Long-term health-related quality of life of surgically treated pituitary adenoma patients: a descriptive study.

Context. The literature concerning the health-related quality of life (HRQoL) of patients with surgically treated PA is controversial. Objective. To describe the long-term HRQoL of surgically treated patients in all PA classes. Design and subjects. The 15D, a generic HRQoL instrument producing a 15-dimensional profile and a single 15D index score (a difference ≥0.03 on a 0-1 scale is considered clinically important), was used to assess the HRQoL of a 13-year surgical cohort of PA patients in Northern Finland. Results and Conclusion. Nighty-eight eligible consecutive patients with surgically treated PA were studied at an average of 6.3 years after their latest pituitary operation. The average postoperative 15D profiles in patients with non-functioning PA and in acromegalics without GH-suppressive medical treatment were similar to those of the age-standardized general population. However, after this rather long followup, the mean 15D score and the number of statistically significant 15D dimension impairments, compared with those of their reference population, were 0.11 and 9/15, 0.10 and 3/15, and 0.08 and 7/15 for Cushing's disease, acromegalics needing somatostatin analog, and prolactinoma patients, respectively. Hypopituitarism with replacement medication was not associated with impaired HRQoL. The somatostatin-analog-associated HRQoL finding warrants further clinical research.

Aryl hydrocarbon receptor interacting protein mutations seem not to associate with familial non-medullary thyroid cancer.

BACKGROUND: Over 95% of all thyroid malignancies are non-medullary thyroid carcinomas (NMTC). Familial NMTC are more aggressive and mortality is higher as compared with sporadic carcinomas. Known genetic factors do not explain all familial NMTC. Recently, thyroid disorders have been observed in families with germline mutations in aryl hydrocarbon receptor interacting protein (AIP) but, due to frequent occurrence of these conditions in the population, the significance of this co-occurrence is not clear. AIM, SUBJECTS AND METHODS: To examine whether AIP is involved in familial NMTC, we performed AIP mutation screening in 93 familial NMTC cases. In addition, the AIP status was studied in one follicular thyroid adenoma patient with a known AIP mutation from an additional cohort. RESULTS: No potentially pathogenic changes were identified, but two likely rare polymorphisms were detected. AIP mutation-positive patient's follicular thyroid adenoma showed no loss of heterozygosity or lack of immunohistochemical AIP staining. CONCLUSION: Our study indicates that germline AIP mutations are rare or do not exist in familial NMTC.

Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition.

OBJECTIVE: Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition. PATIENTS AND DESIGN: Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1- related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B. RESULTS: Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected. CONCLUSIONS: Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.

Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Nocturnal hypoglycaemia may contribute to sudden death in diabetic patients. However, it is not well known why hypoglycaemia makes these patients prone to death. METHODS: We assessed the effects of controlled hypoglycaemia on cardiac repolarisation using novel electrocardiographic descriptors of T-wave and QRS complex morphology in 16 type 1 diabetic patients and eight healthy counterparts. Several electrocardiographic variables characterising repolarisation were analysed from digitised 12-lead electrocardiograms during a euglycaemic and a hypoglycaemic clamp. RESULTS: Hypoglycaemia did not result in significant changes either in the QT interval corrected for heart rate by the nomogram method or in QT dispersion. However, the morphology of the T-wave changed significantly during hypoglycaemia. The T-wave amplitude and area in precordial leads decreased significantly in both groups (p<0.05 to p<0.001). The spatial QRS-T angle (total cosine R to T) (p<0.05) and the height and the width of the T-wave loop (p<0.05 and p<0.01, respectively) were also reduced in the diabetic patients. The changes in the repolarisation parameters did not exhibit any significant association with changes in catecholamine levels or in heart rate variability in either group. CONCLUSIONS/INTERPRETATION: Hypoglycaemia results in distinct alterations in cardiac repolarisation, which may increase the vulnerability to arrhythmic events.

Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation.

OBJECTIVE: The existence of genotype-phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. DESIGN AND METHODS: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982-2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. RESULTS: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27-8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29-9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31-35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73-131.9, P = 0.014). CONCLUSIONS: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.

Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.

BACKGROUND: Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. METHODS: The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. RESULTS: The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. CONCLUSIONS: The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.

Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies. With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (+/- sd) of death of affected males (n = 16) was 61.1 +/- 12.0 yr vs. 65.8 +/- 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 +/- 10.7 yr vs. 67.7 +/- 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.

The real contamination of femoral head allografts washed with pulse lavage.

At the Tampere Bone Bank, all the discarded femoral heads from September 1997 to May 2000 were recultured. The grafts had been washed with pulse lavage at harvesting. 48 grafts had been discarded because of a positive culture and 85 with negative cultures because of positive or insufficient serological information. The femoral heads were split into halves, which were recultured as a whole in thioglycolate broth for 14 days. The contamination of previously culture positive and negative femoral heads did not differ. In only 2 cases did we find the same type of bacteria in the primary as in the new culture. Most of the primary contamination proved to be false positive. The real contamination seems to be very low, at least after pulse lavage washing of the femoral head.

MR imaging of pituitary adenomas treated with the prolactin inhibitor quinagolide.

PURPOSE: To evaluate the volume of micro- and macroadenomas in quinagolide-treated patients with resistance to or intolerance of bromocriptine. MATERIAL AND METHODS: The effect of the prolactin inhibitor quinagolide on the volume of pituitary adenoma was evaluated retrospectively in 11 female patients. Prolactin levels before and after the treatment were also recorded. The indications for quinagolide therapy were side-effects of bromocriptine in 5 cases, a poor response to bromocriptine in 5 cases and both in 1 case. MR imaging with a 1.0-T magnet was performed to determine the volume reduction of the adenomas. RESULTS: The average volume reduction of macroadenomas was 324 mm3 (46%) and that of microadenomas 73 mm3 (57%). The level of prolactin secreted by macroadenomas was reduced by an average of 163 microg/l (65%) and that by microadenomas of 113 microg (73%). In 2 microadenomas and in 1 macroadenoma, signal intensity changed during the treatment in T1-weighted images. In follow-up no changes in signal intensity were seen in 8 adenomas in non-contrast T1-weighted images. A haemorrhagic lesion was seen in 1 macroadenoma before treatment, but it disappeared during treatment. CONCLUSION: Quinagolide was found to be an effective alternative to bromocriptine in cases with drug intolerance or resistance, and MR imaging a suitable method for the follow-up of macro- and microadenomas.

High-pressure saline washing of allografts reduces bacterial contamination.

60 fresh-frozen bone allografts were contaminated on the operating room floor. No bacterial growth was detected in 5 of them after contamination. The remaining 55 grafts had positive bacterial cultures and were processed with three methods: soaking in saline, soaking in antibiotic solution or washing by high-pressure saline. After high-pressure lavage, the cultures were negative in three fourths of the contaminated allografts. The corresponding figures after soaking grafts in saline and antibiotic solution were one tenth and two tenths, respectively. High-pressure saline cleansing of allografts can be recommended because it improves safety by reducing the superficial bacterial bioburden.

Surveillance of ruminant diseases in the Nordic countries.

All the Nordic countries have a basis for their surveillance and disease control in ruminants in national legislation and regulations listing notifiable diseases of concern to the countries. The Nordic countries are a disease-free zone comparing to other parts of the world and the aim of the surveillance is to keep that status and be able to document it. Following is a short summary from each country.

Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes.

OBJECTIVE: To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later. RESEARCH DESIGN AND METHODS: We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis. RESULTS: The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children. CONCLUSIONS: Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.

Microcirculatory response of skin to benzoic acid and methyl nicotinate in patients with diabetes.

AIMS: In view of the relationship between microvascular pathology and organ complications in diabetes mellitus, the aim of the present study was to examine the microvascular response of upper arm skin to non-immunological contact irritants in 17 insulin-dependent diabetic patients and 11 non-diabetic controls. METHODS: Non-immunological contact urticaria, an inflammatory reaction mediated in a unique way, not previously studied in diabetic patients, was examined. The test agents were benzoic acid and methyl nicotinate. The intensity of the reactions was measured using laser-Doppler flowmetry and colorimetry. The patients were divided into two groups, depending on whether they had had diabetes for less or more than 10 years. RESULTS: There were no differences in the maximal blood flow responses between the groups, but the diabetic patients showed increased blood flow responses to the lowest irritant concentrations compared to the controls. The reactions in the two groups of diabetic patients were similar. CONCLUSIONS: The present study suggests that the microvascular reactivity of diabetic skin to non-immunological contact irritants is increased.

Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms.

PURPOSE: To evaluate the prolonged release (PR) of the long-acting somatostatin analog lanreotide in patients with gastrointestinal neuroendocrine tumors and its effect on hormone-related symptomatology, tumor markers, tumor size, tolerability, and quality of life (QOL). PATIENTS AND METHODS: Eligible patients had the following substantial daily symptoms: for patients with carcinoid tumors, three or more stools and/or 1.5 or more flushing episodes; for patients with gastrinoma, greater than 50% elevated basic acid output; and for patients with vasoactive intestinal peptide-secreting tumors (VIPomas), four or more stools and/or a stool volume of >/= 800 mL, a measurable tumor, and an elevated biochemical tumor marker (>/= two times the upper limit of the normal reference range). Lanreotide PR was administered intramuscularly every 14 days at 30 mg for 6 months. We measured efficacy by studying symptoms, tumor markers, tumor size, and QOL. Side effects were scored according to the National Cancer Institute's toxicity grading system and ultrasound examination of the gallbladder. RESULTS: Fifty-five patients were included in the study (48 patients with carcinoid tumors, six patients with gastrinoma, and one patient with VIPoma). Symptomatic improvement (> 50% reduction) occurred in 38% of the assessable patients with carcinoid tumors, in 67% of the gastrinoma patients, and in the VIPoma patient. Tumor markers normalized in two of 45 assessable patients, 19 patients exhibited a reduction (> 50%), 19 patients exhibited no change, and tumor markers rose by more than 50% in five patients. Tumor size was reduced in two of 31 assessable patients and remained stable in 25 patients; four patients experienced progression. QOL assessments after 1 month showed improvements in emotional and cognitive function, and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones. CONCLUSION: Lanreotide PR is a well-tolerated somatostatin analog with significant clinical, biochemical, and antitumor effects that bring about a significant improvement in QOL for patients with neuroendocrine tumors.

Delayed restoration of epidermal barrier function after suction blister injury in patients with diabetes mellitus.

AIMS: Diabetes mellitus is a risk factor for compromised wound healing. The present study examines the restoration of the epidermal barrier function using the suction blister wound model. METHODS: The healing process was evaluated over time by measuring water evaporation (WE) and blood flow (BF) in the wound area. Seventeen Type 1 diabetic males and 11 non-diabetic control males were studied. RESULTS: At the onset, the WE of diabetic patients was 116 +/- 11 g x m(-2) x h(-1) and that of controls 95 +/- 13 g x m(-2) x h(-1) (P < 0.001). On the second day, the WE of diabetic patients was 90 +/- 21 g x m(-2) x h(-1) and that of controls 60 +/- 24 g x m(-2) x h(-1) (P < 0.02). The most profound difference was encountered during the fourth day, when the WE of diabetic patients was 40 +/- 17 g x m(-2) x h(-1) and that of controls 14 +/- 8 g x m(-2) x h(-1) (P < 0.001). The value recorded on the fourth day was 37% of the onset value in diabetic patients and 16% in controls (P < 0.001). Eight days after wounding the values were close to that of normal skin in both diabetic and control subjects. At the onset, the BF was 93 +/- 20 (arbitrary units) in diabetic men and 112 +/- 18 in controls (P = 0.02). On the second, fourth and eighth day there was no significant differences. CONCLUSIONS: The results suggest that restoration of the epidermal barrier function is delayed in the patients with diabetes. There were also a trend toward an initially weaker inflammatory response.

Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults.

OBJECTIVE: To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover. DESIGN AND METHODS: BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxy-terminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment. RESULTS: The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P<0. 001), 5.9% (P<0.01) in the femoral neck, 4.9% (NS, P>0.05) in the Ward's triangle and 8.2% (P<0.001) in the trochanter area. The serum concentrations of PICP (202.6+/-11.5 vs 116.3+/-5.4 microg/l; mean+/-s.e.m.) and ICTP (10.5+/-0.6 vs 4.4+/-0.3 microg/l) doubled (P<0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0+/-10.4 and 5.6+/-0.7 microg/l respectively), despite constantly elevated serum IGF-I levels (39. 6+/-4.1 nmol/l at 42 months vs 11.9+/-0.9 nmol/l at baseline; P<0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P<0.001 for all; ANOVA) and of the BMD in the lumbar spine (P<0.05), in the femoral neck and the trochanter (P<0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P<0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P<0.05) in those with normal bone status (P<0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P<0. 05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD. CONCLUSIONS: GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.

Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes.

AIMS/HYPOTHESIS: Inflammation could play a part in insulin resistance. Thiazolidinediones, new antidiabetic drugs, possess anti-inflammatory effects in vitro. We investigated if acute-phase serum proteins are increased in patients with Type II (non-insulin-dependent) diabetes mellitus who had been treated with insulin and whether troglitazone has anti-inflammatory effects in vivo. METHODS: A total of 27 patients (age 63.0+/-1.7 years, HbA1c 8.8+/-0.3%, BMI 32.7+/-0.8 kg/m2, duration 15.2+/-1.4 years, insulin dose 73.3+/-7.0 U/day) participated in the study. The patients received daily either 400 mg troglitazone or placebo for 16 weeks. Blood samples were taken at baseline, at the end of therapy and after a follow-up time of 23+/-4 days. RESULTS: The concentrations of serum amyloid A (6.2+/-1.1 mg/l) and C-reactive protein (6.1+/-1.1 mg/l) were increased (p < 0.001) and complement protein C3 (1.69+/-0.05 g/l) was also above the reference range for healthy subjects. Placebo treatment had no effect on glucose or inflammation, whereas troglitazone reduced fasting glucose (from 10.4+/-0.6 mmol/l to 8.1+/-0.5 mmol/l, p < 0.01), HbA1c (from 8.7+/-0.3% to 7.5+/-0.3%, p < 0.01), insulin requirements (from 75+/-10 U/day to 63+/-10 U/day, p < 0.05), serum amyloid A (from 6.3+/-1.5 mg/l to 4.0+/-1.3 mg/l, p = 0.001), alpha-1-acid glycoprotein (from 906+/-51 mg/l to 729+/-52 mg/l, p = 0.001) and C3 (from 1.72+/-0.07 g/l to 1.66+/-0.06 g/l, p < 0.05) but not alpha-1-antitrypsin, ceruloplasmin, C-reactive protein or haptoglobin significantly. Concentrations of glucose and acute-phase reactants had returned to those before treatment at the follow-up visit. CONCLUSION/INTERPRETATION: In Type II diabetic patients serum amyloid A and complement protein C3 are raised. Troglitazone exerts a selective reversible action on some acute-phase proteins and C3 but not on others in conjunction with the improvement in glucose metabolism.