Psychological adjustment to invasive surgical and medicamentous tumor treatment of osteosarcoma patients with rotation-plasty]

Ten patients with osteosarcomas and rotation plasties made themselves available for a psychological survey. The time elapsed after their operations was between two and ten years, giving an average of six years. All patients were free of tumours at the time of the follow-up examination. Both in personal interviews and in psychological tests, it was possible to observe a very positive development of these patients' attitudes. Contributory factors in this context were discussions with the doctors administering treatment, the cheerful atmosphere of the hospital and the nursing staff, the physicotherapists and ergotherapists, and the excellent social support which all those interviewed also received from their relatives. Continuous positive motivation, a favourable social dialogue and patients' ability to control their own lives would appear to be the key factors in helping patients to come to terms with their illness.     

Radiotherapy for pediatric brain stem glioma: radiation dose, response, and survival.

An analysis of 39 patients under 20 years of age with brain stem glioma treated with radiotherapy between 1977 and 1991 was undertaken. Twenty-eight (71.2%) of the patients responded well to initial radiotherapy, and 11 (28.8%) responded poorly. Median survival for the total patient population was 10 months. Response rates and median survivals were influenced by radiation dose: 45.5% and 9 months at doses less than 4499 cGy (n = 11), 83.3% and 13 months at doses between 4500 and 5499 cGy (n = 12), 66.7% and 11.5 months at doses between 5500 and 6499 cGy (n = 9), and 100% and 10 months at doses more than 6500 cGy (n = 7). Multivariate analysis revealed the response to initial radiotherapy was the only predictor of survival with radiation doses up to 6499 cGy. Four of the patients who responded well demonstrated radiological and/or histological calcification within or around the tumor at the time of clinical deterioration. Radiation injury was confirmed in two autopsy cases. The possibility that intratumoral radiation injury causes clinical deterioration is suggested.     

Ex vivo removal of IgE in atopic asthma by extracorporeal plasmoimmunoadsorption (EPIA): development of a clinical adsorbent

We have developed an immunoadsorbent (IA) for ex vivo removal of IgE after in vitro screening of matrix (Sepharose and tresyl-activated Toyopearl) and ligand (monospecific rabbit polyclonal anti-IgE antiserum and monoclonal antibodies (Abs) or their Fab fragments). Specific adsorptive capacity (SAC) for IgE was maximal in Sepharose-based IA with both types of Abs. Fab-containing IA on Sepharose retained 70-90% of the SAC of native Ab-containing IA. Toyopearl-based IA showed comparable SAC under static conditions but worked unsatisfactorily under continuous flow conditions. To assess the complement-activating capacity (CAC) of IA in vitro anaphylatoxin (C3a, C4a, C5a) generation was applied. CAC was directly related with the amount of immobilized Ab ligand, without depending on Ab specific activity. Fab-containing IA showed more CAC than native Ab-containing IA, and polyclonal IA more than monoclonal IA. Therefore, IA for IgE apheresis were prepared from native monoclonal Abs and CNBr-activated Sepharose CL 4B under aseptic conditions and packed into a glass column. This IA was used in 17 clinical IgE apheresis treatments of five atopic asthma patients. No substantial side effects were observed; in vivo IA effectively removed IgE from plasma (83 to 98%).     

Non-linear pharmacokinetics of high-dose intravenous verapamil

Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil. Methods We studied nine patients [ seven males, two females; median age 46 years (range, 31–57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg⁻¹ followed by 12 h continuous i.v. infusion at 0.20 mg kg⁻¹ h⁻¹ ), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg⁻¹ h⁻¹ ). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL=ko/C_ss ) and renal clearance (CLr) of verapamil and nor-verapamil. The C_ssvs rate relationship was fitted to a Michaelis-Menten equation: C_ss=ko(K_m+C_ss )/(V V_m ). Results CL was dose-dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL±s.d. were 0.51±0.31, 0.38±0.16, 0.32±0.18, and 0.27±0.11 l h⁻¹ kg⁻¹, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg⁻¹ h⁻¹; P=0.0001). C_ss increased more than proportionally to the dose rate and the C_ssvs rate relationship was best defined by a Michaelis-Menten equation (K_m=730 μg l⁻¹; V V_m=0.55 mg kg⁻¹ h⁻¹ ), (r=0.994; P=0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose. Conclusions These findings suggest a non-linear, capacity-limited metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500–2500 ng ml⁻¹ ) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.     

Characterization of purinoceptors mediating depolarization of rat isolated vagus nerve.

1. As part of a broader study to characterize neuronal purinoceptors, the effects of adenosine 5'-triphosphate (ATP) and a range of ATP analogues were investigated on the extracellularly recorded membrane potential of the rat isolated vagus nerve, using a 'grease-gap' technique. 2. ATP evoked depolarization of the rat vagus nerve. The concentration-effect curve to ATP was not monophasic: at the lower concentrations (1 x 10(-5)-1 x 10(-3) M) the curve was shallow (< 50% of the near maximal response to 5-hydroxytryptamine (5-HT)) whilst at higher concentrations the relationship between concentration and amplitude of depolarization was steeper (> 135% of the response to 5-HT at the highest concentration tested, 1 x 10(-2) M). On washout of the high drug concentrations large after-hyperpolarizations were often observed. 3. alpha,beta-methylene ATP (1 x 10(-6)-3 x 10(-4) M), beta,gamma-methylene ATP (1 x 10(-6)-1 x 10(-3) M), and 5'-adenylylimidodiphosphate (beta,gamma-imido ATP; 1 x 10(-6)-1 x 10(-3) M) were all more potent than ATP and produced large depolarizations of the rat vagus nerve at the highest concentrations tested (> 150% of the response to 5-HT). The overall rank order of potency was alpha,beta-methylene ATP > beta,gamma-methylene ATP = beta,gamma-imido ATP > ATP. 4. In contrast, 2-methylthio ATP (1 x 10(-6)-1 x 10(-3) M) produced relatively small depolarizations (< 100% of the response to 5-HT). As was the case with low concentrations of ATP, the concentration-effect curve to 2-methylthio ATP was very shallow.(ABSTRACT TRUNCATED AT 250 WORDS)     

The avidity of specific IgM detected in primary rubella and reinfection

An IgM capture enzyme-linked immunosorbent assay for rubella-specific IgM was used to assess the avidity of specific IgM by comparing the results obtained with and without a mild protein denaturant in the washing fluid used after incubation of IgM with rubella haemagglutinating antigen. An avidity index (AI) was calculated with AIs less than 50% considered to indicate low avidity. Sera from recent primary rubella, rubella reinfection and from patients persistently reactive for specific IgM were tested. Urea and diethylamine (DEA) were compared as the protein denaturants. Twenty-six of 28 sera from cases of primary rubella gave an AI less than 50% with DEA, compared with 25 of 28 with urea. Seventeen of 20 sera from cases of reinfection gave an AI greater than 50% with DEA whereas only 14 of 20 had a similarly high avidity with urea. Eight of 10 sera from 4 cases of persistent specific IgM reactivity gave AIs greater than 50% with DEA, although this was reduced to 5 when urea was used. Thus a difference has been demonstrated between the avidity of specific IgM in primary infection from that demonstrated after a secondary antigenic challenge (reinfection). This may help in serologically distinguishing primary infection from reinfection.     

Retinoblastoma. The relationship of proliferating cells to blood vessels

In 150 retinoblastomas the authors found a uniform thickness of the cuff of viable retinoblastoma cells that surrounds blood vessels. The mean thickness was 98.7 microns with a standard deviation of 11.9 microns. The cross-sectional area of the cuff was negatively correlated with the mitotic activity in the cuff and positively correlated with the diameter of the central vessel. The mitotic activity in the cuff of cells was inversely related to the distance from the central blood vessel. When the cuff was divided into three concentric rings, the inner ring contained a mean of 6.2 mitotic figures, the middle ring contained a mean of 2.9 mitotic figures, and the outer ring contained a mean of 0.6 mitotic figures. This pattern of growth is similar to that observed in other rapidly growing neoplasms in humans and experimental animals. In these tumors this pattern results from reduction in oxygen tension with increased distance from the central blood vessel.     

Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine

Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.