Donor sepsis is not a contraindication to cadaveric organ donation

Systemic donor infection is regarded as being an absolute contraindication to cadaveric organ donation for transplantation. This is largely due to fear of transmitting pathogenic organisms to the immunosuppressed recipient. However, due to the current shortage of organs available for transplantation, clinicians are faced with the option of using organs from 'non-ideal' donors, such as those patients with documented evidence of infection. We report the successful outcome of six orthotopic liver transplants, 11 renal transplants, one combined heart lung transplant and one simultaneous kidney and pancreas transplant with organs from eight donors in whom bacterial meningitis (n = 7) and acute bacterial epiglottitis (n = 1) were the antecedent causes of death.      

FcR gamma-chain is essential for both surface expression and function of human Fc gamma RI (CD64) in vivo

Most Ig receptors exist as hetero-oligomeric complexes with separate ligand binding (alpha) and signal transducing (beta, gamma, or zeta) subunits. For Fc gamma RIIIa and Fc epsilon RI, association with the FcR gamma-chain is essential for surface expression. However, the human high affinity IgG receptor, hFc gamma RI, was found to be surface- expressed by itself in transient transfection models. We have now analyzed the integrity of hFc gamma RI expression in more detail in stable transfectants. In vitro we noted that, in the absence of FcR gamma-chain, surface expression of hFc gamma RI rapidly declined to background levels, in both IIA1.6 B cells and NIH3T3 fibroblasts. The effect of FcR gamma-chain on hFc gamma RI surface expression in vivo was evaluated by using two newly generated transgenic mouse lines, selectively expressing hFc gamma RI on myeloid cells. These transgenic mice were crossed with FcR gamma-chain-deficient mice. Analysis of blood monocytes and peritoneal macrophages showed that surface expression of hFc gamma RI was reduced by approximately 80%. The remaining approximately 20% of receptors were still capable of binding IgG-opsonized RBC, suggesting FcR gamma-chain not to be critical for hFc gamma RI ligand-binding capacity. Importantly, however, hFc gamma RI signaling capacity was lost in FcR gamma-chain-deficient cells. No phagocytosis could be observed using either ligand sensitized (EA- IgG2a) or CD64-targeted erythrocytes (using a bispecific antibody) in both hFc gamma RI transgenic lines. This documents the FcR gamma-chain to be indispensable for both surface membrane expression and function of human Fc gamma RI in vivo.     

Knowledge of pressure ulcer prevention: a cross-sectional and comparative study among nurses

Background  

Pressure ulcers are a common, painful and costly condition. Results of a 1991 study into the knowledge among Dutch hospital nurses on the usefulness of measures to prevent pressure ulcers showed moderate knowledge. Results were confirmed by subsequent studies. In recent years, Dutch guidelines have been updated and the attention given to pressure ulcer care has been increased. This was expected to improve pressure ulcer care and to increase nurses' knowledge. The aims of the current study were to investigate (1) how much nurses employed in Dutch hospitals know about the usefulness of 28 preventive measures considered in the most recent national pressure ulcer guideline; (2) whether differences in knowledge exist between nurses working in hospitals that audit pressure ulcers and those employed in hospitals that do not; and (3) to study whether knowledge among Dutch hospital nurses regarding the usefulness of preventive measures had changed between 1991 and 2003.     

Biochemical and behavioural characterization of EMPA,a novel high-affinity,selective antagonist for the OX2 receptor

Background and purpose:

The OX₂ receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX₂ receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA).

Experimental approach:

The affinity of [³H]EMPA was assessed in membranes from HEK293-hOX₂-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A-or orexin-B-induced accumulation of [³H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX₂ receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala¹¹,D-Leu¹⁵]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats.

Key results:

[³H]EMPA bound to human and rat OX₂-HEK293 membranes with K_D values of 1.1 and 1.4 nmol·L⁻¹ respectively. EMPA competitively antagonized orexin-A-and orexin-B-evoked accumulation of [³H]IP at hOX₂ receptors with pA₂ values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [³H]EMPA for OX₂ receptors. EMPA significantly reversed [Ala¹¹,D-Leu¹⁵]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure.

Conclusions and implications:

EMPA is a high-affinity, reversible and selective OX₂ receptor antagonist, active in vivo, which should prove useful for analysis of OX₂ receptor function.     

Regulation by FK506 and rapamycin of Ca2+ release from the sarcoplasmic reticulum in vascular smooth muscle: the role of FK506 binding proteins and mTOR

Background and purpose:

The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca²⁺ concentration ([Ca²⁺]_cyto) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP₃R). These receptors may be regulated by the accessory FK506-binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR).

Experimental approach:

Single portal vein myocytes were voltage-clamped in whole cell configuration and [Ca²⁺]_cyto measured using fluo-3. IP₃Rs were activated by photolysis of caged IP₃ and RyRs activated by hydrostatic application of caffeine.

Key results:

FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca²⁺]_cyto rise evoked by activation of either RyR or IP₃R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine-evoked, but reduced the IP₃-evoked [Ca²⁺]_cyto rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine- or IP₃-evoked [Ca²⁺]_cyto release; calcineurin did not contribute to FK506-mediated potentiation of RyR- or IP₃R-mediated Ca²⁺ release. The mTOR inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, like rapamycin, decreased IP₃-evoked Ca²⁺ release.

Conclusions and implications:

Ca²⁺ release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP₃R-mediated Ca²⁺ release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP₃-mediated Ca²⁺ release may be explained by mTOR inhibition.     

Comorbidity Is a Prognostic Factor in Elderly Patients with Head and Neck Cancer

Background The number of aged patients with head and neck cancer is increasing. Comorbidities are common in this population. It is necessary to evaluate the effect of comorbidities as measured with the ACE-27 index on recurrence and survival of elderly patients with head and neck cancer, adjusting by other prognostic factors as age, clinical stage and functional status index. Patients Three hundred and ten patients greater than 70 years of age with head and neck cancer in a referral cancer center were studied. Comorbidity measured with the ACE-27 index was the main independent variable. The outcomes were recurrence and survival. Results Comorbidities were present in 75% of patients. Five-year disease-free survival, overall survival and cancer-specific survival were 63.1, 42.8 and 55.8%, respectively. Advanced clinical stage and Karnofsky index ≤70 were associated with recurrence. Age >80 years, male gender, Karnofsky index ≤80, advanced clinical stage, and ACE value ≥2 were independently associated with overall survival. The ACE-27 value was not associated with cancer-specific survival. The Karnofsky performance index was associated with overall survival and mortality and acted as a confounding factor on multivariable analysis on overall and cancer-specific survival. Conclusions Comorbidity measured with ACE-27 was a prognostic factor for overall survival in patients older than 70 years with head and neck cancer. The Karnofsky performance index could be included in multivariable analysis of survival for older patients with head and neck cancer.     

Role of specific brain peptide factors in the pathogenesis and compensation of neurologic disorders and their use in the treatment of nervous system diseases]

New concepts of the molecular mechanisms implicated in the pathogenesis and compensation of central motor disorders are presented. It has been shown experimentally that specific peptide, postural asymmetry, and inactivation factors, play the leading part in these processes. The detection of these specific factors in the cerebrospinal fluid (CSF) of patients and convalescents allowed one to work out and test clinically a new method of treatment (CSF therapy) of patients with central motor disorders of varying genesis. The results of the clinical observations of two patients' groups (with cerebrovascular brain lesions and multiple sclerosis) are provided.     

Structure-activity studies on benzhydrol-containing nipecotic acid and guvacine derivatives as potent, orally-active inhibitors of GABA uptake.

The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs. A series of compounds is reported which explores the structure-activity relationships (SAR) in this series. Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring. The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro IC50 values for GABA uptake of < 1 microM (including 5, Table I; 37, 43, Table IV; and 44, Table V). Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans.     

Problem of chemical structural specificity of the brain]

The structurally specific chemical factors (SSCF) are considered as are differentiation-, regeneration- and normal function-promoting factors of embryonic and adult brain tissue. From this point of view the authors' data concerning SSCF expression after brain lesion are discussed. Analysis is made of the importance of further studies into the identification of these factors and elucidation of the biological role they play in the compensatory processes after brain damage in order to develop new approaches to the treatment of brain diseases.