Showing papers by "Rappaport Faculty of Medicine published in 1996"

Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy

Abstract: To examine whether the concomitant administration of a gonadotrophin-releasing hormone agonist (GnRHa) during combination chemotherapy to young women with lymphoma may facilitate preservation of gonadal function, a prospective clinical protocol was undertaken in 18 cycling women with lymphoma, aged 15-40 years. Thirteen patients suffered from Hodgkin disease (HD) and 5 from non-Hodgkin lymphoma. After informed consent a monthly injection of depot D-TRP6-GnRHa was administered for a maximum of 6 months starting prior to chemotherapy. Most of these patients (15/18) were treated with the MOPP/ABV(D) combination chemotherapy followed by mantle field irradiation in 10 patients. Hormonal profile [luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol, testosterone, progesterone, insulin-like growth factor (IGF)-1, prolactin] was taken before the GnRHa/chemotherapy co-treatment, and monthly thereafter until resuming spontaneous ovulation and menses. This group of prospectively treated lymphoma patients was compared to a matched control group of 18 women (aged 17-40 years) who have been treated with chemotherapy, mostly MOPP/ABV (14/18), with (11) or without (7) mantle field radiotherapy. Fourteen had Hodgkin's and four non-Hodgkin's lymphoma. Gonadal function was determined clinically, hormonally (LH, FSH, oestradiol, progesterone), and sonographically. Two of the patients in each group died from refractory disease. Of the remaining 16 patients, 15 (93.7%) resumed spontaneous ovulation and menses within 3-8 months of termination of the combined chemotherapy/GnRHa co-treatment. In contrast, only seven (39%) of the 18 similarly treated patients in the control group (chemotherapy without GnRHa) resumed ovarian cyclic activity (regular menses). The other 11 experienced premature ovarian failure (POF) (61%). Out preliminary data suggest a possible significant protective effect of GnRHa co-treatment with chemotherapy from irreversible ovarian damage (POF).

Activation of NADPH oxidase is required for macrophage-mediated oxidation of low-density lipoprotein

Abstract: Low-density lipoprotein (LDL) oxidation by arterial wall cells, a key event during early atherogenesis, was suggested to involve the activation of 15-lipoxygenase and/or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We sought to analyze the role of these oxygenases in macrophage-mediated oxidation of LDL under oxidative stress. Upon incubation of LDL with the J-774 A.1 macrophage-like cell line or with human monocyte-derived macrophages (HMDM) in the presence of 1 micromol/L CuSO4, the release of superoxide anions to the medium was demonstrated. Under these conditions, the cytosolic protein components of the NADPH oxidase complex, P-47 and P-67, translocated to the plasma membrane, indicating LDL-mediated activation of the NADPH oxidase complex. Under the above-mentioned experimental conditions, the macrophage 15-lipoxygenase was also activated, as determined by the release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE) to the medium. Inhibition of the macrophage NADPH oxidase with apocynin or dismutation of superoxide anions, the product of NADPH oxidase activation, with superoxide dismutase (SOD) significantly inhibited macrophage-mediated oxidation of LDL (by 61% to 89%) under these conditions. Phorbol myristate acetate (PMA), which causes NADPH oxidase activation in J-774 A.1 macrophages, had no significant effect on 15-lipoxygenase activity, but still resulted in cell-mediated oxidation of LDL. Finally, HMDM from two patients with chronic granulomatous disease (CGD) that were shown to lack active NADPH oxidase, but to possess almost normal 15-lipoxygenase activity failed to oxidize LDL. We thus conclude that LDL-induced NADPH oxidase activation (under oxidative stress) is required for macrophage-mediated oxidation of LDL, whereas activation of 15-lipoxygenase may not be sufficient for LDL oxidation under these conditions.

Pharmacology and neuroprotective properties of rasagiline

Abstract: Rasagiline [R(+)-N-propargyl-1-aminoindane] is a selective irreversible inhibitor of MAO-B which is not metabolised to amphetamine-like derivatives. Like deprenyl, when given to rats in a dose selective for inhibition of MAO-B, it does not affect striatal extracellular fluid dopamine levels, but when administered chronically (21 days) it increased striatal microdialysate dopamine without reduction in deaminated metabolites. Similarly to deprenyl, rasagiline (10-6M) increased the percentage of tyrosine hydroxylase positive cells in a primary culture of rat fetal mesencephalic cells (6 days in culture). Rasagiline, but not deprenyl, also increased the number of neurons per field in this organotypic culture.

Diagnosis of cancer‐associated vascular disorders

Abstract: BACKGROUND Unexplained thromboembolism may be an early indicator of the presence of a malignant tumor before signs and symptoms of the tumor itself become obvious. METHODS A survey of the MEDLINE data-base was conducted concerning cancer-associated vascular disorders and their role in the diagnosis of hidden cancer. The spectrum of vascular disorders hearalding occult cancer and the associated laboratory abnormalities were scrutinized. RESULTS Deep venous thrombosis was associated with a significantly higher frequency of malignancy during the first 6 months after diagnosis. Malignancies were found using simple clinical and diagnostic methods; additional screening was not cost-efficient. Other signs associated with deep venous thrombosis that increased the probability of an occult cancer were age older than 50 years, multiple sites of venous thrombosis, associated venous and arterial thromboembolism, thromboembolism resistant to warfarin therapy, and paraneoplastic syndrome. Among vascular syndromes, only cutaneous leukocytoclastic vasculitis presenting after the age of 50 years was consistently associated with cancer. Preliminary data with an antigen specific to tumor tissue, the cancer procoagulant, suggested its possible role as a tumor marker. The sensitivity for all samples analyzed from cancer patients was 80% and the specificity was 83%. CONCLUSIONS Data from the literature enabled us to outline clinical clues that might distinguish patients with cancer-associated vasculopathies from those unaffected by malignancies. Preliminary data with an antigen specific to tumor tissue, the cancer procoagulant, suggested its possible role in detecting early stage cancer. However, large-scale prospective studies are not currently available to evaluate the role of these clues and laboratory assays in the diagnosis of early stage cancer. Cancer 1996;77:1759-67.

HELLP syndrome associated with factor V R506Q mutation.

Abstract: The pathogenesis of HELLP (haemolysis, elevated liver enzyme and low platelet count) syndrome, a severe presentation of pre-eclampsia, is still an enigma. Activated protein C resistance resulting from a mutation in coagulation factor V has recently emerged as the leading cause of thrombosis in pregnancy. We report on two patients with HELLP syndrome who were found to be heterozygous for factor V R506Q mutation, leading to activated protein C resistance. These findings suggest that the pathogenesis of HELLP syndrome is associated with a thrombotic process, and point to the potential benefit of anti-thrombotic therapy in this condition.

Islets of Langerhans generate wavelike electric activity modulated by glucose concentration.

Abstract: The electric activity of whole islets of Langerhans was monitored for the first time in this study. Measurements were made from single islets isolated from mice, hamsters, gerbils, and rats by means of external electrodes. Well-structured synchronized potential spikes up to 0.5 mV in amplitude with a stable frequency of 0.5–2 Hz were measured. Spike generation had a glucose concentration threshold. In the physiological range of each animal species, firing rate was an approximate linear function of glucose concentration. At low glucose concentrations, firing became intermittent, i.e., in bursts, while in the physiological range and above, firing was typically continuous. Simultaneous measurements from two locations on an islet indicate that the measured activity reflects the propagation of an excitation wave throughout the islet. This, together with signal synchronization, suggests that the islets contain a functional pacemaker (FPM) from which excitation propagates by means of gap junctions to the rest of the islet cells (mostly β-cells). Thus, the electric characteristics of the individual β-cells are functionally masked so that the islet acts as a single functional unit. In view of the dependency of insulin secretion on the islet9s electric activity, the islet glucose-insulin dose-response characteristics must be determined by those of the FPM.

Coexistence of familial antiphospholipid syndrome and factor V Leiden: impact on thrombotic diathesis.

Abstract: Two young siblings who presented with an unusual recurrent severe thromboembolic phenomenon were found to have familial anti-phospholipid syndrome and were heterozygous for the factor V R506Q mutation. The coexistence of hereditary and acquired APC-resistance may explain the severity of thromboembolism.

Effect of myocardial swelling on residual strain in the left ventricle of the rat.

Abstract: Left ventricular (LV) residual strain in the unloaded state was shown previously to affect LV performance. The interrelationship between myocardial swelling and LV residual strain was studied, both experimentally and theoretically. Myocardial swelling was induced by retrograde perfusion of beating, nonworking, isolated rat hearts with perfusate of graded osmolarities (200-420 mosM). The opening angle (an index of residual strain), in radially cut equatorial cross-sectional slices, and their water content were measured in 40 arrested rat LV. Both water content and opening angle decreased significantly with osmolarity from 84.2 +/- 0.45% and 77.2 +/- 9.2 degrees at 200 mosM to 76.5 +/- 1.05% and 36.3 +/- 9.8 degrees at 420 mosM (P < 0.001, respectively). A morphologically based theoretical model was developed and yielded as swelling residual strain relationship, which agrees well with the data. Our results indicate that myocardial swelling is strongly related to LV residual strain, suggesting that swelling, through its effect on residual strain, can affect both LV function and its adaptation to varying loading conditions.

Generation of biologically active anti-Cryptococcus neoformans IgG, IgE and IgA isotype switch variant antibodies by acridine orange mutagenesis

Abstract: Administration of MoAbs to Cryptococcus neoformans capsular glucuronoxylomannan (GXM) can alter the course of infection in mouse models. However, the effectiveness of these antibodies appears to depend on isotype and specificity. Comparison of isotype protection efficacy requires families of MoAbs with identical fine specificity and different constant region domain. The generation of such families by hybridoma technology is not always possible because the immune response produces MoAbs of limited classes or subclasses. In these instances isotype switch variants can be isolated in vitro. Unfortunately, standard methods of recovering spontaneous switch variants are often unsuccessful, mainly because of the low frequency of switching. In this study we demonstrate that acridine orange stimulation of an IgG3 anti-C. neoformans-producing hybridoma can be used to recover the entire set of isotype switch variants: IgGl, IgG2b, IgG2a, IgE and IgA. All isotype switch variants bind to GXM; fine specificity mapping, using an 11 amino acid peptide polysaccharide mimetope, revealed conservation of binding site specificity. Furthermore, all isotype switch variants reacted with an anti-idiotopic MoAb. The functional activity of this set of MoAbs was demonstrated by their ability to enhance phagocytosis and antifungal efficacy of human macrophage-like THP-1 cells, with IgG3 being the most effective and IgE being the least effective.

Growth Hormone (GH) Retardation of Muscle Damage due to Immobilization in Old Rats

Abstract: Four weeks immobilization of the right leg of aged rats (26 months old) caused a marked 31% and 27% reduction of muscle mass of the plantaris and soleus muscles, respectively. In animals treated with 0.6 mg/kg body weight of growth hormone (GH), the reduction of weight of the above muscles was only 14.7 and 16.1%, respectively. Biochemical studies of the level of acid phosphatase as a marker of muscle catabolism showed a significant increase of this enzyme in the immobilized muscles. GH treatment had a positive effect in curtailing the increase due to immobilization. Studies on muscle protein oxidation used as another measure of damage in immobilized animals, showed a 400% increase in protein carbonyls in plantaris muscles. GH administration reduced this value significantly. One major issue hampering the clinical use of human GH (hGH) is its short half-life in vivo (14 min). In a previous work it was possible to enhance the in vivo longevity of other hormones such as follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) by fusing carboxyl-terminal peptide (CTP) of the hCG gene to the above hormones. The CTP has four serine-linked oligosaccharides, which have been shown to be important in maintaining the longer half-lives of these hormones. With the above rationale of using the CTP as a general target to increase the potency of bioactive hormones, we have now fused the CTP with hGH. This has provided us with a new successfully constructed recombinant hGH, which is currently being tested for its biological potency and for possible use in aging animals.

K+ channel antisense oligodeoxynucleotides inhibit cytokine-induced expansion of human hemopoietic progenitors.

Abstract: Primitive human hemopoietic progenitor cells identified by surface membrane markers CD33−CD34+ are capable of expansion into lineage-restricted precursors following in vitro stimulation by hemopoietic regulators such as stem cell factor (SCF) and interleukin-3 (IL-3). In search of ionic currents involved in cytokine-induced progenitor cell growth and differentiation, human umbilical cord blood CD33−CD34+ cells were subjected to perforated patch-clamp recordings following overnight incubation with SCF and/or IL-3. An inward rectifying potassium channel (Kir) was found in 33% of control unstimulated cells, in 34% of cells incubated with IL-3, in 31 % of cells incubated with SCF and in 75% of cells incubated with IL-3 plus SCE Kir activity increased with elevation of extracellular potassium and was blocked by extracellular Cs+ or Ba2+. Antisense oligodeoxynucleotides directed against Kir blocked both mRNA and functional expression of Kir channels. Kir antisense also inhibited the in vitro expansion of cytokine-stimulated CD33−CD34+ cells into erythroid (BFU-E) and myeloid (GM-CFU) progenitors in 7-day suspension cultures. Extracellular Cs+ or Ba2+ induced a similar degree of inhibition (40–60%) of progenitor cell generation. These findings strongly suggest an essential role for Kir in the process of cytokine-induced primitive progenitor cell growth and differentiation.

A polymyalgia rheumatica-like syndrome as presentation of metastatic cancer.

Abstract: A polymyalgia rheumatica-like syndrome is occasionally the first clinical expression of disseminated cancer. Patients admitted to the medical ward of a general hospital during a 10-year period were surveyed for the presence of polymyalgia rheumatica (PMR) in the context of cancer. Five patients were identified with a PMR-like syndrome characterized by prominent systemic symptoms and one or more features dissimilar from PMR, such as a) age of fewer than 50 years, b) only one typical site involved, c) asymmetrical involvement at typical sites, d) additional painful joints, and e) no improvement on 10 mg/d prednisone treatment. There were four men and one woman. The ages ranged from 37 to 84 years. The onset of PMR-like symptoms preceded the initial diagnosis of cancer or of recurrent cancer by 1 to 3 months. On x-ray of the shoulder and pelvic girdles, lytic lesions were observed in one patient. Bone scintigraphy showed pathologic uptake suggestive of metastatic spread, particularly in the symptomatic segments, in all patients. The primary sites of cancer in the five patients were lung (n = 1), kidney (n = 1), colon (n = 2) and unknown (n = 1). Although a search for malignancy may not be justified in patients presenting with typical PMR, the present survey suggests that in patients with atypical PMR-like syndromes, there is significant risk of cancer involving bones and joints. Isotopic bone scan is an appropriate screening test for such a possibility.

Regulation of Cellular Rabbit Growth Hormone (GH) Receptor and GH-Binding Protein Generation in Vitro

Abstract: In rabbits and probably in man, GH-binding protein (GHBP) is generated from proteolysis of GH receptor (GHR). The present study describes the modulation of spontaneous release of GHBP into the culture medium in relation to cellular GH receptor (GHR) in Chinese hamster ovary cells transfected with rabbit GHR complementary DNA. Secretion of GHBP (approximately 50K protein) from these cells was dependent on time, percentage of FCS, temperature, and protein synthesis. GHBP was detected in the medium at 30 min, and a linear increase was observed over the next 4 h. GHBP release was reduced by low incubation temperature, suggesting that GHBP cleavage is an energy-requiring mechanism. N-Ethylmaleimide (500 microM for 30 min at 30 C) markedly increased GHBP secretion, matched by a corresponding decrease in GHR. However, the lack of effect of N-ethyl-maleimide observed at 4 C further confirms the temperature dependence of GHBP release. We have attempted to characterize the GHBP release protease with a number of rec...

Multiple myeloma with pericardial involvement and cardiac tamponade: a report of three patients.

Abstract: Pericardial involvement and cardiac tamponade are rare complications of multiple myeloma (MM) and in most reported cases it has been diagnosed only at autopsy. Three cases of multiple myeloma with pericardial involvement seen at a single institution are described. The approach to the treatment is discussed and the literature on this rare complication of MM is briefly reviewed.

Interaction of Cytotoxic T Lymphocytes and Guinea Pig Ventricular Myocytes: Pharmacological Modulation by Blocking K+ Currents in Cytotoxic T Lymphocytes

Abstract: Infiltrating cytotoxic T lymphocytes (CTLs) are important immune effectors that damage the myocardium during heart transplant rejection as well as in cardiomyopathy and Chagas' heart disease. We have previously shown that in an in vitro model of murine-derived peritoneal exudate CTL (PEL)-guinea pig ventricular myocyte interaction, PEL induced in conjugated myocytes reduction of resting membrane potential and action potential (AP) amplitude, shortening of AP duration, delayed afterdepolarizations (DADs), and myocyte contracture and destruction. Since these findings indicated that cytotoxicity was largely caused by [Ca2+]i overload, in the present study we tested the hypothesis that blocking the L-type Ca2+ current (ICa,L) in the myocyte will eliminate the trigger for Ca2+ release from intracellular stores and will reduce [Ca2+]i overload and subsequent myocyte deterioration. CoCl2 (3 mmol/L) prevented PEL-induced AP changes, induction of DADs, and myocyte destruction. Since verapamil (2 mumol/L) was ineffective, indicating that the CoCl2 protection was not due to block of ICa,L, we tested whether the different action of these Ca2+ channel blockers was due to their differential effect on the PEL's K+ current (IK), previously shown to participate in lymphocyte activation and cytotoxicity. In agreement with their protective efficacy, CoCl2 but not verapamil blocked IK in PELs, suggesting that this is the mechanism for the protection provided by CoCl2. To support this notion, we tested the effect of the scorpion-derived peptide margatoxin (10 nmol/L), a specific K+ channel blocker in lymphocytes, on PEL-myocyte interaction and on PEL's IK; margatoxin prevented PEL-induced cytotoxicity and also blocked IK in PEL. Based on these findings, an alternative modality for attenuating CTL-induced lymphocytotoxicity is proposed.

In search of the cellular site of growth hormone (GH)-binding protein cleavage from the rabbit GH receptor.

Abstract: Transfection of Chinese hamster ovary cells with rabbit GH receptor (GHR) complementary DNA resulted in high expression of cellular GHR as well as markedly time- and temperature-dependent secretion of soluble GH-binding protein (GHBP) into the culture medium. In the present study, these cells were used as an in vitro model system to examine GHBP secretion in relation to GHR internalization, degradation, recycling, and biosynthesis. Incubation for 20 h with the lysosomotropic agents NH4Cl and monensin inhibited GH internalization and reduced cell surface GHR, whereas no significant effect on the level of secreted GHBP was observed. Cytochalasin B, a microfilament-disrupting agent, reduced the GHR level, but GHBP was not affected. Colchicine, a microfilament depolymerization agent, had no effect on the GHR level; however, it stimulated GHBP secretion approximately 2-fold. Brefeldin A (5 micrograms/ml), a transport blocker, incubated for 15-180 min resulted in a time-dependent decline in GHR, whereas no significant modulation effect on GHBP was apparent. The capacity of these cells to synthesize and incorporate GHR at the plasma membrane in relation to the generation of soluble GHBP was obtained by destruction of cell surface GHR by mild trypsinization and subsequently monitoring the rate of recovered GHR and GHBP. The rate of reappearance of GHR and GHBP was rapid, being observed within 1 h, whereas full recovery occurred within 2 and 3 h, respectively. The recovery was completely blocked by cycloheximide and brefeldin A. NH4Cl and monensin reduced GHR restoration by about 50%, but the recovery of GHBP was not affected. These data emphasize the importance of lysosomes and vesicular traffic in the regulation of secreted GHBP that might be derived from the internalized GHR and may provide insight into a better understanding of the cleavage process of GHBP from GHR.

Spreadsheet evaluation of computerized medical records: the impact on quality, time, and money

Abstract: Information and communication technologies are presumed to play a critical role in improving effectiveness and efficiency of clinical care. Although the most promising directions of technological development are microcomputer-generated computerized medical record systems, documenting their value has been a major challenge for health care providers. This paper proposes a 15-item spreadsheet instrument for evaluating computerized medical records, and demonstrates how it was experimentally applied to a 6-year long experience at three sites. In conclusion, preliminary implications and guidelines are drawn with regard to practice and research in this area.

Effects of growth hormone on skeletal muscles of aging systems

Abstract: Growth Hormone (GH) is an anabolic hormone responsible for the somatic growth of young people. However, there is a progressive decline of the level of GH secretion with age where its level in old people is 20% of peak puberty level. Similarly, the level of Insulin-like Growth Factor I (IGF-I), the local mediator of GH action, is also reduced significantly with age. Several studies in the last decade have tried to use GH replacement therapy in attempts to alleviate some of the age-accelerated symptoms. GH administration to elderly people have improved nitrogen retention and reduced urinary excretion of phosphate, sodium and nitrogen. In elderly people over 60 y old, provision of GH for 6 mo improved lean body mass by 8.8% and decreased fat tissue by 14.4%. Other reports also claimed that GH had positive effect on increasing bone cortical strength in aging 24 mo old male rats. One of the main target tissues for GH is the skeletal muscle, especially in the process of differentiation of muscle cells to form postmitotic myotubes and myofibers. Studies on the effects of GH on skeletal muscles of aging systems have led to some mixed results. Some early studies have shown that GH administration to old rats can improve muscle mass and denervation associated with muscle atrophy. Other studies on GH-deficient adult humans also claimed that GH can considerably improve muscle volume in these patients. More recent studies in models of muscle immobilization of old animals have shown that GH had a very positive influence in reducing muscle damage associated with immobilization. However, studies on adult patients suffering from post polio syndrome of muscle weakness have shown no improvement by GH treatment. Similarly, studies on the effect of GH on muscle strength in elderly people subjected to resistance exercise demonstrated that training indeed increases muscle strength. But addition of GH to the regimen of elderly subjects did not further increase the effect of training alone. Thus, it appears that GH may have positive effect on aging and particularly in aging skeletal muscles; however, other studies could not corroborate this positive effect. More work is needed to ascertain the effect and mode of action of GH in aging animals and humans.

The Effects of Induced Kynurenine Pathway on Immunocytochemical Changes in Rat Tissues Following Excessive L-Tryptophan Consumption

Abstract: During the past decade it has been reported that diets containing excessive L-tryptophan have caused multisystemic manifestations in humans, known as Eosinophilia Myalgia Syndrome (EMS) (Duffy, 1992). Abnormal metabolism of tryptophan was also reported in clinical syndromes such as carcinoid syndrome (Cooper et al., 1991), scleroderma-like syndrome (Varge et al., 1990; Bruce et al., 1990; Smith et al., 1990), eosinophilic fasciitis (Freis et al., 1973), idiopathic scleroderma (Stenerg et al., 1980) and systemic sclerosis (Freis et al., 1973). Inflammatory responses were elicited in all these syndromes as leukocyte infiltration and fibroblast proliferation were constantly seen in histological sections from lung skin and muscle tissues. It is thus possible that excessive L-tryptophan intake is involved in stimulation of the immune system. However, the mechanism by which tryptophan or its metabolites are involved in these processes is not yet understood. Since it is impossible to precisely follow such effects in humans, it was the purpose of the present study to follow the effects of L- tryptophan and its metabolites in an animal model that demonstrates similar effects to those observed in human tissues.

Increased Plasma Oxidizability in Subjects with Severe Obesity

Abstract: Present data suggest that obesity is an independent risk factor for cardiovascular diseases. Enhanced lipid peroxidation leading to oxidative modification of lipoproteins may link obesity to cardiovascular morbidity. We investigated the oxidizability and plasma antioxidant vitamins in 22 subjects divided into very obese and lean groups (body mass index 36 ± vs 23 ± 1 kg m−2 respectively). The obese subjects showed a significant elevation in plasma low-density lipoprotein (LDL)-cholesterol and insulin levels. Plasma oxidizability was studied after incubation with a free radical initiator 2, 2'-azobis-2-amidinopropane hydrochloride (AAPH). Lipid peroxidation was measured by malondialdehyde (MDA) and conjugated dienes (CD) generation. Comparing the obese group with the lean group, the rises in the levels of MDA and CD after incubation with AAPH were significantly greater in the former by 23% (MDA; p < 0.05) and 65% (CD; p < 0.01). The levels of plasma carotenoids were also significantly lower (p < 0.05) in o...

Experimental Iron Deficiency in Rats: Mechanical and Electrophysiological Alterations in the Cardiac Muscle

Abstract: 1. Our aim was to investigate the effect of experimental iron deficiency on cardiac functional properties. We recorded ventricular isometric twitch, action potentials and the L-type Ca2+ current in isolate ventricular myocytes from iron-deficient rats and control rats. 2. Twitch tension and maximal rates of tension activation and relaxation were reduced in iron-deficient compared with control rats, whereas twitch duration was prolonged. Isoproterenol (10-(6) mol/l) augmented tension in iron-deficient rats (P < 0.05), but only moderately affected control rats. In contrast, maximal rates of tension activation and relaxation were increased equally by isoproterenol in the two groups. 3. To determine the mechanism(s) responsible for the reduced mechanical function in iron-deficient rats, action potentials and the L-type Ca2+ current (with or without isoproterenol) were recorded in both groups. 4. The L-type Ca2+ current was smaller in ventricular myocytes from control rats than in those from iron-deficient rats; at a membrane potential of 0 mV, L-type Ca2+ current amplitudes were -1.44 +/- 0.18 and -0.97 +/- 0.07 nA in myocytes from control and iron-deficient rats respectively (P < 0.05). 5. Action potential duration was markedly shortened in myocytes from iron-deficient compared with control rats; action potential duration at 50% repolarization was 12.0 +/- 1.6 and 7.2 +/- 1.4 ms in myocytes from control and iron-deficient rats respectively (P < 0.01). These iron deficiency-induced electrophysiological alterations most probably contribute to the depressed mechanical function in iron-deficient rats. 6. The L-type Ca2+ current was augmented equally by isoproterenol in the two groups, suggesting that the enhanced inotropic responsiveness in iron-deficient rats was not due to an increased response of the L-type Ca2+ current. 7. These results may have an important implication for anaemic (iron-deficient) patients; the attenuation of their cardiac mechanical performance may be compensated by an increased reactivity to beta-adrenergic stimulation.

Paraneoplastic leukocytoclastic vasculitis.

Abstract: Widespread eruptive purpura, hematuria and proteinuria developed in a 56-year-old woman. A skin biopsy showed leukocytoclastic vasculitis. During a 31-month follow-up, the purpura repeatedly cleared with corticosteroid treatment only to flare with tapering of the medication. Awareness of possible cancer-associated vasculitis led us to search for an occult malignancy, and an asymptomatic lung tumor was discovered. During a 32-month observation period, after resection of a well differentiated peripheral pulmonary adenocarcinoma, the purpuric skin eruption did not recur, although steroid therapy was withheld.

Aplasia cutis congenita, high myopia, and cone‐rod dysfunction in two sibs: A new autosomal recessive disorder

Abstract: We report on a brother and a sister with congenital nystagmus, cone-rod dysfunction, high myopia, and aplasia cutis congenita on the midline of the scalp vertex. To our knowledge this familial oculocutaneous condition, transmitted as an autosomal recessive trait, has not been reported previously.

Sorting variables for each case: a new algorithm to calculate injury severity score (ISS) using SPSS-PC

Abstract: One of the more often used measures of multiple injuries is the injury severity score (ISS). Determination of the ISS is based on the abbreviated injury scale (AIS). This paper suggests a new algorithm to sort the AISs for each case and calculate ISS. The program uses unsorted abbreviated injury scale (AIS) levels for each case and rearranges them in descending order. The first three sorted AISs representing the three most severe injuries of a person are then used to calculate injury severity score (ISS). This algorithm should be useful for analyses of clusters of injuries especially when more patients have multiple injuries.

Reversed-flow tracheal gas insufflation (rf-tgi) alleviates intractable hypercapnia in ventilated premature infants and children. 1351

Abstract: REVERSED-FLOW TRACHEAL GAS INSUFFLATION (RF-TGI) ALLEVIATES INTRACTABLE HYPERCAPNIA IN VENTILATED PREMATURE INFANTS AND CHILDREN. 1351