contacted before their pharmacy visit and to estimate the cost to the National Health Service (NHS) when children with oral pain who visit pharmacies also see health professionals outside dentistry. DESIGN: A cross-sectional study. SETTING: 1862 pharmacies in London in November 2016-January 2017. PARTICIPANTS: Parents, carers and adolescents purchasing over-the-counter pain medications or collecting pain prescriptions for children (0-19 years). BRIEF INTERVENTION: A survey administered by pharmacy staff to participants and a guidance pack. MAIN OUTCOME MEASURES: The number of parents who visited pharmacies seeking pain medications for their children's pain and oral pain and the number of parents who contacted health professionals outside dentistry before their pharmacy visit. Estimated costs of visits by children with oral pain to health professionals outside dentistry. RESULTS: One in two (951) pharmacies participated collecting information from 6915 parents seeking pain medications for their children. The majority (65%) of parents sought pain medications to relieve their children's oral pain. Only 30% of children with oral pain had seen a dentist before the pharmacy visit, while 28% of children had seen between one and four different health professionals. The cost to the NHS of children contacting health professionals outside dentistry was £36 573, extrapolated to an annual cost of £373 288. Replicating these findings across all pharmacies in England could mean that the NHS spends an estimated £2.3 million annually when children with oral pain inappropriately use multiple health services. CONCLUSION: Most parents who visited pharmacies for children's pain medications in London sought pain medications for children's oral pain. Children's inappropriate contact with multiple health services when they have oral pain adds significant costs to the NHS.

Claudin-2 Expression Levels in Ulcerative Colitis: Development and Validation of an In-Situ Hybridisation Assay for Therapeutic Studies.

Ulcerative colitis is a chronic inflammatory disease affecting the colon and is characterized by epithelial damage and barrier dysfunction. Upregulation of the tight junction protein claudin-2 by cytokines is hypothesized to contribute to the dysregulation of the epithelial barrier. New therapeutic agents which block the action of cytokines are being investigated in patients with ulcerative colitis. In order to understand the potential of these therapies, it is important to have reliable assays that can assess downstream endpoints that reflect drug mechanism of action. The aim of the current study was therefore to establish & validate an assay to reproducibly assess the expression and distribution of claudin-2 in human colon biopsy samples. Initially, the potential to measure claudin-2 protein by immunohistochemistry (IHC) was investigated. To identify suitable reagents to develop an IHC assay, pre-established criteria were used to screen five commercial antibodies by Western blotting, immunofluorescence and immunohistochemistry on claudin-2 positive and negative cells and healthy and ulcerative colitis colon tissue. Despite some of these antibodies specifically detecting claudin-2 using some of these techniques, none of the antibodies showed the expected specific staining pattern in formalin fixed human colon samples. As an alternative method to detect claudin-2 expression and distribution in formalin fixed biopsy sections, an in situ hybridization assay was developed. This assay underwent a novel tiered approach of validation to establish that it was fit-for-purpose, and suitable for clinical deployment. In addition, to understand the possible relationship of claudin-2 in the context of disease severity, expression was compared to the Geboes score. Overall, the microscopical Geboes score correlated with the claudin-2 biomarker score for samples that retained crypt morphology; samples with the highest Geboes score were not specifically distinguished, probably due to crypt destruction. In summary, we have applied a strategy for identifying target-specific antibodies in formalin fixed biopsy samples and highlighted that (published) antibodies may not correctly identify the intended antigen in tissues fixed using this method. Furthermore, we have developed and, for the first time, validated an in situ hybridization assay for detection of claudin-2 mRNA, suitable for use as a supportative method in clinical trials. Using our validated assay, we have demonstrated that increased claudin-2 expression correlates with the severity of ulcerative colitis, where crypt destruction is not seen.

Coated Solid Substrate Microbe Formulations: Pseudomonas spp. and Zeolite.

Formulation provides a means to stabilize for storage and delivery biocontrol and bioremediation agents based on microbes such as bacteria and fungi. Typically it is difficult to both stabilize and deliver fragile non-spore-forming bacteria. Fungal spores might intuitively appear to be easy to stabilize; however, their tendency to germinate in low moisture environments presents challenges for the formulation scientist. Here we present a light background regarding issues with formulating microbes and strategies to help overcome instability and delivery issues.

Use of a Canine Model of Atopic Dermatitis to Investigate the Efficacy of a CCR4 Antagonist in Allergen-Induced Skin Inflammation in a Randomized Study.

Atopic dermatitis (AD) is an inflammatory skin disease characterized by infiltration of skin homing lymphocytes into the dermis. Most of these lymphocytes express the chemokine receptor CCR4, and the frequency of blood CCR4(+) lymphocytes correlates with AD disease severity. Canine AD is a pruritic inflammatory condition that shows many features of the human disease, including CCR4 overexpression. Therefore, we tested a potent selective CCR4 antagonist in an allergen challenge model of canine AD, both clinically and histologically, to investigate whether this chemokine pathway plays a role in the inflammatory response. Using a four-period randomized cross-over study design, 14 beagles were challenged with allergen and clinically monitored. Biopsy samples were taken before and after allergen challenge. A clear reduction of clinical scores was observed with oral prednisolone (P < 0.0001) but not for the CCR4 inhibitor. A subset of the dogs (5/13) showed partial inhibition (30-49%) of the clinical signs with CCR4 inhibitor treatment, and this finding was supported by the results of histopathologic analysis of skin biopsy samples. This partial response is consistent with redundancy in chemokine pathways and highlights the need for therapies blocking multiple pathways. This study shows the utility of this canine model of AD for testing new therapeutic agents.

Active vitamin D potentiates the anti-neoplastic effects of calcium in the colon: A cross talk through the calcium-sensing receptor.

Epidemiological studies suggest an inverse correlation between dietary calcium (Ca(2+)) and vitamin D intake and the risk of colorectal cancer (CRC). It has been shown in vitro that the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-D3) can upregulate expression of the calcium-sensing receptor (CaSR). In the colon, CaSR has been suggested to regulate proliferation of colonocytes. However, during tumorigenesis colonic CaSR expression is downregulated and we hypothesized that the loss of CaSR could influence the anti-tumorigenic effects of Ca(2+) and vitamin D. Our aim was to assess the impact of CaSR expression and function on the anti-neoplastic effects of 1,25-D3 in colon cancer cell lines. We demonstrated that in the healthy colon of mice, high vitamin D diet (2500 IU/kg diet) increased expression of differentiation and apoptosis markers, decreased expression of proliferation markers and significantly upregulated CaSR mRNA expression, compared with low vitamin D diet (100 IU/kg diet). To determine the role of CaSR in this process, we transfected Caco2-15 and HT29 CRC cells with wild type CaSR (CaSR-WT) or a dominant negative CaSR mutant (CaSR-DN) and treated them with 1,25-D3 alone, or in combination with CaSR activators (Ca(2+) and NPS R-568). 1,25-D3 enhanced the anti-proliferative effects of Ca(2+) and induced differentiation and apoptosis only in cells with a functional CaSR, which were further enhanced in the presence of NPS R-568, a positive allosteric modulator of CaSR. The mutant CaSR inhibited the anti-tumorigenic effects of 1,25-D3 suggesting that the anti-neoplastic effects of 1,25-D3 are, at least in part, mediated by the CaSR. Taken together, our data provides molecular evidence to support the epidemiological observation that both, vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

A new primary dental care service compared with standard care for child and family to reduce the re-occurrence of childhood dental caries (Dental RECUR): study protocol for a randomised controlled trial.

BACKGROUND: In England and Scotland, dental extraction is the single highest cause of planned admission to the hospital for children under 11 years. Traditional dental services have had limited success in reducing this disease burden. Interventions based on motivational interviewing have been shown to impact positively dental health behaviours and could facilitate the prevention of re-occurrence of dental caries in this high-risk population. The objective of the study is to evaluate whether a new, dental nurse-led service, delivered using a brief negotiated interview based on motivational interviewing, is a more cost-effective service than treatment as usual, in reducing the re-occurrence of dental decay in young children with previous dental extractions. METHODS/DESIGN: This 2-year, two-arm, multicentre, randomised controlled trial will include 224 child participants, initially aged 5 to 7 years, who are scheduled to have one or more primary teeth extracted for dental caries under general anaesthesia (GA), relative analgesia (RA: inhalation sedation) or local anaesthesia (LA). The trial will be conducted in University Dental Hospitals, Secondary Care Centres or other providers of dental extraction services across the United Kingdom. The intervention will include a brief negotiated interview (based on the principles of motivational interviewing) delivered between enrollment and 6 weeks post-extraction, followed by directed prevention in primary dental care. Participants will be followed up for 2 years. The main outcome measure will be the dental caries experienced by 2 years post-enrollment at the level of dentine involvement on any tooth in either dentition, which had been caries-free at the baseline assessment. DISCUSSION: The participants are a hard-to-reach group in which secondary prevention is a challenge. Lack of engagement with dental care makes the children and their families scheduled for extraction particularly difficult to recruit to an RCT. Variations in service delivery between sites have also added to the challenges in implementing the Dental RECUR protocol during the recruitment phase. TRIAL REGISTRATION: ISRCTN24958829 (date of registration: 27 September 2013), Current protocol version: 5.0.

Case report: Recurrent glossopharyngeal neuralgia after previous glossopharyngeal rhizotomy: Microvascular decompression with intra-operative neurophysiology.

We present a case of recurrent vago-glossopharyngeal neuralgia after previous surgery, treated successfully with microvascular decompression using intra-operative neurophysiology monitoring.

An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity.

Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers.

Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers.

Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathological injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clinical standards of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathological evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.

Tissue expression and correlation of a panel of urinary biomarkers following cisplatin-induced kidney injury.

In recent years, there has been considerable activity to identify urinary biomarkers of nephrotoxicity as noninvasive measurements with greater sensitivity and specificity than traditional biomarkers, such as serum creatinine and blood urea nitrogen. Our study aimed to use cisplatin-treated rats to evaluate the use of immunohistochemistry directed at multiple urinary biomarkers in kidney tissue. Tissue levels were compared to urinary levels of these biomarkers to demonstrate tissue specificity and sensitivity. These techniques could also be used in studies where urine samples are not available, such as retrospective studies in drug safety testing, to demonstrate the potential utility of using these biomarkers in future preclinical or clinical studies. All of the biomarkers investigated showed either an increase (kidney injury molecule [KIM-1], osteopontin [OPN], and, clusterin) or a decrease (alpha-glutathione S-transferase and trefoil factor 3) except beta 2 microglobulin (ß2MG) that showed no significant changes 5 days after 1.0 mg/kg or 2.5 mg/kg cisplatin treatment. All of the biomarkers except ß2MG showed utility as tissue biomarkers, but KIM-1 and OPN expression correlated closely with urinary biomarker measurements and reflect tissue damage. Future studies are needed to determine the wider application of these two markers for detecting renal toxicity following administration of other nephrotoxicants.

Significant attenuation of stimulated cortisol in early Graves disease without adrenal autoimmunity.

OBJECTIVE: To investigate cortisol responses to adrenocorticotropic hormone during thyrotoxic (G1) and euthyroid (G2) phases in patients with Graves disease (GD) who were without adrenal autoimmunity. METHODS: Fifteen patients with GD, who were thyrotropin receptor antibody positive and 21-hydroxylase antibody negative, were recruited to this prospective pilot study. A modified short Synacthen test (SST) was performed, in which cortisol was measured every 30 minutes for 2 hours during G1 and G2. RESULTS: The median times to SST were 3 weeks (G1) and 27 weeks (G2) after diagnosis of GD. Integrated stimulated cortisol levels were significantly lower at G1 in comparison with G2: mean ± standard error of the mean for area under the curve was 78,091.6 ± 4,462.1 nmol/L (G1) versus 89,055 ± 4,434 nmol/L at 120 minutes (G2), P = .017; and for delta area under the curve was 36,309.9 ± 3,526 nmol/L (G1) versus 44,041.7 ± 2,147 nmol/L at 120 minutes (G2), P = .039. Mean cortisol levels were significantly lower for G1 versus G2 at 60, 90, and 120 minutes of the SST (P = .001 to .013). The cortisol level was abnormal in 2 patients (13%) at 30 minutes during G1 but in none during G2. There was no correlation of integrated cortisol with free thyroxine or thyrotropin receptor antibody. There was no significant difference in median adrenocorticotropic hormone level (17 versus 20.4 ng/mL at G1 and G2, respectively; P = .14). CONCLUSION: Significant attenuation of stimulated cortisol occurs in the early thyrotoxic phase in comparison with the euthyroid phase in patients with GD without adrenal autoimmunity. Clinicians treating patients with GD should have a low threshold for investigating symptoms suggestive of hypoadrenalism at times of "stress."