Influence of thyroglobulin on basal and stimulated human thyroid adenylate cyclase activity.

The interaction of thyroglobulin (Tg), thyroid-stimulating immunoglobulins (TSI), and TSH on human thyroid plasma membranes from nontoxic goiter was studied in vitro by an adenylate cyclase assay system using human thyroid homogenate. Purified Tg [3 X 10(-10) M (0.2 micrograms/ml) to 3 X 10(-8) M (20 micrograms/ml)] exerted a dose- and time-dependent inhibitory influence on basal adenylate cyclase activity. The inhibition was prevented by preincubation with Tg antibody in excess. Tg (3 X 10(-8) M) caused a significant reduction in the TSH- and TSI-stimulated adenylate cyclase activities, but did not influence stimulation with NaF (8 mM). Fractions of thyroid homogenates were obtained by differential centrifugation, and the maximal inhibitory influence of Tg was located in the 5000 X g fraction. Thus, Tg is an efficient inhibitor of basal and TSH- or TSI- stimulated adenylate cyclase activities, and might be involved in a short loop counterregulation of thyroid adenylate cyclase sensitivity in vivo.

Thyroid-stimulating immunoglobulins in Hashimoto's thyroiditis measured by radioreceptor assay and adenylate cyclase stimulation and their relationship to HLA-D alleles.

The relationship between thyroid-stimulating immunoglobulins, measured by both radioreceptor assay and adenylate cyclase stimulation, and the HLA alleles was studied in 41 patients with Hashimoto's thyroiditis. TSH binding-inhibiting immunoglobulins (TBII) were detected in 9 (22%) patients, and human thyroid adenylate cyclase-stimulating immunoglobulins (HTACS) were found in 21 (51%) patients. Only 2 patients were positive in both assays, and an inverse relationship was observed between TBII and HTACS. In the 21 HTACS-positive patients, HLA-Dw5 was only found in 1 subject, compared to 8 of the 20 HTACs-negative patients (P less than 0.01), while 4 of the 9 TBII-positive patients had HLA-Dw5 compared to 5 of the 32 TBII-negative subjects (P = -0.09). No significant relations were observed between the presence of HTACS or TBII and HLA-Dw3 or HLA-B8. It is concluded, that TBII and HTACS are produced independently in Hashimoto's thyroiditis, and that the production of these autoantibodies seems to be related to the HLA-D region in this disease.

Human thyroid epithelial cells cultured in monolayers. I. Decreased thyroglobulin and cAMP response to TSH in 12-week-old secondary and tertiary cultures.

An in vitro system of secondary and tertiary cultures of human thyroid epithelial cells (TFECs) in monolayer is described. The function of the cells was evaluated by the second messenger cAMP and the end product thyroglobulin (Tg). The Tg production from the cells was measured in the supernatant by a newly developed enzyme-linked immunosorbent assay. The TFECs in secondary monolayer cultures had preserved the ability to produce Tg and cAMP despite lack of polarization. Furthermore, a preserved ability of TSH-stimulated production of Tg and cAMP in 12-week-old secondary and tertiary cultures was found. However, the Tg and cAMP levels decreased gradually with the age of the cultures. In the secondary culture the TSH-stimulated Tg production decreased from 253 ng/micrograms DNA (205-263) after 3 weeks to 18 ng/micrograms DNA (6-81), P < 0.001, n = 6 after 12 weeks and TSH-stimulated cAMP production from 660 pmol/micrograms DNA (500-840) to 60 (40-200), P < 0.001, n = 6. The decreased responsiveness of long-term cultures results in preference of short-term secondary cultures, which provide a more suitable experimental model for in vitro investigation of human thyroid cell functions.

Human thyroid epithelial cells cultured in monolayers. II. Influence of serum on thyroglobulin and cAMP production.

An in vitro system of secondary cultures of human thyroid follicular epithelial cells in monolayer is described. The 72-h influence of serum and six supplements (thyrotropin, insulin, somatostatin, transferrin, hydrocortisone, glycyl-histidyl-lysine acetate) on growth and function in presence of 3-isobutyl-L-methyl-xanthine (IBMX) was investigated. The function of the cells was evaluated by production of the second messenger adenylate cyclase (cAMP) and the end product thyroglobulin (Tg). Growth was measured as the 3H-thymidine uptake of the cells. Three days of TSH-depletion preceeded the experiments. In presence of IBMX TSH stimulated cAMP production, while stimulation of Tg was only present in some cultures. In absence of IBMX TSH always stimulated the Tg production. The stimulation was independent of the presence of the other five investigated nutritional factors in physiological concentrations. TSH in concentrations from 0.1-10 U/1 stimulated the 72ih 3H-thymidine uptake of the cells. The TSH-stimulated production of Tg and cAMP decreased significantly with increasing concentrations of fetal calf serum (0-10%), (tau = 0.49, P < 0.001, n = 6-29 and tau = 0.75, P < 0.001, n = 6-29, respectively). Thus, serum as a complex, variable and not fully characterized mixture of hormones and growth factors was crucial to the attachment of the cells to the substrate, but inhibited differentiated functions of the human thyroid cells.

Yersinia enterocolitica and thyroid autoimmunity.

The concordance rate of Graves' disease in pairs of identical twins of 30 to 60% points to the influence of environmental factors, and infections have often been incriminated in the pathogenesis. More than 15 years ago we demonstrated an increased frequency of antibodies to Yersinia enterocolitica (Y. ent.) serotype 3, which later was confirmed by others, suggesting a link between infection with Y. ent. and autoimmune thyroid diseases.

Interleukin-6 production by thyroid epithelial cells. Enhancement by interleukin-1.

Interleukin-1 is a potent inhibitor of thyroglobulin and cAMP production in human thyroid cells and the inhibitory effect is enhanced by tumor necrosis factor-alpha and interferon-gamma. In the present study secondary cultures of human thyroid cells produced interleukin-6 and the production was significantly increased after exposure of the cells to recombinant interleukin-1 alpha and -1 beta. This increase was dose-dependent and concomitant of the IL-1 induced decrease in cAMP and thyroglobulin production. Both tumor necrosis factor-alpha and -beta also augmented interleukin-6 production, but less potently than interleukin-1. Interferon-gamma did not affect the production of interleukin-6. The rat thyroid cell line FRTL-5 produced interleukin-6 spontaneously, and the production was enhanced after addition of recombinant interleukin-1 beta. A pathogenetic role of interleukin-6 in autoimmune thyroid disease is suggested.

Anti-thyroid peroxidase antibodies in thyroid disorders and non-thyroid autoimmune diseases.

A new commercial method for measurement of anti-thyroid peroxidase (anti-TPO DYNOtest, Henning, Berlin) was evaluated in normal subjects and in patients with autoimmune thyroid and non-thyroid diseases, and compared to an immune fluorescence method for measurement of anti-microsomal antibodies (MicAb), and a radioimmunological method for quantifying thyroglobulin antibodies (TgAb). The majority of normal subjects had anti-TPO levels below 52 U/ml and patients with Hashimoto's thyroiditis had levels above 200 U/ml, with a good correlation to MicAb. In other autoimmune thyroid diseases the correlation was less pronounced. In non-thyroid autoimmune diseases MicAb showed falsely positive reactions in the presence of other autoantibodies, e.g. mitochondrial antibodies. The present study indicates that the anti-TPO method should probably replace measurements of MicAb for routine clinical use, thus providing a sensitive, precise, antigen specific method with the ability to reveal quantitative fluctuations. The study also indicates that TgAb could be abolished in routine diagnosis of autoimmune thyroid diseases and be reserved for special clinical situations, research purposes as well as measurement in sera before evaluation of serum thyroglobulin levels.

Pain after primary inguinal herniorrhaphy: influence of surgical technique.

BACKGROUND: Pain is an important problem after ambulatory hernia repair. To assess the influence of the surgical technique on postoperative pain, two separate randomized, patient-blinded, controlled trials were performed in men with an indirect inguinal hernia. STUDY DESIGN: In study A, 48 patients with an internal inguinal ring smaller than 1.5 cm were randomly allocated to either simple extirpation of the hernial sac or extirpation plus annulorrhaphy. In study B, 84 patients with an internal inguinal ring wider than 1.5 cm were randomly allocated to extirpation plus annulorrhaphy or extirpation plus Lichtenstein mesh repair (modified). All operations were performed under unmonitored local anesthesia with standardized perioperative analgesia using methadone and tenoxicam. Pain was scored daily for the first postoperative week and after 4 weeks on a four-point verbal-rank scale (no, light, moderate, or severe pain) during rest, while coughing, and during mobilization (rising to the sitting position). Use of supplementary analgesics (paracetamol) was recorded. Cumulative daily pain scores for the first postoperative week and the number of patients who used supplementary analgesics were the main outcome measures. RESULTS: There were no significant differences in cumulative pain scores or use of supplementary analgesics between the treatment groups in either study. Cumulative pain scores were significantly higher during coughing and mobilization than during rest in both studies. CONCLUSIONS: Choice of surgical technique for open repair of a primary indirect inguinal hernia has no influence on postoperative pain.

Immunoglobulins of patients recovering from Yersinia enterocolitica infections exhibit Graves' disease-like activity in human thyroid membranes.

Substantial evidence suggests a link between infections with Yersinia enterocolitica (YE) and Graves' disease. We have now examined the sera of 72 patients recovering from YE infection for immunoglobulins that interacted with the TSH receptor in human thyroid membranes. Compared with controls, in concentrations between 1 and 4 mg/mL, patient IgG produced a significant, concentration-dependent inhibition of TSH binding (p less than 0.001) and stimulation of adenylate cyclase activity (p less than 0.005-0.05). Whereas IgG from normal individuals caused no stimulation of adenylate cyclase, IgG from controls caused some concentration-dependent displacement of TSH, as previously reported. However, IgG from convalescents of YE infections was significantly more potent than normal IgG in reducing the binding of TSH to the membrane. Thus, at each examined concentration, YE patients' IgG displaced more TSH than IgG from normal controls. For each milligram per milliliter increment of IgG in the assay, patients' IgG caused a 10.2% inhibition of TSH binding (r -0.90, p less than 0.001), significantly greater than that seen with normal IgG (p less than 0.02). The present studies provide the first demonstration that IgG of patients recovering from YE infections react with the human TSH receptor. The antibodies presumably are produced against the TSH-binding protein present in YE. However, in view of lack of evidence for thyroid dysfunction in the sera of patients recovering from yersiniosis and the presence of TSH-binding proteins in other bacteria, we postulate that infection with YE is neither necessary nor sufficient to cause thyroid autoimmune disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Recruiting a community sample of adolescent children of alcoholics: a comparison of three subject sources.

Although there has been substantial research interest in adolescent children of alcoholics, the generalizability and consistency of previous findings have been limited by the specialized nature of the research samples (e.g., treatment samples, school-based samples). However, attempting to address this problem by recruiting subjects from community sources raises a variety of sampling issues, including the comparability and accessibility of subjects from different sources. This article compares the recruitment rates and characteristics of families enrolled from three sources--DUI records, HMO records and telephone surveys. Implications for research on children of alcoholics are discussed.

[Requirement of hospital beds in connection with screening for colorectal cancer. The first 5-years of a randomized population survey]. / Sengedagsforbrug i forbindelse med screening for tarmkraeft. De første fem år af en randomiseret befolkningsundersøgelse.

Colorectal cancer puts a major burden on the hospital resources because of its frequency and demands for extensive surgery. Screening with Hemoccult-II detects the disease at an earlier stage in a number of persons. The possible influence upon length of hospital stay is investigated in a randomised trial of 61,938 persons between 45 and 74 years, 30,970 being invited to screening with Hemoccult-II bianually. The first screening was accomplished in 20,672 persons and 17,284 have completed three screenings from 1985 to 1990. The test was positive in 1%, and further examination (colonoscopy) among these revealed cancer in 74 and adenomas in 248 persons. The whole screening group contained 239 persons with cancer and 380 with adenomas, the figures among controls being 216 and 181, respectively. The excess hospital stay in the screening group was 487 days (7%), the major part being one-day admissions for colonoscopy. The average stay was shorter in the screening group and shortest among those with colorectal neoplasia being detected because of positive Hemoccult-II. Measurements of hospital stay included admissions for diagnosis, treatment and complications as well as recurrence within the first year of diagnosis. In conclusion, the excess use of hospital days introduced by screening was limited in the first five years. This will probably later disappear and become negative because of decreasing numbers of cancers in the screening group. Advanced cancers and admissions for possible colorectal cancer will also be less frequent in the screening group.

[Peroperative "lavage" and primary anastomosis in acute left-sided colon ileus]. / Peroperativ "lavage" og primaer anastomose ved akut venstresidig colonileus.

AIM: A description of technique, course and results of operation for left-sided obstruction of the colon with primary resection, perioperative lavage of the colon and primary anastomosis. DESIGN: Retrospective examination of case records. MATERIAL: From January 1st 1994-December 31st 1997 eight operations were performed including primary resection, perioperative lavage and primary anastomosis. RESULTS: No anastomotic leaks were found. One patient died five days postoperatively due to cardiac complications. Three patients had postoperative cardiopulmonary complications treated medically. One patient had rupture of the fascia, was reoperated, experienced wound infection, transient serum elevation of liver enzymes and underwent ERCP with papillotomy and extraction of stones from the common bile duct two months postoperatively. CONCLUSION: In this small series the technique has appeared safe, thus confirming previous reports.

[Segmental "portal hypertension". A rare cause of severe tractable variceal bleeding]. / Segmentaer "portal hypertension". Sjoelden årsag til svoert traktabel variceblødning.

We present a 33 year-old man with massive upper gastrointestinal bleeding caused by a rare form of segmental portal hypertension. The patient developed a pancreatic abscess, which caused an isolated thrombosis in the splenic vein and the development of pronounced collaterals and bleeding fundus varices. The patient underwent splenectomy and recovered quickly hereafter. The literature is sparse on severe bleeding complications due to acute pancreatitis. The present case emphasizes the importance of recognition of unusual manifestations of common clinical conditions.

[The pH and acidity of feces in colorectal neoplasms]. / pH og aciditet i faeces ved kolorektal neoplasi.

The pH and faecal titratable acidity in fresh faeces were measured in patients with colo-rectal carcinoma or adenoma and in normal individuals. Significantly higher pH values and lower acidity were found in patients with cancer than in normal individuals. Patients with cancer had pH greater than 6.90 more frequently than normal. Patients with adenomata did not differ significantly from normal individuals. These results support performance of intervention trials with lowering of the pH in the colon with the object of cancer prophylaxis even although the causal connection is obscure.

[Surgical treatment of stomach cancer at a university hospital. A retrospective survey of the period 1990-1995]. / Kirurgisk behandling af cancer ventriculi på et universitetshospital. En retrospektiv opgørelse for perioden 1990-1995.

AIM: A retrospective study of 69 cases of gastric cancer seen during the period from 1/1-1990 to 31/12-1994 treated in a University Hospital. The aim of the study was to describe morbidity, mortality and identify independent prognostic variables for mortality. METHOD: Patient data were recovered from the hospital's central database. Mortality was chosen as end-parameter. Univariate log-rank-test identified statistically significant variables which were then analysed by Cox backward stepwise regressional analysis. MATERIAL: Sixty-nine patients were available for analysis, median age 73 years. Fifty-one patients underwent operation. Eighteen patients did not have a surgical procedure due to disseminated disease. The overall postoperative morbidity was 25% and postoperative mortality 10%. The overall five-year survival rate was 8%, 12% for operated patients, 35% after radical and 0% after non-radical or omitted surgery. Age, radicality of operation, type of operation, Borrmann's tumour classification, and degree of depth of local infiltration were identified as significant factors for survival. Cox's analysis identified type of operation (p = 0.0002) and Borrmann's tumour classification (p = 0.001) as independent variables. DISCUSSION: The overall five-year survival is low and has not changed over two decades in Denmark, whereas mortality and morbidity rates have improved. It should be recommended that: The treatment of gastric cancer must be centralised in order to develop preoperative examinations, operative technique and the necessary routine for the surgeons. All gastric ulcers must be considered malignant and biopsies taken accordingly.

[Patient satisfaction and duration of breast feeding]. / Patienttilfredshed og ammevarighed.

INTRODUCTION: Only two out of three Danish women follow the recommendations for duration of breast-feeding given by The Danish National Board of Health, which recommend it as the sole source of nutrition for at least the first four months of life. The present study was carried out to investigate the influence of patient satisfaction on the duration of breast-feeding. MATERIAL AND METHODS: Based on an earlier investigation into the satisfaction of primiparas with the public health service during pregnancy, delivery, and the puerperium, 145 women were interviewed by telephone about the period in which their child was fed solely by mother's milk. Mothers of twins and those who had had an elective caesarean or whose child had been transferred to the neonatal care unit were excluded. Data from the patient satisfaction study and data on the delivery retrieved from a local obstetric database were related to the duration of breast-feeding. RESULTS: The mean duration of breast-feeding only was four months with no association to the women's satisfaction with the public health service in general. There was, however, an association between the period of breast-feeding only and satisfaction with issues dealing specifically with breast-feeding. In women who had had an oxytocin infusion breast-feeding was more often well-established. No other event during labour related to the initiation or duration of breast-feeding. There was an insignificant trend towards more use of a pacifier or formula supplementation in the first days in women, who did not initiate breast-feeding. It is unknown whether this is a cause or a consequence. DISCUSSION: The initiation of breast-feeding is influenced by the woman's satisfaction with the public service in matters relating to breastfeeding. In other ways, it is a process that is difficult to disturb.

[Spontaneous esophageal rupture during the 3rd trimester]. / Spontan esophagusruptur i tredje trimester.

A 30-year-old woman, 35 weeks pregnant, developed spontaneous rupture of the oesophagus following severe vomiting, probably caused by treatment with Ritodrin (Utopar). The symptoms, diagnosis and treatment of spontaneous oesophageal rupture are discussed.

[Recurrence of inguinal hernia: ambulatory surgery under local anesthesia]. / Recidiv af ingvinalhernie: ambulant operation i lokal anaestesi.

In order to assess the feasibility of repair of a recurrent inguinal hernia in unmonitored local anaesthesia in an ambulatory set-up pain scores and data on patient satisfaction were obtained from 76 unselected patients after 79 consecutive operations. Median age was 63 years, and 25%- and 75% quartiles were 49 and 72 years respectively. All operations were conducted in local anesthesia. Three patients stayed in hospital overnight after the operation. Pain: After one, six and 28 days 27, 14 og 7% respectively had severe pain during function (cough and/or rising). Satisfaction: 82% were satisfied with ambulatory surgery in local anaesthesia, 82% were satisfied with the analgesic therapy (tenoxicam and methadone), but one third needed supplementary analgesics during the first week (acetaminophen was recommended). It is concluded, that ambulatory repair of a recurrent inguinal hernia in unmonitored local anaesthesia is a safe and cost effective alternative to operation in general or spinal anaesthesia.

[Organization and results of ambulatory surgery for inguinal hernia]. / Organisation og resultater af ambulant kirurgi for hernia inguinalis.

The results of a reorganization of surgery for inguinal hernias within a department of surgical gastroenterology were assessed concerning staff simplifications, feasibility, patient satisfaction, safety, complications and resources. Five hundred consecutive, elective, open operations for unilateral reducible inguinal hernias were performed in 466 patients under local anaesthesia in an ambulatory setup. One hundred and fourteen of the operations were for a recurrent hernia. The median age was 60 years (44-74 years as 25% and 75% quartiles). Two of the operations were converted to general anaesthesia. The patients were discharged 85 min (median) post-operatively, but 12 patients were not discharged on the same day. Bleeding or wound infections in need of treatment were seen postoperatively in 1.6% and 1.6%, respectively. All patients were given a postoperative questionnaires with a response rate of 95%, 89% of the respondents were satisfied with the whole procedure, 11% were dissatisfied. A reorganization of surgery for inguinal hernias to a standardized ambulatory setup induced staff simplifications and saved resources with a preserved high patient satisfaction, safety and a low complication rate.

[Incidence of adverse events in hospitals. A retrospective study of medical records]. / Forekomsten af utilsigtede haendelser på sygehuse. En retrospektiv gennemgang af journaler.

INTRODUCTION: Over the past decade a number of studies on the incidence and preventability of adverse events in the health care have been published in the US, Australia and the UK. So far no similar study has been performed in Denmark. In order to determine whether foreign findings could be generalised to Danish health care, a pilot study on adverse events was carried out in Danish acute care hospitals. METHOD: Chart reviews were carried out on 1.097 acute care hospital admissions, sampled from the central Danish National Patient Register. The sample was truly proportional with no over-sampling of high-risks groups. Chart reviews was done in 17 different acute care hospitals, reviewing between 20 and 204 admissions per hospital. Adverse events was identified using a three-step procedure: 1) Nurse screening by 18 criteria identifying high-risk groups. 2) Independent reviews by pairs of consultants. 3) In case of disagreement between second step consultants, two additional independent reviews was performed by new consultants (internist and surgeon) followed by conference. All chart reviews were performed independent of medical specialty. All nurses and doctors were senior and experienced clinicians. RESULTS: In 114 admissions 176 Adverse Events (AEs) were identified. The prevalence of admissions with adverse events were 9.0% of all admissions. Preventability of adverse events was found in 46 of admissions (40.4% of AEs). The adverse events caused on average a 7.0 days prolonged hospital stay. Most adverse events resulted in minor, transient disabilities. Permanent disability or death in relation to adverse event were recorded in 30 admissions. DISCUSSION: The findings from the Danish Adverse Event Study are similar to the results found in Australia, United Kingdom and the United States. It is therefore recommended that further Danish research, is directed towards high-risk groups focussing on narratives and intervention and towards research in primary health care.