Prevalence of glucose intolerance in primary hyperparathyroidism and the benefit of parathyroidectomy.

BACKGROUND: Increased prevalence of diabetes mellitus (DM) in primary hyperparathyroidism (PHPT) is established, but not glucose intolerance (GI), nor benefit from parathyroidectomy on GI. We determined these during management of a continuous series of patients with PHPT routinely followed after surgery. PATIENTS AND METHODS: WHO criteria classified 75 g oral glucose tolerance tests (OGTT) in 51/54 consecutively proven PHPT patients, into normal glucose tolerance (NGT), DM, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG); GI was derived by adding those with DM and IGT/IFG. OGTT were repeated after parathyroidectomy (mean follow up 2.4 +/- SD 1.6 years). Paired student t tests were used to compare fasting and 2-h plasma glucose (PG). RESULTS: At presentation 32/54 patients (59%) had NGT, 10 IGT/IFG (19%) and 12 type 2 DM (22%), nine newly diagnosed. Before parathyroidectomy 17/35 patients had NGT (49%), 18 GI (51%), 12 DM (34%) and 6 IGT/IFG (17%). Five out of six patients with IGT/IFG had NGT, one with NGT developed IGT. At completion 23 patients (66%) had NGT, 12 GI (34%), 4 IGT/IFG (11%) and 8 DM (23%). After parathyroidectomy fasting and 2-h. PG fell in 30/34 normocalcaemic patients not on hypoglycaemic agents, 5.6 +/- 1.0 to 5.4 +/- 0.8 mmol/l, 7.2 +/- 3.0 to 6.3 +/- 3.1 mmol/l (p < 0.05, p < 0.01). CONCLUSIONS: 1. At presentation with PHPT, OGTT commonly identifies Type 2 DM and GI.2. After successful parathyroidectomy fasting and 2-h. PG fall significantly (p < 0.05, p < 0.01). DM and IGT/IFG often ameliorates to IGT or NGT, persistently.

Comparative pepstatin inhibition studies on individual human pepsins and pepsinogens 1,3 and 5(gastricsin) and pig pepsin A.

Human gastric juice contains 3 major proteolytic components (pepsins1,3 and 5 or gastricsin). Pepsin 1 is increased in peptic ulcer and it's properties are relatively poorly understood. Studies with pepstatin the highly specific aspartic-protease inhibitor have therefore been carried out on individual active and proenzymes to assess any enzymic similarities. Human pepsin 1 was inhibited with high affinity similar to pepsin 3, whereas pepsin 5(gastricsin) was at least 40 times less sensitive. Inhibition of human pepsinogens 1,3 and 5 and pig pepsinogen A showed similar trends to the active enzymes. Studies using Sephadex gel filtration showed that pepstatin does not bind to pepsinogens and inhibition arises from pepstatin binding the pepsins released upon activation. Pepstatin inhibition was shown to be relatively independent of pH between 1.5 and 3.8 although at higher pH inhibition was less effective. The evidence suggests that pepsin 1 is similar to pepsin 3 and pepstatin inhibits by a one to one molecular binding to the active site. The explanation for the reduced affinity of pepstatin to pepsin 5(gastricsin) needs further study by co-crystallisation X-ray analysis.

Coincident diabetes mellitus and primary hyperparathyroidism.

The prevalence of diabetes mellitus in primary hyperparathyroidism is approximately 8% and that of primary hyperparathyroidism in diabetic patients is approximately 1%. Both values are about three-fold higher than the respective expected prevalences in general populations. Patients with both disorders are over 40 years of age and 80% are female; 22% have type 1 and 78% type 2 diabetes. Primary hyperparathyroidism presents first in approximately 20% of patients, and diabetes mellitus in 40%; both disorders present together, or within 1 year, in 40%. Approximately 40% of patients with primary hyperparathyroidism have impaired glucose tolerance. Insulin resistance is present in hyperparathyroidism and probably arises from a raised intracellular free calcium concentration which, by decreasing normal insulin-stimulated glucose transport, increases the requirement for insulin: if this insulin resistance progresses, impaired glucose tolerance and diabetes mellitus would result. Parathyroidectomy has been followed by regression of diabetes and of impaired glucose tolerance in some but not all patients. Early diagnosis of the second disorder is clinically desirable when one disorder is present. Hyperparathyroid patients should therefore be screened for impaired glucose tolerance and diabetes annually, and pre-operatively. Diabetic patients should be checked for hypercalcaemia at appropriate intervals; although only 1% of them may have hyperparathyroidism, this disorder if untreated is associated with hypertension, to which diabetic patients are already prone.

Neuroleptic malignant syndrome due to olanzapine.

Neuroleptic malignant syndrome (NMS) is a rare and potentially fatal complication precipitated by the use of antipsychotic medications, most notably haloperidol. Criteria previously described include: exposure to the neuroleptic class of medications; hyperthermia; muscle rigidity; a cluster of laboratory and physical findings that may include mental status changes, autonomic instability, creatine phosphokinase elevation and leukocytosis, and exclusion of other causes for the patient's condition. A prodrome of mental status changes, autonomic instability, tremors, diaphoresis, excess salivation, and extrapyramidal signs may precede NMS. Prior reports of NMS linked to olanzapine have been in patients who had been previously treated with other neuroleptic agents or in patients who had previous episodes of NMS precipitated by other neuroleptics. Several cases included patients treated with olanzapine in addition to another neuroleptic. This report describes a case of NMS associated with olanzapine in a patient who had not previously been exposed to the neuroleptic drug class. At the time this patient presented, there were no reports in the literature of NMS associated with olanzapine alone. Treatment of NMS includes: immediate withdrawal of all neuroleptics; supportive care; fever control; management of autonomic instability (tachycardia, tachypnea, blood pressure fluctuations); and pharmacologic management with dantrolene and bromocriptine.

Glycoside primers of Psittacanthus cucullaris.

Bioassay-directed chromatographic separation of the ethyl acetate extract of the whole plant of Psittacanthus cucullaris afforded a new phenolic xyloside, ellagic acid-4-O-beta-xyloside-3,3', 4'-trimethyl ether (1) together with four known compounds, ellagic acid-4-O-beta-xyloside-3,3'-dimethyl ether (2), gallic acid, beta-sitosterol, and beta-sitosterol beta-D-glucoside. The structure of the new compound was determined by spectroscopic methods. Like other beta-D-xylosides, compounds 1 and 2 stimulated the formation of glycosaminoglycan chains when fed to the cultured Chinese hamster ovary cells.

Radio-enzymatic determination of histamine: interference by fluoride and possible activation of histamine methyl transferase.

The reproducibility of a radio-enzymatic method for determining plasma histamine was found to be affected by the anti-coagulant used for collecting blood. Recovery experiments from whole blood indicated that heparin yielded values that were more accurate than with EDTA or sodium fluoride; fluoride gave a mean value which was +41% higher than with heparin (P=0.054). Addition of fluoride to a standard calibration curve, and of increasing amounts to aliquots of 5 ng histamine also yielded higher values than in controls, up to +15% (P<0.1) and +14.1% (P=0.03) respectively. Fluoride did not affect the detecting system and was not contaminated with histamine; nor did it breakdown the methyl donor, S-adenosyl-L-methionine. It is concluded that heparin is the anti-coagulant of choice and that fluoride may activate histamine methyl transferase from pig brain. Fluoride may possibly have a biological role as an enzyme-activator and a usefulness in the therapy of mastocytosis.

Primers of glycosaminoglycan biosynthesis from Peruvian rain forest plants.

We have developed a rapid, high throughput screening assay for compounds that alter the assembly of glycosaminoglycan chains in Chinese hamster ovary cells. The assay uses autoradiography to measure the binding of newly synthesized [35S]proteoglycans and [35S]glycosaminoglycans to a positively charged membrane. Screening over 1000 extracts from a random plant collection obtained from the Amazon rain forest yielded five plants that stimulated glycosaminoglycan assembly in both wild-type cells and a mutant cell line defective in xylosyltransferase (the first committed enzyme involved in glycosaminoglycan biosynthesis). Fractionation of an extract of Maieta guianensis by silica gel and reverse-phase chromatography yielded two pure compounds with stimulatory activity. Spectroscopic analysis by NMR and mass spectrometry revealed that the active principles were xylosides of dimethylated ellagic acid. One of the compounds also contained a galloyl group at C-3 of the xylose moiety. These findings suggest that plants and other natural products may be a source of agents that can potentially alter glycosaminoglycan and proteoglycan formation in animal cells.

Automated ground-based star-pointing UV -visible spectrometer for stratospheric measurements.

A novel automated ground-based star-pointing spectrometer system has been constructed for long-term deployment in Antarctica. Similar to our earlier stellar system, a two-dimensional detector array measures the spectra of the star and the adjacent sky, so that auroral emission from the sky can be subtracted from the stellar signal. Some new features are an altitude -azimuth pointing mirror, so that the spectrometer does not move; slip rings to provide its power thereby avoiding flexing of cables and restriction of all-around viewing; and a glazed enclosure around the mirror to ensure protection from rain and snow, made from flat plates to avoid changing the focal length of the telescope. The optical system can also view sunlight scattered from the zenith sky. The system automatically points and tracks selected stars and switches to other views on command. The system is now installed at Halley in Antarctica, and some preliminary measurements of ozone from Antarctica are shown.

Prevalence of primary hyperparathyroidism in patients with diabetes mellitus.

The prevalence of previous or current primary hyperparathyroidism in 704 patients (390 male) with proven diabetes mellitus was 0.99% (7 patients, all female). One patient was known to have both disorders when the study commenced and 6 were discovered from the past history or by screening for hypercalcaemia. Diabetes was diagnosed at age 12 years or later, hyperparathyroidism from 45 years. Two patients were insulin-dependent. Diabetes preceded hyperparathyroidism in 3 patients, followed it in 2, and occurred during the same year in 2. The prevalence is significantly greater (p < 0.02 to <0.001) than that of hyperparathyroidism in general populations (0.10-0.36%). When adjusted for the age and sex distribution of the population of the Halton Health District the expected prevalence of 0.82% remains significantly greater, except for the general population with 0.36% prevalence (0.1 > p > 0.05). This increased three- to fourfold prevalence of hyperparathyroidism in diabetes arises mainly from females, in whom the prevalences at age 15 years or over and at age 45 years or over are 2.23% and 2.54%, respectively.

Intracavernous anterior cerebral artery origin with associated arteriovenous malformations: a developmental analysis: case report.

OBJECTIVE AND IMPORTANCE: This case demonstrates an unusual association between arteriovenous malformations and an intracavernous anterior cerebral artery origin. To the best of our knowledge, this relationship has not been previously described. Identification and understanding of this relationship are important in pre-embolization and surgical planning and in offering some insight into neurovascular development. CLINICAL PRESENTATION: The patient presented with severe recurring headaches and an otherwise nonfocal neurological examination. He maintained a stable neurological course throughout evaluation and therapy. INTERVENTION: The patient underwent endovascular embolization of the arteriovenous malformations without consequence. He was then scheduled for radiosurgical treatment planning. CONCLUSION: This case demonstrates an unusual neurovascular anomaly with associated arteriovenous malformations. To the best of our knowledge, this is the first reported case of such an association. An understanding of anomalous angioarchitecture and neurovascular development is essential for prudent endov ascular and surgical planning.

Plasma histamine in patients with tropical disorders and acute asthma who exhibit eosinophilia.

The mean venous plasma histamine of 14 patients with eosinophilia was 18.7 nmol/L (range 0-86.4) and significantly higher than that of 4.0 nmol/L for 29 normal subjects [range 0-10.8 (P < 0.01)]. The eosinophilia of schistosomiasis (two patients), strongyloidiasis (one patient), and asthma (four patients) was accompanied by raised plasma histamine concentrations. Normal levels occurred in onchocerciasis (four patients) and in two of three patients with non-specific eosinophilia. Plasma histamine concentrations in the tropical disorders are not thought to have been reported previously. The initial arterial and venous plasma histamine concentrations of 14 acute asthmatics, were significantly positively correlated with the respective arterial (P < 0.01) and venous (P < 0.05) eosinophil counts. The results in acute asthma support the hypothesis that increased plasma histamine may have a role in promoting eosinophil release from the bone-marrow. Eosinophilia is not dependent upon a raised plasma histamine in some disorders, but may be in others, such as schistosomiasis.

Disaccharide uptake and priming in animal cells: inhibition of sialyl Lewis X by acetylated Gal beta 1-->4GlcNAc beta-O-naphthalenemethanol.

Inhibitors of glycosylation provide a tool for studying the biology of glycoconjugates. One class of inhibitors consists of glycosides that block glycoconjugate synthesis by acting as primers of free oligosaccharide chains. A typical primer contains one sugar linked to a hydrophobic aglycone. In this report, we describe a way to use disaccharides as primers. Chinese hamster ovary cells readily take up glycosides containing a pentose linked to naphthol, but they take up hexosides less efficiently and disaccharides not at all. Linking phenanthrol to a hexose improves its uptake dramatically but has no effect on disaccharides. To circumvent this problem, analogs of Xyl beta 1-->6Gal beta-O-2-naphthol were tested as primers of glycosaminoglycan chains. The unmodified disaccharide did not prime, but methylated derivatives had activity in the order Xyl beta 1-->6Gal(Me)3-beta-O-2-naphthol > Xyl beta 1-->6Gal (Me)2 beta-O-2-naphthol >> Xyl beta 1-->6Gal(Me)beta-O-2-naphthol. Acetylated Xyl beta 1-->6Gal beta-O-2-naphthol also primed glycosaminoglycans efficiently, suggesting that the terminal xylose residue was exposed by removing the acetyl groups. The general utility of using acetyl groups to create disaccharide primers was shown by the priming of oligosaccharides on peracetylated Gal beta 1-->4GlcNAc beta-O-naphthalenemethanol. This disaccharide inhibited sialyl Lewis X expression on HL-60 cells.

Five human gastric aspartic proteinases: N-terminal amino acid sequences and amino acid composition.

Human pepsin A consists of 4 or more isoenzymes (designated 1, 3a, 3b and 3c) one of which, pepsin 1, contains up to 50% carbohydrate moieties. The amino-acid composition and N-terminal sequence of pepsin 1 and the other isoforms have been determined and compared with data obtained for pepsin 3b and gastricsin (pepsin C or pepsin 5). Pepsins were isolated from penta-gastrin stimulated gastric juice using repetitive chromatography on DEAE-cellulose, or high performance ion-exchange chromatography. Sequencing was performed using automated solid-phase Edman degradation with a microsequence facility. The amino-acid compositions were similar for pepsins 1, 3a, b and c and the N-terminal sequences of pepsins 1, 3a and c, reported for the first time, were shown to be identical with that for pepsin 3b (the main component of pepsin A) although residue 28 was unassigned in pepsin 1. Residue 30 in all four isoenzymes is valine and we cannot confirm reports of major pepsins with leucine in this position. For gastricsin the sequence differed from the pepsin isoenzymes and in position 24 we find pro rather than ala as was first described. These observations suggest that pepsin 1 is identical to 3b or a mixture of 3a, 3b and 3c but not gastricsin. This data supports the hypotheses that the four pepsin isoenzymes are products of the same gene(s) but have undergone varying levels of post translational modification.

Production of acute gastric erosions in the cat by individual human pepsins.

1. Differing amounts of human pepsins 1, 3 (pepsin A) and 5 (pepsin C or gastriscin) in aqueous HCl/NaCl at pH 1.3 were placed in Perspex rings on the exposed luminal surface of the perfused cat stomach to test for mucolytic and erosive activity in vivo, with the acid medium in control rings. 2. After incubation at 37 degrees C for 60 or 120 min, the test and control solutions were replaced by the same volume of each test or control solution containing 18 mg of aspirin and incubated for a further 120 min. 3. The number of bleeding points or erosions was counted at 15 min intervals. None was observed with human pepsins 1, 3 and 5 or with pig pepsin A or in the control rings. 4. With aspirin, erosions developed in all ringed areas. Their rate of development with time for pepsin 1 and pig pepsin did not differ from controls. Significantly more erosions developed with human pepsins 3 (5 mg per ring, P < 0.001) and 5 (0.32 mg per ring, P < 0.05). 5. Human pepsins 3 and 5, applied at pH 1.3 to the mucosal surface of the perfused cat stomach, therefore cause erosions when administered with aspirin, but do not produce erosions when given alone. In man, pepsins secreted in increased amount or concentration may therefore be unlikely to cause significant mucosal erosion unless human gastric mucosa is less resistant to pepsins than cat mucosa. Pepsins may perhaps facilitate the action of a second factor, such as aspirin, or infection with Helicobacter pylori.

The prevalence of diabetes mellitus in patients with primary hyperparathyroidism and among their relatives.

The prevalence of diabetes mellitus in a series of 205 patients with proven primary hyperparathyroidism was 7.8% (16 patients). Eight patients were known to have diabetes at first attendance (prevalence 3.9%), four were discovered at the time of diagnosis of hyperparathyroidism (combined prevalence 5.9%) and four subsequently. Diabetes had been diagnosed from age 39 yr onwards, and in those with diabetes hyperparathyroidism was diagnosed at age 44 yr or later. The prevalence of diabetes in primary hyperparathyroidism is significantly greater than in a series of 200 consecutive non-hyperparathyroid outpatients attending the same unit (3.0%, p less than 0.05), or in the general populations of Oxford and Poole, after matching for age and sex (p less than 0.05), or in the combined populations of Oxford, Poole, and Southall (white population) (p less than 0.05) after similar matching. However, the prevalence of diabetes in hyperparathyroidism did not differ significantly from that of the white population of Coventry, where the prevalence is higher than that of Oxford, Poole and Southall. For hyperparathyroid patients presenting at age 40 yr or over, the prevalence of known diabetes (4.7%) is significantly greater than in the general populations at similar age of Oxford, Poole, and Southall.

Application of the method of phage T4 DNA ligase-catalyzed ring-closure to the study of DNA structure. II. NaCl-dependence of DNA flexibility and helical repeat.

In this work, we demonstrate that it is possible to determine the molar cyclization factor jM from single ligation reactions in which both circular and linear dimer DNA species are formed concurrently from linear monomers. This approach represents a significant improvement over previous methods, in which jM is evaluated from the ratio of the rate constants for two separate processes; namely (1) the cyclization of linear DNA and (2) the association of two linear molecules to form linear dimers. Determination of jM for a 366 base-pair molecule yields 5.8 X 10(-8) M, in close agreement with the value of 5.6 X 10(-8) M determined by Shore et al. for the same molecule. Using the current approach for the determination of jM, we have investigated the dependence on NaCl concentration (0 to 162 mM-NaCl, 1 mM-MgCl2) of both the lateral and torsional flexibilities of DNA. The principal observation is that both quantities are essentially constant over the above range of NaCl concentrations, with the persistence length P approximately 450 (+/- 15) A, and the torsional elastic constant C approximately 2.0 (+/- 0.2) X 10(-19) erg cm. These observations are in accord with the previous theoretical prediction that P becomes essentially independent of NaCl concentration above 10 to 20 mM. We have examined the dependence of the helical repeat of DNA on NaCl concentration over the above range, and have found the value of 10.44 base-pairs per turn to be essentially constant over that range. This last result suggests that earlier studies have overestimated the dependence of DNA helical twist on salt concentration.

Erythrocyte acetyl cholinesterase in elderly patients with dementia and depression compared with normal controls.

A reference range for erythrocyte acetyl cholinesterase (EAChE) in 46 mentally normal subjects aged 65 years or over has been established. Previous reports of a relationship between changes in (EAChE) levels and mental illness (dementia and depression) in the elderly suggested that this determination may be useful in screening elderly subjects for these illnesses or as an aid to diagnostic classification. A study of normal and mentally ill elderly subjects in the community in Liverpool does not confirm a relationship with either senile dementia or depression and many of the changes in EAChE levels noted previously can be accounted for either by variations in the haematocrit or by a hitherto unreported lowering of EAChE levels in normal women over 80 years of age.

Improved separation of human pepsins from gastric juice by high-performance ion-exchange chromatography.

A simple and precise separative procedure can now be used to isolate individual pepsins from gastric juice, and by measurement of the protein absorbance at 280 nm enable their direct quantitation. This will facilitate the study of pepsin secretion, particularly in patients with peptic ulcer disease.

Heterogeneity of human pepsin 1, as shown by high-performance ion-exchange chromatography.

We have shown that pepsin 1 can be prepared in milligram quantities from human gastric juice by semi-preparative high-performance ion-exchange chromatography. Further investigation into the elution of this enzyme using linear chloride gradients have shown it to be a heterogeneous mixture, the components of which all have peptic activity, but differing specific activities. These components are changed in number and retention time by incubation with hyaluronidase and aryl sulphatase, but not by neuraminidase or acid phosphatase, implying the presence of a sulphated proteoglycan.