Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11

 Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD₅₀) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. Received: 16 June 1997 / Accepted: 23 September 1997     

Newly developed hybrid suture without lubricant: noninvasive in vivo assessment of biocompatibility with multiparametric MR imaging.

Magnetic resonance imaging (MRI) and magnetic resonance (MR) relaxometry were used to assess noninvasively the tissue response of a new uncoated hybrid braided suture made from a combination of ultra-high-molecular-weight polyethylene (UHMWPE) and polyester (polyethylene terephthalate) (PET) yarns in comparison to a silicone impregnated braided 100% polyester (PET) control suture (Ticron). Both biomaterials were monitored for a period of 30 days following implantation in both incised and nonincised paravertebral rabbit muscles. In all cases, MR images and relaxometry demonstrated that the hybrid suture elicited either a milder or a similar tissue and cellular response compared to the control suture. These findings were confirmed by conventional histological analysis of the surrounding tissues. They also demonstrated that the hybrid suture promoted faster healing in terms of collagen infiltration between the yarns and individual filaments. This milder inflammatory reaction and improved biocompatibility represent a real advantage in the healing performance of sutures for cardiac and vascular surgery, and support the need for continued research and development of hybrid structures. This study also demonstrated the ability of MRI techniques to noninvasively evaluate the biocompatibility of biomaterials. By extending the capacity of MR diagnostic tools from patients to experimental animals, it is now possible to validate the healing performance of foreign materials with statistical reliability and fewer animals.     

Transcultural nursing: a perspective derived from Jean-Paul Sartre

Transcultural nursing care is a well-established theoretical framework. This theory, developed by Madeleine Leininger, can have an impact on clinical practice, academic preparation and nursing research. The heightened interest in applying transcultural care and the increased need to espouse this framework have been triggered by constant population changes. This paper defines transcultural nursing care and expands its definition further by comparing and contrasting it with Jean-Paul Sartre's existentialist perspective. The two modes of existence as defined by Sartre are closely examined. Concrete examples are offered as cultural phenomena and the components of a cultural assessment are discussed and applied. The philosophical thesis is approached from a transcultural nursing perspective and existentialism is shown to serve as a foundation for transcultural nursing. The advantages and disadvantages of transcultural nursing practice and the preparation of transcultural nurses are finally addressed.     

Mitochondrial DNA variability detected in a single wheat regenerant involves a rare recombination event across a short repeat

The mitochondrial genome of the selfed progeny of a plant regenerated from long-term somatic tissue culture displays specific structural rearrangements characterized by the appearance of novel restriction fragments. A mitochondrial DNA library was constructed from this selfed progeny in the SalI site of cosmid pHC79 and the novel fragments were subsequently studied. They were shown to arise from reciprocal recombination events involving DNA sequences present in the parental plant. The regions of recombination were sequenced and the nucleotide sequences were aligned with those of the presumptive parental fragments. We characterized an imperfect short repeated DNA sequence, 242 bp long, within which a 7-bb DNA repeat could act as a region of recombination. The use of PCR technology allowed us to show that these fragments were present in both parental plants and tissue cultures as low-abundance sequence arrangements.     

Hypertension following renal transplantation in children

The files of 334 consecutive cadaver kidney (CK) and of 27 living related (LR) transplantations (T) in children and adolescents performed from 1973 to 1984 have been reviewed. Following cadaver transplantation, 52 patients (15%) never had hypertension (HT), 41 patients (12%) had only initial HT up to 6 months after transplantation and 18 other patients (5%) exhibited transient HT episodes while on high-dose steroid therapy. Finally, 209 patients (62%) had HT for periods longer than 6 months and 16 patients (5%) until death or graft failure within the first 3 months. Chronic graft rejection was the major cause of HT, but other factors either isolated or in association were also present. Renal artery stenosis (RAS) was diagnosed in 43 cases (13%) 2–17 months post-transplantation; 10 of these were operated upon (5 successfully) and 9 underwent transluminal angioplasty with a single success. Nine cases of RAS resolved spontaneously. HT was attributed to the host kidney in 10 cases (3%) and to recurrence of primary renal disease in 9 (3%). HT observed after CKT was sometimes severe and difficult to control. Acute complications from HT were recorded in 35 cases, with 6 deaths and 2 severe neurological sequelae. Among 25 LRT, 11 cases (40%) had no HT 13 (48%) had HT for longer than 6 months. In this group, no case of RAS was observed and only one complication (without sequelae) was noted. In conclusion, HT is a frequent and sometimes severe complication post-transplantation in children and adolescents.     

Chemoprevention of melanoma: an unexplored strategy.

The incidence and mortality of melanoma has continued to increase steeply-faster than most other preventable cancers in the United States. Current sun protection strategies have yet to reduce this increased incidence and mortality. Chemoprevention, defined as the use of natural or synthetic agents to delay, reverse, suppress, or prevent premalignant molecular or histologic lesions from progressing to invasive cancer, has become an important area in cancer research. Melanoma, with its associated risk factors and its known precursors or premalignant lesions, should lend itself well to chemoprevention. Prerequisites for this research should include determination of the molecular mechanisms of ultraviolet (UV) melanomagenesis; use of animal models to test candidate prevention agents; use of molecular and histologic markers as surrogate end point markers; collection of epidemiological, basic science, or in vitro data on potential chemoprevention candidate drugs; and selection of a high-risk patient population in which to carry out clinical chemoprevention trials. Preliminary data available in all these areas are reviewed. Possible mechanisms and molecular targets for the chemoprevention of UV-induced melanoma are discussed. This recent information should stimulate research in the chemoprevention of melanoma.     

Practice makes perfect: preparing graduate nurses for professional licensure.

In the fall of 2000, the licensing examination for nursing taken by candidates in the Province of Quebec was altered to include an oral practical component. This article describes how a group of nurse clinician educators, despite severe time and human resources constraints, developed a unique and interactive program to assist graduate unlicensed nurses to successfully prepare for this new examination process.     

Detection of Antiendothelial Cell Antibodies by an Enzyme-Linked Immunosorbent Assay Using Antigens from Cell Lysate: Minimal Interference with Antinuclear Antibodies and Rheumatoid Factors

The objective of the present work was to set up a routine test adapted to screening for antiendothelial cell antibodies (AECAs) in serum samples with minimal interference from antinuclear antibodies (ANAs) or rheumatoid factors (RFs). We compared the titers of AECAs titrated following two enzyme-linked immunosorbent assays (ELISAs): (i) an ELISA with ethanol-fixed EA.hy926 monolayers as the antigenic substrate and (ii) an ELISA with nucleus-depleted lysates prepared from EA.hy926 cells and normalized for protein (1.0 to 1.7 mg/ml) and DNA (≤0.1 μg/ml) contents as a surrogate substrate (postnuclear supernatant ELISA [PNS-ELISA]). The AECA titers in 51 serum samples, including 28 samples containing ANAs, were compared. A significantly positive correlation (r = 0.77; P < 0.001) between the two series was shown only for the ANA-negative serum samples. Conversely, ANAs or RFs in samples were shown not to interfere in tests for AECAs by the PNS-ELISA. AECAs recognize their antigenic targets in postnuclear supernatants, which is representative of the endothelial antigenic content, with improvement of the reliability of the assay, a prerequisite to application of the assay for their evaluation in clinical practice.     

Distinctive alterations of invasiveness, drug resistance and cell-cell organization in 3D-cultures of MCF-7, a human breast cancer cell line, and its multidrug resistant variant

Growth of human tumor cells as three-dimensional (3D) multicellular spheroids modifies their invasive properties. Here we study the differences in the biological features of MCF-7, a human breast cancer cell line, and its multidrug resistant variant (MDR-MCF-7) cultured as spheroids or as monolayers. Three-dimensional culture decreased the proliferative rate of both cell lines, reduced the drug sensitivity of MCF-7 cells and did not affect the resistance of MDR-MCF-7 cells. Transmission electron microscopic studies and intercellular junctions labeling showed that MCF-7 spheroids had a junctional system involving E-cadherin, tight-junctions and desmosomes. In MDR-MCF-7 cell spheroids, cell cohesion was mostly due to membrane interdigitations. MDR-MCF-7 cells, but not their parental counterpart, displayed a higher invasive potential when cultured as spheroids, as shown in the Boyden chamber assay. 3D-induced invasiveness was correlated with serine protease and plasminogen activator (PA) secretion. MCF-7 cells did not show any tendency to invade, whatever the mode of culture. These results show that 3D-cultures as spheroids distinctively altered structural features of parental and MDR-MCF-7 cells. In MCF-7 cells, 3D-culture increased cell-cell contacts and drug resistance; in MDR-MCF-7 cells, it induced invasive properties.