Peter Wiesli

Roxithromycin Treatment Prevents Progression of Peripheral Arterial Occlusive Disease in Chlamydia pneumoniae Seropositive Men A Randomized, Double-Blind, Placebo-Controlled Trial

Background—Evidence has been provided that the atherosclerotic process may be associated with chronic infection with Chlamydia pneumoniae. The effect of antibiotic treatment on peripheral arterial occlusive disease has not been investigated yet. Methods and Results—Forty C pneumoniae seropositive men suffering from peripheral arterial occlusive disease were randomly assigned to receive either roxithromycin (300 mg daily) or placebo for 28 days. During the 2.7-year follow-up, the number of invasive revascularizations per patient, the walking distance before intervention (in patients without intervention at study end), and the change of carotid plaque size were assessed. Five interventions were performed on 4 patients (20%) in the roxithromycin group, and 29 interventions were performed on 9 patients (45%) in the placebo group. Limitation of walking distance to 200 m or less was observed in 4 patients (20%) in the roxithromycin group and in 13 patients (65%) in the placebo group. The effect of macrolide treatment on the number of interventions per patient and on preinterventional walking distance was significant. Possible confounding variables such as classical vascular risk factors were excluded by multiple regression analyses. Carotid plaque areas monitored over 6 months decreased in the roxithromycin group (mean relative value, 94.4%) but remained constant in the placebo group (100.2%). Regression of carotid plaque size observed in roxithromycin-treated patients was significant for soft plaques. Conclusions—This study indicates that macrolide treatment for 1 month is effective in preventing C pneumoniae seropositive men from progression of lower limb atherosclerosis for several years.

Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient.

The tumorigenesis of sporadic endocrine tumors is still not fully understood. It is well known that patients with von Recklinghausen syndrome (NF-1) (OMIM 162200) carrying NF1 germline mutations are predisposed to endocrine tumors including pheochromocytomas and duodenal somatostatinomas. It is unclear, however, whether the rarely reported occurrence of pancreatic insulinomas in NF-1 patients represents a coincidental finding or whether insulinomas are a rare manifestation of the NF-1 syndrome. To determine the potential association between the NF-1 syndrome and pancreatic endocrine tumors, we analyzed a NF-1 patient with a well-differentiated pancreatic endocrine carcinoma for NF1 mutation, allelic loss of the NF1 gene and its expression in peripheral blood and tumor cells. The germline mutation c. 499 del TGTT known in the family was confirmed by polymerase chain reaction (PCR) and direct sequencing of exon 4 in DNA extracted from peripheral blood. Loss of heterozygosity (LOH) analysis of the NF1 gene was carried out using 3 intragenic microsatellite markers on 17q11.2. RNA expression was examined by reverse transcription and a consecutive PCR spanning intron 3 of the NF1 gene including the mutated site in exon 4. Immunohistochemistry was used to analyze NF-1 protein expression. Mutation analysis of peripheral blood leukocytes confirmed the 4 base pair deletion in exon 4 starting at codon 167 (499 del TGTT). LOH analysis of tumor tissue revealed retention of both NF1 alleles. While reverse transcriptase-PCR of peripheral blood showed bi-allelic expression of both the wild-type NF1 and the mutated form, reverse transcriptase-PCR of tumor extracts demonstrated expression of the mutated but not the wild-type NF1 allele. Additionally, neurofibromin, the NF1 gene product, was absent in the tumor tissue of the NF-1 patient. These results show that the wild-type NF1 transcrips and protein are reduced, in the reported insulinoma, supposedly by epigenetic mechanisms. This provides strong evidence that there is a relationship between von Recklinghausen disease and the patients insulinoma. In this line, insulinomas may be viewed as a rare manifestation of the NF-1 syndrome. Furthermore, the NF1 gene must be considered as a candidate tumor suppressor gene for sporadic insulinomas and probably other pancreatic endocrine tumors.

Hypoglycemia in response to glucose and glucagon in insulinoma patients with a negative prolonged fast: Functional and morphological properties

A negative 72-h fast is usually considered to preclude the diagnosis of insulinoma. The aim of this study was to describe the functional and morphological properties of two exceptional patients with an insulinoma who had exhibited pre-operatively a negative 72-h fast. Despite the ability of tumor cells to turn off insulin secretion in response to low plasma glucose during 72 h of fasting, hyperinsulinemic hypoglycemia occurred in both patients in response to stimulation by classical secretagogues. Pre-operatively, both patients underwent oral and iv glucose challenge tests and iv glucagon stimulation test. Insulin secretion was rapidly stimulated by these secretagogues to an exaggerated extent and thereby caused hypoglycemia due to an insulin mass effect. In contrast to the common functional features during suppression and stimulation tests, the tumors differed widely with regard to insulin and proinsulin response to calcium during ASVS tests and morphological properties. In patient 1, the immunohistochemical proinsulin distribution pattern resembled that of normal γ-cells, i.e. the staining was restricted to the perinuclear area; insulin and proinsulin were not stimulated by calcium during the ASVS test. In patient 2, the proinsulin staining pattern was abnormal, i.e. proinsulin was also found in the periphery of tumor cells; insulin and proinsulin were stimulated by calcium. We conclude that normal or exaggerated rather than defective glucose sensing may explain hypoglycemia in these exceptional insulinoma patients. Different functional characteristics of these tumors can be correlated with distinct morphological properties.

Pregnancy-induced changes in insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) in patients with growth hormone (GH) deficiency and excess

Background. Under most circumstances with altered growth hormone (GH) secretion, the changes of insulin‐like growth factor I (IGF‐I), insulin‐like growth factor binding protein 3 (IGFBP‐3), and acid‐labile subunit (ALS) are in parallel. The aim of the present study was to compare the effects of pregnancy in a hypopituitary patient with those of pregnancy in an acromegalic patient on IGF‐I, IGFBP‐3, and ALS. Methods and results. IGF‐I and ALS were low before pregnancy in the hypopituitary patient under glucocorticoid and thyroxine treatment. Gonadotropin treatment allowed her to become pregnant; IGF‐I and ALS levels rose in the second half of pregnancy and fell again after delivery. IGF‐I concentrations were elevated in the patient with persistent acromegaly before and dropped into the normal range during the first half of pregnancy. In the second half of pregnancy and following delivery, IGF‐I levels increased again. IGFBP‐3 levels (as assessed by immunoblot analysis as well as by 125I‐IGF II ligand blotting) decreased markedly during pregnancy in both patients, suggesting that the placenta rather than pituitary GH regulates IGFBP‐3 proteolysis in human pregnancy. The increase of IGF‐I (and ALS) during the second half of pregnancy in the individual with pituitary GH deficiency may be attributed to placental GH. The fall of IGF‐I (and ALS) into the normal range in the acromegalic patient during the first trimester of pregnancy may be related to decreased production or decreased half‐life of these proteins. Conclusion. Our data suggest that measures to continuously replace GH or to suppress GH secretion during pregnancy in patients with GH deficiency or excess, respectively, may not be warranted.

Effect of thyroxine replacement on serum IGF‐I, IGFBP‐3 and the acid‐labile subunit in patients with hypothyroidism and hypopituitarism

Objective  To describe the effect of T4 replacement in patients with primary and central hypothyroidism on components of the IGF binding protein complex: IGF‐I, the acid‐labile subunit (ALS) and IGFBP‐3.

Increased insulin dose requirement of long-acting insulin analogues in obese patients with type 2 diabetes

To the Editor: Obesity, type 2 diabetes, insulin resistance and hyperinsulinaemia are associated with an increased risk of some types of cancer, and recent epidemiological data have refuelled discussions on the safety of insulin therapy [1]. The data published in the last issue of Diabetologia raise concern but do not provide evidence that any of the specific insulin preparations cause harm; there are too many confounders for which adjustment remains imperfect. Whether the potential risks of insulin preparations with increased affinity to type 1 IGF receptors are acceptable remains a matter of debate. We wish to point out that (apart from the intrinsic properties of an insulin preparation) higher levels of continuous insulin exposure resulting from the choice of insulin preparation should also be considered as a potential drawback. A similar (unit-based) glucose-lowering efficacy of NPH insulin and the long-acting analogues has been suggested, but it remains unclear whether this is also true for obese patients with type 2 diabetes. In our recently published prospective study comparing the effect of NPH insulin, insulin detemir (NN304) [B29Lys(e-tetradecanoyl),desB30 human insulin] and insulin glargine (A21Gly,B31Arg,B32Arg human insulin) injected at bedtime in patients with type 2 diabetes [2], each patient was sequentially treated with all three longacting insulin preparations. Comparable predefined glucose targets were achieved at midnight (00:00 hours) and in the morning (at 07:00 hours) with all three insulin preparations tested; none of them could totally prevent the rise of glucose between 05:00 and 08:00 hours. As mentioned (but not shown) in our communication, a trend for increased analogue (compared with NPH) insulin dose requirements (especially in obese patients on high total doses) to reach glucose targets was observed. The difference was significant in patients with a BMI of >30 kg/m, as shown in Table 1. In patients with type 2 diabetes, it has previously been reported that a higher dose of insulin analogues relative to NPH insulin is required to achieve similar glucose control, e.g. in the Treat-to-Target Trial, in which doses of insulin glargine were higher than those of NPH [3]. An increased insulin dose requirement compared with NPH insulin in patients with type 2 diabetes has also been reported for insulin detemir [4, 5]. Whereas such differences have not been found in all studies (e.g. in the LANMET study [6]), to the best of our knowledge, the opposite, i.e. a lower insulin dose requirement of the long-acting analogues compared with NPH insulin in patients with type 2 diabetes, has not been reported. Good glycaemic control and prevention of cardiovascular disease remain major goals when treating patients with type 2 diabetes. Lifestyle changes are difficult to achieve, C. Schmid Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland

Prognostic factors for impaired plasma sodium homeostasis after transsphenoidal surgery

Abstract Objective. Surgical manipulation of the pituitary stalk, neurohypophysis or the hypothalamus may disturb control of the plasma sodium level. The factors that might predict the risk of postoperative sodium imbalance are not clear, and were investigated in this study. Methods. A retrospective survey of 129 surgical records for the occurrence of plasma sodium levels outside the normal range, following transsphenoidal procedures. Median patient age was 49 (range 20–78) years, 65 female. 73 of the operated lesions were non-functioning pituitary adenomas. Patients were considered to have impaired plasma sodium balance if the range of 135–145 mmol/L was not maintained. Results. Of all 129 surgical cases, 68 (53%) experienced an imbalance in sodium levels. Severe sodium imbalance (≥ 149 or ≤ 131 mmol/L) was observed in 28 patients (22%). 13 showed hypernatraemia (median day 1), and 15 hyponatraemia (median day 6). Tumour size was associated with an increased incidence of sodium imbalance, particularly in patients younger than 49 years; surgery resulted in sodium imbalance in 38% of young patients operated on for tumours < 22 mm and in 76% of young patients, operated on for tumours ≥ 22 mm. Overall, tumour size increased with patients’ age, and tumour size was less predictive for sodium disturbances in elderly patients. Median time in hospital was 5 days for patients without sodium imbalance, 6 days for patients with hypernatraemia and 11 days for patients with hyponatraemia. Conclusions. Following pituitary surgery, patients with large tumours, in particular those of young age, are at higher risk for losing control of their plasma sodium level. Increased ADH secretion (hyponatraemia), but not transient diabetes insipidus was associated with a prolonged hospital stay. Postoperative follow-up of patients with sellar tumours should include careful monitoring of plasma sodium levels within the first two postoperative weeks and clear patients’ instructions.

Abnormalities of proinsulin processing in functioning insulinomas: clinical implications

objective  Abnormal proinsulin processing in insulinomas may result in secretory granules containing both insulin and proinsulin, a finding not encountered in healthy β‐cells. The aim of this study was to test whether such abnormalities in the proinsulin to insulin conversion have clinical implications in patients with hypoglycaemic disorders.

Effect of roxithromycin treatment on the endothelial function of Chlamydia pneumoniae seropositive men suffering from peripheral arterial occlusive disease.

To the Editor: Parchure et al1 have recently reported that azithromycin therapy for 5 weeks significantly improved flow-mediated dilation (FMD) of the brachial artery in Chlamydia pneumoniae seropositive men suffering from coronary heart disease. Our group has recently reported that roxithromycin treatment for 1 month significantly improved the walking distance and reduced the number of revascularization procedures in C pneumoniae seropositive men suffering from peripheral arterial occlusive disease.2 In this prospective, randomized, double-blind, placebo-controlled study, we also investigated the effect of roxithromycin on the endothelial function. Determination of radial artery hemodynamics was performed at study entry, at the end of 1-month treatment with either roxithromycin or placebo, and at the 6-month follow-up. Radial artery diameter was measured using a high-precision A-mode echo-tracking device (NIUS 02, Asulab) to determine FMD and glyceryl trinitrate-induced dilation, which was 10.9±4.2% (mean ±1 SD). At baseline, no FMD of the radial artery could be detected in 6 of 20 patients in the placebo group and in 9 of 20 patients in the roxithromycin group. …

Gender dependence of serum soluble Klotho in acromegaly

In acromegaly, disease activity is biochemically assessed by growth hormone (GH) and insulin‐like growth factor‐1 (IGF‐1) levels. However, they are often discrepant, as several factors including gender influence their relationship. We recently found excessively high serum levels of soluble Klotho (sKl) in acromegalic patients, which depended on GH to a comparable extent as IGF‐1. To further elucidate the relationship between GH and sKl, we examined the effect of gender on sKl in patients with untreated acromegaly.