ORION laser target diagnostics.

The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

Excystation of Giardia muris induced by a phosphate-bicarbonate medium: localization of acid phosphatase.

Giardia muris cysts were incubated briefly in an aqueous induction medium of 0.1 M potassium phosphate with 0.1, 0.2, or 0.3 M sodium bicarbonate. High rates of excystation (91.1-96.7%) were recorded within 5 min after the cysts were placed in trypticase-yeast extract-iron-serum (TYI-S) medium. Substitution of phosphate-buffered saline for TYI-S as the excystation medium resulted in high rates (95.9%) of excystation but required an incubation of 15 min. Excystation was inhibited by the presence of 4-4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS), a specific inhibitor of vacuolar and lysosomal acidification. Microscopic observation showed the loss of the peritrophic space and a change in the refractile nature of the cyst wall prior to excystation. Histochemical studies demonstrated a reaction product of acid phosphatase activity in the lysosomelike peripheral vacuoles in induced cysts and in the peritrophic space of cysts placed in excystation medium. Staining with acridine orange suggested that the peripheral vacuoles become acidified during induction. This staining was inhibited also by DIDS. These studies show that in vitro excystation can be produced at high rates by easily prepared media without exogenous enzymes, low pH, reducing agents, or complex components. The data also suggest that excystation may be stimulated by the bicarbonate-phosphate medium accompanied by acidification of the peripheral vacuoles and the release of their contents into the peritrophic space.

Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy.

The mechanisms of hypercalcemia were assessed in 15 patients with humoral hypercalcemia of malignancy (HHM) who had tumors at various stages of progression. In patients with early tumors, bone biopsies were generally normal and the hypercalcemia was due to an elevation in renal tubular resorption of calcium. Conversely, osteoclastic resorption was markedly increased in patients with advanced tumors, particularly those in whom the biopsies were obtained postmortem. Osteoclast surface (Oc.S) correlated positively with the stage of tumor progression (r = 0.80, p less than 0.002), degree of immobility (r = 0.87, p less than 0.002), and level of urinary cyclic AMP excretion (r = 0.60, p less than 0.02). When compared with a group of ambulant patients with primary hyperparathyroidism (HPT), osteoblast surface (Ob.S%) in HHM was depressed (median and range): 1.2% (0-11.6%) versus 5.3% (1.1-32.0%) (p less than 0.001). However, a relatively low Ob.S (4%) and raised Oc.S (43.5%) were also seen in an immobilized patient with severe HPT. These data suggest that the PTH-related peptides currently invoked in the pathogenesis of HHM may initially cause hypercalcemia by enhancing renal tubular calcium resorption. The increase in osteoclastic activity and depression of osteoblastic activity that subsequently occurs is probably due to the combined effects of immobilization and higher circulating levels of PTHrP on the skeleton. However, the release of other bone-resorbing factors by the tumor, which have a depressant effect on osteoblastic activity, remains possible.

Clinical experience with aminohydroxypropylidene bisphosphonate (APD) in the management of cancer-associated hypercalcaemia.

Fifty-five patients with symptoms caused by hypercalcaemia associated with cancer were treated with varying regimens of intravenously-administered aminohydroxypropylidene bisphosphonate after initial rehydration. Of 48 patients where adequate data were available, 32 (66 per cent) were rendered normocalcaemic and 16 (33 per cent) remained mildly hypercalcaemic. In these cases, failure to restore normocalcaemia was attributable to elevated renal tubular reabsorption of calcium in nine (18 per cent) and to inadequate suppression of bone resorption in seven (14 per cent). There was no significant difference in response and duration of effect (median 20 days) between single doses of 15, 25 and 45 mg, or when the 45 mg dose was administered over three, six or 24 h. These single dose regimens were similar in terms of effect on calcium levels and duration of action, to multiple daily doses of 15 mg for a mean of six days. While the effect of 5 mg dose was not significantly different from the higher doses, suppression of serum calcium levels was less marked and the effect on duration of action significantly shorter than with the 45 mg dose. In seven cases, treatment with a second course was less effective even with higher doses because suppression of bone resorption was poorer. These data indicate that there is little difference between the therapeutic effects of multiple 15 mg and single 15-45 mg intravenous infusions of aminohydroxypropylidene bisphosphonate in hypercalcaemia associated with cancer. A single intravenous infusion of a moderate dose (for example 15-30 mg) would be a convenient and effective way of treating most patients.

Treatment of hypercalcaemia in thyrotoxicosis with aminohydroxypropylidene diphosphonate.

Two patients had symptomatic hypercalcaemia accompanying thyrotoxicosis, despite initial treatment with volume repletion, beta blockade and antithyroid drugs. They were further managed with intravenous infusions of aminohydroxypropylidene diphosphonate resulting in rapid normalization of the serum calcium, with relief of symptoms. Aminohydroxypropylidene diphosphonate effectively suppressed the increased bone resorption of thyrotoxicosis without any undesirable adverse effects.

Malignancy-associated hypercalcaemia: relationship between mechanisms of hypercalcaemia and response to antihypercalcaemic therapy.

The pathophysiological mechanisms of hypercalcaemia were assessed in 50 rehydrated patients with cancer-associated hypercalcaemia. Surprisingly, renal tubular calcium reabsorption appeared to increase progressively as serum calcium rose, suggesting that the nomogram used for the calculation may have been inaccurate, in absolute terms, probably due to its failure to take account of the levels of urinary sodium excretion. There were significant differences in the mechanisms of hypercalcaemia in different patient subgroups, however, independent of differences in urinary sodium excretion. In those with few or no bone metastases, increased renal tubular calcium reabsorption was the principal cause of hypercalcaemia, often in association with increased bone resorption. These abnormalities were thought to reflect the renal and skeletal actions of a tumour-associated humoral mediator. The main cause of hypercalcaemia in those with extensive metastatic bone disease was increased bone resorption, with contributions from impairment of glomerular filtration rate and, to a minor extent, increased renal tubular calcium reabsorption. These abnormalities were thought to reflect a mainly local-osteolytic mechanism of hypercalcaemia with secondary impairment of GFR. Of all the biochemical variables assessed pre-treatment, the renal tubular component of hypercalcaemia correlated most strongly with post-treatment serum calcium values (r = 0.61, P less than 0.001). Because of their generally lower levels of renal tubular calcium reabsorption, patients with extensive skeletal metastases also had significantly lower post treatment calcium values than patients with few or no metastases (P less than 0.05). These data indicate that the pathophysiological mechanisms of hypercalcaemia are a major determinant of the calcium lowering response after antihypercalcaemic treatment. This should be taken into account during comparative studies of antihypercalcaemic therapy in patients with malignancy.

Comparison of intestinal calcium absorption and circulating 1,25-dihydroxyvitamin D levels in malignancy-associated hypercalcaemia and primary hyperparathyroidism.

The relation between circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and intestinal calcium absorption--as determined by an oral calcium load test--was studied in 16 patients with hypercalcaemia of malignancy (HM) and 16 with hypercalcaemic primary parathyroidism (HPT). In the HPT group serum calcium rose significantly after the oral calcium load and the increment correlated significantly with 1,25(OH)2D levels. While 1,25(OH)2D levels were raised to within the hyperparathyroid range in a number of HM patients, there was no correlation between change in serum calcium and 1,25(OH)2D level in the HM group and serum calcium did not rise significantly after the oral calcium load. HM patients with detectable or raised 1,25(OH)2D levels typically had few, or no, bone metastases in association with squamous lung cancers. A high proportion of these patients exhibited other aspects of hyperparathyroid-like activity such as increased renal tubular calcium reabsorption, depressed renal tubular phosphate reabsorption and elevated urinary cyclic AMP excretion. Conversely, HM patients with undetectable 1,25(OH)2D levels typically had extensive metastatic bone disease in association with breast carcinoma and were less likely to exhibit other hyperparathyroid-like features. It is postulated that in the former, the 'inappropriately' detectable or raised 1,25(OH)2D levels may have been due to enhanced renal 1 alpha-hydroxylase activity stimulated by the parathyroid hormone (PTH)-like effect of a non-PTH ectopic humoral mediator. In the latter the suppressed 1,25(OH)2D levels would be the predicted result of a non-humorally mediated hypercalcaemia. It is currently unclear why intestinal calcium absorption was depressed in all HM patients when 1,25(OH)2D levels were normal or raised in some cases. It is possible, however, that in HM there is 'end organ' resistance to the effects of 1,25(OH)2D due to a generalized malabsorptive process.

Patients with suspected myocardial infarction: their test request patterns for clinical biochemistry in a British and a Canadian cardiac care unit.

The total number of routine clinical biochemistry tests requested for patients admitted to a coronary care unit with a diagnosis of "query myocardial infarction" were recorded over four to eight months. There were 156 sequential admissions in a British teaching hospital and 163 in a Canadian counterpart; the incidence of confirmed myocardial infarction was 53% and 50%, respectively. The pattern of tests ordered was substantially similar in each unit, unlike the rate of testing. For example, total creatine kinase was requested five times less often per patient in the British hospital than in the Canadian unit in cases of confirmed myocardial infarction (2.17 and 10.17, respectively; p less than 0.0001): the difference was much less, but still significant, when there was no infarction (2.01 and 3.55; p less than 0.0001). This study suggests a significant international difference in the use of clinical biochemistry services between coronary care units. Physicians (clinical and laboratory) need to be more critical of their use of protocols, which may prove wasteful of limited health care resources.

Influence of urinary sodium excretion on the clinical assessment of renal tubular calcium reabsorption in hypercalcaemic man.

The relation between urinary sodium excretion (NaE) and renal tubular calcium reabsorption (TmCa/GFR) was assessed in patients with hypercalcaemia associated with malignancy and primary hyperparathyroidism. On acute saline loading of seven normally hydrated patients with primary hyperparathyroidism and five patients with malignancy, raised values of TmCa/GFR were reduced to normal in most cases, in association with increases in NaE. The reduction in TmCa/GFR, which occurred, may have been due to a reduction in proximal tubular calcium reabsorption associated with sodium: this would have obscured the effect of humorally mediated increases in distal tubular calcium reabsorption, which are stimulated either by parathyroid hormone or by a putative humoral mediator in hypercalcaemia of malignancy. In patients who were normally hydrated NaE and TmCa/GFR were not significantly correlated. When data were included from patients who were dehydrated and from those undergoing acute saline loading, significant inverse correlations between NaE and TmCa/GFR were observed both in primary hyperparathyroidism (r = -0.49; p less than 0.02) and malignancy (r = -0.60; p less than 0.001). In clinical practice changes in TmCa/GFR associated with sodium seem to be of minor importance under normal circumstances, but they become evident at the upper and lower extremes of urinary sodium excretion. In clinical studies of renal calcium handling urinary sodium excretion must also be assessed, as interpreting TmCa/GFR data is difficult in states of excessive sodium loading or depletion.

Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphonate and calcitonin.

Eight patients with cancer associated hypercalcaemia were treated with the combination of aminohydroxypropylidene diphosphonate and salmon calcitonin for six days. Serum calcium concentration fell significantly within 24 hours of starting treatment due to a reduction in bone resorption and renal tubular calcium reabsorption. In the longer term hypercalcaemia was controlled by a further progressive reduction in bone resorption, which persisted for six days after treatment was stopped. Renal tubular calcium reabsorption, however, remained suppressed only during drug treatment. The rapid fall in serum calcium was attributable to the acute renal and skeletal effects of calcitonin, whereas in the longer term control of hypercalcaemia was due to diphosphonate mediated suppression of bone resorption. In view of the rapid effect and lack of toxicity, combined treatment with aminohydroxypropylidene diphosphonate and calcitonin would be of particular value in patients with severe hypercalcaemia in whom a quick but sustained reduction in the serum calcium concentration is desired.

Humoral hypercalcaemia of malignancy: metabolic and histomorphometric studies during surgical management of the primary tumour.

Several aspects of calcium metabolism were studied in five patients during the surgical exploration of malignant tumours associated with humorally-mediated hypercalcaemia. Before operation in all patients the renal tubular threshold for calcium reabsorption was raised and the threshold for renal tubular phosphate reabsorption depressed. On removal of the primary tumour in three cases, serum calcium returned to normal, renal calcium threshold fell, renal phosphate threshold rose, but urinary hydroxyproline excretion did not change. In two patients where the tumour proved inoperable, serum calcium remained elevated and no changes in renal calcium threshold or phosphate threshold occurred. Histomorphometry carried out on biopsy specimens from four patients showed normal bone resorption in three, and slightly increased resorption in one, without depression of osteoblastic bone formation. It is suggested that hypercalcaemia in these patients resulted mainly from an alteration in renal calcium threshold caused by a humoral substance released by tumour cells. Correction of hypercalcaemia on removal of the primary tumour was achieved rapidly and could be explained principally by a reduction in renal calcium threshold with increased loss of calcium into the urine. These data contrast with those of many previous studies which have emphasised the predominant role of accelerated osteoclastic bone resorption as the principal cause of hypercalcaemia in malignancy and suggest that a renal effect of the putative humoral agent may predominate in some cases.

Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia.

Thirty-nine patients with cancer-associated hypercalcaemia were randomly allocated to receive aminohydroxypropylidene diphosphonate (APD), mithramycin, or corticosteroids and salmon calcitonin. Corticosteroids/calcitonin had the fastest calcium-lowering effect, owing mainly to an acute reduction in renal tubular calcium reabsorption; continued therapy over 9 days failed to suppress accelerated bone resorption, however, and most patients remained hypercalcaemic. Mithramycin also substantially reduced serum calcium within 24 h. A further dose on day 2 generally controlled hypercalcaemia until day 6 by reducing both bone resorption and renal tubular calcium reabsorption. By day 9, however, about 50% of the mithramycin-treated patients had started to relapse as bone resorption increased again. With APD serum calcium levels fell more slowly but progressively owing to effective suppression of bone resorption; by day 9 the control of hypercalcaemia was significantly better than in the other treatment groups. Symptoms of hypercalcaemia were greatly relieved, especially by APD.

Circulating vitamin D metabolites and hypercalcaemia of malignancy.

Plasma concentrations of 1.25 dihydroxycholecalciferol were measured in 44 patients with malignancy associated hypercalcaemia and related to other hormonal regulators of calcium metabolism. Immunoreactive PTH concentrations were suppressed in all but 2 patients and, as a group, patients with hypercalcaemia of malignancy had lower 1.25 dihydroxycholecalciferol concentrations than normocalcaemic cancer patients. 1.25 dihydroxycholecalciferol concentrations were clearly detectable in a significant proportion (43%) of hypercalcaemia cases however, suggesting that in these patients the active vitamin D metabolite may contribute to the pathogenesis and maintenance of the hypercalcaemia by stimulating bone resorption, and/or by increasing absorption of calcium from the intestine. Measurement of plasma 1.25 dihydroxycholecalciferol concentration does not provide a wholly reliable method for distinguishing the hypercalcaemia of malignancy from primary hyperparathyroidism.

Hypercalcaemia of malignancy: evidence for a nonparathyroid humoral agent with an effect on renal tubular handling of calcium.

The renal handling of calcium was examined in 31 patients with hypercalcaemia of malignancy. Results were compared with those from patients with primary hyperparathyroidism, and normal controls rendered hypercalcaemic by calcium infusion. On relating the urinary calcium excretion indices to serum calcium values, inappropriately low rates of urinary calcium excretion were generally found in patients with malignancy associated hypercalcaemia. Further, the pattern of urinary calcium excretion in these subjects was similar to that found in patients with primary hyperparathyroidism. These observations suggest that, in many solid tumours, the development of hypercalcaemia may be attributable to a humoral mediator with a parathyroid hormone-like effect on renal tubular calcium reabsorption. The relatively frequent occurrence of hypercalcaemia in malignant disease thus may be partially explained by the presence of this humoral agent, which may impair the renal excretion of an increase in filtered calcium load, whether due to bone metastases, or humorally mediated osteolysis.

Test-request patterns for clinical chemistry in a British and a Canadian renal dialysis unit.

We recorded, during four months, the total number of routine clinical chemistry tests requested for patients with end-stage renal failure who were on regular maintenance hemodialysis during the study: 20 in the Renal Dialysis Unit of a British and 20 in a Canadian teaching hospital. The pattern of tests ordered was substantially the same in each unit, but the frequency of testing was not. The total number of tests (and tests per patient per month) was 1616 (20.2) for the British and 6939 (86.7) for the Canadian unit (significant at p less than 0.001). This study suggests a significant difference between the two countries in the utilization of laboratory services, and supports our earlier findings on total clinical chemical workloads in hospitals.

Pre-operative localisation of parathyroid tumours using neck vein catheterisation and radioimmunoassay for parathyroid hormone: the Glasgow experience.

Reliable pre-operative localisation of parathyroid tumours can be of value in surgery for primary hyperparathyroidism, and particularly so where re-exploration of the neck is required. Neck vein catheterisation and parathyroid hormone radioimmunoassay have been suggested as a sensitive means of tumour localisation, and we report our experience of the technique over the last five years. A total of 46 patients with primary hyperparathyroidism had 50 studies performed with positive localisation and a pre-operative prediction made on 38 occasions (76%). Forty-two operations were carried out and a parathyroid tumour confirmed in 39 cases for a localisation efficiency of 69 per cent. No negative neck exploration followed a positive localisation. Twelve studies were performed in patients with renal osteodystrophy and localisation to a single site was achieved on only three occasions. It is concluded that neck vein catheterisation and parathyroid hormone assay can correctly localise parathyroid tumours in most cases of primary hyperparathyroidism, but it is suggested that its use be restricted to selected cases such as those subjects with previous negative neck exploration or patients for whom prolonged or repeated surgery may be a particular hazard.