[Ocular blood flow regulation in glaucoma - examination with the ocular pressure flow analyzer (OPFA)]. / Okuläre Durchblutungsregulation beim Glaukom. Untersuchungen mit dem Ocular Pressure Flow Analyzer (OPFA).

BACKGROUND: The results of studies of ocular blood flow (BF) regulation of patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG) and ocular hypertension (OH) are presented. METHODS AND PATIENTS: Examinations were carried out with the "OPFA", a newly developed ocular pressure flow analyzer (producer: tpm Lüneburg) on 92 patients with newly diagnosed glaucomas, among whom 48 patients had POAG, 22 NTG and 22 OH, and compared with age-matched groups of healthy subjects. The OPFA uses pneumatic coupling through special scleral suction cups to record ocular pulses with highly sensitive transducers and a suction pump for simultaneously increasing intraocular pressure (IOP). Following local drop anaesthesia on both eyes, IOP is artificially raised to suprasystolic values. While continuously lowering IOP, the ocular pulse is then recorded with increasing ocular perfusion pressure. We obtain the relative ocular pulse blood volume by correlating the ocular pulse amplitudes with a calibration volume of 1 µl. This enables us to collect reproducible data on intra- and inter-individual pulse blood volume (PVoc). The ocular perfusion pressure pulse blood volume curve characterizes the respective individual ocular circulation as well as systolic and diastolic ocular perfusion pressures. RESULTS: In healthy subjects, the ocular pulse blood volume remains stable over a certain range of ocular perfusion pressure (ppoc) changes. After exceeding a critical point (CP), the ocular pulse blood volume drops. We refer to the difference between the CP and IOP as the autoregulatory capacity (AC). In patients with POAG and in patients with NTG, the AC was reduced significantly compared with the groups of healthy subjects. The mean AC of patients with OH remained within the normal range. The ROC curves showed at an optimal cut-off value for POAG a sensitivity of 75.0 % and a specificity of 97.9 %, for NTG a sensitivity of 77.3 % and a specificity of 100 %. In patients with POAG and OH, the ocular arterial pressures were elevated. In patients with NTG they remained unchanged compared with the healthy subjects. The ocular perfusion pressures did not change in POAG as well as in NTG and OH. CONCLUSIONS: In patients with POAG and in patients with NTG the ocular BF regulation was impaired and detected by the OPFA device with a high level of reliability. Ocular arterial blood pressures were increased as a result of vascular regulation to keep up the ocular perfusion pressure and to maintain ocular perfusion.

Relationship between sonographically estimated fetal subcutaneous adipose tissue measurements and neonatal skinfold measurements.

OBJECTIVE: Increased subcutaneous adipose tissue is a well known characteristic of diabetic fetopathy. Prenatal estimation of adipose tissue can be performed by ultrasound, while postnatally skinfold measurements are performed using a Holtain caliper. The aim of this study was to compare these methods in the same patients. METHODS: This was a prospective study of 172 pregnant patients (142 controls and 30 with gestational diabetes) at ≥ 37 gestational weeks. In addition to fetal weight estimation, fetal subcutaneous tissue was measured at the anterior abdomen lateral to the umbilicus (SonoSfAbd) and at the middle of the femur (SonoSfFem). Within 72 h after delivery, a Holtain caliper was used to measure neonatal skinfold thickness at the left anterior iliac spine (SfAbd), at the lower angle of the left scapula (SfSca), at the middle of the femur, above the left quadriceps femoris (SfFem) and at the middle of the left triceps (SfHum). Ultrasound and mechanical measurements were correlated. RESULTS: The sonographic and mechanical methods showed good correlation with each other. Linear regression analysis gave the following equations: SfAbd (mm) = SonoSfAbd (mm) × 0.489 + 1.988 (r(2) = 0.34, P < 0.001); SfSca (mm) = SonoSfAbd (mm) 0.457 + 2.043 (r(2) = 0.40, P < 0.001); SfFem (mm) = SonoSfFem (mm) × 0.714 + 1.763 (r(2) = 0.41, P < 0.001); SfHum (mm) = SonoSfFem (mm) 0.564 + 2.09 (r(2) = 0.39, P < 0.001). CONCLUSIONS: Ultrasound examination is a reliable method for non-invasive intrauterine measurement of fetal subcutaneous tissue and can be used to predict mechanical neonatal skinfold thickness measurements.

Control of immunoglobulin secretion in the murine plasmacytoma line MOPC 315.

Cells of the 315LV-1 (derived from NP1) variant line of MOPC 315 contain approximately 1% the normal intracellular level of the heavy (alpha) chain of IgA and no detectable light (lambda2) chain. The synthesis rate of alpha-chain in the variant, however, is similar to that in cells of the parent line. Moreover the relative amount of translatable alpha-chain mRNA that can be extracted from 315LV-1 cells is about the same as for parental cells. No light-chain synthesis can be detected either in vivo or in vitro in a wheat germ cell-free system. The 315LV-1 heavy chain synthesized in vivo or in vitro has slightly greater electrophoretic mobility than normal H chain and turns over rapidly intracellularly. The variant fails to secrete any of its heavy chain, despite the fact that its H chain mRNA is bound to membranes, as one would expect for a secretory protein message. Fusion of 315LV-1 cells with cells of a kappa-producing MPC 11 variant line leads to stabilization of the intracellular H chain and also to full recovery of secretion of the H chain as an H2L2 molecule.

Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicentre randomized phase II trial.

BACKGROUND: Most patients (pts) with metastatic non-small cell lung cancer (NSCLC) receive either single agents or chemotherapy doublets. Recent studies have demonstrated that triple-agent therapies may improve the response rate, but are associated with significant toxicity, and frequently do not prolong survival. A sequential triple-agent schedule may combine acceptable tolerability and good efficacy. We therefore conducted a multicentre, prospectively randomized study that evaluates a sequential three-drug schedule and a platinum-free doublet regimen. PATIENTS AND METHODS: The pts with union international contre le cancer (UICC) stage IV NSCLC were randomized to one of two schedules: in arm Doc-Gem, they received gemcitabine (900 mg/m(2), 30 min infusion) on days 1 and 8, and docetaxel (75 mg/m(2), 1 h infusion) on day 1, repeated every 3 weeks up to six cycles. In arm Cis-Gem-->Doc, gemcitabine (900 mg/m(2), days 1 and 8) and cisplatin (70 mg/m(2), 1 h infusion, day 1) were given for three cycles, followed by three cycles of docetaxel (100 mg/m(2), day 1, repeated every 3 weeks). RESULTS: One hundred and thirteen pts were randomized to arms Doc-Gem (55 pts) and Cis-Gem-->Doc (58 pts). With Doc-Gem, 20.4% of pts responded to the treatment whereas 31.0% responded in arm Cis-Gem-->Doc (overall response, intent-to-treat, difference not significant). The median time to progression was 3.6 months in arm Doc-Gem [95% confidence interval (CI) 1.4, 5.9] and 5.2 months in arm Cis-Gem-->Doc (95% CI 3.1, 7.3). The median survival was 8.7 months with treatment Doc-Gem (95% CI 5.7, 11.6) and 9.4 months with treatment Cis-Gem-->Doc (95% CI 7.8, 11.0). The 1-year survival rates were 34 and 35%, respectively. Mild to moderate leukopenia was frequently seen with both schedules. Other common adverse events (AE) were nausea/vomiting, thrombocytopenia, anaemia, diarrhoea, and infections. No significant differences in AEs were observed between the schedules except for nausea/vomiting, which occurred more frequently with Cis-Gem-->Doc. CONCLUSION: The sequential therapy comprising cisplatin, gemcitabine, and docetaxel demonstrated promising tumour control whereas the platinum-free combination (docetaxel/gemcitabine) was very well tolerated. However, the schedules resulted in comparable survival to recent large trials in pts with advanced NSCLC. The present results do not justify further phase III investigation.

Further evidence for oxidant-induced vascular endothelial growth factor up-regulation in the bronchoalveolar lavage fluid of lung cancer patients undergoing radio-chemotherapy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent inducer of physiological and neoplastic blood vessel growth. Moreover, in vitro studies have demonstrated that VEGF can be up-regulated by conditions associated with the generation of free radicals and reactive oxygen species. In a previous study we reported on strongly increased VEGF concentrations in the bronchoalveolar lavage fluid (BALF) of patients with lung cancer under therapy. In this study we aimed to reveal whether this increase was due to the therapy-associated intrapulmonary oxidative burden. PATIENTS AND METHODS: A total of 103 BALF samples from 94 patients with lung cancer (82 patients with non-small-cell lung cancer, 12 patients with small-cell lung cancer) were studied at different times before, during or after cancer treatment. VEGF levels in the lavage fluid and ratios of oxidised methionine in proteins of epithelial lining fluid (ELF) were determined. RESULTS: As reported previously, strongly increased VEGF levels in the ELF were observed in patients undergoing chemotherapy when radiotherapy had been administered before. Increased levels of oxidised methionine indicated that these patients suffered from severe pulmonary oxidative stress that was significantly less in patients undergoing only chemotherapy. Similarly, VEGF concentrations in the ELF were significantly elevated in cancer patients at the time of diagnosis, but the oxidised methionine levels did not reveal significant oxidant/antioxidant imbalances in these patients. CONCLUSION: Systemic chemotherapy is associated with oxidative stress in vivo, which is more pronounced if patients are additionally treated with radiation. VEGF levels in the ELF are increased by this condition as well as by the activity of the tumour itself.

Further characterisation of the interaction of haloperidol metabolites with neurotransmitter transporters in rat neuronal cultures and in transfected COS-7 cells.

It has been proposed that the extrapyramidal symptoms such as tardive dyskinesia developed by patients on long-term haloperidol treatment may be the result of uptake of haloperidol metabolites into neurons via the monoamine neurotransmitter transporters followed by neurotoxic events, as occurs for MPP+, the pyridinium metabolite of MPTP. We recently showed that haloperidol and its metabolites are inhibitors of the human noradrenaline transporter (NAT), dopamine transporter (DAT) and serotonin transporter (SERT), and determined their Ki values for inhibition of the three transporters expressed in transfected COS-7 cells. In this study, we extended the investigation of these compounds to their inhibitory effects on DAT, SERT and the high affinity choline uptake (HACU) in neuronal cultures from embryonic rat brain, and investigated whether the compounds are substrates or non-transported inhibitors of the NAT, DAT and SERT in transfected COS-7 cells and DAT and SERT in the neuronal cultures. Haloperidol and its metabolites inhibited DAT, SERT and HACU in the neuronal cultures, indicating that they are not specific inhibitors of the monoamine neurotransmitter transporters. The ratio of the Ki values of the least and most potent inhibitors were found to be 2.8 for DAT, 24 for SERT and 7.6 for HACU. The compounds were more potent inhibitors of DAT and SERT in neuronal cultures than we found previously in transfected COS-7 cells. The question of whether the compounds are substrates or non-transported inhibitors of the monoamine transporters was investigated by determining whether they caused an increase in efflux of [3H]amine in transfected COS-7 cells or neuronal cultures preloaded with [3H]amine. Haloperidol metabolites were weak substrates for SERT, but not for NAT or DAT, in transporter-transfected COS-7 cells. In neuronal cultures, the metabolites appeared to be non-transported inhibitors or very weak substrates of DAT and SERT. Despite inhibition of the monoamine transporters by haloperidol and its metabolites, there is little evidence to support the proposal that these compounds are likely to cause neurotoxic effects via neuronal uptake using the monoamine transporters. The mechanisms of the side effects of haloperidol therapy, such as tardive dyskinesia, are still unclear, but are unlikely to depend on interactions of the drug or its metabolites with NAT, DAT or SERT.

Potencies of haloperidol metabolites as inhibitors of the human noradrenaline, dopamine and serotonin transporters in transfected COS-7 cells.

Extrapyramidal symptoms, such as tardive dyskinesia, often develop in patients on long-term treatment with haloperidol. It has been proposed that these symptoms could be caused by neurotoxic effects of haloperidol metabolites following uptake by monoamine transporters, in an analogous mechanism to the neurotoxic effect of MPP+ (1-methyl-4-phenylpyridinium) metabolised from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this study, the hypothesis was partially investigated by determining the potencies of haloperidol and reduced haloperidol and the corresponding pyridinium and tetrahydropyridine metabolites, compared with MPP+ and MPTP, as inhibitors of the noradrenaline transporter (NAT), dopamine transporter (DAT) and 5-HT transporter (SERT). Two days after COS-7 cells were transiently transfected with the cDNA for the human NAT, DAT or SERT (Lipofectamine method), the cells were incubated with 10 nM [3H]noradrenaline, dopamine or 5-HT, respectively, for 2 min at 37 C, in the absence or presence of various concentrations of the eight compounds or a specific uptake inhibitor (NAT: nisoxetine 1 microM; DAT: GBR 12909 1 microM; SERT: citalopram 10 microM). Specific amine uptake (fmol/ mg protein) was calculated as the difference in uptake in the absence and presence of the specific uptake inhibitor. Ki values were calculated for the eight compounds for inhibition of NAT, DAT and SERT. Haloperidol, its five metabolites and MPP+ and MPTP all inhibited NAT, DAT and SERT. For the pyridinium and tetrahydropyridine metabolites of haloperidol, there were not marked differences between their potencies as inhibitors between each other for NAT or DAT or between NAT and DAT, with all of the Ki values in the range of 5.8-16 microM. However, there were more marked differences for SERT, with all but one of the metabolites showing selectivity for inhibition of SERT relative to NAT and DAT. Haloperidol and reduced haloperidol had similar inhibitory potencies for all three transporters, and were clearly less potent than the other haloperidol metabolites only for inhibition of SERT. The lack of correlation between the inhibitory potencies of the haloperidol metabolites and their structural analogues, MPTP and MPP+, suggests that they are not likely to cause neurotoxicity by a mechanism analogous to that of the latter neurotoxin.

Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat.

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 microg/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 microg/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two- to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy.

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.

Introductory experience with the continuous glucose monitoring system (CGMS; Medtronic Minimed) in detecting hyperglycemia by comparing the self-monitoring of blood glucose (SMBG) in non-pregnant women and in pregnant women with impaired glucose tolerance and gestational diabetes.

OBJECTIVE: To assess the detection rate of hyperglycemia with a continuous glucose monitoring system compared to a self-monitoring blood glucose profile in non-pregnant, non-diabetic pregnant women, and patients with impaired glucose tolerance or gestational diabetes.. METHODS: Eight non-pregnant (NP) and 56 pregnant women (17 dietary-treated gestational diabetics (GDM), 15 women with impaired glucose tolerance (IGT), and 24 non-diabetic pregnant women (NDP)) underwent a 72-hour measurement with the CGMS (Medtronic Minimed, Northridge, CA, USA). Self-monitored blood glucose measurements, performed 30 minutes before and 120 minutes after each meal, were compared to the duration of hyperglycemia monitored by the continuous glucose monitoring system. RESULTS: No clinically observable infection was found at the subcutaneous tissue where the electrode was placed. A statistically significant difference was found between the groups in body mass index, HbA1c, and in gestational age, but not in age or parity. Using the self-monitored blood glucose (SMBG), 88 % (7/8) of the NP and 54 % (13/24) of the NDP had no measurement above 6.7 mmol/l. However, 17 % (4/24) of the NDP and 40 % (6/15) of the IGT showed more than two measurements above 6.7 mmol/l compared to 24 % (4/17) of the dietary-treated GDM. The differences between these groups were not significant (p = 0.21). The mean durations (+/- SD) of hyperglycemia above 6.7 mmol/l/24 h were: NP 111 +/- 120 min, NDP 138 +/- 120 min, IGT 381.8 +/- 295 min, and GDM 190 +/- 155 min, p = 0.017; above 7.8 mmol/l/24 h NP 24 +/- 49 min, NDP 38 +/- 47 min, IGT 170.7 +/- 190 min, and GDM 64 +/- 88 min, p = 0.016; and above 8.9 mmol/l/24 h NP 9.3 +/- 25 min, NDP 7.5 +/- 14 min, IGT 59 +/- 77 min, and GDM 14 +/- 21 min, p = 0.026. There was no significant difference in the fetal outcome or rate of birth percentiles using the sensor data. CONCLUSIONS: The use of the sensor in pregnant women is unproblematic. a) The CGMS detected more frequent and longer durations of hyperglycemia in GDM compared to non-diabetic pregnant women than the SMBG. b) Women with an IGT exhibited higher glucose levels than patients with gestational diabetes. c) The clinical importance of these hyperglycemic intervals, e.g. with respect to the risk for macrosomia, must be assessed in larger trials.

Release of anti-PAF activity from PAF-binding human ovarian cancer cells in culture.

The human ovarian cancer cell line EFO-27 in culture spontaneously produced anti-PAF activity, which eluted from HPLC in the range of synthetic PAF. The activity therefore appears to be due to an antagonistic PAF-analogue. It was detected by a suppressed PAF-induced platelet aggregation in vitro. EFO-27 cells were found to be able to bind synthetic PAF with saturable binding kinetics. This binding led to reduced cell proliferation. The production of anti-PAF activity by EFO-27 cells resembles an autocrine growth regulation in the light of recent findings that other malignant transformed cell lines produce PAF-like activity in vitro if stimulated appropriately.

Preliminary report on the application of pulsed CO2 laser radiation on root canals with AgCl fibers: a scanning and transmission electron microscopic study.

Fifteen maxillary central incisors were treated in vitro with pulsed CO2 laser radiation (wavelength:9.6-microns pulse duration:135-microseconds pulse energy:60 mJ energy density:12 J/cm2) delivered by an AgCl fiber into the root canal. Preliminary results show opening of dentin tubules as well as fused areas of hydroxyapatite in the root canal after laser treatment. Temperature measurement at the root surface showed that 40 degrees C was not exceeded. These preliminary results show the ability of this laser system to open dentin tubules and to fuse hydroxyapatite but further development in fiber technology is necessary to achieve predictable results.

An experimental study of bio-availability of fluoride from dietary sources in man.

After single, oral doses, 8 h profiles of fluoride (F) concentrations in plasma and saliva, and 24 h urinary excretions were determined in healthy adult volunteers. Bio-availability of F from dietary sources was evaluated in relation to that of NaF. Between 2 and 10 mg of F administered all 3 variables were dose-dependent. However, digestion, the chemical state of F, and interaction with accompanying foods may modify the kinetics of F passage through the human body. Low bio-availabilities were observed for most solid foods such as fish and algal flour and for mammalian and fish bones, when used as typical components of fluoride-rich foods such as meat- and fish-products. This data is important in the determination of optimum levels of F supplementation in human nutrition for caries-prevention programmes.

Increased levels of vascular endothelial growth factor in bronchoalveolar lavage of patients with bronchial carcinoma effect of tumour activity and oxidative stress due to radio-chemotherapy?

BACKGROUND: Vascular endothelial growth factor (VEGF) plays a crucial role in physiological and neoplastic angiogenesis. Moreover, VEGF has been found to be upregulated by conditions associated with the generation of free radicals and reactive oxygen intermediates. In patients with cancer, studies to evaluate VEGF as a measure of tumour activity were carried out. We tested the hypothesis that VEGF is additionally affected by oxidative stress due to anticancer therapy. Moreover, the suitability of epidermal growth factor (EGF) to estimate tumour activity was studied. PATIENTS AND METHODS: 60 patients with non-small cell lung cancer (NSCLC) covering different therapy progress and modalities underwent bronchoalveolar lavage. VEGF-, EGF-, albumin- and total protein-concentrations in bronchoalveolar lavage fluid (BALF) and VEGF-levels in blood plasma were studied. RESULTS: BALF VEGF-levels were increased in patients with advanced NSCLC before and in anticancer therapy. In patients who had received radiotherapy to the lung prior to chemotherapy, VEGF concentrations were noticeably higher than under sole chemotherapy. Pulmonary endothelial hyperpermeability was found in patients with recently diagnosed tumours and patients undergoing anti-cancer therapy. Evaluation of EGF-levels in BALF revealed no significant influence of tumour activity or cancer therapy on this parameter. CONCLUSION: BALF-levels of VEGF are affected by tumour activity and oxidative stress due to anticancer therapy.

Vitamin status of inpatients with chronic cephalgia and dysfunction pain syndrome and effects of a vitamin supplementation.

66 female inpatients with dysfunction pain syndrome, chronic cephalgia and facial pain participated in a randomized, placebo-controlled double-blind study, half the patients receiving a multivitamin preparation for 12 days and the other half a placebo. The biochemically determined vitamin status at the start of the study revealed gaps in the coverage of the vitamin supply, particularly with regard to the vitamins thiamin, riboflavin and folic acid. 65% of the patients showed a subclinical vitamin deficiency of two or more vitamins. With regard to the development of pain during the study no statistically significant differences could be determined, however, between the active-treatment and placebo groups. Nevertheless, a clear reduction in pain was more frequently observed in the active-treatment group, and a deterioration of pain more frequently in the placebo group. A reduction in pain was reported more often by patients in whom the values of alpha-ETK, alpha-EGOT, folic acid and cyanocobalamin improved in the course of the study. Vitamin administration in physiological doses evidently have only weak effects on the behavior of pain; analgesic vitamin effects may be presumed in the case of correspondingly high therapeutic doses for a prolonged period.

Emergency department duty: a training model for the future.

Air National Guard (ANG) medical units perform 2 weeks of active duty training each year to develop and maintain essential medical skills. Providing meaningful training is, however, a great challenge to both the Guard unit and its active duty counterpart. Too often, annual training is not a relevant learning experience and so the ability of some Guard medical units to respond to actual medical taskings is compromised. The 135th Tactical Clinic, an ANG medical unit, devised and implemented a unique plan--a plan particularly relevant to the medical support requirements of Operation Desert Shield.