Macular recovery time, diabetic retinopathy, and clinical variables after 7 years of improved glycemic control.

Effects of long-term improved glucose control on neurosensory retinal function are investigated. Changes in macular recovery of nyctometry (photostress) are assessed in 45 insulin-dependent diabetic patients between study start and after 7 years prospective follow-up (the Oslo Study). Intensified insulin treatment improved glycosylated hemoglobin (HbA1) from 11.7 +/- 2.2% at start to a 7-year cumulative mean of 9.5 +/- 1.5% (p less than 0.0001). Improved macular recovery performance was observed in patients with 7-year mean HbA1 below 10%, compared to a worsening in those above 10% (p less than 0.001-0.02), and non-proliferative retinopathy progressed less in those with HbA1 below 10%, than in those above (p less than 0.01). Macular recovery at study start did not predict progression or outcome of retinopathy 7 years later. Intraocular pressure fell during the 7 years (p less than 0.001) and was cross-sectionally negatively correlated to macular recovery at the 7-year end-point (p less than 0.001-0.002). Macular recovery was not related to age, duration of diabetes, systemic blood pressure, or urinary albumin excretion level. The study indicates that severity of retinopathy, glycemic control and intraocular pressure are interesting covariants to neurosensory dysfunction in diabetes. Furthermore, the study suggests a critical level of long-term blood glucose or retinopathy, or both, above which neurosensory function of macular recovery is significantly reduced.     

A 9.6 kilobase deletion in the low density lipoprotein receptor gene in Norwegian familial hypercholesterolemia subjects

Haplotype analysis of the low density lipoprotein receptor (LDLR) gene was performed in Norwegian subjects heterozygous for familial hypercholesterolemia (FH). Southern blot analysis of genomic DNA, using an exon 18 specific probe and the restriction enzyme NcoI, showed that two out of 57 unrelated FH subjects had an abnormal 3.6 kb band. Further analyses revealed that this abnormal band was due to a 9.6 kb deletion that included exons 16 and 17. The 5' deletion breakpoint was after 245 bp of intron 15, and the 3' deletion breakpoint was in exon 18 after nucleotide 3390 of cDNA. Thus, both the membrane-spanning and cytoplasmatic domains of the receptor had been deleted. A polymerase chain reaction (PCR) method was developed to identify this deletion among other Norwegian FH subjects. As a result of this screening one additional subject was found out of 124 subjects screened. Thus, three out of 181 (1.7%) unrelated Norwegian FH subject possessed this deletion. The deletion was found on the same haplotype in the three unrelated subjects, suggesting a common mutagenic event. The deletion is identical to a deletion (FH-Helsinki) that is very common among Finnish FH subjects. However, it is not yet known whether the mutations evolved separately in the two countries.     

Marfan syndrome: Evolving organ manifestations—A 10‐year follow‐up study

The age‐dependent penetrance of organ manifestations in Marfan syndrome (MFS) is not known. The aims of this follow‐up study were to explore how clinical features change over a 10‐year period in the same Norwegian MFS cohort. In 2003–2004, we investigated 105 adults for all manifestations in the 1996 Ghent nosology. Ten years later, we performed follow‐up investigations of the survivors (n = 48) who consented. Forty‐six fulfilled the revised Ghent criteria. Median age: females 51 years, range 32–80 years; males 45 years, range 30–67 years. New aortic root dilatation was detected in patients up to 70 years. Ascending aortic pathology was diagnosed in 93 versus 72% at baseline. Sixty‐five percent had undergone aortic surgery compared to 39% at baseline. Pulmonary trunk mean diameter had increased significantly compared to baseline. From inclusion to follow‐up, two patients (three eyes) developed ectopia lentis, four developed dural ectasia, four developed scoliosis, three developed incisional or recurrent herniae, and 14 developed hindfoot deformity. No changes were found regarding protrusio acetabuli, spontaneous pneumothorax, or striae atrophicae. The study confirms that knowledge of incidence and progression of organ manifestations throughout life is important for diagnosis, treatment, and follow‐up of patients with verified or suspected MFS.     

Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia

The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenuated. Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days. Plasma gastrin and histamine, gastric endocrine cell densities and mRNA abundances were measured. Ciprofibrate increased gastrin mRNA abundance (P<0.05), gastrin cell number (P<0. 001) and cell area (P<0.01), and induced hypergastrinemia (P<0.001). These rats had profound ECL cell hyperplasia, confirmed by an increase in chromogranin A (CgA) and histidine decarboxylase (HDC) mRNA, density of neuroendocrine and ECL cells and plasma histamine levels (all P<0.001). Octreotide LAR did not affect ciprofibrate stimulation of gastrin cells, but all parameters of ECL cell hyperplasia were reduced (P<0.001). Octreotide LAR also significantly inhibited basal ECL cell function and growth. Ciprofibrate stimulates gastrin cell activity by a mechanism unaffected by octreotide, but octreotide does inhibit basal and gastrin-stimulated ECL cell function and growth.     

The effect of omeprazole-induced hypergastrinemia on the oxyntic mucosa of mastomys

Mastomys is a rodent with a high incidence of spontaneous carcinoids in the acid-producing part of the stomach. The present study was conducted to examine whether hypergastrinemia could promote tumor formation in this species. Mastomys, 4 months of age, were treated for 5 months with omeprazole subcutaneously, 100 mumol/kg body weight daily, and compared with mastomys given the vehicle only. The plasma gastrin concentration and the number of antral gastrin cells were increased in the omeprazole-treated group. The hypergastrinemia was associated with elevated histidine decarboxylase activity and histamine content in the oxyntic mucosa and with a trophic effect on the oxyntic mucosa and the enterochromaffin-like cells. However, no carcinoid tumors were observed, possibly because the strain of mastomys studied does not produce carcinoids spontaneously.     

One-year follow-up study of patients with enterochromaffin-like cell carcinoids after treatment with octreotide long-acting release

OBJECTIVE: In a one-year study of 5 patients with chronic atrophic gastritis (CAG), pernicious anaemia (PA), hypergastrinaemia and enterochromaffin-like (ECL) cell tumours, the somatostatin analogue octreotide LAR (long-acting release) in a dose of 20 mg given intramuscularly at monthly intervals had an antiproliferative effect on the ECL cells. The aim of the present study was to follow neuroendocrine (NE) markers in the blood and macroscopic and histopathological changes in the stomach during a 12-month follow-up after discontinuation of octreotide LAR treatment. MATERIAL AND METHODS: Five patients underwent upper gastrointestinal endoscopy at 6 and 12 months' follow-up after octreotide LAR treatment. Biopsies from flat, oxyntic mucosa and from tumours were obtained. Sections were stained with haematoxylin-erythrosin and immunostained for the NE cell marker chromogranin A (CgA). Serum gastrin and CgA were measured every 3 months. RESULTS: The number of visible tumours was unchanged (7) at 12 months' follow-up. One lesion showed carcinoid tumour and the others various degrees of linear and micronodular NE hyperplasia. At the same time-point, biopsies from flat, oxyntic mucosa showed a slightly (non-significant) elevated number of CgA immunoreactive (IR) cells. Serum gastrin increased from 186+/-50 pM (mean+/-SEM) to 603+/-109 pM (normal < 40 pM); p<0.05, and serum CgA increased non-significantly from 25+/-2 ng/ml (normal < 30 ng/ml) to 61+/-11 ng/ml. CONCLUSIONS: During follow-up, slightly elevated levels of serum CgA and CgA IR cells in the oxyntic mucosa, without significant recurrence of ECL cell carcinoids, were observed.     

Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes

Aims/hypothesis Intima media thickness (IMT) of the common carotid artery (CCA) is a validated surrogate marker of early atherosclerosis. The aim of our study was to assess the association between IMT in CCA and long-term mean HbA₁c in type 1 diabetes. We also elucidated the association between carotid IMT and preclinical coronary atherosclerosis.Methods In 39 individuals with type 1 diabetes, HbA₁c was measured prospectively over 18 years. The IMT examinations were performed with high-resolution ultrasound. The association between carotid IMT and preclinical coronary atherosclerosis (assessed by intravascular ultrasound [IVUS]) was tested in 29 of the patients.Results Mean HbA₁c over 18 years was 8.2% (range: 6.6–11.3%). Mean age at follow-up after 18 years was 43 years and mean duration of diabetes was 30 years. IMT was significantly higher in diabetic patients than in an age- and sex-matched reference population. The IMT values were at the same level as for controls who were 20 years older. In women, HbA₁c was significantly associated with mean average CCA IMT (r²=0.77, p<0.0001 when adjusted for age), whereas there was no significant association for men. Among women, a significant association was also found between carotid IMT and the percentage of coronary vessel area stenosis (r=0.65, p=0.03).Conclusions/interpretation The present findings suggest an important role of long-term hyperglycaemia in the development of atherosclerosis, especially in women with type 1 diabetes.Type 1 diabetes patients have earlier development of, and more advanced, atherosclerosis compared with an age- and sex-matched reference population. In women, carotid IMT reflects preclinical coronary atherosclerosis.     

An algorithm-based genotypic resistance score is associated with clinical outcome in HIV-1-infected adults on antiretroviral therapy

OBJECTIVES: The aim of this study was to evaluate the association between genotypic drug resistance and the occurrence of HIV-related diseases and death in HIV-1-infected adults on antiretroviral therapy. METHODS: We performed an observational study on patients from an out-patient clinic in a university hospital. Genotypic drug resistance analysis after virological treatment failure was performed in 141 patients receiving two or more antiretroviral drugs. All patients had follow up of at least 6 months after the resistance test. An algorithm was developed to estimate the level of genotypic drug resistance and to assign an actual resistance score (ARS) for the drugs prescribed to each patient. The patient population was divided into quartiles according to patients' ARS values. Our endpoint was the risk of developing an HIV-related disease [Centers for Disease Control and Prevention (CDC) category B or C] during the period starting 6 months prior to and ending 6 months after the genotypic resistance test, or death during the 6 months following the resistance test. RESULTS: There was a significant association between the level of resistance to the drugs prescribed (ARS) and our clinical endpoint: the odds ratio for an endpoint (with 95% confidence interval) was 3.20 (1.28-7.99), adjusted for CD4 cell count and HIV RNA, in patients in the highest ARS quartile compared with patients in the other three quartiles. CONCLUSIONS: Our study indicates that patients with high-level genotypic drug resistance are at increased risk of developing an HIV-related disease. This association could not be explained by differences in CD4 cell count or HIV RNA levels.