Unique skin changes in a case of Albright hereditary osteodystrophy caused by a rare GNAS1 mutation.

Albright hereditary osteodystrophy (AHO) is a syndrome of short stature, obesity, brachydactyly and subcutaneous calcifications with pseudohypoparathyroidism (PHP; leading to hypocalcaemia, hyperphosphataemia and elevated levels of parathyroid hormone, PTH). It was first described over 60 years ago. Since then, much has been learned about the aetiology of AHO which has been shown to be caused by heterozygous loss-of-function mutations within the GNAS1 gene. GNAS1 is subject to imprinting leading to phenotypic heterogeneity within kindreds with one mutation. Patients with AHO often present with symptoms of hypocalcaemia and/or with subcutaneous calcifications. The latter is thought to be the typical skin abnormality in AHO. We describe a family with AHO and hormone resistance (PHP type Ia) resulting from a rare mutation in GNAS1. The proband presented with small subcutaneous calcifications in the helix of the right ear and concentrated in a sharply demarcated zone of subcutaneous and dermal hypoplasia. This abnormality has so far not been described in patients with AHO. We speculate on the mechanism of dermal hypoplasia and resistance to PTH and suggest that subcutanous or dermal hypoplasia might be another feature which can be present in patients with AHO.

Predicting mortality of psychogeriatric patients: a simple prognostic frailty risk score.

BACKGROUND AND AIMS: Frailty and mortality in psychogeriatric patients are hard to predict but important in counselling and therapeutic decision making. We have therefore developed a simple frailty risk score to predict mortality this population. STUDY DESIGN: Prospective observational study including 401 community dwelling psychogeriatric patients (249 women; mean (SD) age 78.0 (6.5) years), who had been referred to a multidisciplinary diagnostic observation centre. We used Cox proportional hazards regression models to identify and select baseline characteristics for the development and validation of a risk score for the prediction of 3 year mortality. RESULTS: A total of 116 subjects died during follow-up (median follow-up duration of 26 months). Baseline characteristics associated with mortality were: age (hazard ratio (HR) 1.44, 95% confidence interval (CI)1.02 to 2.04), male sex (HR 2.93, 95% CI 1.89 to 4.59), living alone (HR 1.53, 95% CI 0.99 to 2.38), body mass index (BMI) <18.5 kg/m(2) (HR 4.09, 95% CI 2.06 to 8.14), cardiovascular disease (HR 1.42, 95% CI 0.94 to 2.15), elderly mobility score <20 (HR 1.92, 95% CI 1.24 to 2.98), number of medicines > or =2 (HR 2.28, 95% CI 1.21 to 4.31), and impaired motor (HR 1.47, 95% CI 0.93 to 2.32) and process skills (HR 1.92, 95% CI 1.12 to 2.98) in activities of daily living. These predictors were translated into an easy-to-use frailty risk score and patients were stratified into very good (<45 points), good (45-50) moderate (51-55), poor (56-61) and very poor (>61) prognosis groups. Three year mortality rates across these groups were 8.0%, 15.9%, 25.9%, 41.5%, and 68.8%, respectively (p<0.001). The area under the receiver operating characteristic curve (AUC) of the risk score was 0.78 (95% CI 0.73 to 0.82), indicating good discriminative performance. CONCLUSIONS: We developed and validated a risk score for the prediction of 3 year mortality. This risk score can be used to stratify patients into different risk categories, thereby informing patient counselling and tailored diagnostic and therapeutic decisions in clinical practice.

Progressive vertebral deformities despite unchanged bone mineral density in patients with sarcoidosis: a 4-year follow-up study.

UNLABELLED: To evaluate the incidence of new and/or progressive vertebral deformities and changes in bone mineral density, we re-examined 66 patients with sarcoidosis after a follow-up period of four years. In 17 subjects (26%) new and/or progressive vertebral deformities were found, though BMD did not change significantly. INTRODUCTION: Previous studies from our group have shown that morphometric vertebral deformities suggestive of fractures can be found in 20% of patients with sarcoidosis, despite a normal bone mineral density (BMD). The aim of this study was to determine the incidence of new and/or progressive vertebral deformities and the evolution of BMD during the course of this disease. METHODS: BMD of the hip (DXA) and vertebral fracture assessment (VFA) with lateral single energy densitometry was performed at baseline and after 45 months in 66 patients with sarcoidosis. Potential predictors of new/ progressive vertebral deformities were assessed using logistic regression analysis. RESULTS: The BMD of the total group was unchanged after follow-up. The prevalence of vertebral deformities increased from 20 to 32% (p < 0.05); in 17 subjects (26%) new or progressive vertebral deformities were diagnosed. A lower T-score of the femoral neck [(OR = 2.5 (CI: 1.0-5.9), p < 0.05)] and mother with a hip fracture [(OR = 14.1 (CI: 1.4-142.6), p < 0.05)] were independent predictors of new/progressive deformities. CONCLUSIONS: In subjects with sarcoidosis the number of vertebral deformities increases in the course of this disease, despite unchanged BMD. The combination of low normal BMD and family history of fragility fractures confers an increased risk of the incidence of these deformities.

Intracranial multiple midline germinomas: is histological verification crucial for therapy?

In this report we present two patients with intracranial multiple midline tumours in the suprasellar region and pineal gland. We postulate that in a patient with multiple midline tumours and normal values of the tumour markers human chorionic gonadotropin and alpha-fetoprotein in serum and cerebrospinal fluid, the only possible diagnosis is a germinoma. In such a situation no histological confirmation is required to start low-dose radiotherapy.

[Late-onset hypogonadism in men: uncertain disease entity and reservations regarding treatment with testosterone]. / Laat hypogonadisme ('late-onset hypogonadism') bij mannen: onzekere ziekte-entiteit en reserves bij de behandeling met testosteron.

Late-onset hypogonadism (LOH) is defined as insufficient testosterone levels in combination with associated psychological, somatovegetative and sexual symptoms in elderly men. Because the symptomatology of LOH is not specific, it is unclear whether LOH can be considered a clinically relevant entity. At this time, treatment of LOH with testosterone has been shown to have favourable effects on body composition only. The risks of treatment with testosterone appear to be minimal when absolute contraindications (prostate cancer) are observed, although long-term studies on the safety of testosterone therapy are lacking. Restraint in the diagnosis and treatment of LOH is therefore warranted.

Health-related quality of life of diabetic foot ulcer patients and their caregivers.

AIMS/HYPOTHESIS: The effect of a foot ulcer on health-related quality of life (HRQoL) of patients with diabetes mellitus and their caregivers is unclear, and was therefore evaluated prospectively in this multicentre study. METHODS: HRQoL according to the 36-item health-related quality of life questionnaire (SF-36) of 294 patients (ulcer duration > or = 4 weeks) and 153 caregivers was analysed at baseline (time-point zero [T0]), once the ulcer was healed or after 20 weeks (time-point 1 [T1]), and 3 months later (time-point 2 [T2]). Patients with severe ischaemia were excluded. RESULTS: The mean age of the patients was 60 years, 72% were male, and time since diagnosis of diabetes was 17 years. Patients reported a low HRQoL on all SF-36 subscales. At T1, HRQoL scores in physical and social functioning were higher in patients with a healed vs a non-healed ulcer (p<0.05). At T2, these differences were larger, with higher scores for physical and social functioning, role physical and the physical summary score (all p<0.05). Within-group analysis revealed that HRQoL improved in different subscales in patients with a healed ulcer and worsened in patients with a persistent ulcer from T0 to T2 (all p<0.05). The caregivers of patients with a persisting ulcer had more emotional difficulties at T2. CONCLUSIONS/INTERPRETATION: Diabetic patients with a healed foot ulcer had a higher HRQoL than patients with a persisting ulcer. Healing of a foot ulcer resulted in a marked improvement of several SF-36 subscales 3 months after healing (from T0 to T2). HRQoL declined progressively when the ulcer did not heal. A diabetic foot ulcer appeared to be a large emotional burden on the patients' caregivers, as well.

[Hormonal and metabolic causes of muscular weakness and the increased risk of fractures in elderly people]. / Hormonale en metabole oorzaken van spierzwakte en fractuurrisico bij ouderen

The increased risk of fractures in elderly people is due not only to a decrease in bone mass and bone quality but also to an increased risk of falling. The increased risk of falling is partly a consequence of muscular weakness caused by a decrease in both muscular mass and strength (sarcopenia), in which the hormonal changes that are typical of aging play a pivotal role, as well as of malnutrition, in particular a deficiency of protein, amino acids, calcium and vitamin D. Measures that limit the risk of falling and fractures due to muscular weakness consist mainly of adequate nutrition, extra calcium and vitamin D, reduction of the factors that increase the risk of falling, weight-bearing exercise to strengthen the muscles and the use of hip protectors. Hormonal suppletion has not yet been shown to have a favourable effect, whereas the disadvantages appear to be substantial.

What can we learn from undergraduate medical education?

As in undergraduate medical training, postgraduate training of medical specialists requires clear learning objectives, a structured learning process, a challenging learning environment, valid and reliable assessment procedures, and an effective learning organization. One may wonder, however, whether such a structured approach is more theory than practice in the majority, if not all, teaching hospitals involved in graduate medical education.

Correlation of serum osteocalcin fractions with bone mineral density in women during the first 10 years after menopause.

Serum immunoreactive osteocalcin (irOC) consists of two fractions that differ from each other by their affinity for hydroxyapatite. The high and low affinity fractions are referred to as irOCbound and irOCfree, respectively. To evaluate whether these fractions are determinants for different characteristics of bone or bone metabolism, we have performed a cross-sectional study among 212 apparently healthy women between 20 and 90 years of age. Bone mineral density (BMD) was determined at the lumbar spine, and the right femur neck, trochanter, and Ward's triangle using dual-energy X-ray absorptiometry (DXA). Biochemical markers for bone formation and resorption were determined in serum and in urine. After classification according to menopausal age, an inverse correlation was found in the 1-10 years postmenopausal women between irOCfree and BMD, notably of the Ward's triangle and femur neck. It is concluded that in 1-10 years postmenopausal women, irOCfree is an independent marker for BMD, but that in other age groups the association is less clear or is absent.

Impaired arterial but not venous responsiveness to nitroglycerin in non-insulin-dependent diabetes mellitus.

In earlier studies, the response of the arterioles to nitroglycerin (NTG) was found to be impaired in non-insulin-dependent diabetes mellitus (NIDDM) patients. NTG has major therapeutic effects in reducing cardiac after- and preload. Thus, the vasorelaxing efficacy of a therapeutic dose of 0-4 mg of NTG sublingually (s.l.) was evaluated in the conduit femoral artery and large veins of normotensive, normoalbuminuric NIDDM patients. After NTG, the increase in the femoral artery diameter was significantly lower in the NIDDM patients than in control subjects: 0.49 (0.29-0.79) vs. 0.75 (0.47-1.00) mm respectively (median, interquartile ranges). NTG resulted in an increase of pulse wave transit time in the aorta in control subjects but not in the NIDDM patients: from 64 (60-73) to 70 (63-80) ms, P < 0.02; and from 62 (53-69) to 66 (51-72) ms, P = NS, respectively. The reduction in the venous tone of the forearm to NTG was similar in both groups. These results suggest that the response to NTG is impaired in the arterial system but not in the venous system in well-regulated NIDDM patients without diabetic complications.

Comparison of different insulin regimens in elderly patients with NIDDM.

OBJECTIVE: To compare the metabolic effects of three different frequently used regimens of insulin administration on blood glucose control and serum lipids, and the costs associated with this treatment, in subjects with NIDDM, who were poorly controlled with oral antihyperglycemic agents. RESEARCH DESIGN AND METHODS: We studied 95 elderly patients with NIDDM (age 68 +/- 9 years, BMI 26.0 +/- 4.6 kg/m2, and median time since diagnosis of diabetes 9 years [range 1-37]; 37 men, 58 women), who were poorly controlled, despite diet and maximal doses of oral antihyperglycemic agents. Three insulin administration regimens were compared during a 6-month period: patients were randomized for treatment with a two-injection scheme (regimen A) or a combination of glibenclamide with one injection of NPH insulin, administered either at bedtime (regimen B) or before breakfast (regimen C), and insulin treatment was mainly instituted in an outpatient setting. RESULTS: After 6 months of insulin treatment, fasting blood glucose of the total patient population had decreased from an average of 14.1 +/- 2.2 to 8.3 +/- 2.0 mmol/L (P < 0.001), and HbA1c fell from 11.0 +/- 1.3 to 8.3 +/- 1.2% (P < 0.001); 34 patients reached HbA1c levels below 8.0%, 25 of them even below 7.5%. With two insulin injections daily, HbA1c decreased from 11.2 +/- 1.3 to 8.2 +/- 1.2%, while during combined treatment, HbA1c fell from 10.5 +/- 1.2 to 8.1 +/- 1.1% (regimen B) and from 11.1 +/- 1.3 to 8.5 +/- 1.1% (regimen C). Comparable improvement of the other measures of glycemic control, lipids and lipoproteins, was observed in the different treatment regimens. Body weight increase was moderate (mean +/- 4.0 kg) and similar in all patient groups. One-third of patients starting with one insulin injection daily needed a second injection to control glycemia. One episode of severe hypoglycemia was observed. Combined insulin-sulfonylurea treatment was almost 20% more expensive than twice-daily administration of insulin alone. CONCLUSIONS: Insulin treatment can safely be instituted in elderly patients with NIDDM. However, it is difficult to obtain optimal glycemic control. Insulin has moderate beneficial effects on serum lipoproteins. Although on the basis of glycemic control and weight gain, no preference for any treatment regimen can be discerned, twice-daily insulin administration is the most simple and cost-effective regimen.

Miglitol (Bay m 1099) has no extraintestinal effects on glucose control in healthy volunteers.

In this double-blind, cross-over, placebo-controlled, randomized study, possible extraintestinal effects of miglitol, an absorbable alpha-glucosidase inhibitor, were investigated. Sixteen healthy male volunteers underwent two 75 g oral glucose tolerance tests with concomitant administration of miglitol or placebo. Peak and post-peak areas under the curve values for blood glucose, serum insulin and serum C-peptide after miglitol were not different from those found after placebo. The post-peak AUC-ratio (AUC (peak, 180 min) on miglitol/AUC (peak, 180 min) on placebo) was for glucose 1.15 (CI 0.94-1.40, P = 0.16), for insulin 1.12 (CI 0.95-1.33, P = 0.17) and for C-peptide 0.98 (CI 0.81-1.18, P = 0.82). It is concluded that miglitol exerts no clinically relevant extraintestinal effects on glucose control.

Subclinical thyroid disease.

Thyroid disease can roughly be divided into functional and anatomical disorders. Subclinical disease is by definition not accompanied by symptoms or signs and usually goes unrecognized for the bearer (and the observer). In this communication an overview will be given of existing literature and some own results concerning subclinical hypothyroidism, subclinical thyrotoxicosis and thyroid incidentalomas. Apart from definitions, data on prevalence, clinical effects, prognostic significance and the need for and response to therapy will be discussed.

The effect of GHRH on TSH release in rats in vivo and in vitro.

In man, GHRH has been shown to potentiate the TSH-releasing activity of TRH. To study the way by which GHRH affects TRH-stimulated TSH release, we examined the effect of GHRH (1-29)NH2 on basal and stimulated TSH secretion in intact male rats and superfused dispersed rat pituitary cells. In the intact rats, GHRH(1-29)NH2 potentiated TRH-stimulated TSH release in the evening, but potentiation was not observed in the morning and in dispersed pituitary cells. Basal TSH levels were not changed by GHRH(1-29)NH2. It is concluded that GHRH(1-29)NH2 potentiates the TSH-releasing activity of TRH in the evening in rats possibly through suprahypophyseal disinhibition.

Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism.

OBJECTIVE: There is recent evidence that both exogenous and endogenous subclinical thyrotoxicoses are associated with decreased bone mineral density. Scanty information is available on bone metabolism in these conditions when euthyroidism is restored. We evaluated the effect of anti-thyroid drug treatment on bone metabolism in endogenous subclinical hyperthyroidism. DESIGN: Prospective follow-up study over 2 years during treatment with methimazole, with an untreated control group. SUBJECTS: Sixteen post-menopausal women with endogenous subclinical hyperthyroidism associated with multinodular goitre, eight of whom were treated with methimazole. MEASUREMENTS: Serum concentrations of free T4, total T3, TSH, osteocalcin, urinary excretion of hydroxyproline and forearm bone mineral density were measured at regular intervals. RESULTS: Significant changes in serum osteocalcin concentration or urinary hydroxyproline excretion were not observed in either group. Distal, but not proximal, forearm bone mineral density, expressed as a percentage of the base-line value, was significantly (P < 0.05) higher in the treated than in the untreated subjects in the second year of treatment. CONCLUSION: Treatment with methimazole in post-menopausal women with endogenous subclinical hyperthyroidism associated with multinodular goitre can prevent excessive loss of bone, at least in the distal forearm.

The effects of 7-hour local hyperglycaemia on forearm macro and microcirculatory blood flow and vascular reactivity in healthy man.

Animal studies suggest that hyperglycaemia directly affects local blood flow and vascular reactivity. We studied the effects of 7 h of local forearm hyperglycaemia, on forearm (muscle) and skin microcirculatory blood flow in 12 healthy men. Furthermore, the effects of this local hyperglycaemia on forearm vasoreactivity to noradrenaline were studied. Using the perfused forearm technique, a local hyperglycaemia of approximately 16 mmol/l was induced by continuous intraarterial infusion of 5% glucose. All subjects received both glucose and placebo (0.9% NaCl) infusions on two different occasions, in random order and blinded for the subjects. Forearm (muscle) blood flow and vascular reactivity to noradrenaline were measured using venous occlusion plethysmography. Skin microcirculatory blood flow was evaluated using intravital capillary microscopy (nutritive blood flow) and laser-Doppler fluxmetry (thermoregulatory blood flow). Measurements were performed at baseline, after 4 h, and after 7 h of intraarterial glucose or placebo infusion. During local glucose infusion there was a slight increase in the levels of insulin, C-peptide, systemic glucose, and blood pressure, compared to the placebo experiments. No differences were observed in forearm blood flow and laser-Doppler flux ratio (infused: contralateral arm), as well as in capillary blood cell velocity between glucose and placebo experiments. Noradrenaline produced similar reductions in forearm blood flow ratio during glucose and placebo experiments. We conclude that in contrast to animal studies, local hyperglycaemia (approximately 16 mmol/l) for 7 h does not affect forearm macro and microcirculatory blood flow or vascular reactivity to noradrenaline in man.