Evaluation of the QBC Star centrifugal three-part differential haematology system.

The QBC Star haematology system includes the QBC Star centrifugal analytical analyser and the QBC Star tube system. Together, they are capable of producing a haematology profile on venous or capillary whole blood. The aim of this study is to compare full blood count (FBC) including differential white cell count performance between the QBC Star analyser and a gold standard Sysmex XE-2100 haematology analyser. The FBC performance was evaluated according to the National Committee for Clinical Laboratory Standards (NCCLS) document H20-A. Imprecision, correlation and linearity studies all showed excellent results. Overall, the haemoglobin, haematocrit, white cell count (WCC) and platelet count parameters showed excellent correlation. Mean corpuscular haemoglobin concentration (MCHC) results showed poor comparability. The white cell differential parameters showed good correlation within certain clinically significant limits. Imprecision for haemoglobin, haematocrit, WCC, MCHC and platelet count was considered acceptable. The re-read function was found to be stable over the five-hour testing period under the authors' laboratory environmental conditions. The subjective assessment by biomedical scientist staff demonstrated that the system was user friendly, required little maintenance, and no user calibration was required. Staff considered the user manual to be excellent. Overall, the QBC Star appears to be an excellent point-of-care (POC) dry haematology analyser that delivers clinically significant nine-parameter complete blood count and will make a good POC analyser for use in field hospitals, research, screening programmes, GP surgeries as well as in emergency and intensive care units. It is a health and safety-friendly analyser considering the fact that it uses dry haematology reagents instead of the bulky wet reagents that are often associated with liquid biohazard waste.

Comparative genomic and proteomic analysis of high grade glioma primary cultures and matched tumor in situ.

Developing targeted therapies for high grade gliomas (HGG), the most common primary brain tumor in adults, relies largely on glioma cultures. However, it is unclear if HGG tumorigenic signaling pathways are retained under in-vitro conditions. Using array comparative genomic hybridization and immunohistochemical profiling, we contrasted the epidermal and platelet-derived growth factor receptor (EGFR/PDGFR) in-vitro pathway status of twenty-six primary HGG cultures with the pathway status of their original HGG biopsies. Genomic gains or amplifications were lost during culturing while genomic losses were more likely to be retained. Loss of EGFR amplification was further verified immunohistochemically when EGFR over expression was decreased in the majority of cultures. Conversely, PDGFRα and PDGFRß were more abundantly expressed in primary cultures than in the original tumor (p<0.05). Despite these genomic and proteomic differences, primary HGG cultures retained key aspects of dysregulated tumorigenic signaling. Both in-vivo and in-vitro the presence of EGFR resulted in downstream activation of P70s6K while reduced downstream activation was associated with the presence of PDGFR and the tumor suppressor, PTEN. The preserved pathway dysregulation make this glioma model suitable for further studies of glioma tumorigenesis, however individual culture related differences must be taken into consideration when testing responsiveness to chemotherapeutic agents.

A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer.

PURPOSE: Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines. METHODS: We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m(2)) in combination with escalating oral doses of sulindac (0-800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3. RESULTS: Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease. CONCLUSION: Epirubicin 75 mg/m(2) and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.

The PWH Grieve Memorial Award. A study looking at regional general practice training schemes in Britain and Ireland.

BACKGROUND: This is a report of a study tour of four regional GP training schemes in Britain and Ireland. The award was made in 1997 for a study that occurred during 1998. OBJECTIVE: The aim of the study was to gather experience for the new Gippsland Regional Training Program and to look at the levels of support given to GP supervisors in the schemes visited. DISCUSSION: There appears to be a greater focus on the professional development of GP supervisors in the UK and Ireland than here in Australia. Other key features of support for supervisors include feedback from the program to supervisors and accreditation/reaccreditation by the program of teaching practices.

Practical skills to overcome emotional problems. Developing a model of cognitive behavioural therapy nursing for acute inpatient psychiatric care.

1. Cognitive behavioural therapy is increasingly being found helpful in treating various psychiatric disorders. 2. A nursing model is proposed that incorporates this therapy into inpatient psychiatric care. 3. The model may be helpful in panic, agoraphobia, self-harm and psychosis, and has the attraction that progress is measurable.

A case of pregnancy associated osteoporosis and empty sella syndrome.

We report an unusual case of pregnancy associated osteoporosis and empty Sella Syndrome with normal pituitary function. Pregnancy associated osteoporosis has been described rarely in the literature. Primary empty Sella Syndrome may occur in 5.5% of all autopsies. Primary empty Sella Syndrome with normal pituitary function has not previously been reported in association with an uncomplicated pregnancy and delivery. The occurrence of these two conditions in our patient is probably coincidental.

Pediatric transvenous pacing: a concern for venous thrombosis?

Transvenous pacing has become the preferred method of pediatric cardiac pacing. Although no clinically important venous thromboses have been reported, concern has arisen about occult venous thrombosis. We evaluated 19 randomly selected children who had transvenous pacing implants. Sixteen were evaluated by venous plethysmography and Doppler while three had venous angiography and one had both. The leads had all been inserted by subclavian vein puncture. Ages at time of implant ranged from 17 months to 25 years; mean 9.8 years, median 9.0 years. Implant weights were from 9.6 kg to 56.0 kg, mean 31 kg, median 31 kg. The interval from implant to time of procedure ranged from 1 month to 46 months, mean 22.5 months, median 24 months. Four patients had one lead while 14 had two and one had four. Eleven leads were unipolar and 25 were bipolar. The bipolar leads were 6.6 French diameter. In the 19 patients evaluated, no thromboses were detected nor any narrowing greater than 10% of proximal diameter as seen by angiography. No disturbances of blood flow in the subclavian vein was noted. Transvenous pacing did not result in venous flow abnormalities in these pediatric patients.

Cadmium uptake and toxicity via voltage-sensitive calcium channels.

The mechanism of cellular uptake of cadmium, a highly toxic metal ion, is not known. We have studied cadmium uptake and toxicity in an established secretory cell line, GH4C1, which has well characterized calcium channels. Nimodipine, an antagonist of voltage-sensitive calcium channels, protected cells against cadmium toxicity by increasing the LD50 for CdCl2 from 15 to 45 microM, whereas the calcium channel agonist BAY K8644 decreased the LD50. Organic calcium channel blockers of three classes protected cells from cadmium toxicity at concentrations previously shown to block high K+-induced 45Ca2+ influx and secretion. Half-maximal protective effects were obtained at 20 nM nifedipine, 4 microM verapamil, and 7 microM diltiazem. Increasing the extracellular calcium concentration from 20 microM to 10 mM also protected cells from cadmium by causing a 5-fold increase in the LD50 for CdCl2. Neither the calcium channel antagonist nimodipine nor the agonist BAY K8644 altered intracellular metallothionein concentrations, while cadmium caused a 9-20-fold increase in metallothionein over 18 h. Cadmium was a potent blocker of depolarization-stimulated 45Ca2+ uptake (IC50 = 4 microM), and the net uptake of cadmium measured with 109Cd2+ was less than 0.3% that of calcium. Although the rate of cadmium uptake was low relative to that of calcium, entry via voltage-sensitive calcium channels appeared to account for a significant portion of cadmium uptake; 109Cd2+ uptake at 30 min was increased 57% by high K+/BAY K8644, which facilitates entry through channels. Furthermore, calcium channel blockade with 100 nM nimodipine decreased total cell 109Cd2+ accumulation after 24 h by 63%. These data indicate that flux of cadmium through dihydropyridine-sensitive, voltage-sensitive calcium channels is a major mechanism for cadmium uptake by GH4C1 cells, and that pharmacologic blockade of calcium channels can afford dramatic protection against cadmium toxicity.

Fibrinogen concentration and coronary artery reperfusion after intravenous anisoylated plasminogen streptokinase activator complex or intracoronary streptokinase therapy.

In a US study, anisoylated plasminogen streptokinase activator complex (APSAC), 30U intravenously over 2 minutes, was compared with streptokinase, about 150,000U by intracoronary infusion over 60 minutes. Included in the study were 106 patients with acute myocardial infarction for whom both angiographic data and coagulation study results were available. 58 of these patients received APSAC and 48 streptokinase. The degree of hypofibrinogenaemia and the percentage of patients who had a drop of greater than 10% in plasma fibrinogen was more evident with high dose intravenous APSAC treatment than with lower dosages of intracoronary streptokinase. This laboratory abnormality was not predictive of successful reperfusion in APSAC-treated patients. The dose of streptokinase administered was not correlated with the presence or absence of the lytic state or with reperfusion. However, 10 patients treated with streptokinase showed reperfusion without an apparent effect on the fibrinogen concentration and further studies are needed to determine whether treatment effects were limited to the coronary artery by regional infusion. Similarly, 2 APSAC-treated patients had groin bleeding without a decrease in plasma fibrinogen. Therefore, a final conclusion regarding the contribution of a lytic state to bleeding must await further analysis.

Thyroid hormone induction of an autocrine growth factor secreted by pituitary tumor cells.

Thyroid hormones stimulate the rate of cell division by poorly understood mechanisms. The possibility that thyroid hormones increase cell growth by stimulating secretion of a growth factor was investigated. Thyroid hormones are nearly an absolute requirement for the division of GH4C1 rat pituitary tumor cells plated at low density. Conditioned media from cells grown with or without L-triiodothyronine (T3) were treated with an ion exchange resin to remove T3 and were tested for ability to stimulate the division of GH4C1 cells. Conditioned medium from T3-treated cells was as active as thyroid hormone at promoting GH4C1 cell growth but did not elicit other thyroid hormone responses, induction of growth hormone, and down-regulation of thyrotropin-releasing hormone receptors, as effectively as T3 did. A substance or substances associated with T3-induced growth stimulatory activity migrated at high molecular weight at neutral pH and was different from known growth-promoting hormones induced by T3. The results demonstrate that thyroid hormones stimulate the division of GH4C1 pituitary cells by stimulating the secretion of an autocrine growth factor.

Long-term survival with the right lower lobe as the only lung tissue.

The case of a patient who underwent left pneumonectomy at 23 years of age is described. When he was 54 years old, he required resection of the right upper and middle lobes. He survived and lived an active life for more than three years with the right lower lobe as his only lung tissue.

Regulation of thyrotropin-releasing hormone binding by monovalent cations and guanyl nucleotides.

Binding of thyrotropin-releasing hormone (TRH) to specific receptors on membranes isolated from GH4C1 pituitary cells was inhibited by monovalent cations and guanyl nucleotides. NaCl and LiCl inhibited TRH binding by 70%, with half-maximal inhibition at 30 mM; RbCl and KCl inhibited only 10% at concentrations up to 150 mM. NaCl decreased both the apparent number and the affinity of TRH receptors and increased the rate of dissociation of TRH from both membrane and Triton X-100-solubilized receptors. Guanyl nucleotides inhibited TRH binding up to 80%, with guanyl-5'-yl imidodiphosphate (Gpp(NH)p) approximately GTP much greater than GDP approximately ATP greater than GMP. GTP and Gpp(NH)p exerted half-maximal effects at 0.3 microM and decreased receptor affinity to one-third of control but did not change receptor number. Gpp(NH)p accelerated the dissociation of TRH from membranes but not from solubilized receptors. The effects of NaCl were independent of temperature, while GTP and Gpp(NH)p were much more inhibitory at 22 degrees C (70%) than at 0 degrees C (10%). Inhibition by NaCl could be reversed by washing the membranes, and inhibition by GTP was reversed if membranes were chilled to 0 degrees C. The inhibitory effects of low concentrations of NaCl and Gpp(NH)p were additive. Neither monovalent cations nor GTP prevented the TRH-receptor complex from undergoing transformation from a state with rapid dissociation kinetics to a slower dissociating form. The results suggest that sodium ion regulates TRH binding by interacting with a site on the receptor, while guanyl nucleotides regulate TRH binding indirectly.

Stress fractures of the lower limb in patients with rheumatoid arthritis.

Thirteen patients suffering from rheumatoid arthritis had 19 stress fractures of the tibia or fibula. These patients characteristically presented with sudden, severe, unexplained pain with localised tenderness just below the knee or above the ankle. In seven patients examination of the adjacent joint indicated a flare-up of disease activity or a pyogenic arthritis. In six patients the diagnosis was delayed by the late appearance of callus in minute fractures. All patients had rheumatoid deformities of the ipsilateral lower limb: valgus deformities of the knee and subtalar joints occurred most frequently. All patients had osteoporosis; all except two had received steroid treatment and five had abnormalities of calcium metabolism. We suggest that deformities of the knee and ankle predispose patients with rheumatoid arthritis and osteoporosis to stress fractures of the tibia and fibula.

Gold in psoriatic arthopathy.

It has been suggested that gold is not effective in psoriatic arthropathy. We did not agree and therefore did a retrospective study of 98 patients. Gold had been given to 27 and was effective in 22, 14 of whom are still receiving it. The incidence of side effects was low and comparable to those in rheumatoid arthritis.

Cimetidine for peptic ulcer in patients with arthritis.

Patients taking anti-inflammatory drugs for arthritis are prone to dyspepsia, and management of peptic ulcer is difficult because surgery is poorly tolerated. In this open study cimetidine treatment was associated with ulcer healing in 17 out of 21 patients with arthritis even when anti-inflammatory treatment was continued. Remission was maintained for 1 year by continued cimetidine therapy.