Improved differential diagnosis of hypercalcemia by hypocalcemic stimulation of parathyroid hormone secretion

In vitro experiments have indicated that in primary hyperparathyroidism (HPT) the hyperfunctioning glands have a set point error, i.e., they are not autonomous but regulate serum calcium around a hypercalcémie value. In contrast, parathyroid function is suppressed in patients with hypercalcemia of causes other than HPT (e.g., malignancy or sarcoidosis). The basal measurements of serum parathyroid hormone (PTH) levels, however, cannot, alone, separate with precision HPT from other causes of hypercalcemia.Lowering of calcium, in order to stimulate secretion of PTH, was, therefore, achieved by either infusion of Na₂ EDTA (24 mg/kg per hr) for 1 hour, or intramuscular injection of 100 IU salmon calcitonin. All 35 patients with primary HPT displayed a significant increase of serum PTH concentrations, evaluated by a midregion/intact hormone assay, during the EDTA infusion, which lowered plasma ionized calcium by an average of 0.16 mmol/l. The injection with calcitonin reduced the calcium concentrations by 0.10 mmol/l after 8 hours and caused a rise in PTH in 80% of HPT patients. With both tests, the secretory response by PTH to the reduction of plasma calcium was generally evident while the patients were still hypercalcemic. In 32 patients with other causes for hypercalcemia, primarily malignancy and sarcoidosis, similar reductions of plasma ionized calcium were obtained. In contrast to the HPT patients, none of them raised their serum PTH values during the test. Thus, stimulation of PTH secretion by a moderate reduction of serum calcium considerably improves the differential diagnosis of hypercalcemia since a significant secretory response appears to be exclusive for HPT.

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Resumen Experimentos in vitro han señalado que en el hiperparatiroidismo primario (HPT) las glándulas hiperfuncionantes tienen un error en su set point, o sea que no son autónomas sino que regulan el calcio sérico alrededor de un valor hipercalcémico. Por el contrario, la función paratiroidea es suprimida en pacientes con hipercalcemia de causa diferente de HPT (e.g., neoplasias malignas o sarcoidosis). Las mediciones basales de los nivelés séricos de hormona paratiroidea (PTH) de por sí no son capaces de diferenciar con precision entre el HPT y la hipercalcemia de otras causas.La disminución del nivel de calcio sérico, con el objeto de estimular secreciones de PTH, fue lograda con la infusión de Na₂ EDTA (24 mg/Kg por hora) por 1 hora o la inyección i.m. de 100 UI de calcitonina de salmón.Todos los 35 pacientes con HPT primario exhibieron un aumento significativo de las concentraciones séricas de PTH, determinadas mediante la medición de la fraction media/intacta de PTH en el curso de la infusion de EDTA, la cual redujo el nivel plasmático de calcio ionizado en un promedio de 0.16 mmol/l. La inyección de calcitonina redujo las concentraciones de sérico en 0.10 mmol/l a las 8 horas y resultó en un aumento de la PTH en 80% de los pacientes con HPT. Con ambas pruebas la respuesta secretoria de PTH a la reducción del calcio plasmático generalmente apareció evidente aún mientras los pacientes se hallaban hipercalcémicos.En 32 pacientes con hipercalcemia de causa diferente, se lograron reducciones similares de la concentration plasmática del calcio ionizado. Por el contrario de lo observado en los patientes con HPT, ninguno demostró elevatión de sus niveles séricos de PTH en el curso de la prueba. Por consiguiente, el estímulo de la secretión de PTH mediante la reductión moderada de calcio sérico incrementa considerablemente la (ie501-01)acidad de establecer el diagnóstico diferencial de la hipercalcemia, puesto que una significativa respuesta secretoria parece ser caracteristíca exclusiva del HPT.

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Résumé L'expérimentation in vitro a démontré que dans l'hyperparathyroïdisme (HPT), les glandes hyperactives ont un point mort erroné, c'est-à-dire qu'elles ne sont pas autonomes mais règlent la calcémie autour d'une valeur de référence déjà hypercalcémique. En revanche, la fonction parathyroîde est déprimée chez le patient dont l'hypercalcémie est due à une cause autre que l'HPT (cancer ou sarcoïdose par exemple). La mesure des niveaux de base de la parathormone (PTH), cependant, ne permet pas de distinguer l'hypercalcémie de l'HPT des autres causes d'hypercalcémie avec précision.Dans le but de stimuler la sécrétion de PTH, la calcémie était abaissée soit en perfusant les patients avec une solution de Na₂ EDTA (24 mg/Kg) pendant une heure, soit par une injection intramusculaire de 100 U de calcitonine de saumon.Trente-cinq patients ayant un HPT primitif présentaient une augmentation significative des concentrations en PTH sérique, évaluée par l'étude immunologique de la portion moyenne intacte, pendant la perfusion d'EDTA. La portion de calcium plasmatique ionisée a été abaissée en moyenne de 0.16 mmol/l. L'injection de calcitonine a réduit la concentration en calcium par 0.10 mmol/l après huit heures et a provoqué une augmentation en PTH chez 80% des patients à HPT. Quel que soit le test, la réponse de PTH à la réduction de calcium plasmatique était généralement évidente alors que le patient était toujours hypercalcémique.Chez 32 autres patients ayant pour cause d'hypercalcémie cancer ou sarcoïdose, des réductions similaires en calcium plasmatique ionisé ont été obtenues. Aucun malade, contrairement aux patients HPT, n'a vu son niveau de PTH monter pendant le test. Ainsi, la stimulation de sécrétion de PTH par une réduction modérée de calcium sérique améliore considérablement le diagnostic différentiel des hypercalcémies puisque la réponse sécrétoire significative paraît être le fait exclusif des HPT.

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Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.

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Supported by the Swedish Medical Research Council.     

Optic disc morphometry in chronic primary open-angle glaucoma

Four hundred twenty-seven optic discs of 233 unselected patients suffering from chronic primary open-angle glaucoma were morphometrically evaluated and compared with the optic nerve heads of 253 unselected normal subjects. Only one randomly chosen eye per patient was taken into consideration. We found that glaucoma leads to a change in the characteristic configuration of the neuroretinal rim that in normal eyes is significantly (P < 0.001) largest at the lower disc pole, smaller at the upper and nasal disc side, and smallest in the temporal disc region. Based on this information, significant (P < 0.001) morphometric differences between early glaucomatous and normal discs are: (a) the neuroretinal rim area in the lower temporal disc sector is smaller than in the upper temporal disc sector; the smallest rim width is outside the horizontal temporal disc sector (pathognomonic); the quotient of horizontal to vertical c/d ratio is lowered; and (d) the lower temporal, upper temporal, and total rim area are decreased. No significant difference in overall optic disc size and form exists between normal and glaucomatous eyes. Smaller optic nerve heads are not more susceptible to glaucoma.Parts of this study have been presented at the 85th meeting of the German Ophthalmic Society held in Heidelberg, 20–23 September, 1987. This study was supported by Deutsche Forschungsgemeinschaft, grant DFG Jo/155/2-1, Ernst-Muck Foundation, and Meyer-Schwarting-Foundation     

Can a clinician predict the technical equipment a patient will need during intensive care unit treatment? An approach to standardize and redesign the intensive care unit workstation

The technical equipment of today's intensive care unit (ICU) workstation has been characterized by a gradual, incremental accumulation of individual devices, whose presence is dictated by patient needs. These devices usually present differently designed controls, operate under different alarm philosophies, and cannot communicate with each other. By contrast, ICU workstations could be equipped permanently and in a standardized manner with electronically linked modules if the attending physicians could reliably predict, at the time of admission, the patient's equipment needs. Over a period of 3 1/2 months, the doctors working in our 20-bed surgical ICU made 1,000 predictions concerning outcome, equipment need, duration of artificial ventilation, and duration of hospitalization for 300 recently admitted patients. The interviews were made within the first 24 hours after admission. The doctors being interviewed were usually (i.e., in over 90% of cases) unfamiliar with the patient. Information concerning the patient's general state of health, special pre-ICU events, and complications was offered to the interviewed clinician because this information represents standard admission data. It was found that the equipment need (represented by two different setups, high tech and low tech) could be predicted most reliably (96.4% correct predictions) compared with a prediction on outcome of ICU treatment (94.5%), on duration of artificial ventilation (75.4%), and on duration of stay (43.4%). There was no significant (p>0.05) difference in the reliability of predictions between residents and consultants. Factors influencing the postoperative equipment need varied with surgical specialty. The general state of health, as indicated by the ASA classification (p<0.001), and the specific intervention (all multiple-valve replacements needed the high-level equipment standard) appeared to be most important in cardiac surgery, while a state of septicemia was important in general surgery (p<0.001). Our findings suggest that ICU workstations may be standardized into at least two types.     

The retinal nerve fiber layer in normal and glaucomatous eyes. II. Correlations

The retinal nerve fiber layer is different in normal and glaucomatous eyes. We correlated semi-quantitative data of the retinal nerve fiber layer of 398 eyes with chronic primary open-angle glaucoma and of 234 normal eyes with the intra- and parapapillary morphometric signs and with the perimetric indices. The three parameters "sequence of the fundus sectors concerning the best visibility of the retinal nerve fiber bundles", "visibility of the nerve fiber bundles", and "localized defects" were significantly (p less than 0.001) correlated to 1) area of the neuroretinal rim as a whole and in four different optic disc sectors, 2) neuroretinal rim width determined every 30 degrees, 3) optic cup area, diameters and form, 4) horizontal and vertical cup/disc ratios and the quotient of the horizontal to vertical cup/disc ratio, 5) area and width of zone "Alpha", zone "Beta", and the total parapapillary chorio-retinal atrophy, 6) diameter of the retinal vessels, 7) grade of a "tesselated fundus", and 8) the visual field loss. If only the inferior temporal and the superior temporal sectors were considered, the retinal nerve fiber bundles were less visible in that sector with the largest notch in the neuroretinal rim, the smaller neuroretinal rim area and width, the thinner retinal vessels, and the larger zone "Alpha", zone "Beta", and total parapapillary chorio-retinal atrophy. The glaucomatous changes in the retinal nerve fiber layer are correlated in time and location with the intra- and parapapillary and the perimetric alterations. Evaluation of the retinal nerve fiber layer is a useful method to detect a glaucomatous optic nerve damage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.

Connective tissue growth factor (CTGF) is reported to be a target gene of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) in vitro. Its physiological role in angiogenesis and skeletogenesis during mouse development has been described recently. Here, we have mapped expression of CTGF mRNA during mouse heart development, postnatal adult life, and after experimental myocardial infarction. Furthermore, we investigated the relationship between CTGF and the BMP/TGFbeta signaling pathway in particular during heart development in mutant mice. Postnatally, CTGF expression in the heart became restricted to the atrium. Strikingly, 1 week after myocardial infarction, when myocytes have disappeared from the infarct zone, CTGF and TGFbeta expression as well as activated forms of TGFbeta but not BMP, Smad effector proteins are colocalized exclusively in the fibroblasts of the scar tissue, suggesting possible cooperation between CTGF and TGFbeta during the pathological fibrotic response.     

A controlled family history study of bulimia

Using the family history method, we assessed the morbid risk for psychiatric disorders in the first-degree relatives of 69 probands with bulimia, 24 probands with major depression, and 28 nonpsychiatric control probands. The morbid risk for major affective disorder among the first-degree relatives of the bulimic probands was 32%, significantly greater than that found in the nonpsychiatric control probands. The rate of familial major affective disorder was significantly greater in bulimic probands who had a history of major affective disorder themselves than in bulimic probands without such a history - but the latter group, in turn, displayed significantly higher rates than the nonpsychiatric control probands. Eating disorders were slightly, but not significantly, more prevalent in the families of bulimic probands than nonpsychiatric control probands. We present two alternative hypotheses which might explain these findings.     

Improvement in histological diagnosis of primary hyperparathyroidism with a monoclonal antiparathyroid antibody

The monoclonal antiparathyroid antibody E11 reacts with a glycoprotein of high molecular weight, which acts as a calcium receptor on the surface of parathyroid cells and mediates calcium regulation of parathyroid hormone (PTH) release. Reduced expression of the calcium receptor has been implicated as a cause of the defect in PTH regulation in the pathological parathyroid parenchyma of patients with hyperparathyroidism (HPT). The present study evaluated the efficacy of immunostainings with the E11 antibody in comparison with routine histopathological methods including staining by the oil red O technique for histological discrimination between normal and pathological parathyroid glands. Parathyroid tissue from euparathyroid individuals invariably presented intense and homogeneous surface staining, with the antibody on virtually all chief cells, while the pathological glands from patients with HPT consistently showed heterogeneous and reduced immunostaining. Even minimally enlarged pathological glands from individuals with mild hypercalcemia and the normal-sized glands associated with adenomas displayed parathyroid chief cells with reduced antibody reactivity. The monoclonal antiparathyroid antibody should constitute a useful tool in parathyroid histopathology not only by its ability to identify the parathyroid tissue, but also by directly demonstrating the functionally normal and abnormal cells within the parathyroid tissue.     

Genotyping hepatitis C virus by heteroduplex mobility analysis using temperature gradient capillary electrophoresis

The genotype of the infecting hepatitis C virus (HCV) helps determine the patient's prognosis and the duration of treatment. Heteroduplex mobility analysis (HMA) is a rapid, inexpensive method for genotyping of HCV that does not require sequencing. We developed an HMA that uses temperature gradient capillary electrophoresis (TGCE) to differentiate HCV genotypes. A 56-bp region of the HCV 5' untranslated region (UTR) that was conserved within a genotype yet whose sequence differed between genotypes was amplified for HMA-TGCE analysis. HCV amplicons of types 1, 2a, 2b, 3a, 4, and 6a were hybridized in pairs and analyzed by TGCE. Amplicons hybridized to the same subtype yielded one homoduplex peak, while hybridization of different subtypes resulted in heteroduplexes and generated multiple TGCE peaks. Heteroduplexes contain thermodynamically unstable nucleotide mismatches that reduced their TGCE mobilities compared to those of homoduplexes. Three HCV subtypes (subtypes 1a, 3a, and 4) generated unique peak patterns when they were combined with each genotype analyzed and were chosen as the reference genotypes. A blinded study with 200 HCV-infected samples was 97% accurate compared to genotyping by 5' UTR sequence analysis. The majority of discordant results were unexpected sequence variants; however, five of nine sequence variants were correctly genotyped. The assay also detected and correctly genotyped mixed HCV infections. Compared to conventional HMA, TGCE improves the resolution, with better separation of heteroduplexes and homoduplexes. All common HCV genotypes can be detected and differentiated by this HMA-TGCE assay.     

Serum lipids and lipoproteins in relation to endogenous and exogenous female sex steroids and age. The Women's Health in the Lund Area (WHILA) study

BACKGROUND: Different studies have presented conflicting results concerning the effect of menopause on lipid levels. AIMS: To describe the serum lipid profile and the prevalence of hyperlipidemia in women aged 50-60 and the perceived relation to endogenous and exogenous hormones and age. METHODS: Out of a total population of 10,766 women aged 50-59 years, 6908 (64%) participated in a health assessment program, including a lipid profile evaluation. The women were grouped according to hormonal status into pre-menopausal (PM), post-menopausal without hormone replacement therapy (PM0) (HRT) and post-menopausal with hormone replacement therapy (PMT). Age groups used were 50-54, 55-59 and >60 years. RESULTS: Serum cholesterol and triglycerides increased significantly by age in PM0 (P < 0.0001) and triglycerides also in PMT (P < 0.0001). Serum high-density lipoprotein cholesterol (HDL) levels decreased significantly by age in PMT (P = 0.002) and low-density lipoprotein cholesterol (LDL) increased in PM0 (P < 0.0001) and PMT (P = 0.007). The co-prevalence of levels of cholesterol >7 and triglycerides >2 mmol/l decreased by age in PM, but increased by age in PM0 and PMT. The prevalence of high-risk lipid levels and the prevalence of coexisting additional two metabolic risk factors were higher in the PM0 compared to the PMT group. The prevalence of serum triglycerides >1.5 and serum cholesterol >5 mmol/l were increasing by age in each of the hormonal groups. CONCLUSIONS: These data suggest that loss of endogenous sex steroids contribute substantially to an increased atherogenic lipid profile. Hormone replacement therapy may partly reverse these differences.