The use of naloxone to facilitate the generation of the locomotor rhythm in spinal cats. The locomotor rhythm evoked by perineal stimulation in clonidine-treated acute and chronic spinal cats can be produced more easily when the opioid receptor antagonist naloxone is also administered. Naloxone increases the frequency of the locomotor rhythm and decreases the intensity of skin stimulation required for evoking the rhythm. A useful property of naloxone is that it can restore the locomotor rhythm when the rhythm wanes, thus prolonging the time period over which locomotor activity can be generated. Administration of naloxone without clonidine does not enable the locomotor rhythm to be generated by skin stimulation, but it does reduce the concentration of clonidine required for the expression of a robust rhythm and may increase the chance of a successful preparation. We conclude that naloxone is a useful pharmacological tool for studies on the locomotor pattern generator.


Separation of synaptic and spike activity in intracellular recordings for selective analysis. A software spike filter has been developed which allows the separation of synaptic activity and action potentials in intracellular recordings. The algorithm uses the different velocities of the membrane potential during synaptic and spike activity and a time window to identify action potentials. When spikes are recognized, they are removed and the membrane potential is substituted by interpolated values. The spike filter makes possible a separate quantitative evaluation of postsynaptic potentials and spike activity. Thus a comprehensive characterization of neuron activity can be obtained. The spike filter is part of a modular software package designed for the evaluation of neurobiological data.


Model invariant method for extracting single-channel mean open and closed times from heterogeneous multichannel records. We present a proof that the mean open (and closed) times of the individual channels in a multichannel record can be found in a model-independent fashion. As the results are model independent, they can be derived by assuming the simplest model for all the channels, namely that they all have the basic CLOSED in equilibrium with OPEN scheme. In particular, the method can be applied to patches where the channel population is heterogenous with respect to open probability. Multichannel simulations are performed to test the limits of applicability of this method to restricted amounts of data. One conclusion is that increasing the number of channels does not substantially reduce the errors in estimating the mean times, in spite of the 'increased information' present. We also prove the general applicability of the algorithm of Fenwick et al. (1982) in estimating the mean times without knowledge of the number of channels present, and discuss its limitations. An illustration using experimental data is also given.


Continuous scan cyclic voltammetry (CSCV): a new high-speed electrochemical method for monitoring neuronal dopamine release. This report describes a new form of fast cyclic voltammetry which samples electrochemical reactions of dopamine at one every 10 ms. We have called this technique 'continuous scan cyclic voltammetry' (CSCV). The technique uses a carbon fibre microelectrode which is connected to a continuously active sine-wave source. The applied voltage is a 100 Hz precision sine wave. Faradaic signals due to cycles of continuous oxidation and reduction of dopamine at the tip of the electrode can be observed superimposed on a fixed charging current. The technique is insensitive to moderate concentrations of ascorbate as a depletion zone for ascorbate is rapidly established around the electrode. In a brain slice preparation the technique can show the time course of dopamine release on a millisecond time scale. It should prove a valuable new tool for the investigation of dopamine transmission in the brain.


Intracellular recording from dopamine neurons in the substantia nigra: double labelling for identification of projection site and morphological features. We have adapted an intracellular recording technique that allows differentiation of dopamine neurons in vitro based on their projection sites and morphology. We pre-labelled 'nigrostriatal' dopamine neurons in vivo by stereotaxically injecting rhodamine-labelled microspheres (RFM) into the dorsal striatum. Following slice preparation, dense neuronal labelling with RFM was observed in the medial two-thirds of the substantia nigra zona compacta. The visible neurons in the superficial layers were not viable; consequently, we recorded from dopamine neurons that were located directly below the clusters of fluorescent neurons. Each recorded neuron was subsequently filled with N-(2-aminoethyl) biotinamide (1) to confirm whether it projected to the dorsal striatum (by presence of both RFM and biotinamide) and (2) to examine its morphological features. Four of 7 dopamine neurons successfully recovered were double labelled and exhibited multipolar cell bodies with dendrites projecting into the zona reticulata. No differences in the resting membrane potential, spontaneous activity, or membrane response to constant current injections were observed between the confirmed nigrostriatal dopamine neurons and the others. Our technique should allow pharmacological manipulations of selective dopamine pathways in vitro and help in elucidating various factors responsible for differential regulation of populations of dopamine neurons.


Extracellular perfusion controller for electrophysiology. This paper describes the design and utility of a perfusion controller to facilitate the handling of multiple extracellular solutions. The controller consists of an interface box with both manual and computer controls and a set of solenoid valves. This provides remote handling of the switching of multiple solutions into an experimental chamber. It is described how this system can be used in whole-cell patch-clamp experiments to measure various ion channel currents as well as Na/K pump currents. Other possible uses are discussed along with suggestions for interfacing the perfusion controller with existing perfusion systems.


The playground maze: a new method for measuring directed exploration in the rat. A new test, called the 'playground maze', is described. Rat exploratory responses to a single novel object are measured in the context of responses to 7 familiar objects in a familiar environment. Responses are measured as time spent in areas around the objects on a circular open field. These times are expressed as percentages of the total time spent exploring all the objects and a value which is significantly greater than the expected chance level (12.5%) indicates a novelty response. The paths traversed by the animals on the maze are also recorded and the lengths of these give a measure of locomotion. Preliminary experiments on the effects of chlordiazepoxide (CDP) (1-5 mg/kg) and amphetamine (1.5-4 mg/kg) are reported. CDP significantly increased the novelty response but had no effect on locomotion. Amphetamine treatment at 4 mg/kg abolished the response to novel objects while lower doses (1.5 and 2 mg/kg) did not affect it. All 3 doses of amphetamine significantly increased locomotion. This test provides a new way of measuring the exploratory response to novelty under low stress conditions and allows the separation of drug effects on directed exploration and locomotion.


Construction of a microdialysis probe with attached microinjection catheter. We describe a microdialysis probe with attached side catheter for making submicroliter injections at the site of the probe in the awake, freely moving rat. This design allows the local application of drugs which cannot be applied in the perfusion medium either because of their inability to pass through the dialysis membrane or because of their interference with chromatographic detection of compounds of interest.


Quantitative analysis of reflex responses in the averaged surface electromyogram. The relationship between the averaged surface electromyogram (EMG) and the activity of motoneurones in reflex studies is analysed mathematically. This analysis reveals that, subject to certain conditions being met, the integral of the average of the unrectified EMG is linearly related to the activity of motor units in the muscle. This was tested with experimental data. The activity of 2 motor units, and the surface EMG, were recorded directly in a reflex paradigm. A close match was found between the integral of the average of the unrectified EMG and the summed peristimulus time histograms (PSTHs) of the units' activity. This analysis gives more quantitative measurements of the timing of motoneuronal activity in reflexes than the conventional analysis of the EMG. It also offers the potential for making quantitative measurements of changes in motor unit activity evoked by different stimuli. This analysis avoids the pitfall of the artefactual peaks that can occur in the average of the rectified EMG as a consequence of the full-wave rectification. It is concluded that the integral of the unrectified average offers a valuable adjunct to the conventional analysis in many reflex studies. The analysis can also be applied to quantitative studies of neurograms.


Monitoring neuronal activity during discrete behaviors: a crawling, swimming and shortening device for tethered leeches. An apparatus is described which facilities continuous electrophysiological recordings in segmental ganglia of leeches while the animal performs different behavioral patterns: crawling, swimming or shortening. Both the behaviors and neuronal recordings are monitored by a video camera system and can be evaluated simultaneously. The device is well suited to investigate questions of behavioral choice and neuronal decision-making mechanisms in these animals. It can also be modified to study the neural control of behavior in other aquatic animals, such as snails.


A simple and rapid method for improving recording characteristics using multibarrelled micropipettes. A method for the simple and rapid fabrication of multibarrelled micropipettes with improved signal-to-noise characteristics is described. The process of silicone coating the exterior of the multibarrel assembly was found to improve recording characteristics greatly and to reduce recording noise during the passage of ionophoretic current. This simple process of fabrication and silicone coating is completed within 15-20 min and is technically undemanding.


NeuronC: a computational language for investigating functional architecture of neural circuits. A computational language was developed to simulate neural circuits. A model of a neural circuit with up to 50,000 compartments is constructed from predefined parts of neurons, called "neural elements". A 2-dimensional (2-D) light stimulus and a photoreceptor model allow simulating a visual physiology experiment. Circuit function is computed by integrating difference equations according to standard methods. Large-scale structure in the neural circuit, such as whole neurons, their synaptic connections, and arrays of neurons, are constructed with procedural rules. The language was evaluated with a simulation of the receptive field of a single cone in cat retina, which required a model of cone-horizontal cell network on the order of 1000 neurons. The model was calibrated by adjusting biophysical parameters to match known physiological data. Eliminating specific synaptic connections from the circuit suggested the influence of individual neuron types on the receptive field of a single cone. An advantage of using neural elements in such a model is to simplify the description of a neuron's structure. An advantage of using procedural rules to define connections between neurons is to simplify the network definition.


Tissue tonometry: a useful tool for assessing filarial lymphedema. A tissue tonometer was used to assess peripheral lymphedema in patients with filariasis in a Bancroftian endemic community. Matched populations of 34 patients with Grade II and 29 patients with Grade III unilateral lower limb edema and 26 healthy subjects were assessed for leg tissue compressibility and circumference. Tonometry was performed at three fixed points on the leg using three weight levels (70, 140, and 210 gms). The mean value of compressibility for each weight level and points measured in the edematous leg were significantly less compared with the contralateral non-edematous leg in the filarial patients and the legs of healthy subjects. Patients with Grade III lymphedema were more resistant to compression than Grade II patients throughout the leg but especially at the foot. The least mean square analyses of circumference and compressibility differential values of edematous compared with non-edematous legs revealed a positive correlation at the foot in Grade II and the proximal and distal parts of Grade III lymphedema; moreover, the slopes were significantly different from zero. These findings support progressive tissue changes of edema and fibrosis first in the foot and later in the more proximal portions of the leg which correspond to progressive volume expansion with protein-rich fluid. Tissue tonometry appears to be a sensitive measure for assessing progression of both edema and fibroplasia in patients with peripheral lymphedema associated with filariasis, and, therefore, may be a useful tool to measure the efficacy of drugs commonly used to treat this condition.


Chyle leakage after blunt trauma.

Chyle leakage after blunt trauma. Three patients developed chylous leakage after major blunt trauma. In one patient with non-remitting right-sided chylothorax, lymphangioscintigraphy as well as conventional oil contrast lymphography demonstrated disruption of the thoracic duct at the aortic hiatus which eventually required transpleural mediastinal ductal ligation proximal to the fistula. The other two patients had chylous retroperitoneum and/or chylous peritoneum which was self-limited although one patient (a three-year-old boy) died of multiorgan failure from associated pulmonary contusions and cervical spine injuries. Chylous leak after non-penetrating trauma is usually attributed to hyperflexion-extension of the vertebral column with shearing of tethered lymphatics. Alternatively, sudden compression of lipemic and engorged mesenteric lymphatics, adjacent nodes and the lower thoracic duct aggravated by deformations associated with stretching and tearing motions may also directly disrupt chyle-containing lymphatics.


The efferent cardiac lymphatic pathways in the macaque monkey. In ten postmortem hearts of the Macaque monkey (M. mulatta), the coronary lymphatics were visualized using an India ink suspension in 2% gelatin. The left coronary lymphatic initially passed to the dorsal surface of the aortic arch. In five hearts, this lymphatic went directly to the cardiac lymph node, whereas in the others, it first ascended to the left superior tracheobronchial node and then interconnected with the cardiac lymph node. The right coronary lymphatic usually passed in front of the ascending aorta and common arterial (brachiocephalic) trunk and entered the cardiac lymph node. In two hearts, however, the right coronary lymphatic first ascended to an anterior transverse mediastinal node and from here lymphatics joined the cardiac lymph node. Those lymphatics that passed cephalad from the cardiac lymph node to the right anterior mediastinal nodes and the right paratracheal nodes ultimately emptied into the right venous angle. Those lymphatics that passed cephalad from the cardiac lymph node to the anterior transverse mediastinal nodes ultimately emptied into the left venous angle. In five other Macaque monkeys (M. mulatta and M. fascicularis) after marker injection (T1824 blue dye and micropulverized barium sulfate) into the living heart or pericardium, lymphatic drainage beyond the base of the heart could not be demonstrated. Whereas postmortem morphologic studies suggest that the monkey coronary lymphatic system is amenable to obstruction by removal of the cardiac lymph node and interruption of its adjacent lymphatic connections, effective methods for visualizing the mediastinal lymphatic collecting system in the living monkey must be developed before experimental cardiac lymphatic ablation can be accomplished in this species.


Development of antiserum against veiled (dendritic) cells of canine afferent lymph: implications for transplantation biology. A method is described for production of anti-veiled cell serum against veiled cells (VC) or dendritic cells obtained from canine skin lymph. By use of discontinuous Percoll gradient, VC from lymph were enriched to about 50% of the entire lymph cell population. After immunization of rabbits with the priming total dose of 10(7) VC (intramuscular, subcutaneous, intracutaneous) and with the same total booster injection (intravenous), the sera obtained were cytotoxic mainly for VC, with cytotoxin titer 1:16-1:32 and for agglutinin 1:256-1:512, respectively. Antisera used in vitro blocked the Ia and CD1 antigens of VC on smears and inhibited the accessory function of VC in cell response to phytohemagglutinin (PHA) and their stimulatory activity in mixed leukocyte reaction (MLR). In vivo, the local, intracutaneous administration of antisera led to transient depletion of VC from afferent lymph, and to reduction of mononuclear cells in the T-dependent areas in regional lymph nodes.


Lymphatic vessels in the broad ligament of the uterus in swine. The lymphatics of the broad ligament were depicted in 24 pigs by multiple interstitial injections of latex into the ovary and subserosa of the mesometrial margin of the uterine horn. Two morphologically different networks of lymphatics emanating from the uterus and ovary were established. Ovarian lymphatics leave the hilus, invariably enter the parovarian plexus, lie superficially under the perimetrium of the mesovarium, and run a parallel course closely intertwined with the blood vessels in this region. Some lymphatics are thus located close to the branches of the ovarian artery and the utero-ovarian vein. Whereas the ovarian and uterine lymphatics in the swine are not directly connected, the uterine lymphatics enter the mesovarium and lie in close proximity to both the ovarian lymphatics and nearby blood vessels.


Differentiation and maturation of growth factor expanded human hematopoietic progenitors assessed by multidimensional flow cytometry. Non-adherent cord blood and bone marrow mononuclear cells were analyzed by multiparameter flow cytometry before and at day 2, 4, 7, and 11 of culture in recombinant interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF, cord blood) or stem cell factor (SCF), IL3 and granulocyte-macrophage colony-stimulating factor (GM-CSF, BM) to assess the differentiation and maturational pathway of myeloid cells. Before cell culture cord blood contained progenitor cells (CD34+) in various differentiation stages (CD38(-)----CD38bright), mature lymphocytes, monocytes, and neutrophils, but no immature neutrophils and immature monocytes. During cell culture, all CD34+ cells acquired the CD38 antigen between day 2 and 5 of cell culture, the CD34 antigen was lost between day 5 and 11 of cell culture. Differentiation of cells into the myeloid cell lineage was characterized by the acquisition of both CD33 and CD71. The latter is indicative for the active proliferation of these cells. Maturation of the cells into the neutrophilic pathway was indicated by the acquisition of first the CD15 antigen followed by CD11b and CD16 respectively. Whereas maturation of the cells into the monocytic pathway was indicated by the acquisition of first CD11b followed by CD14 and a dim expression of both CD15 and CD16. In normal bone marrow, cells of various maturational stages are already present before cell culture. During cell culture differentiation of cells into the myeloid lineage and maturation of the cells along the monocyte and neutrophilic lineage followed identical pathways as was observed before cell culture. Differentiation and maturational pathways of cord blood and adult bone marrow were identical. The results confirm the surface-antigen-defined pathways of myeloid cell differentiation described previously for non-cultured normal bone marrow aspirates. The detailed assessment of cell maturation and differentiation of cultured cells by multidimensional flow cytometry permits the determination of the specific effects of various recombinant human growth factors on myeloid cells.


The effects of IL-1 beta and IL-4 on the proliferation and endogenous secretion of growth factors by acute myeloblastic leukemic cells. The effects of interleukin-1 beta (IL-1) and IL-4 were studied on the proliferation of acute myeloid leukemia (AML) cells. IL-1 stimulated tritiated thymidine (3H-TdR) uptake of AML cells in 8/12 cases, whereas IL-4 enhanced 3H-TdR uptake in 5/12. Combination of both factors resulted in an additive effect in 6/12 cases which could be abrogated by the addition of anti-granulocyte-macrophage colony stimulating factor (GM-CSF). To study whether IL-1, IL-4, or IL-1 plus IL-4 affects the AML progenitor cell directly or indirectly by the release of endogenous factors, supernatants of stimulated AML cells (n = 6) were analyzed for GM-CSF, IL-6, and tumor necrosis factor-alpha (TNF) production. IL-1 induced the endogenous secretion of GM-CSF, IL-6, and TNF in most cases. In contrast, no secretion of growth factors was induced by IL-4, whereas in 2 cases IL-4 suppressed the IL-1-induced secretion of GM-CSF, TNF, and IL-6. This was associated with a decline in the proliferative response to IL-1 measured in a clonogenic assay. In addition it was shown that exogenous supplied GM-CSF and TNF could raise the suppressive effects of IL-4 on the IL-1-supported proliferation. In summary these data indicate that the IL-4-supported proliferation is not caused by the endogenous secretion of GM-CSF, IL-6, and TNF. Furthermore the suppressive effect of IL-4 on the IL-1-induced proliferation in some cases may be caused by a reduced secretion of GM-CSF, TNF, and IL-6.


Interleukin 2 production and interleukin 2 receptor expression by human immature leukemic T cells. In order to determine the role of interleukin 2 (IL2) on the proliferation of leukemic cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) we studied the production of IL2, the function of IL2 receptors (IL2R) expressed on T-ALL cells and their IL-2-dependent in vitro proliferation. Leukemic cells from six out of 17 T-ALL/T-cell non-Hodgkin's lymphoma patients with a prothymocyte (stage I) or a mature thymocyte (stage III), but not with a common thymocyte (stage II) phenotype, could proliferate, in a dose-dependent manner, in response to recombinant IL2 (rIL2) and anti-Tac and TU27 moAbs as well as polyclonal anti-IL2 purified immunoglobulin G could inhibit this IL2-induced cell proliferation. Both crude or/and Amicon-concentrated media conditioned by T-ALL cells from 10 out of 13 tested patients contained IL2 activity as assessed by colorimetric biological and immunoenzymatic assays; this biologic activity was due to a 14.5 kDa molecule adsorbed by anti-IL2 antibodies in an immunoaffinity assay. Although less than 10% of fresh leukemic cells expressed IL2R alpha (Tac) chain, a 24 h cell incubation in the absence of any mitogenic stimulation induced IL2R alpha chain expression in five out of 13 patients (11-83% Tac+ cells). Morever, Tac mRNA transcripts could be detected in fresh cells from all 10 patients tested. Staining of fresh leukemic cells with an IL-2R beta-chain-specific monoclonal antibody and flow cytometry analysis revealed that 4-13% of leukemic cells were positive. Binding experiments with 125I-rIL2 showed a small number of high affinity IL2R on fresh cells from three T-ALL patients (114-200 sites/cell, dissociation constant = 101-181 pm). Finally, antibodies against IL2R alpha, IL2R beta and IL2 could inhibit both IL2 driven and spontaneous cell proliferation of most patients' T-ALL cells, although in some cases an heterogenous pattern of inhibition was observed. Taken together, these findings strongly suggest that an IL2/IL2R-dependent mechanism could be involved in the proliferation of some T-ALL cells.


Beneficial effects of post-transfusional hepatitis in acute myelogenous leukemia may be mediated by lipopolysaccharides, tumor necrosis factor alpha and interferon gamma. Post-transfusional hepatitis is often a complication in patients with acute myelogenous leukemia (AML) in whom survival is paradoxically prolonged. The etiology is unknown. In previous studies, we showed that impaired hepatic endotoxin (lipopolysaccharide, LPS) clearance in patients with acute viral hepatitis A, B, or C versus controls results in endotoxemia and tumor necrosis factor alpha (TNF-alpha) release. TNF-alpha mediates anti-proliferative and differentiating effects in AML cell lines. Interferon-gamma (IFN-gamma) released in acute viral hepatitis, acts in synergy with TNF-alpha. HL60, KG1, and U937 AML cells treated 3, 6, and 9 days with physiologically attainable TNF-alpha (10 U/ml), IFN-gamma (100 U/ml) and LPS (10 ng/ml) levels, have significantly diminished viability and cell growth versus controls. Treatment of HL60 AML cells with LPS/TNF-alpha/IFN-gamma also resulted in significantly increased monocytic pathway differentiation not seen with KG1 or U937 AML cells. HL60 AML cells treated with TNF-alpha/IFN-gamma for 6 days released endogenous TNF-alpha (1.57 U/10(6) cells) upon LPS stimulation compared to less than 0.01 U/10(6) cells in non-LPS-stimulated TNF-alpha/IFN-gamma-treated cells or untreated cells (p less than 0.0001). Untreated HL60 AML cells co-cultured with HL60 cells pretreated for 6 days with TNF-alpha/IFN-gamma and then subjected to LPS stimulation had significantly diminished cell growth compared to controls (p less than 0.0001). This effect could be reversed with anti-TNF-alpha antibody, supporting the concept that endogenous TNF-alpha release by LPS/TNF-alpha/IFN-gamma treated HL60 AML cells may act by paracrine means to suppress growth of other AML cells. The beneficial effects of post-transfusional hepatitis in AML patients may be mediated via LPS/TNF-alpha/IFN-gamma-induced AML cell growth suppression and/or terminal differentiation in which AML cells participate by releasing TNF-alpha after being acted upon by LPS/TNF-alpha/IFN-gamma. Endogenously released TNF-alpha might then act by autocrine/paracrine means to mediate further suppression and terminal differentiation.


Inhibitory effects of AcSDKP on the mixed lymphocyte reaction (MLR). Part I. MLR with mouse spleen cells. AcSDKP (inhibitor of entry into cycle of pluripotent hemopoietic stem cells) is able to decrease mixed lymphocyte reaction intensity when H-2 incompatible allogeneic spleen cells are used as stimulators. This is a first approach to determining whether AcSDKP has potential therapeutic value for clinical bone marrow transplantation.


Inhibitory effects of AcSDKP on the mixed lymphocyte reaction (MLR). Part II. Human whole blood cells. AcSDKP is a physiological negative regulator of hematopoietic stem cell proliferation. To investigate the applicability of AcSDKP in the prevention of graft-versus-host disease, this tetrapeptide was tested in mice and showed an inhibitory effect on the mixed lymphocyte reaction (MLR). In this paper we report MLR using human whole blood cells. The maximum inhibitory effect (50%) was obtained at 2.5 ng/ml AcSDKP. All experiments showed a constant dose response. Experiments are now being conducted to elucidate the mechanism of this inhibition.


Dolastatin 10 and dolastatin 15: effects of two natural peptides on growth and differentiation of leukemia cells. The effects of two natural peptides, dolastatin 10 and dolastatin 15, on growth and differentiation of hematopoietic cells were studied using freshly explanted leukemia cells and continuous leukemia cell lines. The proliferation of several myeloid cell lines and of growth-factor-stimulated peripheral blood cells from patients with acute myeloid leukemia (AML) was efficiently inhibited by the two agents at concentrations between 1 and 0.01 nM. Growth inhibition was dose-dependent and reversible. Neither of the dolastatins exhibited significant cytotoxicity on dividing cells, nor did they interfere with the viability of resting cells. The 12-O-tetradecanoylphorbol 13-acetate or bryostatin I induced differentiation of AML cells was not affected by the dolastatins. Short-term exposure to the phorbol ester conferred reduced sensitivity of the cell line HL-60 to the antiproliferative effect of the drugs. Our data suggest that the dolastatins alone or in combination with other drugs could exert a role in the treatment of human myeloid leukemia.


Resistance circumvention strategies tested in clinical leukaemia specimens using the MTT colorimetric assay. We have used a 4-day MTT colorimetric assay to study drug sensitivity of leucocytes from leukaemia patients and from normal donors. Response to Adriamycin, vincristine, aclacinomycin A, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), and melphalan has been determined, together with the effects of the resistance modifiers verapamil, cyclosporin A, and ethacrynic acid. Sensitivity of chronic lymphoblastic leukemia (CLL) lymphocytes to vincristine was much greater than that of normal lymphocytes or of leucocytes from myeloid leukaemia patients. These cells were also more sensitive to melphalan. Verapamil and cyclosporin A at clinically achievable doses of 1 microgram/ml produced significant chemosensitisation in normal and leukaemic specimens, but the sensitisation ratio was greater than or equal to 2 only in a minority of specimens, except in the case of sensitisation to vincristine seen in the majority of CLL specimens. Sensitisation was generally greater in the more chemo-resistant specimens. The ratio of sensitivities of cells to Adriamycin compared with aclacinomycin A was greatest in the more Adriamycin-resistant specimens which supports the idea that cross-resistance between these agents may not be great. This was not, however, true for the ratio of Adriamycin/MX2 sensitivity. Use of the MTT assay may allow the identification of patients who would benefit from treatment with resistance modifiers or with 'low-resistance' anthracyclines.


Phase II clinical trial of carboplatin in relapsed and refractory leukemia. Carboplatin is a second-generation platinum complex drug which has demonstrated activity against a variety of neoplasms including acute leukemia, particularly when given by continuous intravenous (i.v.) infusion. Adults with acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), either refractory or in first or second relapse, were given a continuous i.v. infusion of carboplatin at a dose of 315 mg/m2 daily for 5 days. A second course was given if the bone marrow at day 14 showed persistent leukemia. If the marrow was hypoplastic, treatment was delayed until marrow recovery was documented. Those with residual leukemia were given a second course. Those achieving complete remission (CR) were given an additional course as consolidation. Of the 46 eligible patients entered (36 AML and 10 ALL) eight achieved CR (17%) of which 6 were AML and 2 ALL. Of nine primary refractory patients, two achieved CR, one AML and one ALL. Excluding the inevaluable patients (protocol violations, patient refused further therapy, early deaths prior to day 14, the CR rate was eight of 28 (29%). All except two CRs required two courses of induction. The non-hematologic toxicity was minimal except for renal and auditory toxicity. Renal toxicity greater than grade 2 was seen in 17 patients and was associated with concomitant use of nephrotoxic antibiotics. In two patients, renal failure was a major factor in the cause of death. Ototoxicity was observed in 11 patients, but was grade 3 in only three. There were 18 deaths during the study. Fourteen died of infection, two died of infection and hemorrhage, one died of hemorrhage while aplastic, and one died of other causes. This trial indicates that carboplatin is an active agent in acute leukemia and warrants further investigation.


Prognostic relevance of serum beta 2-microglobulin in acute myeloid leukemia. Serum levels of beta 2-microglobulin (S-B2m) were analysed at diagnosis in 69 cases of acute myeloid leukemias (AML) as a possible prognostic indicator. S-B2m was correlated to various clinical and laboratory features and with respect to response to chemotherapy and following clinical outcome. S-B2m was found to be increased (greater than 3 mg/l) in 40.6% of tested patients and, in particular, in the monocytic variants (M4, M5) of AML (4.2 versus 2.3 mg/l, p less than 0.01). S-B-B2m values paralleled white blood cell count, serum lysozyme levels and expression of monocytic membrane markers at presentation, but no correlation was found with age, renal function or immunological myeloid antigens. Increased levels of S-B2m were associated with a lower likelihood of obtaining a complete remission (25 versus 58.5%, p less than 0.01), while in the multivariate analysis S-B2m greater than 3 mg/l and white blood cell count greater than 20 x 10(9)/l were independent variables significantly influencing disease-free survival in responsive patients (five years DFS for S-B2m greater than or less than 3 mg/l: 28 versus 62%, p less than 0.05). In conclusion, the measurement of S-B2m at diagnosis may have prognostic relevance in AML.


Anti-sense oligodeoxynucleotides--promises and pitfalls. The high specificity of binding of oligodeoxynucleotides to their target mRNA has resulted in suggestions that these compounds may be useful as therapeutic agents against human cancer. While many successful anti-sense experiments have been reported in the literature, significant obstacles to widespread therapeutic use remain. These include nuclease sensitivity, non-sequence specificity, and uncertainties regarding optimum choice of mRNA target. Other significant problems include lack of information concerning cellular pharmacology and pharmacokinetics, and relatively little data concerning optimum dosing schedules. This review attempts to provide current information about these issues, which have such a strong impact on this exciting and rapidly growing field.


Cell surface proteins of chicken hematopoietic progenitors, thrombocytes and eosinophils detected by novel monoclonal antibodies. E26 is an acute avian leukemia virus that contains two nuclear oncogenes, v-myb and v-ets, and that is capable of transforming early cells of the erythroid and myeloid lineages. In another study, we have found that TPA (phorbol 12,13-dibutyrate) treatment of E26-transformants displaying an 'early erythroid' phenotype results in the production of cells with either myeloid or eosinophil characteristics. To analyze this induction in greater detail we have produced a panel of four monoclonal antibodies against E26-transformants before and after TPA-induced differentiation. Two antibodies, MEP21 and MEP26, reacted with proteins of 150 and 47-60 kDa, respectively, which are expressed on the surface of E26 progenitor cells but whose expression is extinguished following TPA-induced differentiation. A third antibody, EOS47, recognizes a 100 kDa molecule that is expressed on the surface of TPA-induced peroxidase positive cells (an enzyme that in avian species is restricted to cells of the eosinophilic lineage). MEP21, MEP26, and EOS47 do not react with lymphoid, myeloid, or more mature erythroid lineage cell lines. The fourth antibody, MEP17, recognizes a heterodimer of 140 and 150 kDa chains which is expressed at high levels by E26-transformed progenitor cells and at lower levels by TPA-induced cells. Further biochemical characterization of the MEP17 antigen revealed a structure similar to that of the leukocyte adhesion molecule VLA-4; a member of the integrin family of adhesion proteins. All four antibodies react with subpopulations of cells in the bone marrow and spleens of 1-day-old chickens. Although the MEP21 and MEP26 antibodies do not appear to react with mature cells of most hematopoietic lineages they are expressed at high levels by mature thrombocytes. In addition, MEP17 is expressed at high levels by the majority of bursal B-cells, thrombocytes, and more weakly by thymocytes. The reagents described should be useful as markers for the study of development, migration, and differentiation of normal avian hematopoietic progenitor cells and eosinophilic precursors, and for the study of retrovirus-induced neoplasia.


Musculoskeletal and soft tissue Aeromonas infection: an environmental disease. During a 4-year period from November 1985 to November 1989, Aeromonas was isolated from wounds and soft tissues with clinical evidence of infection in 28 patients at our institution. Of the 28 patients, 23 (82%) had sustained an acute open or penetrating injury, more than half of which (13 of the 23) were water-related trauma. One patient had Aeromonas osteomyelitis. Five patients had no history of trauma, and three of these five had an underlying chronic disease. Treatment included débridement and antimicrobial agents. Susceptibility testing on 25 isolates from 23 patients showed uniform resistance to ampicillin and considerable resistance to cefazolin sodium (68%), but all isolates were sensitive to gentamicin sulfate, cefuroxime sodium, and the third-generation cephalosporins.


Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period. Between 1961 and 1990, 52 patients with biopsy-proven familial amyloidosis born in North America were examined at the Mayo Clinic. At the time of diagnosis of familial amyloidosis, 83% of these patients had peripheral neuropathy, 33% had autonomic neuropathy, and 27% had cardiomyopathy. Renal disease was noted in fewer than 10%, and liver involvement was rare. The median age at diagnosis was 64 years. The sensitivity of various diagnostic biopsies was similar to that for primary amyloidosis: deposits of amyloid were found in 77 and 78% of the subcutaneous fat aspirates or rectal biopsy specimens, respectively, and in 41% of specimens of bone marrow. The median duration of survival of 5.8 years for patients with inherited amyloidosis was superior to that for patients with primary amyloidosis. When patients were stratified by organ involvement, the survival of patients with familial amyloidosis remained superior. The presence of cardiomyopathy and an interactive variable of age and the presence of autonomic neuropathy were powerful predictors of survival. Of the 52 patients, 22 died, 12 (55%) of cardiac failure or cardiac arrhythmia. Nine patients (41%) died of inanition in conjunction with progressive peripheral or autonomic neuropathy. Transthyretin was identified by immunohistochemical studies in 31 of the 34 tissue specimens tested. A transthyretin mutation was identified in 24 of the 31. A transthyretin mutation was found in five additional patients for whom tissue was unavailable for immunostaining.


Laparoscopic cholecystectomy: operative technique. Laparoscopic cholecystectomy has become the routine procedure for most patients with symptomatic cholelithiasis. At our institution, a two-surgeon, four-cannula technique is used. In almost all patients, a pneumoperitoneum can be established with use of a closed technique. Adherence to standard operative principles and careful attention to details in the laparoscopic technique will routinely result in the safe completion of laparoscopic cholecystectomy. Cautery provides excellent hemostasis during dissection of the gallbladder from its attachments. Cholangiography through the gallbladder or the cystic duct is easily performed in selected patients. Minimal perioperative care is necessary for patients who undergo laparoscopic cholecystectomy, and the hospitalization time is usually less than 24 hours.


Laparoscopic cholecystectomy: early Mayo Clinic experience. Prospective data and follow-up information were collected on the initial 200 patients who underwent laparoscopic cholecystectomy at the Mayo Clinic. The operation was completed laparoscopically in all but five patients, who required conversion to laparotomy because of dense scarring or stones in the common bile duct. The median surgical time was 85 minutes. The major postoperative complications were retained stones in the common bile duct (in seven patients), intraperitoneal hemorrhage that necessitated transfusion (in two patients), and intra-abdominal abscess and pulmonary infection (in one patient each). The median hospital stay was 1 day (range, 0 to 8 days), and the median times to full activity and normal employment were 8 days and 12 days, respectively. Laparoscopic cholecystectomy is associated with a low frequency of complications in most patients with symptomatic gallstones and allows a rapid return to normal activity. Currently, laparoscopic cholecystectomy is the treatment of choice for most patients with symptomatic cholelithiasis.


A clinical update on chronic lymphocytic leukemia. II. Critical analysis of current chemotherapeutic modalities. Not all patients with B-cell chronic lymphocytic leukemia require therapy. Patients with stable early stage disease do not need treatment, whereas those with progressive early stage disease or advanced stage disease do. The standard initial therapeutic regimen is orally administered chlorambucil and prednisone. The overall response rate to initial chemotherapy is approximately 80%; the median duration of response is 2 years. Conventional chemotherapy, however, does not provide long-term remission for patients in whom the disease becomes refractory to chlorambucil. For such patients, alternative treatment approaches including the use of purine nucleoside analogues or bone marrow transplantation may be considered. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are three analogues of the naturally occurring deoxypurine nucleoside, deoxyadenosine, and all have shown activity in chronic lymphocytic leukemia. Overall response rates of 57 to 79% have been reported with use of fludarabine. A dose-related toxic effect is myelosuppression. Experience with bone marrow transplantation is limited. The number of eligible patients with histocompatible sibling donors is low. The future role of allogeneic bone marrow transplantation in patients with B-cell chronic lymphocytic leukemia will depend on the ability to identify poor-risk groups and the long-term therapeutic efficacy of the purine nucleoside analogues or other new agents.


Video-assisted thoracic surgical procedure: management of a solitary pulmonary nodule. Solitary pulmonary nodules continue to challenge all diagnostic skills. Herein we describe video-assisted thoracic surgical intervention, a new, minimally invasive technique that aids physicians in obtaining a definitive histologic diagnosis in a select group of patients with an indeterminate solitary pulmonary nodule.


Nicotinic acid-induced toxicity associated with cytopenia and decreased levels of thyroxine-binding globulin. We report the occurrence of cytopenia and hypothyroxinemia attributed to decreased levels of thyroxine-binding globulin in patients receiving nicotinic acid. We describe two patients in whom hypothyroxinemia developed while they were taking nicotinic acid; these patients also had decreased levels of thyroxine-binding globulin. Results of all thyroid function tests returned to normal when use of the nicotinic acid was discontinued. In one patient, leukopenia and thrombocytopenia developed during nicotinic acid therapy alone. These conditions were reversed after the drug regimen was discontinued. In another patient, leukopenia and thrombocytopenia developed during combination nicotinic acid and lovastatin therapy. When administration of both drugs was discontinued, the hematologic abnormalities, which could have been due to either nicotinic acid or lovastatin, diminished. We suggest that cytopenia may develop in patients receiving nicotinic acid; thus, thyroid function tests should be interpreted in light of a possible decreased level of thyroxine-binding globulin.


Thermoregulation and fever in normal persons and in those with spinal cord injuries. Thermoregulation and fever are primarily mediated through the hypothalamus and its effector mechanisms. In persons with complete spinal cord injuries above T-6, thermoregulation is substantially impaired because of the interruption of neuronal pathways to and from the hypothalamus. These same pathways are important in the production of fever in response to infections, and injury to these pathways in patients with high-level spinal cord injuries should diminish their ability to mount a febrile response. In clinical practice, however, measurements of body temperature are used to make decisions in patients with spinal cord injuries in a manner similar to that in patients without spinal cord injuries. In this article, we review the literature on thermoregulation and fever in normal persons and in those with complete spinal cord injuries and propose possible mechanisms for fever in persons with high-level spinal cord injuries.


The development of cardiac transplantation. The history of cardiac transplantation provides an excellent prototype for the development of a therapeutic technique. The first observations on cardiac transplantation were made in animal models in the early 20th century. Surgical problems were solved through a series of technologic advances, and problems associated with immune-mediated rejection were discovered and successfully addressed. By the late 1960s, cardiac transplantation in humans had become feasible. Since the first successful transplantation of a heart in a human in 1967, the management of rejection and infection has steadily progressed, and the long-term outcome after cardiac transplantation has improved dramatically. The success of cardiac transplantation has led to an expansion of the potential recipient pool to include children and adults in the eighth decade of life. Unfortunately, the growth of cardiac transplantation has resulted in an inadequate supply of suitable donor hearts. The limited supply of donor hearts has provided the impetus for further research in xenotopic cardiac transplantation and for the development of implantable circulatory assist devices.


Prognostic features in patients with congestive heart failure and selection criteria for cardiac transplantation. Cardiac transplantation can be a highly successful therapeutic option for patients with end-stage congestive heart failure. Successful results, however, depend on the appropriate selection of patients for the procedure. Patients whose survival or quality of life would be compromised without cardiac transplantation and who are likely to benefit from this intensive type of treatment are potential candidates. Each patient should undergo a thorough assessment to identify any medical or psychologic contraindications to cardiac transplantation. In this review, we discuss the important predictors of survival in patients with congestive heart failure: the cause of heart failure, the patient's symptomatic and functional status, the hemodynamic and pathologic findings, the evaluation of neurohumoral activity, and the presence of cardiac arrhythmias. Once a patient with congestive heart failure has been identified as having a limited life expectancy and severely impaired quality of life, cardiac transplantation should be considered.


Immunohistochemical study of extracellular material in the aged human synovial membrane. Types III, IV, VI collagen and laminin distribution in synovial tissue of seven autopsy knee joints from old human donors (69-94 years of age) were investigated with immunocytochemical and immunohistochemical methods. The synovial intima is separated from the subintimal tissue by an intermediate fibrillar zone rich in staining for type III collagen. In the intima basement membrane-like material associated with synovial lining cells stains for type IV collagen and laminin. Fine fibrils surrounding the lining cells stain for type VI collagen. In two of the cases type VI collagen occurs mainly as long-spacing collagen, the distinct aggregated form of type VI collagen. This staining pattern was qualitatively the same in all different regions and cases investigated. However, considerable quantitative differences were seen.


The effect of aging on protein synthesis in the yeast Saccharomyces cerevisiae. The protein synthetic rate in the yeast S. cerevisiae, measured by the incorporation of radioactive amino acids per unit amount of proteins, decreased linearly with age reaching 50% of the rate of 2nd generation cells (young cells) in 20th generation cells (old cells), whereas the RNA content of the old cells was increased three times. Using a cell-free system for poly(U)-directed poly-phenylalanine synthesis, the activity of run-off ribosomes from old cells was shown to be about 40% less than the activity of ribosomes from young cells and the polysome level in old cells was much decreased compared to that in young cells. However, as protein content was increased twice in 20 generations, the cell is considered to maintain a constant level of protein synthesis during the process of aging compensating the decrease in the activity of ribosomes. Thus, it is likely that the decrease in the synthesis of certain proteins whose requirement was raised by the increase in cell volume, which is twice the increase in protein content, causes prolongation of the unbudded phase in old cells.


In vivo microscopic studies of age-related changes in the structure and the reactivity of cerebral microvessels. To determine if hemodynamic changes in cerebral microvessels could contribute to the age-related changes in the blood-brain barrier (BBB) function, the cerebral microvessels of male Fischer 344 rats at different ages were studied using intravital fluorescence microscopy. Aging in rats was associated with significant arteriovenous shunting in the cerebral microvessels without alterations in blood flow characteristics or changes in vascular permeability to FITC dextran (150 kDa). The basal diameter of terminal arterioles examined in 24- to 27-month-old (aged) rats (28.6 +/- 2.8 microns) was not different from that in 12- to 15-month-old (intermediate age) rats (32.5 +/- 2.5 microns) or in 3- to 6-month-old (young) rats (28.6 +/- 3.0 microns). At 3 s following addition of 5% BaCl2 there was 23.3 +/- 3.47% constriction of arterioles in young rats and 14.8 +/- 5.16% constriction in intermediate age rats, but only a 3.43 +/- 5.69% change in aged rats (P less than 0.03). This initial brief constriction phase was followed by a dilatory response which was similar in all age groups. One minute following suffusion with artificial cerebrospinal fluid, the arteriolar diameter essentially returned to baseline in all rats examined. It is concluded that aging in rats is associated with alterations in cerebral microvascular reactivity in vivo along with arteriovenous shunting. These changes may contribute to age-related alterations in the BBB function.


Formation of cerebrovascular anomalies in the ageing rat is delayed by chronic nimodipine application. At the ultrastructural level two main categories of microvascular anomalies can be distinguished in the aged rat brain. These categories comprise [1] membranous inclusions within the basement membrane and [2] microvascular deposits, which include microvascular fibrosis and thickening of the basement membrane (BMT). In this study we examined the percentage of microvessels displaying ageing-related malformations in the frontoparietal motor cortex of rats aged 16, 24, 30 and 32 months. The percentage microvessels with membranous inclusions and microvascular deposits both gradually increased until the age of 30 months, after which no further increase was observed. The percentage fibrotic microvessels, however, increased until the age of 30 months, but was decreased at 32 months. This decrease of fibrotic microvessels at 32 months coincided with a proportional increase of cerebral microvessels provided with a thickened basement membrane. Combined with qualitative observations these data suggest that in a very late stage of the ageing process collagen fibrils in microvascular fibrotic plaques are depolymerized and degradated. By this mechanism it appears that microvascular fibrosis is transformed into basement membrane thickening. Long-term application of the calcium entry blocker nimodipine did not influence the amount of microvessels with membranous inclusions within the basement membrane, but in contrast resulted in a prominent reduction of ageing-related microvascular deposits when administered from 24 to 30 months. The effect of a prolonged nimodipine treatment from 24 to 32 months on the amount of microvascular deposits was still significant, however, much less conspicuous. We now conclude that chronic administration of nimodipine delays the formation of microvascular deposits up to the age of 30 months. Furthermore, the beneficial effect of nimodipine treatment from 24 to 30 months on microvascular integrity is not accompanied by a reduced systolic blood pressure.


Age-related alterations in antioxidant capacity and lipid peroxidation in brain, liver, and lung homogenates of normal and vitamin E-deficient rats. Age-related alterations in both antioxidant capacity and lipid peroxidation in the cerebrum, lung and liver homogenates of normal and vitamin E-deficient rats were investigated. The antioxidant capacity, which includes superoxide dismutase, catalase and glutathione peroxidase activities and vitamin E (alpha-tocopherol) concentration, was relatively stable throughout the lifespan. It was observed, however, that catalase and glutathione peroxidase activities in livers of old rats decreased and that vitamin E concentration in lung and liver increased with age. In vitamin E-deficient animals, catalase activity in liver increased and glutathione peroxidase activity in liver and lung decreased. Lipid peroxidation was monitored by use of three different indices, i.e. the thiobarbituric acid (TBA) value, oxygen absorption and conjugated-diene formation. In the absence of any initiator, neither oxygen absorption into tissue homogenates nor conjugated-diene formation in lipid extracts from the homogenates occurred. The TBA value of each cerebrum homogenate incubated under air or an oxygen atmosphere was larger than that of the corresponding unincubated cerebrum homogenate. From comparison between the TBA value and oxygen absorption, this increase in the TBA value was suggested to be due to some reactions other than lipid peroxidation. Although tissue homogenates examined contained TBA-reacting materials, no lipid peroxidation seems to arise during incubation of them. No age-related alterations in the TBA value and oxygen absorption in rat tissue homogenates were observed. Vitamin E deficiency had no effect on the TBA values of cerebrum and lung homogenates, while it seemed to increase the TBA values of liver homogenates. Vitamin E deficiency had no effect on oxygen absorption in these tissue homogenates. The induction period of initiator-induced conjugated-diene formation in lipid extracts from liver and lung homogenates from normal and vitamin E-deficient rats tended to be extended with age. Vitamin E deficiency decreased the induction period of initiator-induced conjugated-diene formation. As a result, the length of the induction period was found to be proportional to vitamin E concentration in lipid extracts. The overall antioxidant capacity of rat tissues appears to be maintained without large variation during ageing. Decreases in the capacity of some antioxidant factors may be compensated by increases in the capacity of other factors.


Chromatography and spectrofluorometry of brain fluorophores in neuronal ceroid lipofuscinosis (NCL). The aim of the present work was to develop a chromatographic system for the separation of individual fluorophores extracted from neuronal ceroid lipofuscinosis (NCL) brain and isolated storage bodies. Extracts from gray matter were best resolved on silica-gel HPTLC plates using a mixture of chloroform/methanol/water (55:45:10 by vol.). Two other chromatographic systems were tested which gave poorer separation. Corrected fluorescence spectra were obtained on the original extract and fluorescence intensity, especially at longer wavelengths was increased in both samples. Yellow and blue fluorophores were detected on HPTLC plates using a primary violet and secondary yellow filter with cut-off levels of 400 and 520 nm, respectively. Plates were photographed at 20 min, 2 h and 1 week after chromatography. With this filter system, up to 12 yellow bands of differing intensity were observed at 20 min but with time, some of these changed to blue as a result of autoxidation. NCL tissues emit yellow fluorescence when viewed under light microscopy, however extracted material did not demonstrate a distinct peak in this region of the spectrum which should be around 575 nm. HPTLC confirmed this observation and time studies revealed that autoxidation changes occur and must be carefully controlled to reduce artifacts. The discrepancy between extracted and non-extracted observations may be the result of superposition of multiple fluorophores with differing maxima and/or a self-absorption phenomenon. The combination of chromatographic separation and spectral analysis as described in this study, may be a valuable technique to further clarify the characteristics of compound fluorescent lipopigments. It is suggested that NCL fluorophores of human brain differ in their properties from other models.


The effect of age, sex and breeding on graft versus host reactivity of spleen cells from C57BL mice. Spleen cell graft versus host (GvH) reactivity was determined in male and female, either virgin or breeder, C57BL mice from 3 to 24 months of age. The GvH reaction was assessed by a local popliteal lymph node assay and by a splenomegaly test for a systemic reaction. Although the GvH reactivity declines progressively with age in both sexes the virgin female response was greater than that of males throughout the period of 6-18 months of age. Two-year-old mice of both sexes were practically unable to mount a GvH reaction. No differences were evident in aging female reactivity after one or two syngeneic pregnancies. On the other hand, 3 or more consecutive pregnancies resulted in enhanced GvH reactivity of 12-24-month-old females, which responded comparably to young virgin mice. This long-lasting immunopotentiating effect of multiparity was similar after 3-4 and 8-9 pregnancies. The possible role of developing foetuses on the maintenance of high GvH reactivity in breeder females is suggested.


Effect of age-related lipid peroxidation on membrane fluidity and phospholipase A2: modulation by dietary restriction. Age-related changes in membrane property are generally accepted phenomena. In this report, using the anti-lipoperoxidative measure of dietary restriction on membranes, the age-related effects of lipid peroxidation on membrane fluidity are explored in conjunction with the membrane-associated phospholipase A2. The fluidity of mitochondrial and microsomal membranes from ad libitum fed rats shows a progressive decline with age as indicated by a substantial decrease in two parameters, l/polarization and l/anisotropy. In contrast, the membrane fluidity of dietary restricted rats shows slight changes between 6 and 24 months of age. Evidence is presented to support the possibility that age-related peroxidation of membrane lipids may play a significant role in bringing about fluidity changes in aged membranes. The findings on the increased phospholipase A2 with age is also consistent with this conclusion.


Ontogenic characteristics of cavian aldolase. In order to extend the available information on the ontogenic significance of the interactions between aldolase and cellular structure, the nature and extent of these associations have been studied in the tissues of the guinea pig during development, along with analyses of the isozyme status in the bound and soluble compartments. In all tissues investigated, a significant degree of binding was evident, along with a considerable variation in the degree of association of aldolase with structure during development. Binding was particularly extensive in the early foetal stages and, in general, binding preference was directed towards A-type activity over the B- and C-type of enzyme. The significance of these ontogenic phenomena have been discussed in relation to the variations in phenotype of individual tissues during maturation and the metabolic correlations of this biphasic micro-organization.


Developmental profiles of antioxidant enzymes and trace metals in chick embryo. It has been previously well documented that partial pressure of oxygen (PO2) and weight-specific rate of O2 consumption in chick embryo (Gallus gallus domesticus) transiently increase midway through the 21-day in ovo incubation period. The present study found that these oxidative changes were paralleled by the concentrations of glutathione (GSH) and Zn in liver and by the specific activity of superoxide dismutase (SOD) in brain. Levels of antioxidant enzymes and their trace metal cofactors were markedly higher in liver than in brain. Hepatic catalase activity changed in parallel with the concentration of its cofactor, Fe. However, the relative abundance of metal cofactors did not appear to be the determining influence on other antioxidant enzyme activities. Rates of extra-mitochondrial hydrogen peroxide release were also much greater in liver than in brain. Taken together, the results of this initial study of embryonic chick antioxidant systems suggest that certain antioxidants may be regulated by PO2 and rate of oxidative metabolism during fetal development.


Aging as a multi-step process characterized by a lowering of entropy production leading the cell to a sequence of defined stages. II. Testing some predictions on aging human fibroblasts in culture. The concepts of irreversible thermodynamics have been used in order to develop a theory of aging considered as a multi-step process leading the cell through a sequence of defined stages characterized by a lower level of entropy production and finally to a critical level of errors involving cell death (Toussaint et al., 1991). One of the predictions of this model is that external stresses which can be considered as fluctuations would accelerate the evolution of the cell from one state to the other according to the intensity of the stress. Seven morphotypes have been observed in the serially cultivated human fibroblasts, cells passing progressively from one morphotype to the other. In this paper, we experimentally tested the effect of two different molecules, tert-butylhydroperoxide and ethanol, in order to determine their influence on the shift from one morphotype to the other. When applied for a single period of time on cultivated cells, both molecules effectively showed a modification in the pattern of the different morphotypes which was dependent on the stress intensity: a decreased proportion of the early morphotypes and an increased proportion of the late and post-mitotic morphotypes were observed within three days after the stresses. Similar results were obtained when successive stresses were performed at every subculture. The results also indicated that all stages are not equally stable with morphotypes III and IV being the most stable. The positive effect on the increased shift of these cells from one morphotype to the other by two different stresses firms one of the prediction of the thermodynamic model which states that cellular aging can be considered as a multi-step process which can be speeded up by various external modifications.


The proliferation theory of rejuvenation. A theory concerning the molecular basis of rejuvenation is presented that postulates a central role for cell proliferation. This theory assumes that aging is due to the accumulation of multiple forms of molecular damage and that rejuvenation is due to repair. The advantages of proliferation as a means of repair are described and it is proposed that cell proliferation is required for full rejuvenation. This proliferation theory offers several advantages: a different perspective on the question of which organisms age; an explanation of aging-related phenomena that are not well handled by traditional aging theories; a novel approach to altering the aging rate; and testable implications for the design of new experimental systems and therapeutic interventions.


Fragile sites, Alzheimer's disease, and aging. The fragile site expression under conditions of folate deprivation was compared in the chromosomes from 5 Alzheimer's disease (AD) female patients, 5 healthy elderly females and 5 healthy young females. Although different fragile sites were observed in the three groups, nevertheless, more similarities were found between the AD patients and elderly normal donors. The only fragile site common to all groups was 3p14. This site was the most frequent in the young donors group. In both AD and elderly control groups we observed a higher frequency of fragility in 6p21, but not in the young controls. Other interesting fragility points observed in these two groups were: 6q21 and 14q24 (in the AD patients) and 9q13, 14q24 and 17q21 (in the healthy aged). 6p21 and 17q21 have been proposed as 'new' fragile sites. We confirm the existence of these fragile sites and comment that in these bands the genes MTBT2 and MTBT1, which are microtubule (beta) associated protein tau-like and tau 1, respectively, are mapped. The tau protein is a component of paired helical filaments which accumulate in degenerating neurons in the brain of patients with AD and with less intensity of normal elderly individuals.


The Medicare cost of renal dialysis. Evidence from a statistical cost function. Medicare's End Stage Renal Dialysis Program currently costs more than $6 billion per year, which covers renal dialysis, kidney transplants and other life-saving medical care for 190,000 patients of all ages suffering from chronic renal failures. Medicare reimburses dialysis units for dialysis treatments using a formula based on accounting costs reported by a small sample of facilities. However, accounting methods may obscure the true economic costs of providing the different type of dialysis treatments such as hemodialysis, continuous ambulatory peritoneal dialysis, and continuous cycling peritoneal dialysis. In this study, a multiproduct, statistical cost function approach to obtain cost estimates was used. Results obtained in this study show that the average cost and marginal cost of hemodialysis treatments are generally in line with current reimbursement rates, whereas the average and marginal costs of continuous ambulatory peritoneal dialysis treatments may be below this rate. For in-center hemodialysis, which is the mainstay of all dialysis units, the authors found evidence of decreasing economies of scale at the mean facility size, but found constant returns to scale for other modalities. Some evidence of economies of scale from chain ownership of dialysis centers was discovered. Finally, the analysis indicates that the Medicare reimbursement formula may be outdated, and further research that could lead to the design of more "rational" payment rules is suggested.


Clinical versus administrative data bases for CABG surgery. Does it matter? This study compared the ability of a clinical and administrative data base in New York State to predict in-hospital mortality and to assess hospital performance for coronary artery bypass graft surgery. The results indicated that the clinical data base, the Cardiac Surgery Reporting System, is substantially better at predicting case-specific mortality than the administrative data base, the Statewide Planning and Research Cooperative System. Also, correlations between hospital mortality rates that are risk-adjusted using the two systems were only moderately high (0.75 to 0.80). The addition of new risk factors from the Statewide Planning and Research Cooperative System improved the predictive power of both systems but did not diminish the difference in effectiveness of the two systems. The three unique clinical risk factors in the Cardiac Surgery Reporting System (ejection fraction, reoperation, and more than 90% narrowing of the left main trunk) seemed to account for much of the difference in effectiveness of the two systems.


The inequality of medical expenditures for several years in a healthy, nonelderly population. Previous studies have shown that the distribution of annual medical expenditures for a population is very unequal and remains so for periods of more than 1 year. The authors use a better measure of inequality, the Gini coefficient, to test its persistence for longer periods. This measure is applied to data collected from the Rand Health Insurance Experiment. The experiment enrolled a nonelderly population typical of those covered by employer health plans for periods up to 5 years. The distributions of annual expenditures for this population are highly unequal, in line with previous studies. Inequality declines substantially when longer periods are considered.


Comparative measurement sensitivity of short and longer health status instruments. Short measures of health status are used increasingly in health services research, yet their sensitivities to clinical change have not been compared with longer, established instruments. In this study, 5 health status measures were administered preoperatively and 3 months postoperatively to 54 patients undergoing total hip arthroplasty. These instruments included the Sickness Impact Profile (SIP)--an established, long measure--and 4 short forms: the SF-36, Functional Status Questionnaire, shortened Arthritis Impact Measurement Scales, and Modified Health Assessment Questionnaire. Scores for physical, psychological, and global dimensions were constructed by aggregating subscales. Sensitivity to change, or responsiveness, was expressed with the standardized response mean (SRM), calculated as the mean change in score divided by the standard deviation of the change in score. The sampling distribution of the SRM was estimated with a jackknife procedure. Preoperative scores were moderately to highly correlated across instruments. The physical and global dimension SRMs of the brief health status measures ranged from 0.85 to 1.27 and were as large as or larger than the corresponding SIP SRMs. The SIP had the highest SRM on the psychological dimension. None of the instruments was significantly more sensitive than the others at the critical value (P = 0.005) adjusted for multiple comparisons. The brief health status measures were equally or more responsive than the SIP after total hip arthroplasty in the physical and global dimensions. Much larger samples are required to demonstrate statistically significant differences in SRMs among instruments.


Prescribing problems and pharmacist interventions in community practice. Interventions performed by 89 community pharmacists in 5 states to correct the prescribing problems they identified on new prescription orders were documented by trained observers. Pharmacists intervened to resolve a prescribing-related problem in 623 (1.9%) of 33,011 new prescription orders that were screened and dispensed during the study period. A panel of three expert evaluators concluded that 28.3% of the prescribing problems identified during the study could have caused patient harm if the pharmacist had not intervened to correct the problem. The rate at which pharmacists identified prescribing problems was negatively related to the number of prescriptions they dispensed per hour, suggesting that in pursuing distributive efficiency, some pharmacists may be exceeding their safe dispensing threshold. The authors recommend that the interprofessional system of oversight and verification (i.e., "checks and balances") in the delivery of pharmaceutical care in the community setting should be maintained and strengthened.


[Monocytic dysfunction by opioid peptides in patients with major depression]. Patients with depression present immunodepression and it has been proposed that, in these patients, endogenous opioid peptides may be mediators between the dysfunction of the central nervous system and immune alterations. The function and the surface markers of monocytes were studied in 15 patients with major unipolar depression and in 24 healthy controls by biological trials of phagocytosis of Candida albicans and latex particles and immunofluorescence with monoclonal antibodies. Most of the patients studied (86%) presented monocytic dysfunction characterized by diminished phagocytic activity and a decrease in the expression of intermediate filaments of vimentin of the cytoskeleton and membrane molecules (CR1, receptor for the Fc fraction of the IgG and HLA DR antigens). Incubation of the patients monocytes with naloxone led to the disappearance of monocytic alterations in most of the patients. Patients with major unipolar depression present a high opioid tone which has consequences in the function of the immune system.


[Evaluation of the demand for tests for the detection of anti-human immunodeficiency virus antibodies in Catalonia]. Most programs for the control of the acquired immunodeficiency syndrome (AIDS) contemplate the registry of cases as the principal source of information. Despite the fact that these data have permitted important epidemiologic and clinical aspects of the disease to become known epidemiologic surveillance systems should be developed based on the detection of infection by the human immunodeficiency virus (HIV). The prevalence and the epidemiologic profile of patients who underwent an anti-HIV test were studied in 17 hospitals in Catalonia in 1989. In addition, a questionnaire concerning demographic and epidemiologic variables was completed by all the patients in whom an ELISA test had been carried out during 4 periods of 15 days. During this period 33,012 serologic tests were performed in 17 centers with a global prevalence of positive results of 20.7% (IC 95% = 20.2%-21.1%). The greatest number of positive serologies corresponded to the collective of intravenous drug users (IVDU), consisting of 68% of all the positive tests with a prevalence of infection of 76.4%. Prevalence was considered as constant throughout the year despite the differences between the prevalence observed in some periods. The fact that the collective of intravenous drug users is most prevalent among the patient with positive results in the serologic detection of the human immunodeficiency virus (HIV) confirms that this is the principal group of transmission in Catalonia. This type of study may provide information on the rate of infection by HIV complementing other surveillance methods of the epidemic. However, the basic function of these tests stems from the study of the demand and use of detection tests.


[Familial outbreak of pneumonia by psittacosis]. A familial outbreak (4 cases) of pneumonia by psittacosis in Vall de Uxó (Castellón) during the month of April in 1990 is described. In addition to the epidemiologic, clinical and serologic (complement fixation) studies carried out a survey and serology of 11 healthy controls (neighbors, and employees from a bird shop) were performed. The serum of a parrot recently acquired by the patients (positive at 1/8) was analyzed. The habit of petting the animal was significantly associated with the disease. The patient's response to treatment was good. The titers of antibodies versus Chlamydia psittaci were higher than those of the controls examined and the established threshold for positivity (1/36). In addition to clinical intervention the roles of epidemiology and the participation of veterinary services are fundamental to control this disease the exact prevalence of which is unknown.


Travel medicine. General advice and medical kit. Physicians must be prepared to provide comprehensive pretravel advice to their patients. Because world conditions are constantly changing, it is necessary to obtain accurate and current information. Common health problems that may be faced by any traveler include accidents, motion sickness, and jet lag. Physicians must familiarize themselves with the many forms of insurance available for the traveler.


Immunizations for international travelers. Immunizations for international travel are an important component of pretravel medical care. Travelers should receive protection against vaccine-preventable exotic diseases, and their immunity against common infectious diseases should be reviewed and updated. There are no immunizations for some important infectious hazards of travel. In the course of considering a traveler's risk for exposure to infectious disease on the basis of geographic destination, style of travel, and anticipated activities, the health care provider should discuss preventive measures and personal behavior with regard to food and water, avoidance of insect bites, personal safety, and sexual activity.


Special health considerations for travelers. Special health considerations include many issues that affect travelers at both ends of the age spectrum. Pulmonary diseases may seriously alter the physiologic responses to both cabin pressures in commercial airliners and exposure to high altitudes, but many of these responses can be predicted by blood gas determinations and simple measurements of pulmonary function conducted at sea level. Cardiac events represent the most common and unpredictable health problems that threaten both serious morbidity and death for adult travelers. Diabetic travelers require insulin dosage adjustments during east-west travel and well-stocked travel kits with adequate supplies. Human immunodeficiency virus-infected travelers require consideration of their levels of immunosuppression at the time of immunizations and special precautions for preventing potentially chronic enteric infections. Young children pose similar questions, and there is the additional problem posed by a limited number of readily available antimalarial agents for pediatric use.


The pregnant traveler.

The pregnant traveler. The pregnant traveler should seek current and specific advice from experts even if she is traveling to a nearby wilderness area. This advice will make a significant contribution to the safety and health of the pregnant woman and her future newborn. There are many situations, for example, travel to Kenya, the Andes, or the Amazon basin in Peru, where the pregnant traveler is best advised to stay at home, or to defer the trip.


Diagnosis, treatment, and prevention of malaria. Optimal treatment of malaria requires rapid case identification, initiation of specific and supportive therapy based on parasitologic and clinical classification of the patient, and recognition of inadequate response to therapy. Health care providers advising travelers should assess the risk of malaria based on itinerary and clinical condition, and counsel to reduce contact with mosquitoes; prescribe appropriate chemoprophylaxis; and counsel regarding potential side effects and requirement for diagnosis and treatment if fever develops.


Travelers' diarrhea. Prevention and treatment. Travelers' diarrhea affects almost half of all travelers from developed to developing nations. Its occurrence frequently alters planned activities. Enterotoxigenic Escherichia coli and other bacterial pathogens endemic to the area visited account for the majority of pathogens isolated. Newer research technologies are assisting in defining virulence properties and epidemiologic characteristics. Prudence exercised during travel remains the preferred mode of prevention, reserving antimicrobial prophylaxis for specific situations. Oral rehydration and early pharmacologic intervention with antimicrobial and antimotility agents significantly decrease length of illness when diarrhea occurs.


Fever in the returned traveler.

Fever in the returned traveler. Febrile infections can be fatal in travelers to tropical countries unless the patient seeks medical care in a timely manner and the physician takes the time and has the skill to make a rapid diagnosis and prescribe appropriate therapy. In addition to the usual febrile illnesses present in temperate climates, the patient may have an "exotic" infection, e.g., malaria, infectious hepatitis, enteric fever, or dengue fever. The potential causes of fever in travelers are extensive. This article provides practical clues to assist the physician in making the correct diagnosis--by using exposure information, symptoms and signs, and concomitant symptom complexes.


Skin problems in returning travelers.

Skin problems in returning travelers. A new skin lesion in a returning traveler often poses a difficult diagnostic problem for the clinician whose knowledge of geographic medicine is limited. To reach a diagnosis the physician has to consider the location and style of travel, exposure to pathogens, length of stay, epidemiology, incubation period, and clinical presentation of dermatologic diseases in the countries visited. As with any dermatologic problem, the appearance of the presenting lesion should help to establish the differential diagnosis. This article is a guide to the diagnosis and investigation of skin lesions in returning travelers; it is not intended as a comprehensive review of tropical dermatology.


Eosinophilia in travelers.

Eosinophilia in travelers. Eosinophilia in travelers may be caused by infections acquired during travels. Infections with helminthic, but not protozoan, parasites are the most likely causes of eosinophilia, although other etiologies may warrant consideration. This article reviews the parasitic and other causes of eosinophilia. Helminthic infections early in their development may elicit the most pronounced eosinophilia yet be difficult to diagnose. Chronic helminthic infections may yield eosinophilia that persists for prolonged periods of time after initial infection.


Intestinal parasites in returned travelers. Travelers returning from third-world countries may become infected with a variety of intestinal parasites. Although protozoan infections are more frequently seen, intestinal worms are also encountered. If considered in the differential diagnosis, these infections usually are readily diagnosed and treated.


Sexually transmitted diseases and travelers. Sexually active travelers are at risk for a variety of STDs, including traditional venereal infections such as gonorrhea, chlamydial urethritis, syphilis, chancroid, and herpes simplex infection. More recently, hepatitis B, hepatitis C, and HIV-1 have also been described. Risk varies depending on the geographic area of travel and the type of sexual contact. Physicians should be aware of the prevalence of antimicrobial resistance of N. gonorrhoeae and H. ducreyi because this will affect empiric antibiotic therapy. Prevention should focus on proper and consistent usage of barrier contraceptives.


Tropical diseases in immigrants and internationally adopted children. Immigrants, particularly those from the developing world, make up a significant number of tropical disease cases seen in a temperate climate. Internationally adopted children are another group in which tropical and other infectious diseases must be considered. The differential diagnoses of various syndromes in these populations in relation to relatively more common tropical diseases are reviewed.


High altitude medicine.

High altitude medicine. Altitude illness is common and may result in major disruption of travel plans. Visitors to altitude need to be aware of the various health problems they might encounter and how they may be prevented. Self-diagnosis and treatment is the norm in many remote locations. The hallmark of therapy remains descent, but with newer treatment modalities, this may be easily forgotten. People with preexisting health problems may desire to visit high altitude destinations. It is reasonable to support some strongly motivated people in undertaking such trips, providing they recognize the difficulties of coping with illness in remote locations.


An integrated approach for the computer-assisted treatment of diabetic patients on insulin. A prototype computer system has been developed to provide advice on the day-to-day adjustment of carbohydrate intake and insulin regimen in the insulin-dependent diabetic patient. The system also produces a 24-h simulation of the patient's blood glucose profile based on these adjustments. Advice is generated by a qualitative knowledge-based system which suggests what the next step in improving glycaemic control might be for a given patient, e.g. 'decrease morning short-acting insulin by 2 units'. The quantitative simulator module contains two different mathematical models. The first is a non-linear model in differential equation form which consists of a one-compartment glucose model linked to a model with free and bound insulin compartments. This physiological model is solved by a general-purpose simulation engine. The second is a linear systems model which uses a transfer function to describe the insulin input/blood glucose response relationship for individual diabetic patients. Results of a preliminary medical validation are presented.


Implications of medical information systems for community health care in Japan. The population of Japan in the 21st century is expected to be distributed heavily on the side of higher ages. In view of the aged society, improved hygienic, medical, and welfare services must be provided in every community. In order to provide these services efficiently it is necessary to implement a community health care system (CHCS). The role and responsibilities of the medical information system, which is intended to support comprehensively the CHCS with respect to providing the necessary information, will become increasingly important. This paper is intended to discuss the structure, features, and required activities of the community medical information system which will have particular importance in the community health care services in the coming years. Problems in establishing and operating future medical information systems in the CHCS also are discussed. Lastly, problems and obstacles confronted when establishing and operating medical information systems in community health care which is organized around the medical association, which plays an important role and takes on heavy responsibility, are discussed, and a proposal is made.


Certainty factor theory and its implementation in a medical expert system shell. In this article some topics related to the MYCIN-model for uncertainty handling are discussed. First, it is pointed out that one of the problems identified by Adams should be considered as evidence supporting the point of view that the probabilistic interpretations of measures of belief and measures of disbelief given by Shortliffe are inappropriate. In this context some results achieved by Heckerman are reviewed, and it is shown that similar problems can be identified in the interpretation given by him. It is also pointed out that Heckerman's argument that the original probabilistic interpretation of certainty factors implies non-commutative evidence-updating is not correct. Then, in the context of the result achieved by Horvitz and Heckerman, in which it was proven that there is an isomorphic mapping from the evidence combination scheme for the likelihood ratio to the evidence combination function in EMYCIN and its successors, it is pointed out that the evidence combination scheme for the likelihood ratio suffers from a great restriction on its applicability in expert systems. Subsequently, some short remarks are made with respect to the complaint that sometimes the MYCIN model cannot work as well as expected. Lastly implementation of the certainty factor mechanism in a HIS-oriented expert system shell with some substantial changes is described.


A microcomputer-based structured journal system for diseases of the female mammary gland. A medical journal system for female patients with diseases of the mammary gland is described. The system is developed in a commercial database system, and is run by microcomputer. The system has been used for almost 3 years in a department with approximately 550 new patients referred per year. Experience from daily use in patient care, and as a tool for retrieval of medical and administrative data, is reported. Further development of the system is discussed.


Comparison of digital and conventional mammography: a ROC study of 270 mammograms. Observer performance tests were conducted to study the visibility of malignancies in digital mammography. Detectabilities of tumours and of microcalcifications were studied separately. For this purpose two sets of images were used, one for tumours consisting of 150 mammograms and one for microcalcifications containing 120 mammograms. Images were digitized at a resolution of 2048 x 2048 pixels using a 12-bit CCD camera. Conventional film mammograms were read on a lightbox, whereas digital mammograms were viewed on a high-resolution monitor. Two experienced radiologists read both sets independently, and ranked their judgements about the presence or absence of tumours or microcalcifications on a confidence-rating scale. Results were evaluated using receiver operating characteristic (ROC) analysis. No statistical differences were found between judgements based on conventional and digitized mammography.


New role of a medical documentation system. Architecture of a new medical documentation system (MDS) is proposed. First, we studied the traditional MDS in terms of organizational structure, main functions, means (resources) and personnel. Special emphasis is given to the information retrieval (IR) system which is the kernel of a MDS. Then, some achievements of information technology is summarized, and concept of a mixed IR system which is the kernel of the new system is presented. New architecture is then presented. Units which compose the entire system are: host documentation centre, local documentation centres, and documentation units. Eventually, objective and features of every part are discussed.


Telestroika in health care informatics: a challenge for standardization in Europe. This article describes the actual user requirements of the health care sector in connection with telematics. The importance of standardization is stressed. The paper further gives an overview of the current standing of the activities of CEN TC 251 (European Standardization Committee, Technical Committee on Health Care Informatics).


Basic health care functions: an object-orientated analysis. All clinical activities carried out by health care professionals can be seen as examples of what we have called the basic health care functions. These are collecting information concerning the patient, assessing the patient in the light of the information gathered, and then planning and administering the care which is deemed necessary. For a computerized clinical support system to be helpful to clinicians it is essential that the information and computer scientists responsible for building such systems have clear and detailed descriptions of the activities carried out by their clinical colleagues. One method of bridging this communication gap is object-orientated modelling. In this paper we present an object-orientated analysis of the basic health care functions, thus establishing a generic model on which descriptions of more specific clinical situations can be based.


Automated diagnostic indexing by natural language processing. Developing tools for natural language understanding by computers represents an important and intense field of research. This paper describes a system developed for interpreting medical natural language in the domain of symptoms and diagnoses from complete discharge summaries and locating the correspondent category into the International Classification of Diseases, through indexing by the Systematized Nomenclature of Medicine. The indexing program makes use of the MEID dictionary and some auxiliary semantic databases for identifying adjectival forms, synonyms, hypernyms and other semantic relations while searching for the longest consistent match into SNOMED. A further subdivision of the SNOMED structure was also proposed in order to find the hierarchically superior representative of a conceptual class when this association is not assigned by the related SNOMED code number. The system can be used by any language that possesses a translation of SNOMED and ICD. The knowledge base was built using a conversion file that maps the terms of the nomenclature into the classification, which can be improved by learning from users.


PACE project: object-orientated modelling of paediatric practice. The need for useful clinical support based on integrated computerized systems is now well recognized. To build systems desired by busy clinicians requires accurate specifications. These specifications in turn require rigorous descriptions of the processes to be automated in a form which is understandable and unambiguous to both clinician and computer scientist. Despite these requirements communication between suppliers and users of computer systems often is poor. Detailed descriptions of health care with particular reference to child health were developed with an object-orientated technique. These descriptions take the form of conceptual models of the basic health care activities (evidence collection, assessing, planning and implementing management) and more specific departmental activities pertaining to paediatric intensive care, accident and emergency, and cystic fibrosis management. We have learned that once a modelling team becomes competent in applying the technique, object-orientated modelling can be a powerful tool for the description of complex processes such as those involved in present-day health care.


[Constant annual incidence of HIV infection among intravenous drug addicts]. Since January 1987 a study of HIV prevalence and risk behaviour among i v drug abusers at the remand prison in Stockholm has been carried out by a research team working independently of the penal system. On a voluntary basis, a standardised interview is carried out and an HIV blood test made. Of the 2,038 i v drug abusers who participated up to December 1991, ten per cent were HIV-positive. Of the 80 per cent who mainly used amphetamines, six per cent were seropositive, as compared with about 28 per cent of the remaining 20 per cent who were heroin addicts. The overall annual incidence of HIV infection was about one per cent. The cumulative prevalence decreased among heroin users during the observation period, but remained constant among amphetamine users. The frequency of injection equipment sharing showed a decline at the beginning of the observation period, but the level of sexual risk behaviour has remained high.


[A pilot study: neuropsychological rehabilitation of patients with solvent-induced toxic encephalopathy]. Fourteen patients with chronic toxic encephalopathy underwent a neuropsychological intervention comprising crisis therapy, information about the disease, and cognitive training. Evaluation showed the patients to have experienced substantial improvement in their daily life and family relations as a result of the intervention. Their affective symptoms decreased and their verbal memory improved. Regional cerebral blood flow (rCBF) measurements showed training-dependent changes of functional activity related to change in memory strategy. This rCBF change had disappeared six months later, however, suggesting that the duration of intervention needs to be extended in order for use of the learned memory techniques to become automatic. We conclude that neuropsychological rehabilitation is effective and should be made available to patients with chronic toxic encephalopathy.


[Prognosis and treatment of symptomatic hyponatremia--a study of 28 intensive care cases]. In symptomatic cases of hyponatraemia, where the serum sodium concentration is less than 115 mmol/l, prognosis has hitherto been considered to be poor, and mortality rates of 50 per cent have been reported. The management of this condition is controversial, particularly concerning the optimal rate of correction, correlations having been reported between the occurrence of central pontine myelinolysis and both over-correction and too rapid correction. During the 3-year duration of the study reported in the article, of 28 cases with a mean sodium concentration of 106 mmol/l, the outcome was fatal in only one case. In both of the only two cases of acute hyponatraemia (i.e., developing within 24 hours), correction had been rapid (mean rate 2.6 mmol/l per hour). In the remaining 26 cases correction of chronic hyponatraemia was slower (mean rate 0.6 mmol/l per hour), adjustment to a slightly hyponatraemic level having been achieved with isotonic saline (N = 25) or water restriction (N = 1). The findings in the study suggest that, provided that the rate of correction is not too rapid, the prognosis in cases of severe symptomatic hyponatraemia is more favourable than previously reported.


[Tumor suppressor genes: mutations in RB and p53 genes are significant carcinogenic factors]. The RB and p53 tumour suppressor genes encode nuclear proteins that exert an inhibitive effect on cell growth. A large variety of human tumour types manifest loss or mutation of the RB or p53 genes, and p53 mutation is the commonest genetic alteration found in tumour cells. In addition, the RB and p53 proteins may be inactivated by complex formation with viral oncoproteins--for instance, in the case of cervical carcinoma carrying human papilloma virus. In vivo introduction of an intact RB or p53 gene into malignant cells lacking the respective gene results in suppression of the neoplastic phenotype and thus of tumourigenicity, p53 being the more potent of the two in this respect. Further elucidation of tumour suppressor genes may well result in future improvement in the diagnosis and treatment of cancer.