GATA2 haploinsufficient patients lack innate lymphoid cells that arise after hematopoietic cell transplantation.

Innate lymphoid cells (ILC) are important barrier tissue immune regulators. They play a pivotal role in early non-specific protection against infiltrating pathogens, regulation of epithelial integrity, suppression of pro-inflammatory immune responses and shaping the intestinal microbiota. GATA2 haploinsufficiency causes an immune disorder that is characterized by bone marrow failure and (near) absence of monocytes, dendritic cells, B cells and natural killer (NK) cells. T cells develop normally, albeit at lower numbers. Here, we describe the absence of ILCs and their progenitors in blood and bone marrow of two patients with GATA2 haploinsufficiency and show that all subsets of ILCs appear after allogeneic hematopoietic stem cell transplantation, irrespective of the preparative conditioning regimen. Our data indicate that GATA2 is involved in the development of hematopoietic precursor cells (HPC) towards the ILC lineage.

Delaying investments in sensor technology: The rationality of dairy farmers' investment decisions illustrated within the framework of real options theory.

The adoption rate of sensors on dairy farms varies widely. Whereas some sensors are hardly adopted, others are adopted by many farmers. A potential rational explanation for the difference in adoption may be the expected future technological progress in the sensor technology and expected future improved decision support possibilities. For some sensors not much progress can be expected because the technology has already made enormous progress in recent years, whereas for sensors that have only recently been introduced on the market, much progress can be expected. The adoption of sensors may thus be partly explained by uncertainty about the investment decision, in which uncertainty lays in the future performance of the sensors and uncertainty about whether improved informed decision support will become available. The overall aim was to offer a plausible example of why a sensor may not be adopted now. To explain this, the role of uncertainty about technological progress in the investment decision was illustrated for highly adopted sensors (automated estrus detection) and hardly adopted sensors (automated body condition score). This theoretical illustration uses the real options theory, which accounts for the role of uncertainty in the timing of investment decisions. A discrete event model, simulating a farm of 100 dairy cows, was developed to estimate the net present value (NPV) of investing now and investing in 5 yr in both sensor systems. The results show that investing now in automated estrus detection resulted in a higher NPV than investing 5 yr from now, whereas for the automated body condition score postponing the investment resulted in a higher NPV compared with investing now. These results are in line with the observation that farmers postpone investments in sensors. Also, the current high adoption of automated estrus detection sensors can be explained because the NPV of investing now is higher than the NPV of investing in 5 yr. The results confirm that uncertainty about future sensor performance and uncertainty about whether improved decision support will become available play a role in investment decisions.

Evaluation of long-term pelvic floor symptoms after an obstetric anal sphincter injury (OASI) at least one year after delivery: A retrospective cohort study of 159 cases.

OBJECTIVES: The aim of this study was to assess long-term pelvic floor symptoms after an obstetric anal sphincter injury (OASI). METHODS: This retrospective cohort study included 237 cases of OASI (0.86% of deliveries) identified at Poitiers University Hospital between 2000 and 2011. Symptoms were assessed using validated self-administered questionnaires, including Female Pelvic Floor Questionnaire, Pescatori anal incontinence score, EuroQoL five-dimension score, and pain visual analogue scale (VAS). RESULTS: One hundred and sixty women (67%) filled out the questionnaires, on average 46 months after delivery (8-152). Among them, 93 (54%) reported at least one symptom occurring "frequently" (the most common being dyspareunia), and 45 (28%) a symptom occurring "daily" (the most common being flatus incontinence). Anal incontinence was reported by 32 (20%) women, flatus incontinence "frequently" or "daily" by 28 (18%), and stool incontinence "frequently" or "daily" by 9 (6%). Urinary incontinence was reported "frequently" or "daily" by 27 women (17%) at stress, 17 (11%) at urge, and 11 (7%) at mixed circumstances. Prolapse symptoms were reported "frequently" or "daily" by 6 women (4%). Pain during intercourse was reported "frequently" or "daily" by 17 women (11%). Twenty-four women (18%) reported chronic pelvic pain (VAS score≥4/10). Ninety-five percent of women reported a normal quality of life for mobility, self-care, and usual activities; however, alterations in pain/discomfort (32%) and anxiety/depression (33%) domains were frequently reported. CONCLUSION: Pelvic floor symptoms 4 years after OASI were highly prevalent.

A prognostic model to predict the success of artificial insemination in dairy cows based on readily available data.

A prognosis of the likelihood of insemination success is valuable information for the decision to start inseminating a cow. This decision is important for the reproduction management of dairy farms. The aim of this study was to develop a prognostic model for the likelihood of successful first insemination. The parameters considered for the model are readily available on farm at the time a farmer makes breeding decisions. In the first step, variables are selected for the prognostic model that have prognostic value for the likelihood of a successful first insemination. In the second step, farm effects on the likelihood of a successful insemination are quantified and the prognostic model is cross-validated. Logistic regression with a random effect for farm was used to develop the prognostic model. Insemination and test-day milk production data from 2,000 commercial Dutch dairy farms were obtained, and 190,541 first inseminations from this data set were used for model selection. The following variables were used in the selection process: parity, days in milk, days to peak production, production level relative to herd mates, milk yield, breed of the cow, insemination season and calving season, log of the ratio of fat to protein content, and body condition score at insemination. Variables were selected in a forward selection and backward elimination, based on the Akaike information criterion. The variables that contributed most to the model were random farm effect, relative production factor, and milk yield at insemination. The parameters were estimated in a bootstrap analysis and a cross-validation was conducted within this bootstrap analysis. The parameter estimates for body condition score at insemination varied most, indicating that this effect varied most among Dutch dairy farms. The cross-validation showed that the prognosis of insemination success closely resembled the mean insemination success observed in the data set. Insemination success depends on physiological conditions of the cow, which are approximated indirectly by production and reproduction data that are routinely recorded on the farm. The model cannot be used as a detection model to distinguish cows that conceive from cows that do not. The model validation indicates, however, that routinely collected farm data and test-day milk yield records have value for the prognosis of insemination success in dairy cows.

An ex ante analysis on the use of activity meters for automated estrus detection: to invest or not to invest?

The technical performance of activity meters for automated detection of estrus in dairy farming has been studied, and such meters are already used in practice. However, information on the economic consequences of using activity meters is lacking. The current study analyzes the economic benefits of a sensor system for detection of estrus and appraises the feasibility of an investment in such a system. A stochastic dynamic simulation model was used to simulate reproductive performance of a dairy herd. The number of cow places in this herd was fixed at 130. The model started with 130 randomly drawn cows (in a Monte Carlo process) and simulated calvings and replacement of these cows in subsequent years. Default herd characteristics were a conception rate of 50%, an 8-wk dry-off period, and an average milk production level of 8,310 kg per cow per 305 d. Model inputs were derived from real farm data and expertise. For the analysis, visual detection by the farmer ("without" situation) was compared with automated detection with activity meters ("with" situation). For visual estrus detection, an estrus detection rate of 50% and a specificity of 100% were assumed. For automated estrus detection, an estrus detection rate of 80% and a specificity of 95% were assumed. The results of the cow simulation model were used to estimate the difference between the annual net cash flows in the "with" and "without" situations (marginal financial effect) and the internal rate of return (IRR) as profitability indicators. The use of activity meters led to improved estrus detection and, therefore, to a decrease in the average calving interval and subsequent increase in annual milk production. For visual estrus detection, the average calving interval was 419 d and average annual milk production was 1,032,278 kg. For activity meters, the average calving interval was 403 d and the average annual milk production was 1,043,398 kg. It was estimated that the initial investment in activity meters would cost €17,728 for a herd of 130 cows, with an additional cost of €90 per year for the replacement of malfunctioning activity meters. Changes in annual net cash flows arising from using an activity meter included extra revenues from increased milk production and number of calves sold, increased costs from more inseminations, calvings, and feed consumption, and reduced costs from fewer culled cows and less labor for estrus detection. These changes in cash flows were caused mainly by changes in the technical results of the simulated dairy herds, which arose from differences in the estrus detection rate and specificity between the "with" and "without" situations. The average marginal financial effect in the "with" and "without" situations was €2,827 for the baseline scenario, with an average IRR of 11%. The IRR is a measure of the return on invested capital. Investment in activity meters was generally profitable. The most influential assumptions on the profitability of this investment were the assumed culling rules and the increase in sensitivity of estrus detection between the "without" and the "with" situation.

E-health to improve work functioning in employees with rheumatoid arthritis in rheumatology practice: a feasibility study.

OBJECTIVES: To evaluate the feasibility of an e-health intervention in rheumatology practice for employees with rheumatoid arthritis (RA) who experience problems with work functioning. METHOD: Twenty-three out of 90 patients with RA from a hospital rheumatology department, invited by letter, participated in a feasibility study. The 3-month internet e-health programme consisted of a self-management programme using a three-step problem-solving strategy: (step 1) analyse your work problems and opportunities; (step 3) identify solutions; and (step 3) work out a strategy (action plan). Support and personal feedback was provided by a rheumatology nurse. Patients completed assignments, received information, and actively worked on their goals. The main feasibility outcome included satisfaction with the programme. Other feasibility outcomes included usefulness, suitability, website use, and work functioning measured at baseline and/or 3 months using questionnaires, semi-structured interviews, and website data. RESULTS: In total, 95% of the participants were satisfied with the programme, and 96% thought the programme was useful for working RA patients and would recommend the programme to other working RA patients (91%). On the website, all patients at least partially completed the assignments in step 1 and 12 patients completed at least one assignment in step 3. Patients judged the website as well arranged with clear tasks. Patients worked on a range of (individual) goals, resolving work challenges using different strategies and actions. CONCLUSIONS: The e-health intervention is a feasible intervention for rheumatology practice justifying further effectiveness evaluation while allowing for further improvements in the selection of RA patients and shaping the intervention.

Invited review: sensors to support health management on dairy farms.

Since the 1980s, efforts have been made to develop sensors that measure a parameter from an individual cow. The development started with individual cow recognition and was followed by sensors that measure the electrical conductivity of milk and pedometers that measure activity. The aim of this review is to provide a structured overview of the published sensor systems for dairy health management. The development of sensor systems can be described by the following 4 levels: (I) techniques that measure something about the cow (e.g., activity); (II) interpretations that summarize changes in the sensor data (e.g., increase in activity) to produce information about the cow's status (e.g., estrus); (III) integration of information where sensor information is supplemented with other information (e.g., economic information) to produce advice (e.g., whether to inseminate a cow or not); and (IV) the farmer makes a decision or the sensor system makes the decision autonomously (e.g., the inseminator is called). This review has structured a total of 126 publications describing 139 sensor systems and compared them based on the 4 levels. The publications were published in the Thomson Reuters (formerly ISI) Web of Science database from January 2002 until June 2012 or in the proceedings of 3 conferences on precision (dairy) farming in 2009, 2010, and 2011. Most studies concerned the detection of mastitis (25%), fertility (33%), and locomotion problems (30%), with fewer studies (16%) related to the detection of metabolic problems. Many studies presented sensor systems at levels I and II, but none did so at levels III and IV. Most of the work for mastitis (92%) and fertility (75%) is done at level II. For locomotion (53%) and metabolism (69%), more than half of the work is done at level I. The performance of sensor systems varies based on the choice of gold standards, algorithms, and test sizes (number of farms and cows). Studies on sensor systems for mastitis and estrus have shown that sensor systems are brought to a higher level; however, the need to improve detection performance still exists. Studies on sensor systems for locomotion problems have shown that the search continues for the most appropriate indicators, sensor techniques, and gold standards. Studies on metabolic problems show that it is still unclear which indicator reflects best the metabolic problems that should be detected. No systems with integrated decision support models have been found.

[Clinical treatment of posttraumatic stress disorder in patients with serious dual diagnosis problems]. / Klinische behandeling van posttraumatische stressstoornis bij patiënten met ernstige dubbele diagnose.

Three patients with severe addiction problems, early sexual trauma, posttraumatic stress disorder PTSD comorbid psychotic vulnerability and personality problems received integrated treatment following admission to a clinic specialising in the care of patients with a dual diagnosis. Treatment was administered in accordance with current guidelines and involved either imaginal exposure or eye movement desensitization and reprocessing EMDR, integrated with relapse management of addiction problems. It is concluded that the current evidence-based guidelines regarding PTSD and addiction can also be applied successfully and effectively to an extremely vulnerable patient population.

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia.

Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4+ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4+ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4+ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4+ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4+ T cells. In conclusion, our results show that CD4+ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4+ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4+ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.

Implementation of outpatient preoperative evaluation clinics: facilitating and limiting factors.

BACKGROUND: Several studies have shown that outpatient preoperative evaluation by anaesthetists increases quality of care and is cost-effective. The aim of this study was to gain insight into the factors that positively or negatively influence the implementation of outpatient preoperative evaluation clinics (OPE clinics). METHODS: After an extensive literature study and pilot interviews, we constructed written questionnaires that were sent to all Dutch hospitals. The respondents were members of the board of directors, members of the medical staff, anaesthetists, internists, and surgeons. RESULTS: Cooperation of anaesthetists was most frequently mentioned as facilitating factor for implementation of an OPE clinic across all medical specialists interviewed. Lack of finance was most frequently reported as limiting factor in all categories of hospitals (with a complete, partial, or no OPE clinic), but it was significantly more often reported in hospitals without OPE clinic (P<0.01). Perceived benefits and disadvantages, financial rewarding system, and organizational structure played a clear role in the implementation of OPE clinics. CONCLUSIONS: A variety of factors play a role in the implementation of an OPE clinic. Besides the more obvious ones, such as financing and cooperation of the professional groups involved, underlying factors, such as perceptions of the professionals involved, were found to be related to implementation of an OPE clinic. These underlying factors explain differences between different kinds of hospitals and between professional groups, regarding their resources and motivation to implement an OPE clinic.

HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia.

Mismatching for human leukocyte antigen (HLA)-DPB1 in unrelated donor hematopoietic stem cell transplantation (URD-SCT) has been associated with a decreased risk of disease relapse, indicating that HLA-DP may represent a target for graft-versus-leukemia (GVL) reactivity in HLA class II-expressing hematological malignancies. To investigate whether HLA-DP-specific T cells could mediate GVL reactivity following HLA-DPB1-mismatched URD-SCT and donor lymphocyte infusion (DLI), we analyzed the immune response in a patient with leukemic lymphoplasmacytic lymphoma responding to DLI without graft-versus-host disease. The emergence of leukemia-reactive CD4+ T cells during the clinical immune response was demonstrated by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot(ELISPOT)analysis. Following clonal isolation of these leukemia-reactive CD4+ T cells, blocking studies, panel studies and retroviral transduction experiments of both mismatched HLA-DPB1 alleles identified HLA-DPB1(*)0201 and HLA-DPB1(*)0301 as the targets of this immune response. The HLA-DPB1-specific CD4+ T-cell clones were capable of recognizing and lysing several HLA-DP-expressing myeloid and lymphoid hematological malignant cells. Since HLA-DP expression is mainly restricted to hematopoietic cells, HLA-DP may be used as a specific target for immunotherapy following T-cell-depleted URD-SCT. Therefore, in patients with HLA class II-expressing hematological malignancies HLA-DP-mismatched SCT may be preferable over fully matched SCT allowing DLI to induce a GVL effect.

Glucose tolerance and lipid profile in longterm exogenous subclinical hyperthyroidism and the effects of restoration of euthyroidism, a randomised controlled trial.

OBJECTIVE: The impact of prolonged subclinical hyperthyroidism on glucose and lipid metabolism is unclear. Therefore, we evaluated glucose and lipid metabolism in patients with differentiated thyroid carcinoma (DTC) on TSH suppressive thyroxine therapy as a model for subclinical hyperthyroidism and investigated whether restoration to euthyroidism affects metabolism. DESIGN: We performed a prospective, single-blinded, placebo-controlled, randomised trial of 6 months duration with 2 parallel groups. PATIENTS: Twenty-five subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with l-thyroxine completed the study. l-thyroxine dose was replaced by study medication containing l-thyroxine or l-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group, 13 patients) and euthyroidism (euthyroidism group, 12 patients). MEASUREMENTS: We evaluated glucose metabolism by glucose tolerance test and HOMA (IR) and lipid metabolism by lipid profile. In addition, we measured plasma concentrations of glucoregulatory hormones. RESULTS: At baseline, glucose tolerance, HOMA (IR), lipid profile and plasma concentrations of glucoregulatory hormones were within the normal range. No significant differences between the low TSH and euthyroidism group were observed. After 6 months, neither glucose nor lipid metabolism in the low TSH group were different from baseline values. CONCLUSION: In summary, glucose and lipid metabolism in patients with DTC and long-term subclinical hyperthyroidism in general are not affected. Restoration of euthyroidism in general does not affect glucose and lipid metabolism.

The effect of national guidelines on the implementation of outpatient preoperative evaluation clinics in Dutch hospitals.

BACKGROUND AND OBJECTIVES: Preoperative evaluation performed by anaesthesiologists primarily aims to estimate the risk of perioperative complications and to create opportunities to optimize the patients' condition before surgery. In this study an inventory was made of the current practice of preoperative evaluation in Dutch hospitals. It was estimated how many hospitals had implemented an outpatient preoperative evaluation clinic in 2004. Subsequently, current practice was compared with the results of a previous inventory (2000). It was also evaluated to what extent the guidelines of the Dutch Health Council and the Netherlands Society of Anaesthesiology were followed. METHODS: The study consisted of two phases. First, a literature research was performed and pilot interviews were constructed. The interviews were conducted face-to-face with anaesthesiologists in a sample of Dutch hospitals. Based on the results, written questionnaires were constructed. In the second phase these questionnaires were sent to all general and academic hospitals in the Netherlands. RESULTS: In 2004, 74% of the hospitals had an outpatient preoperative evaluation clinic, compared with 50% in 2000. The percentage of hospitals with an outpatient preoperative evaluation clinic available for all elective patients increased from 20% to 52%. CONCLUSIONS: The Dutch guidelines on preoperative evaluation seem to have influenced current practice. An increase in the number of outpatient preoperative evaluation clinics was seen after the guidelines were published. The implementation of an outpatient preoperative clinic seems to warrant that anaesthesiologists are carrying out the activities prescribed by the guidelines. Most hospitals without a clinic aim to implement one in the future.

Quality of life in longterm exogenous subclinical hyperthyroidism and the effects of restoration of euthyroidism, a randomized controlled trial.

OBJECTIVE: The impact of prolonged subclinical hyperthyroidism on quality of life is unclear. Therefore, we evaluated quality of life in patients with differentiated thyroid carcinoma (DTC) on TSH-suppressive thyroxine therapy as a model for subclinical hyperthyroidism and we investigated whether restoration to euthyroidism affects quality of life. DESIGN: We performed a prospective, single-blinded, placebo-controlled, randomized trial of 6 months' duration with two parallel groups. PATIENTS AND METHODS: Twenty-four subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with L-thyroxine completed the study. L-thyroxine dose was replaced by study medication containing L-thyroxine or L-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group) and euthyroidism (euthyroid group). Both groups consisted of 12 patients. We evaluated quality of life using five validated questionnaires. RESULTS: At baseline, the somatic disorder questionnaire (SDQ) indicated more somatic dysfunction in patients as compared with reference values, whereas the depression score (HADS) revealed a better score than the reference group. All other quality of life parameters were normal. At baseline, no significant differences between the low-TSH and the euthyroidism groups were observed. After 6 months, none of the quality of life parameters in the low-TSH group was different from baseline values. In the euthyroid group, motivation was significantly improved (Multidimensional Fatigue Index-20, P = 0.003), although this parameter did not differ from the reference group at baseline. A probable worsening in role limitations as a result of physical problems (Short Form-36; P = 0.050) was observed. No improvement in the SDQ score was observed. CONCLUSION: In summary, quality of life in patients with DTC and long-term subclinical hyperthyroidism in general is preserved. Restoration of euthyroidism in general does not affect quality of life.

Pre-operative detection of valvular heart disease by anaesthetists.

We prospectively estimated the prevalence of heart murmurs in 2522 consecutive adult non-cardiac surgery patients during pre-operative evaluation. Factors that contribute to the detection of a heart murmur were identified, and echocardiography was used to evaluate to what extent a murmur reflected presence of valvular heart disease. A cardiac murmur was detected in 106 patients (prevalence 4.2%, 95% CI: 3.5-5.1%). Multivariable logistic regression analyses showed that age and general physical impression were independently associated with detecting a murmur (p-values < 0.01). In 83 (79%) of the patients with a murmur, an echocardiographic diagnosis was available: 39% had aortic valve abnormalities, 24% had mitral valve regurgitation, 7% had other valvular heart disease and 30% did not have any abnormality. Thus, 58 of the 83 patients had valvular heart disease (positive predictive value using routine cardiac auscultation for diagnosing VHD: 70%, 95% CI: 59-79%). Murmurs in patients younger than 40 years never reflected valvular heart disease. Pre-operative cardiac auscultation seems only reasonable in patients aged 40 years or older. Subsequent echocardiography in these selected patients is necessary.

Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: a randomized, placebo-controlled study.

BACKGROUND: Subclinical hyperthyroidism has been reported to affect systolic and diastolic cardiac function. However, the reversibility of these effects is not well established. OBJECTIVE: Our objective was to investigate the presence and reversibility of cardiac abnormalities in patients with long-term exogenous subclinical hyperthyroidism. DESIGN: We conducted a prospective, single-blinded, placebo-controlled randomized trial of 6 months duration with two parallel groups. SETTING: The study occurred at the Leiden University Medical Center, a tertiary referral center for thyroid carcinoma. PATIENTS: As a model for subclinical hyperthyroidism, 25 patients with a history of differentiated thyroid carcinoma with more than 10 yr of TSH suppressive therapy with L-T4 were studied. INTERVENTIONS: L-T4 dose was replaced by study medication containing L-T4 or placebo. Medication was titrated in a single-blinded fashion to establish continuation of TSH suppression (low-TSH group) or euthyroidism (euthyroid group). MEASUREMENTS: We assessed serum levels of free T4 and TSH and used echo Doppler cardiography including tissue Doppler to establish left ventricular (LV) dimensions and function as well as diastolic function. Baseline echocardiography data were compared with 24 controls. RESULTS: There were no differences in baseline cardiac parameters and TSH levels between the two groups. Although mean LV mass index was increased as compared with 24 controls, only four patients had LV hypertrophy at baseline. This was not improved by restoration of euthyroidism. At baseline, diastolic function was impaired in all patients as indicated by abnormal values for the peak flow of the early filling phase (E, 55.3 +/- 9.5 mm/sec), the ratio of E and the peak flow of the atrial filling phase (E/A ratio, 0.87 +/- 0.13), the early diastolic velocity obtained by tissue Doppler (E', 5.7 +/- 1.3 cm/sec), and the peak atrial filling velocity obtained by tissue Doppler (A', 6.8 +/- 1.4 cm/sec), prolonged E deceleration time (234 +/- 34 msec), and isovolumetric relaxation time (121 +/- 15 msec). After 6 months, significant improvements were observed in the euthyroid group in the E/A ratio (+41%; P < 0.001), E deceleration time (-18%; P = 0.006), isovolumetric relaxation time (-25%; P < 0.001), E' (+31%; P < 0.001), and the E'/A' ratio (+40%; P < 0.001). CONCLUSIONS: We conclude that prolonged subclinical hyperthyroidism is accompanied by diastolic dysfunction that is at least partly reversible after restoration of euthyroidism. Because isolated diastolic dysfunction may be associated with increased mortality, this finding is of clinical significance.

Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis.

OBJECTIVE: To investigate to what extent thyroid remnant ablation and withdrawal from thyroxine are required to achieve sufficient accuracy of serum thyroglobulin (Tg) measurements as an indicator of tumour recurrence in the follow-up of patients with differentiated thyroid carcinoma. DESIGN AND METHODS: We conducted a meta-analysis of the literature from 1975 to 2003 on serum Tg measurements in the follow-up of differentiated thyroid carcinoma. In a computer-based search, we initially found 915 articles that were finally narrowed down to 120. These 120 papers were subjected to strict in/and exclusion criteria, leaving 46 articles (totalling 9094 patients). Data from these articles were extracted in a structured fashion and were grouped according to initial therapy, TSH status, Tg assay method and definition of a 'gold standard'. Original 2 x 2 tables were pooled by summary receiver operating characteristic curve analysis (sROCa), best estimates of sensitivity and specificity being obtained by the combination of sROCa and Mantel-Haenszel odds ratios. RESULTS: Despite considerable differences between series in laboratory and clinical methodology, we consistently found higher specificity for Tg measurements after thyroid remnant ablation than after surgery alone. Highest pooled sensitivity 0.961 +/- 0.013 (SE) was found for immunometric assay (IMA) after thyroid remnant ablation and thyroid hormone withdrawal, at a specificity of 0.947 +/- 0.007. Pooled sensitivity decreased significantly if ablated patients were tested while on thyroid hormone (0.778 +/- 0.023, at a specificity of 0.977 +/- 0.005). Significantly decreased pooled specificity was found in patients who did not undergo remnant ablation (sensitivity 0.972 +/- 0.023, at a specificity of 0.759 +/- 0.028). If recombinant human TSH (rhTSH) stimulation was used as a substitute for thyroxine withdrawal, sensitivity remained high (0.925 +/- 0.018) while specificity decreased to 0.880 +/- 0.013. In all analyses, specificity of Tg would decrease when unspecified activity in the thyroid region at scintigraphy was considered benign, whereas sensitivity decreased when such activity was considered malignant. CONCLUSION: This study confirms that the best accuracy of Tg-guided follow-up in patients treated for differentiated thyroid carcinoma is obtained if treatment includes remnant ablation, and Tg testing is performed while off thyroxine.

Role of history and physical examination in preoperative evaluation.

BACKGROUND AND OBJECTIVE: Since reports have shown that outpatient preoperative evaluation increases the quality of care and cost-effectiveness, an increasing number of patients are being evaluated purely on an outpatient basis. To improve cost-effectiveness, it would be appealing if those patients who are healthy and ready for surgery without additional testing could be easily distinguished from those who require more extensive evaluation. This paper examines whether published studies provide sufficient data to determine how detailed preoperative history taking and physical examination need to be in order to assess the health of surgical patients and to meet the objective of easy and early distinction. METHODS: A MEDLINE search was conducted from 1991 to 2000 with respect to preoperative patient history and physical examination. Altogether, 213 articles were found, of which 29 were selected. Additionally, 38 cross-references, 7 articles on additional testing and 4 recently published papers were used. RESULTS: It is questionable to what extent an extensive history is relevant for anaesthesia and long-term prognosis. With respect to physical examination, it seems unreasonable to diagnose valvular heart disease based on cardiac auscultation only, and it is unclear which method should be used to predict the difficulty of endotracheal intubation. The benefits of routine testing for all surgical patients before operation are extremely limited and are not advocated. CONCLUSIONS: The amount of detail of preoperative patient history and the value of physical examination to obtain a reasonable estimate of perioperative risk remains unclear. Although not evidence based, a thorough history taking and physical examination of all patients before surgery seems important until more evidence-based guidelines become available. Diagnostic and prognostic prediction studies may provide this necessary evidence.

Outcome of palliative embolization of bone metastases in differentiated thyroid carcinoma.

We investigated the effects of selective embolization in patients with symptomatic bone metastases of differentiated thyroid carcinoma. A total of 41 embolizations was performed in 16 patients. We studied the follow-up (range, 2 months to 8.6 yr) after the first embolization by evaluation of clinical symptoms and tumor dimensions. Success was defined as an improvement in clinical symptoms without tumor progression. The procedure was successful in 24 of 41 occasions (59%). Twenty-six embolizations were preceded or followed up by additional therapies, consisting of surgery (laminectomy), external irradiation, or radioiodine. Subgroup analysis revealed that these additional therapies did not influence the success rate; however, a potential effect on success duration may be present: for embolizations without additional radioiodine or external irradiation therapy, the median success duration was 6.5 months; for embolizations combined with additional radioiodine or external irradiation, this was 15 months (P = 0.0146). The ultimate outcome of the patients was unfavorable: nine patients died and five patients have progressive disease. We concluded that selective embolization of bone metastases may be considered a palliative therapy that may induce rapid, but transient, relief of symptoms. Combination with radioiodine or external irradiation may prolong the duration of success.