Predicting medical students who will have difficulty during their clinical training.

BACKGROUND: We aimed to classify the difficulties students had passing their clinical attachments, and explore factors which might predict these problems. METHODS: We analysed data from regular student progress meetings 2008-2012. Problem categories were: medical knowledge, professional behaviour and clinical skills. For each category we then undertook a predictive risk analysis. RESULTS: Out of 561 students, 203 were found to have one or more problem category and so were defined as having difficulties. Prevalences of the categories were: clinical skills (67%), knowledge (59%) and professional behaviour (29%). A higher risk for all categories was associated with: male gender, international entry and failure in the first half of the course, but not with any of the minority ethnic groups. Professional and clinical skills problems were associated with lower marks in the Undergraduate Medical Admissions Test paper 2. Clinical skills problems were less likely in graduate students. CONCLUSIONS: In our students, difficulty with clinical skills was just as prevalent as medical knowledge deficit. International entry students were at highest risk for clinical skills problems probably because they were not selected by our usual criteria and had shorter time to become acculturated.

Ultra-thin strut cobalt chromium bare metal stent usage in a complex real-world setting. (SOLSTICE registry).

AIM: To report clinical follow-up at 6 months after implantation of the ultra-thin strut cobalt chromium SolarFlex stent in a real-world setting. METHODS AND RESULTS: Patients (n = 240) with single or multiple vessel coronary artery disease undergoing percutaneous coronary intervention (PCI) at four sites in Europe were enrolled in the SOLSTICE (SolarFlex Stent in Routine Clinical Practice) registry. Follow-up at 6 months was 100 %. Diabetes was present in 29 % of the patients, 30 % presented with acute myocardial infarction and 17 % had unstable angina. Of the patients, 27 % had previously undergone PCI or coronary artery bypass surgery. Lesion complexity was high (50 % B2 + C type lesions). Device success was achieved in 99.7 % of cases and the major adverse cardiac event (MACE) rate was 5.8 % at 6 months of follow-up. Target lesion revascularisation (TLR) was 5.0 % at 6 months. CONCLUSIONS: The SOLSTICE registry showed that in a complex real-world setting the SolarFlex bare metal stent, with ultra-thin struts and customised scaffolding, provided low clinical MACE and TLR rates. These results provide support for the use of the latest generation bare metal stent in contemporary European practice.

Diagnosing variant Creutzfeldt-Jakob disease: a retrospective analysis of the first 150 cases in the UK.

INTRODUCTION: Establishing an early clinical diagnosis in variant Creutzfeldt-Jakob disease (vCJD) can be difficult, resulting in extended periods of uncertainty for many families and sometimes a view that patients have been subjected to unnecessary investigations. This issue is accentuated by the progressive nature of vCJD and by the difficulty in achieving a confident clinical diagnosis before an advanced stage of illness. Although diagnostic delay may be a result of the non-specific early clinical features, a systematic analysis of the process of diagnosis was undertaken, with the aim of trying to achieve earlier diagnosis of vCJD. METHODS: Retrospective case file analysis was undertaken of the first 150 definite and clinically probable cases of vCJD identified by the UK surveillance system. RESULTS: There is a significant interval between illness onset and presentation to a primary care physician, which is influenced by the nature of the initial clinical features. Neurological review is invariably sought following the development of clinical signs and a diagnosis is then established relatively quickly. Despite the progressive clinical course, a confident clinical diagnosis is not usually achieved until a relatively advanced stage of illness (mean time to diagnosis 10.5 months) with a more rapid clinical progression accounting for those cases diagnosed earlier after symptom onset. CONCLUSIONS: Early clinical diagnosis in vCJD is not possible in the great majority of cases because of non-specific initial symptoms. Once neurological signs develop, a diagnosis is usually made promptly but this is often at a relatively advanced stage of illness. The inherent delays in the diagnosis of vCJD have implications for those involved in both public health and therapeutics.

Studies on multiple thyroid cell membrane-directed antibodies in Graves' disease.

Immunoglobulin G was obtained from the serum of a woman who had given birth to three children with a delayed onset of hyperthyroidism; the clinical events were due to the coexistence of thyroid-stimulating antibody (TSAb) and an inhibitor of TSAb in the maternal serum. The current studies explore the possible existence of additional thyroid membrane-directed antibodies. Human thyroid slices, cells in monolayer culture, and functioning rat thyroid cells (FRTL5), with measurement of cyclic AMP concentration, were used for TSAb assays. Assays of the inhibition of binding of 125I-thyrotropin (TSH) to its receptor used human thyroid and FRTL5 cells, and human thyroid and guinea pig fat cell membranes as receptors. All activities were associated with IgG kappa. Fractions of IgG kappa obtained by adsorption to and the desorption from human thyroid and guinea pig fat cell preparations and F(ab')2 and Fab fragments of the parent IgG were tested. Results indicated that there were three activities in the IgG, namely, TSAb; an inhibitor of TSH-binding that was active in all species and preparations tested, and was effective as Fab and F(ab')2 on both particulate and solubilized thyroid membranes; and an enhancer of TSH-binding (e.g., approximately equal to 220% increase in binding) that was relatively specific for human thyroid membranes only in particulate form, was not adsorbed by fat, and was active as F(ab')2, but minimally as Fab. The concept is developed that dilution of the total IgG, experimentally in vitro or by metabolic clearance in vivo in neonates, determines the effect on either thyroid stimulation or TSH-binding. The incidence of such multiple antibodies and their interaction remains to be determined.

Evidence supporting the identity in Graves' disease of thyroid-stimulating antibody and thyroid growth-promoting immunoglobulin G as assayed in FRTL5 cells.

This paper addresses the question: in Graves' disease is there a thyroid-growth stimulating IgG (TGI) separate from thyroid-stimulating antibody (TSAb)? Using the functioning rat thyroid line (FRTL5) cells for TGI (incorporation of [3H]-thymidine into DNA) and TSAb (increase in cAMP concentration) assays, we tested IgG from 30 Graves' patients. Positive TGI assay occurred only if cAMP increased in the cells and responses correlated, i.e., r = 0.95, P less than 0.001. With one very potent TSAb-IgG we showed that Fab was active as TGI and TSAb, IgG with pI of 8.5-9.0 was the most potent fraction in both systems and an inhibitory IgG prevented the action of both TSAb-IgG and TSH in both the TSAb and TGI assays. In the last example, the action was on the cell membrane and not on the TSH or IgG. These data are entirely compatible with the view that in Graves' disease, at least as tested in FRTL5 cells, the same IgG is active in stimulating both growth and adenylate cyclase.

Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves' disease.

Studies were carried out with the serum IgG from a mother and her two children who developed neonatal Graves' disease several weeks after birth. The maternal IgG: (a) stimulated the human thyroid in vitro, but maximal stimulation was found only with dilution of the IgG; (b) was very potent in the long-acting thyroid stimulator (LATS)-protector assay, but only when an inhibitor of the system was diluted out; (c) inhibited a standard preparation of LATS in the mouse bioassay; (d) was biphasic in the thyrotropin-binding inhibition (TBI) assay, i.e., enhanced binding at low concentrations of IgG and inhibited binding at high levels. Enhancement in the TBI assay was found only with particulate preparations of human thyroid membranes as receptor and not when that material was solubilized, nor with guinea pig fat cell membranes as receptor. Serial blood samples from the second child were obtained at birth and until 3 mo of age. In the thyroid slice (cyclic AMP) assay system there was a negative dose-response relationship in testing IgG until age 45 d when it became positive, coinciding with the clinical recognition that hyperthyroidism had developed. The data are compatible with a concept that this mother's IgG contained thyroid-stimulating antibody (TSAb) and another moiety that inhibited TSAb through an action on the thyroid cell membrane, thus delaying the onset of hyperthyroidism in the neonate until the inhibiting IgG was metabolically cleared to an ineffective concentration.

Suppression of peripheral blood natural killer cell activity by excess thyroid hormone.

Natural killer (NK) cells were assessed in patients with hyperthyroxinemia due to Graves' disease or treatment with thyroxine (T4). Cytolytic activity was measured with 51Cr-labeled K562 tumor cells and NK enumeration was by flow cytometry using NKH-1 monoclonal antibody to identify the relevant surface marker. Activity was uniformly decreased in association with hyperthyroxinemia, regardless of the underlying pathology; however, there was no reduction in the number of NKH-1+ cells. NK activity was enhanced by addition of interleukin 2 (IL-2) in both control and patients' cells although the value in the latter instance failed to reach the basal control level. Production of IL-2 by lymphocytes from hyperthyroxinemic subjects, in response to phytohemagglutinin, was also reduced. Since NK cells are thought to act as a defense against viral infections and some malignancies and may play a role in autoregulation of the immune system, this effect of T4 may have significant biological implications.

Systematic review and meta-analysis: Prevalence and possible causes of vitamin D deficiency and insufficiency in pediatric cancer patients.

BACKGROUND AND AIMS: Vitamin D inadequacy is now an internationally recognized health problem and pediatric cancer patients may be at even higher risk than healthy children. We aimed to evaluate primary research to establish the prevalence of vitamin D inadequacy and to explore its possible causes in pediatric cancer patients. METHODS: Electronic databases were searched (no restriction-Aug 2013) with no language restrictions and keywords related to cancer and vitamin D. We included studies of patients aged <18 years, diagnosed with and treated for cancer and reporting plasma vitamin D status. Evidence was critically appraised employing the CASP tool. Meta-analysis was performed when appropriate. RESULTS: We included 19 studies, which were mainly of moderate-quality and heterogeneous in the definitions of vitamin D deficiency and insufficiency. The median (range) prevalence of vitamin D deficiency was 14% (0-61.5%) and insufficiency 23% (0-83%). Finally, a significant effect of younger age with vitamin D inadequacy was shown (effect size: -0.132; 95%CI -0.203, -0.060). CONCLUSION: There is a possibility of a high prevalence of vitamin D inadequacy in pediatric cancer patients, especially older children, urging the need for high-quality population-based longitudinal studies using standard definitions.

Evidence of hyperthyroidism in apparently euthyroid patients treated with levothyroxine.

A concentration of serum thyroxine (T4) above the accepted normal range has recently been recognized to result from commonly prescribed replacement dosages of levothyroxine sodium. To determine if the high levels of serum T4 have undesirable metabolic effects, despite the fact that the subjects are accepted as euthyroid, we studied 28 patients receiving long-term levothyroxine therapy; 19 patients were considered to be receiving replacement dosages and nine suppressive dosages of levothyroxine. To assess the effect of levothyroxine on target tissue, we measured the thyrotropin response to protirelin and systolic time intervals obtained by simultaneous electrocardiography and echocardiography. Thyrotropin response to protirelin was suppressed in patients with elevated serum T4 levels and normal serum triiodothyronine levels. These patients also had shortened systolic time intervals typical of hyperthyroidism. Our data indicate that commonly given replacement dosages of levothyroxine may induce undesirable metabolic consequences and that these patients perhaps ought to be seen as having "subclinical hyperthyroidism." The prescribed dosage of levothyroxine as therapy for hypothyroidism is still frequently excessive.

Psychologic modulation of the human immune response to varicella zoster.

Psychoimmunology, the interrelationship between the brain/mind/psyche and the immune system, is now an established area of scientific research. Based on prior investigations we hypothesized that an experienced meditator could affect her delayed hypersensitivity reaction by a psychological process. A single-case study design was employed in which the subject was skin tested weekly with varicella zoster skin test reagent. After baseline immunologic studies, she was able, as hypothesized, to significantly reduce both the induration of her delayed hypersensitivity skin test reaction and in vitro lymphocyte stimulation to varicella zoster. Then, as predicted, she was able to allow her reaction to return to baseline. As a confirmation of what is to our knowledge this previously undescribed phenomenon, she was able to reproduce the entire sequence nine months later. It appears that this subject can intentionally modulate her immune response by a psychologic mechanism.

The dietary intake of children with IDDM.

OBJECTIVE: To assess the dietary intake of children with IDDM and to determine whether the intake meets the current nutritional recommendations for children with IDDM. RESEARCH DESIGN AND METHODS: A total of 66 children with IDDM who were < 10 years of age were recruited from two suburban Pennsylvania hospitals. To collect dietary intake data, subjects were asked, via telephone interview, to complete three random-day 24-h dietary recalls. Data were analyzed for the content of nutrients and other food components by a computerized database program. Intakes were expressed as a 3-day average intake for each subject. RESULTS: Overall mean intake of protein and cholesterol approximated the current recommendations. The mean intake of saturated fat exceeded recommendations, while fiber intake was less than the recommended level. Many of the children consumed levels of saturated fat well above recommendations. Energy, vitamin, and mineral intakes were adequate for the overall sample. However, from 10 to 40% of the sample had an inadequate intake of vitamin D, vitamin E, and zinc. The percentage of those with inadequate intakes of these nutrients decreased with age. CONCLUSIONS: These data suggest that, on average, among this sample of children with IDDM aged < 10 years, adherence to the current nutritional recommendations for children with IDDM was adequate, but some individual children had intakes that were not consistent with the recommendations for optimal management of IDDM.

Regulation of the rat thyrotropin receptor in vitro.

After our recent finding that the TSH receptor of the rat is regulated by endogenous TSH, we studied the system further by investigations in vitro. After exposure of the tissue to TSH, thyroid lobes showed decreased responsiveness to stimulation by the hormone when cAMP accumulation was measured as an end-point. This state of refractoriness was correlated with a decrease in hormone binding, the nature of which was mainly a loss of receptor sites when data were subjected to Scatchard analysis. Dissociation of bound TSH by washing the membrane preparation with NaCl revealed that occupation of the receptor could be responsible for part of the apparent down-regulatory effect after 14 h of exposure to TSH, whereas after 24 h of exposure, a true decrease in receptor sites prevailed.

Influences of cholera toxin on thyroid stimulation by thyrotropin and thyroid-stimulating antibody.

Thyroid-stimulating antibody (TSAb) is an immunoglobulin G (IgG) occurring in the blood in hyperthyroid Graves' disease patients; it stimulates the thyroid in a manner analogous to the action of TSH, i.e. by activation of adenylate cyclase. Since cholera toxin is also known to stimulate thyroid adenylate cyclase, we studied possible interaction of the enterotoxin on effects of TSAb and TSH using slices of canine thyroid in vitro and an increase in the concentration of cAMP as endpoint. Normal human IgG, known to inhibit the binding of [125I]-iodo-TSH to thyroid membranes, decreased stimulation of thyroid slices by TSH; this inhibitory effect occurred also with preparations of TSAb (inevitably comprised mainly of normal IgG) that were themselves stimulatory. The cholera toxin effect was not prevented by normal IgG and, by factorial analysis of variance, was shown to potentiate the action of subsequently added TSAb or TSH. There was also positive interaction of the effect of TSAb with the combination of TSH and cholera toxin. The data indicate that responses of thyroid tissue to TSAb and TSH are readily influenced by effects of other membrane-active agents (in the present context, normal IgG and cholera toxin).

Variations in the culture medium for FRTL5 cells: effects on growth and iodide uptake.

We evaluated the composition of the medium in which FRTL5 cells were incubated for effects on basal and stimulated growth and differentiated function. Variables included the concentration of calf serum (CS) from 0% (0.2% BSA) to 5% and the addition of insulin or insulin-like growth factor-I (IGF-I); stimulation was by TSH, with some experiments using thyroid-stimulating antibody-immunoglobulin G. The basal rate of incorporation of [3H]thymidine and the content of DNA per well were enhanced progressively by the increasing concentration of CS, whether in a pretreatment period of 3 days or over a subsequent 2 days of incubation. Concomitantly, I- uptake was progressively inhibited. Stimulation of growth by TSH required serum and was greatest with 5% CS; TSH effect on I- uptake was progressively decreased by increments of CS. Insulin and IGF-I had effects comparable to each other, but much smaller concentrations of IGF-I were required; they both augmented growth and enhanced growth stimulation by TSH. These actions were progressively annulled by increasing concentrations of CS. I- uptake (basal and stimulated) was inhibited by insulin and IGF-I, but this inhibitory effect was abolished by CS, particularly at 5% concentrations. Overall, the influences of varying the concentrations of CS and the effects of insulin or IGF-I were consistent; if there was enhancement of growth stimulation, there was inhibition of the TSH effect on I- uptake. Underlying mechanisms for these observations have yet to be elucidated.

Influence of cytokines on growth and differentiated function of FRTL5 cells.

A functioning rat thyroid cell line (FRTL5) was used to study interactions of TSH with interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha). We examined effects on growth and differentiated function. Growth was assessed by DNA, incorporation of [3H]thymidine ([3H]Tdr) into DNA, and cell number; uptake of 125I (I- uptake) and the concentration of cAMP were measured simultaneously with growth assessment. IFN gamma stimulated the 30-min I- uptake and enhanced the effect of TSH. TNF alpha had minimal effects on growth indices (slight increase in [3H]Tdr incorporation) and had no influence on I- uptake; it inhibited TSH stimulation of both growth and I- uptake. When combined, IFN gamma and TNF alpha synergized in inhibiting TSH-stimulated growth. By itself TNF alpha inhibited stimulation of I- uptake by TSH, but augmented the enhancement seen with IFN gamma. The influence of calf serum (CS) was to increase the rate of incorporation of [3H]Tdr, but a similar qualitative pattern for the actions of the cytokines remained. A reverse profile (stimulation by IFN gamma, inhibition by TNF alpha, and stimulation by the combination) was seen for I- uptake, with CS increasingly diminishing all values. TSH stimulation of growth was progressively effective with increments of CS in the medium, but consistently there was inhibition that was greater with IFN gamma than with TNF alpha and was almost total with the combined cytokines. Stimulation of I- uptake by TSH was enhanced by IFN gamma, reduced by TNF alpha, and, when serum was present, increased to a degree that was greater than additive by the combined cytokines. Growth stimulation by insulin or insulin-like growth factor-I was inhibited partially by the individual cytokines and completely by the combination. Both insulin and insulin-like growth factor-I inhibited TSH stimulation of I- uptake, but similar stimulation by the cytokines was not affected. Simultaneous with inhibition of TSH-stimulated growth, both IFN gamma and TNF alpha enhanced cAMP accumulation. The mechanism of these multiple effects of IFN gamma and TNF alpha, especially on the actions of TSH, may not currently be fully explained, but they almost certainly reflect differing modes of action. The relevance to thyroid function in man is conjectural. Especially in Graves' disease, where thyroid infiltration with cells that secrete these cytokines is common, it seems probable that both IFN gamma and TNF alpha will have significant influences on both growth and differentiated cell function.

Influence of cholera toxin on in vitro refractoriness to thyrotropin of thyroids from rats fed propylthiouracil.

Using an increase in the concentration of cAMP as an index of stimulation, we previously reported that in vitro thyroid tissue of rats fed a goitrogenic diet (0.1% propylthiouracil in Purina) were unresponsive to TSH. We now show that the addition of cholera toxin (0.1-1.0 microM) to fragments of normal thyroid enhanced the concentration of cAMP. Subsequent exposure of the tissue to TSH resulted in a further increase in the concentration of cAMP, and there was statistical evidence of interaction or potentiation between the effects of TSH (20 mU/ml) and cholera toxin (1.0 microM). With fragments of thyroid from animals fed propylthiouracil (i.e. unresponsive in vitro to TSH), an increase in the concentration of cAMP was effected by 1 or 9 microM cholera toxin, and prior exposure to 9 microM toxin caused the tissue to be responsive to TSH. Unresponsiveness of the goitrous tissue was associated with a reduced capacity of the membrane to bind [125I]iodo-TSH although the affinity of the binding sites was unaffected. Cholera toxin at 0.1 microM enhanced and at 1 microM diminished the binding of [125I]iodo-TSH to membranes from either normal or goitrous glands, and these effects also reflected influences on the capacity rather than on the affinity of the binding sites. It is postulated that the unresponsiveness to TSH of thyroid tissue from rats fed propylthiouracil represents a down-regulation of receptor capacity, and this is effected by the binding sites becoming relatively inaccessible, rather than nonexistent.

Hypothyroidism-induced changes in triiodothyronine binding to nuclei and cytosol-binding proteins in rat liver.

A tracer dose of [125I]T3 was given iv to normal, thyroidectomized, and propylthiouracil-fed rats and the distribution of radioactivity in serum and liver fractions was studied over 1 h. Total liver homogenate and serum 125I were higher at all times in hypothyroid rats and, in all groups, showed a continuous fall over the period studied. Hepatic nuclear 125I was maximal at 20 min in all and was greater in hypothyroid rats; there was more 125I in the hepatic cytosol of normal rats than in that from either thyroidectomized or propylthiouracil-fed animals. Binding studies with [125I]T3 and purified hepatic neclear preparations in vitro indicated that both the association constant, Ka (1.08-9.0 x 10(9) M-1) and the capacity (500-600 pg/mg DNA) in thyroidectomized and goitrogen-treated rats were similar to those obtained with normal animals. Cytosol, on the other hand, showed a decrease in binding capacity without change in affinity in livers of hypothyroid rats. Analysis of binding data by Hill plots indicated the presence of both positive and negative cooperativity in binding of T3 by rat liver cytosol proteins. In the in vitro experiments, higher serum radioactivity alone could not account for increases in the hepatic nuclear 125I in the hypothyroid rats because cytosol 125I (presumably in dynamic exchange with both blood and nuclei) was less. Consequently, cytosol T3-binding proteins may regulate the free T3 concentration in the cell and, thus influence the distribution of the hormone in other cellular compartments.

Solubilization, purification, and partial characterization of thyrotropin receptor from bovine and human thyroid glands.

In an attempt to purify the thyroid receptor for TSH and to study interaction with the thyroid-stimulating antibody (TSAb) of graves' disease, we used both bovine and human thyroid glands. With either tissue, the 10,000 X g pellet of homogenized material was solubilized with 0.5% Triton N-101; excess Triton was removed by Amberlite XAD-2, and purification was effected by TSH affinity chromatography, followed by gel filtration on Sepharose 6B. Greatest purification was achieved with bovine tissue; this receptor preparation was 183-fold concentrated over the starting material, but contained only 6% of the original TSH-binding activity, due in part to spontaneous loss over the 4 days required for processing. On polyacrylamide gel electrophoresis, there were at least three protein bands, one of which was probably a subunit of thyroglobulin. Purified immunoglobulin G with thyroid-stimulating antibody activity inhibited the binding of TSH at all stages of purification of the receptor.

Thyrotropin binding to rat thyroid membranes: reduced capacity associated with goitrogenesis.

To investigate a possible role of TSH in the regulation of its own receptor, a sensitive assay of [125I]TSH tropin binding to rat thyroid membranes was used. With 1 mM MgCl2 in the buffer, Scatchard analysis of displacement of TSH gave a curvilinear plot with a high affinity, low capacity (K1, 3.4 nM; Q1, 3.1 pmol/microgram) and a low affinity, high capacity binding site (K2, 0.54 microM; Q2, 1.2 X 0.1 nmol/microgram). Feeding rats propylthiouracil led to a decrease in [125I]TSH binding (expressed either per U protein or per wet wt of tissue) that was related to the duration of treatment. Evaluation by Scatchard analysis showed that this was due to a loss of binding sites, e.g. a 50-60% decrease after 1 month of propylthiouracil treatment; affinity was actually slightly increased in the goitrous tissue. This change in the number of TSH-binding sites was readily reversed in association with the suppression of TSH in vivo either by injections of T3 for 3 days or more by feeding a normal diet for 1 month. Thus, the data are compatible with TSH, that is in high concentration in the serum of rats fed propylthiouracil, exerting a downregulatory influence on its own receptors.