Impact of Small Incision Lenticule Extraction for High Myopia on Intraocular Pressure Measurements With Pneumotonometry.

PURPOSE: To evaluate the medium-term impact of small incision lenticule extraction (SMILE) on air-puff tonometry (APT) and how it may be corrected. METHODS: In this controlled prospective study, 69 eyes from 69 patients treated with SMILE for high myopia (mean: -7.22 diopters) were included. Central corneal thickness (CCT), spherical equivalent refraction (SEQ), corneal power, and intraocular pressure (IOP) (assessed by APT) were measured before and 3 months after surgery. RESULTS: The measured IOP decreased significantly after SMILE surgery (mean: -6.43 mm Hg), indicating a significant underestimation of the true IOP by APT. There was a significant correlation between change in SEQ, CCT, and apparent IOP. Correcting the apparent IOP measurement by applying a multiple regression correction did not provide significantly better estimates compared to adding 6.4 mm Hg to the measurement. CONCLUSIONS: This study showed that previous SMILE surgery should be considered when interpreting APT measurements, because the measurements underestimate the true IOP. Multiple regressions cannot estimate the true IOP with certainty. For screening purposes, adding 6.4 mm Hg to the apparent IOP of a patient treated for high myopia may be sufficient. [J Refract Surg. 2023;39(9):606-611.].

Danish population health measured by the EQ-5D-5L.

AIMS: The aims of this study were to provide Danish population norms for the EQ-5D-5L and to assess the measurement properties of the instrument in a Danish population setting. METHODS: We used data from the Danish 5L valuation study in which a representative sample of the Danish population completed the EQ-5D-5L and answered socio-demographic questions. We generated population norms for the five EQ-5D-5L dimensions, corresponding utility scores and the EQ-5D visual analogue scale (EQ VAS) according to age and sex. Measurement properties of ceiling effects, known-group construct validity and convergent validity were assessed. RESULTS: The mean EQ-5D-5L utility score for the 1014 respondents completing the EQ-5D-5L was 0.90 (standard deviation (SD)=0.16). No significant differences emerged across age groups (minimum mean utility score=0.88 (SD=0.19); maximum mean utility score=0.93 (SD=0.11)) or sex (mean utility score for women=0.89 (SD=0.17); mean utility score for men=0.91 (SD=0.15)). Statistical differences were found across educational level, occupational status, income and living situation. Similar patterns were observed for the EQ VAS. Generally, respondents most often reported problems with pain and discomfort, but young women most often reported problems with anxiety/depression. There was a significant strong correlation between EQ-5D-5L utility and the EQ VAS and a significant correlation between overall health and each of the five EQ-5D-5L dimensions. The overall ceiling effect for the EQ-5D-5L was 39% (compared to 56% for the EQ-5D-3L). CONCLUSIONS: Danish population norms for the EQ-5D-5L are now available. We found fewer ceiling effects for the EQ-5D-5L compared to the EQ-5D-3L, and we provide evidence for convergent and known-group validity of the EQ-5D-5L.

Defensive medicine in Danish general practice. Types of defensive actions and reasons for practicing defensively.

OBJECTIVE: To examine the occurrence of and types of defensive medicine (DM), and the reasons for practicing DM in general practice. DESIGN: Prospective survey registration of consecutive consultations regarding defensive medicine defined as: Actions that are not professionally well founded but are carried out due to demands and pressure. The GPs registered the degree of defensiveness, the type(s) of defensive action(s) and the reason(s) for acting defensively. SETTING: Danish general practice. SUBJECTS: A total of 26 GPs registered a total of 1,758 consultations. MAIN OUTCOME MEASURES: Defensive medical actions. RESULTS: Defensive actions were performed in 12% (210/1749) of all consultations. A fifth (46/210) of the defensive actions were characterised by the GPs as 'moderately' or 'highly' defensive. Frequent types of defensive actions were: blood tests, point-of-care-tests (POCTs) and referrals. Common reasons for defensive actions were: Influence from patients, 37% (78/210), concerns of overlooking severe disease, 32% (67/210) and influence from patient relatives, 12% (25/210). CONCLUSION: Danish GPs registered self-perceived defensive actions in a prospective survey. DM was carried out in one out of eight consultations, most often due to patient influence. The most frequent defensive actions were blood tests, POCTs and referrals.

Generation of a Danish TTO value set for EQ-5D health states.

AIMS: Health policy decisions should be based on national social preferences. In the absence of a set of Danish health preferences, patient outcome studies using the EQ-5D instrument have typically used UK health state valuations. This article describes the development of a Danish EQ-5D value set. METHODS: Regression modelling was based on Time Trade-Off (TTO) data derived from computer-assisted interviews conducted with 1,332 respondents from the Danish general population. Using a split-sample technique, 46 health states were directly valued by the respondents. Five different model types were tested and compared on statistical and theoretical grounds. Eleven different specifications were then tested for the chosen model type to identify the most appropriate model that had high explanatory power and parameters that were both consistent (positively signed) and statistically significant. RESULTS: An additive random effects model was found to be superior to ordinary least squares, fixed effects, random coefficient and censored Tobit modelling approaches. From the 11 model specifications tested, the TTO3 model (main effects model, without an N3 factor) performed best and was used to generate a Danish set of health state preferences. CONCLUSIONS: An additive random effects model appears to adequately generate a Danish set of EQ-5D health state preferences. The model has high explanatory power and produces consistent and significant parameters for EQ-5D dimensions and levels. It is recommended that this value set be used in Danish cost-utility studies using EQ-5D.

Effect of Pentavac and measles-mumps-rubella (MMR) vaccination on the intestine.

BACKGROUND: The safety of infant vaccination has been questioned in recent years. In particular it has been suggested that the measles, mumps, and rubella (MMR) vaccination leads to brain damage manifesting as autism consequent to the development of an "enterocolitis" in the immediate post-vaccination period. AIM: To assess if MMR vaccination is associated with subclinical intestinal inflammation, which is central to the autistic "enterocolitis" theory. METHODS: We studied 109/58 infants, before and two and four weeks after immunisation with Pentavac and MMR vaccines, for the presence of intestinal inflammation (faecal calprotectin). RESULTS: Neither vaccination was associated with any significant increase in faecal calprotectin concentrations. CONCLUSIONS: The failure of the MMR vaccination to cause an intestinal inflammatory response provides evidence against the proposed gut-brain interaction that is central to the autistic "enterocolitis" hypothesis.

Serum thyroglobulin as a risk factor for thyroid carcinoma.

Samples from a biological serum bank taken up to 23 years prior to diagnosis of thyroid carcinoma were analysed for human thyroglobulin, thyroid-stimulating hormone and thyroxin. After exclusions, the final study material consisted of 59 cases of papillary and follicular carcinomas. These cases were compared with 164 controls, matched for sex, age and time of sample taking. The most interesting finding was that concentrations of thyroglobulin in serum were abnormally elevated in cases compared with controls, equal to or above 30 microg/L, with odds ratio 7.0 (CI 3.1-15.7). This elevation of serum thyroglobulin occurred in 44% of the carcinoma cases. Sensitivity was around 50 for measurements taken up to 15 years prior to diagnosis, but 21 when the interval was over 15 years. Specificity was 89. No differences were found between cases and controls in values for thyroid-stimulating hormone and thyroxin.

Evidence of Brucella infection in marine mammals in the North Atlantic Ocean.

Between 1983 and 1996 a total of 1386 samples of serum were taken from four species of seal and three species of whale in the waters west of Iceland, the area of pack-ice north-west of Jan Mayen, the northern coast of Norway and the Kola Peninsula, the waters west of Svalbard, and the Barents Sea; they were tested for the presence of anti-Brucella antibodies with an indirect ELISA (protein G conjugate). The positive sera were re-tested with classical brucellosis serological tests, such as the serum agglutination test, the EDTA-modified serum agglutination test, the Rose Bengal test, and the complement fixation test, as well as an anti-complement ELISA. Anti-Brucella antibodies were detected in all the species investigated, except for the bearded seal (Erignathus barbatus), with the following prevalences: hooded seals (Cystophora cristata) 35 per cent; harp seals (Phoca groenlandica) 2 per cent; ringed seals (Phoca hispida) 10 per cent; minke whales (Balaenoptera acutorostrata) 8 per cent; fin whales (Balaenoptera physalus) 11 per cent; and sei whales (Balaenoptera borealis) 14 per cent. An isolate belonging to the genus Brucella was obtained from the liver and spleen of one of the seropositive minke whales. The findings suggest that antibodies against the surface lipopolysaccharide of Brucella species are widely distributed among marine mammals in the North Atlantic Ocean.

[Bilateral oophorectomy before menopause. Late effects on quality of life, lipid metabolism and bone mass.].

OBJECTIVE: Oophorectomy in premenopausal women may profoundly affect health. This study was done to investigate whether it had influenced the quality of life, lipid metabolism and bone mass if removal of the ovaries in premenopausal women was performed more than 15 years ago. MATERIAL AND METHODS: Operation records from the Department of Obstetrics and Gynecology at the National University Hospital, Reykjvík, were scruti-nized to find all women who during 1977-1984 had a bilateral oophorectomy performed at less than 47 years of age at the time of operation. A control group of age-matched women, who during the same period had undergone a hysterectomy with preservation of the ovaries, was chosen. Women with malignant and chronic disabling diseases were excluded. The participants answered 36 standardized questions relating to menopausal symptoms, hormonal use and smo-king. Mesurements of total serum cholesterol, HDL (high density lipoprotein) and LDL (low density lipoprotein) cholesterol, triglycerides and calcium and fasting urine calcium and creatinine, were performed. Bone mineral density was assessed by dual energy X-ray absorptiometry in the lumbar spine, left hip and femoral neck. RESULTS: Thirty-four patients and equally many controls were identified. Fifty women agreed to participate, but two did not attend for the investigation, giving a total of 26 cases and 22 controls. Mean age at the time of operation was 43.3 years for cases and 43.5 and controls. The difference in the duration of hormone use (11.6 and 8.9 years) was not significant. Of the 36 questions on climacteric symptoms there was a significant difference between the groups in only one. Cases and controls were not different with regard to serum lipids and bone mineral density. Mean values of bone mineral density in both groups were within the normal limits for an age-matched general population. CONCLUSIONS: Women who underwent removal of the ovaries before 47 years of age, more than 15 years later, were not shown to have suffered more from longterm effects of estrogen deficiency than age-matched women who had undergone hysterectomy with preservation of the ovaries. A relatively long duration of estrogen use may be the main reason for this outcome.

Potentiating effects of pertussis toxin on leukotriene C4 induced formation of inositol phosphate and prostacyclin in human umbilical vein endothelial cells.

Leukotriene C4 is an arachidonic acid metabolite and an important mediator of inflammation and anaphylaxis that is known to induce production of prostacyclin in endothelial cells. The goal of this study was to examine the signal transduction mechanisms activated by leukotriene C4 stimulation. Formation of inositol phosphates was measured to determine the activation of phospholipase C and pertussis toxin was used to explore the role of G-proteins. Additionally, we evaluated the role of protein kinase C in these events, especially whether there was an interaction between pertussis toxin mediated effects and the activity of protein kinase C. Leukotriene C4 induced a dose- and time-dependent formation of inositol phosphates and prostacyclin. The response to leukotriene C4 was greater than the response to leukotriene D4 even after treatment with L-serine borate complex, suggesting the presence of a specific leukotriene C4 receptor. Exposure to pertussis toxin potentiated, time-dependently, the leukotriene C4 induced formation of inositol phosphates and prostacyclin through a mechanism which was altered by manipulation of protein kinase C activity. The exact mechanism is not clear but our results are consistent with a postulated dual mechanism of phospholipase C control, in which leukotriene C4 induced stimulation is attenuated by a pertussis toxin sensitive G-protein.

Inhibitory effects of meta-iodo-benzylguanidine (MIBG) on endothelial histamine receptor binding.

Meta-iodo-benzylguanidine (MIBG), a selective inhibitor of mono-ADP-ribosylation, has been shown to inhibit histamine induced inositol-trisphosphate and prostacyclin production. The purpose of this study was to evaluate the effect of MIBG on the binding of histamine to the H1-receptor and to study its effects on phospholipid metabolism in human endothelial cells. The effects of MIBG and MIBA (meta-iodo-benzylamine), which does not affect cellular ADP-ribosylation, on agonist induced cGMP production in cultured HUVEC's were measured by RIA and a binding study carried out to evaluate their effects on the binding of [3H]mepyramine to membrane fractions. MIBG (0.3 mM) reduced histamine induced cGMP production by 90.8% but did not inhibit the cGMP production induced by other agonists. MIBA had no effect. MIBG also reduced the binding of [3H]mepyramine (1.0 nM) to membrane fractions with IC50 at 0.094 mM and maximal inhibition (83%) at 0.22mM MIBG. The calculated Ki was 0.076mM. MIBG and MIBA altered phospholipid metabolism in a similar way as the cationic amphiphilic drug propranolol. MIBA caused up to 42% reduction in [3H]mepyramine binding, probably due to its inhibition of nonspecific binding. These results indicate that MIBG reduces histamine induced cGMP production by inhibiting its binding to H1-receptors and alters phospholipid metabolism in cultured endothelial cells in a similar way as known cationic amphiphilic drugs.

A role for tyrosine phosphorylation in generation of inositol phosphates and prostacyclin production in endothelial cells.

We have examined the effects of the protein tyrosine phosphatase inhibitor pervanadate on activation of signal transduction in human umbilical vein endothelial cells. Endothelial cells responded to pervanadate treatment by increasing tyrosine phosphorylation of cellular proteins, including phospholipase C (PLC) gamma 1, generating inositol phosphates (IPs), releasing arachidonic acid, and producing prostacyclin (prostaglandin [PG] I2). The dose and time responses for these events were similar. Tyrosine phosphorylation and formation of IPs in response to pervanadate were reduced by both staurosporine and genistein. Short-term incubation with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, which inhibits thrombin-induced IP generation, did not affect the IP response to pervanadate. To investigate the possible involvement of tyrosine phosphorylation in thrombin or histamine-induced IP generation and PGI2 production, we examined the effects of costimulation with pervanadate and either thrombin or histamine. These responses proved to be different. While the tyrosine phosphorylation of PLC gamma 1 was enhanced after cotreatment with thrombin and pervanadate compared with pervanadate alone, costimulation with pervanadate and histamine resulted in no more tyrosine phosphorylation of PLC gamma 1 than after pervanadate alone. Similarly, while cotreatment with pervanadate and thrombin caused synergistic increase in IP generation, costimulation with pervanadate and histamine resulted in an additive response. However, PGI2 responses to costimulation of pervanadate with either thrombin or histamine were both synergistic. Furthermore, stimulation with histamine, thrombin, or pervanadate all caused tyrosine phosphorylation of a mitogen-activated protein kinase (ERK1/p44). The results suggest that a tyrosine phosphorylation-dependent mechanism has a role in the phosphoinositide signal transduction pathway of human endothelial cells. Moreover, thrombin- but not histamine-induced generation of IPs appears to be partly caused by tyrosine phosphorylation of PLC gamma 1.

Design and in vivo testing of 17 beta-estradiol-HP beta CD sublingual tablets.

17 beta-Estradiol is almost insoluble in water. The effect of various cyclodextrins and two different polymers, polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), on the aqueous solubility of 17 beta-estradiol was investigated. 17 beta-Estradiol was dissolved in aqueous 50% w/v 2-hydroxypropyl-beta- cyclodextrin (HP beta CD) solution containing 0.25% (w/v) CMC and the dry 17 beta-estradiol-HP beta CD complex formed by lyophilisation of the solution. Sublingual tablets from the dry complex were produced by direct compression. The dissolution of 17 beta-estradiol from tablets containing the drug in a lyophilised HP beta CD complex was determined. For reference the dissolution of 17 beta-estradiol was determined from tablets containing physical mixture of 17 beta-estradiol and HP beta CD or tablets containing 17 beta-estradiol without HP beta CD. Sublingual tablets containing 17 beta-estradiol-HP beta CD in the lyophilised complex demonstrated the fastest dissolution profile and those tablets were selected for further studies in humans. Six postmenopausal women received a sublingual tablet containing 17 beta-estradiol-HP beta CD complex equivalent to 100 micrograms 17 beta-estradiol. Blood samples were collected over a 12 h period and the 17 beta-estradiol plasma concentration was determined. 17 beta-Estradiol was rapidly absorbed from the sublingual tablets, resulting in a peak 17 beta-estradiol plasma concentration of 568 +/- 97 pmol/l 15 min after administration of the tablets, followed by a biphasic elimination.

[Measurement of thyroid autoantibodies in Graves' disease.].

It is thought that dietary iodine may play a role in thyroid autoimmune reactivity. Iceland is an iodine rich area and therefore it seemed interesting to measure autoantibodies against TSH receptor (TRAb), thyroid peroxidase (TPO) and thyroglobulin (TG) in Icelandic patients with Graves' disease. Serum samples were collected from 47 patients with untreated Graves' disease, 73 patients with Graves' disease that had been treated with radioiodine (U1I), most of them (56) hypothyroid following the treatment and therefore on T4 replacement, others euthyroid. Measurements were also done on samples from a reference group of 74 healthy volunteers. All reference values are 0.95 fractile. Untreated patients with Graves' disease had TRAb values over reference range in 68.1% of cases being similar to what others have observed. The untreated patients with Graves' disease had TPO antibody measurement positive in 50.0% of cases and TG antibodies in 34.7%. This is much lower frequency of positive tests than observed elsewhere when measured with ELISA. Although methodological factors might play a role, this difference could also be explained by difference in iodine intake. The antibodies were less frequent in radioiodine treated patients than in the untreated ones. This is in agreement with the observation that serum levels of these antibodies tend to decrease with time from treatment. The antibody measurements did not differentiate between radioiodine treated patients with Graves' disease needing T4 replacement and those who did not.

[Results of individually adjusted radioiodine treatment of hyperthyroidism.].

Radioiodine (131I) treatment was started in Iceland in 1960 and the same formula has been used from the beginning to calculate the doses of radioactivity aiming for 70 Gy irradiation of the gland. In the present investigation we studied 468 patients who were treated over a period of 19 years (1973-1991). About 90% of the patients had Graves' disease (GD), 9% toxic adenoma but less than 1% toxic multinodular goiter. Approximately 70% of the GD patients became hypothyroid (subclinical hypothyroidism included) within the first year after a single radioiodine treatment and about 80% were hypothyroid four years after treatment with no significant increase after that. By contrast, only one of 15 patients with toxic adenoma became hypothyroid after a single treatment. For both groups the recurrence rate of hyperthyroidism was approximately 20%. The formula used for dose calculation in this study for GD patients does not seem to be satisfactory. The smaller glands are getting to much irradiation and the larger glands to little as can be seen by the frequency of hypothyroidism in the smaller glands and recurrences (continuing hyperthyroidism) in the larger glands after one treatment (table V). In 1993 blood samples were obtained from a sample group (n=103) of once 131I treated GD patients and measurements were done for serum TSH, T4 and free T4. One third of the patients who were considered euthyroid, and therefore not taking T4, were found to be hypothyroid with elevated TSH and low FT4 and one third of those taking T4 seemed to be overtreated with elevated FT4 and decreased TSH levels. It is concluded that the results of the radioiodine treatment for GD are unsatisfactory and need to be changed, either by adjusting the present regimen so that radiation is decreased in the smaller glands but increased in the larger ones or alternatively, by increasing the radiation dose to all the glands rendering the majority of the patients quickly hypothyroid followed by replacement therapy. The follow up of patients could be improved.

Endothelin secretion is regulated by cyclic AMP and phosphatase 2A in endothelial cells.

Endothelin is a 21 amino acid peptide secreted by endothelial cells and is the most potent vasoconstrictor known. The present study examines regulatory mechanisms of endothelin secretion, focusing on the role of protein phosphorylation. Endothelin secretion was measured by radioimmunoassay in primary cultures of human umbilical vein endothelial cells. While treatment that raised cAMP levels reduced the basal endothelin secretion rate, agents that elevated cGMP had no effect. Downregulation or inhibition of protein kinase C resulted in decreased endothelin secretion, suggesting that protein kinase C regulates endothelin secretion in the opposite direction to cAMP dependent protein kinases. Okadaic acid, at concentrations that selectively inhibit protein phosphatases 2A, reduced the endothelin secretion and the effects of okadaic acid and db-cAMP were additive. Endothelin production was stimulated by fetal calf serum and by the protein kinase inhibitor 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H7), but was inhibited by the calmodulin antagonist trifluoperazine. The present findings that regulators of cAMP-dependent protein kinases, protein kinase C, calmodulin, and protein phosphatase 2A all affect endothelin secretion suggest that endothelin secretion is controlled by phosphorylation/dephosphorylation of as yet unidentified regulatory proteins within the cell.

[Blood haemoglobin concentration in elderly people seeking doctors clinics: opposite changes in men and women].

Anaemia of uncertain origin is common in elderly people and is reported to be more common in men than women. We have investigated retrospectively a database of haematological and biochemical data on 16.332 people referred to an outpatient laboratory and compared the blood haemoglobin (Hb) concentration of the sexes. In men the mean adult Hb values of 151 g/1 started to decline at the age of 60 to reach the level of 138 g/1 by the age of 80 and older. In women, by contrast, the mean adult Hb concentration of 134 g/1 started to increase at the age of 50 to 137 g/1 then declining after the age of 70. A multiple regression analysis of variables likely to influence measured Hb values indicated that 6,7 g/1 of the observed 13 g/1 decrease in elderly men could not be explained by chance or selection bias and that an increase of Hb values in women was sustained until after 80 years of age. Results would suggest that sex or sex hormone related factors influence haemoglobin concentrations in elderly people.

Snoring, hypertension, and the sleep apnea syndrome. An epidemiologic survey of middle-aged women.

The lower limit of the prevalence of sleep apnea syndrome (SAS) was estimated among women 40 to 59 years old by a two-stage procedure. In the first stage 2,016 questionnaires were mailed. The response rate was 75.6 percent. Daytime sleepiness was reported by 8.2 percent, habitual snoring by 11.2 percent, and intermittent snoring by 21.7 percent. There were altogether 128 women described with systemic hypertension and these women were more than twice as often habitual snorers. Logistic multiple regression analyses showed almost a threefold increase in the predicted prevalence of hypertension among intermittent and habitual snorers compared with nonsnorers in the age group 40 to 49 years old and a 60 percent increase in the 50- to 59-year-old age group. In the second stage, a group of 97 women highly suspected of SAS were selected because of their habitual snoring and daytime sleepiness. Eventually, 35 of these came for night studies and 14 were found to have SAS. Among the 35 women, 12 were hypertensive and nine of these had SAS. We estimated the lower limit of the prevalence of SAS to be 2.5 percent for women 40 to 59 years old. It is concluded that SAS is a relatively common occurrence among women, especially postmenopausal ones, and it is strongly related to hypertension.

Role of ADP-ribosylation in endothelial signal transduction and prostacyclin production.

ADP-ribosylation of proteins by the enzymatic transfer of ADP-ribose from NAD has been implicated in a number of biological processes. We report that inhibitors of ADP-ribosylation, most notably the novel inhibitor of arginine specific cellular mono(ADP-ribosyl) transferase, meta-iodobenzylguanidine (MIBG) as well as nicotinamide, L-arginine methyl ester (LAME) and guanyltyramine, inhibit histamine-induced endothelial production of inositol phosphates, release of arachidonic acid and production of prostacyclin (PGI2). Those same responses were unaffected by MIBG when triggered by thrombin or leukotriene C4. These findings suggest that ADP-ribosylation serves a role in histamine-induced production of prostacyclin and imply differences in transduction pathways employed by the different agonists.