Psychometric Properties of the Clinical Dementia Rating - Sum of Boxes and Other Cognitive and Functional Outcomes in a Prodromal Alzheimer's Disease Population.

BACKGROUND: The Clinical Dementia Rating-Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer's Disease Assessment Scale - Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

Compartmentalization of Inflammatory Response Following Gut Ischemia Reperfusion.

OBJECTIVE/BACKGROUND: Gut ischemia reperfusion (IR) is thought to trigger systemic inflammation, multiple organ failure, and death. The aim of this study was to investigate inflammatory responses in blood and in two target organs after gut IR. METHODS: This was a controlled animal study. Adult male Wistar rats were randomized into two groups of eight rats: control group and gut IR group (60 minutes of superior mesenteric artery occlusion followed by 60 minutes of reperfusion). Lactate and four cytokines (tumor necrosis factor-a, interleukin [IL]-1b, IL-6, and IL-10) were measured in mesenteric and systemic blood. The relative gene expression of these cytokines was determined by real time polymerase chain reaction in the gut, liver, and lung. RESULTS: Gut IR significantly increased lactate levels in mesenteric (0.9 ± 0.4 vs. 3.7 ± 1.8 mmol/L; p < .001) and in systemic blood (1.3 ± 0.2 vs. 4.0 ± 0.3 mmol/L; p < .001). Gut IR also increased the levels of four cytokines in mesenteric and systemic blood. IL-6 and IL-10 were the main circulating cytokines; there were no significant differences between mesenteric and systemic cytokine levels. IL-10 was upregulated mainly in the lung,suggesting that this organ could play a major role during gut reperfusion. CONCLUSION: The predominance of IL-10 over other cytokines in plasma and the dissimilar organ responses,especially of the lung, might be a basis for the design of therapies, for example lung protective ventilation strategies, to limit the deleterious effects of the inflammatory cascade. A multi-organ protective approach might involve gut directed therapies, protective ventilation, hemodynamic optimization, and hydric balance.

[VENTILOP survey. Survey in peroperative mechanical ventilation]. / Enquête VENTILOP. Enquête sur la ventilation mécanique peropératoire.

INTRODUCTION: Mechanical ventilation can initiate ventilator-associated lung injury and postoperative pulmonary complications. The aim of this study was to evaluate (1) how mechanical ventilation was comprehended by anaesthetists (physician and nurses) and (2) the need for educational programs. METHODS: A computing questionnary was sent by electronic-mail to the entire anaesthetist from Alsace region in France (297 physicians), and to a pool of 99 nurse anaesthetists. Mechanical ventilation during anaesthesia was considered as optimized when low tidal volume (6-8mL) of ideal body weight was associated with positive end expiratory pressure, FiO2 less than 50%, I/E adjustment and recruitment maneuvers. RESULTS: The participation rate was 50.5% (172 professionals). Only 2.3% of professionals used the five parameters for optimized ventilation. Majority of professionals considered that mechanical ventilation adjustment influenced the patients' postoperative outcome. Majority of the professionals asked for a specific educational program in the field of mechanical ventilation. DISCUSSION: Only 2.3% of professionals optimized mechanical ventilation during anaesthesia. Guidelines and specific educational programs in the field of mechanical ventilation are widely expected.

[Course of the anaesthesiology and intensive care unit residents in Lorraine, France]. / Parcours des anesthésistes-réanimateurs formés en Lorraine depuis 1996.

OBJECTIVE: The anaesthesiology and intensive care physician demography is becoming critical in most French regions; more than 56% of the residents trained in Lorraine are leaving the area after they graduate. METHODOLOGY: A descriptive and retrospective survey was carried out. The aims of the research were threefold: to ascertain firstly, why residents chose Lorraine in the first instance, secondly their experiences of the training and thirdly their expectations. The target group consisted of 76 former anaesthesia residents dating back to 1996. RESULTS: The response rate was 72.4%. Choosing Lorraine was based on its well-established teaching program (64%) and also on results achieved at National Medical Examination (85%). The academic medical training and working conditions were well-rated. A position was offered to 93% of the residents. Fifty-three percent stated having had previous work experience in the hospital as a decisive factor in taking up a position. By the end of the residency program, only 43.5% of anesthesia physicians remained in Lorraine; i.e., 79% were native to Lorraine and 25% born outside. Reasons given for leaving Nancy were: family (81%), more favourable climate (51%) and to go back to their region of origin (45%). CONCLUSION: Desired improvements would be: better performance of the Lorraine born students at the National Medical Examination, earlier and well-defined job offers, better communication within the team and consideration of the family situation as a whole.

Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists?

BACKGROUND: After a vitamin K antagonist (VKA) overdose, 1-2 mg of oral vitamin K can lower the International Normalized Ratio (INR) to the therapeutic range. OBJECTIVE: To establish whether oral vitamin K can substitute for heparin bridging and decrease the INR to < or = 1.5 before elective surgery. METHODS: Patients on long-term VKAs were randomized either to heparin bridging after the last VKA dose on day -5 before surgery (group H) or to VKA treatment until day -2, followed by 1 mg of oral vitamin K on the day before surgery (group K). Blood clotting variables were assessed on days -5/-2, 1 and 0, and postoperatively. If the target INR was not achieved 2 h before incision, surgery was deferred or performed after injection of prothrombin complex concentrate (PCC). RESULTS: In 30 of 94 included patients, baseline INR was outside the chosen range (18, INR < 2; 12, INR > 3.5), leaving 34 eligible patients in group H and 30 in group K. The groups were balanced in terms of body mass index, VKA treatment duration and indication, scheduled surgery, preoperative and postoperative hemoglobin, and blood loss. The INR was significantly higher in group K on days -1 and 0 than in group H. An INR < or = 1.5 was not achieved in 20 group K patients (66%). Surgery was postponed or performed after PCC injection in 12 of these 20 patients. CONCLUSIONS: Oral vitamin K (1 mg) cannot substitute for heparin bridging before surgery. In addition, one-third of patients on VKAs were exposed to a risk of bleeding (overdose) or thrombosis (underdose), thus highlighting the need for new oral anticoagulants.

Immediate hypersensitivity to chlorhexidine: literature review.

Chlorhexidine, an antiseptic belonging to family of biguanides, is used extensively in the medical and surgical environment. Late onset hypersensitivity and eczema occur regularly and are well documented events. Conversely, immediate hypersensitivity, sometimes taking the form of acute urticaria that can result in anaphylactic shock, is rarer. These manifestations can occur during contact of the skin or mucosa with chlorhexidine. Out of the fifty case reports of chlorhexidine-related anaphylaxis published worldwide over the past ten years, fifteen occurred during surgery. Signs generally appear from 15 to 45 minutes after the start of anesthesia. If there is any suspicion of immediate allergy to chlorhexidine, prick-tests or even intradermal reaction (IDR) techniques are highly recommended. In the event of confirmed allergy to chlorhexidine, strict eviction is required, bearing in mind that over a hundred medicinal products currently on the French market contain chlorhexidine.

Portal absorption of 15N and amino nitrogen in the growing pig after ingestion of labelled milk, yogurt or heat-treated yogurt.

The aim of this experiment was to study 15N and amino-nitrogen (AN) portal absorption in the growing pig after ingestion of uniformly (0.2509 APE) labelled 15N milk (M), yogurt ingested just after manufacturing (Y0), yogurt stored for 21 d at 4 degrees C (Y21) and heat-treated yogurt (HY). The highest porto-arterial differences (PAD) in 15N and AN were found in the period between 30 min and 90 min after ingestion. The absorption of nitrogen from M and HY mainly occurred during the 0-120 min time period (about 70% for M and 67% for HY). For Y0 and Y21, a larger displayed absorption period over the 0-240 min time period was observed. Y0 and Y21 presented a quite similar portal absorption profile. The 15N absorption rate was close to 80% for each studied milk product, suggesting that under our experimental conditions, dairy products (M, Y0, Y21 and HY) deliver nearly the same amounts of nitrogen to the organism. AN absorption rates were around 78% with a higher variability between the milk products. These results also indicate that most of the proteins were absorbed within the 240 min postprandial period.

Structure of the product from a novel cyclization reaction involving a C(6)-substituted uridine analog.

5,6,7,7a,9,10,14b,14c-Octahydro-4-[2,3-O-(1-methylethylidene )-beta-D- ribofuranosyl]cyclopenta-[4,5]pyrimido[5',4':3,4]pyrrolo[2,1- a]isoquinoline-1,3(2H,4H)-dione, C25H31N3O6, M(r) = 469.54, tetragonal, P4(3)2(1)2, a = 12.577 (2), b = 12.577 (2), c = 29.893 (4) A, V = 4729 (1) A3, Z = 8, Dx = 1.319 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu = 7.9 cm-1, F(000) = 2000, T = 298 K, final R = 0.038, wR = 0.064 for all 1884 independent reflections and 432 variables. The crystal structure shows a syn conformation around the N(1)--C(1') single bond, consistent with other C(6)-substituted uridine analogs, and an unusual O(1') endo conformation of the ribose ring. The stereochemistries of the three newly created chiral centers are 14cR, 4aR, 7aS.

[Polycythemia after kidney transplantation]. / Polyglobulie après transplantation rénale.

Between 1971 and 1990, 251 kidney transplanted patients with a well functioning graft were evaluated to determine the frequency of post-transplant erythrocytosis (PTE). Thirty-one patients (13 percent) developed polycythaemia 10.6 +/- 10 months after transplantation. Thromboembolic complications occurred in 22 percent of the cases. The frequency of PTE was higher in males than in females (sex ratio: 7.2 vs 2.1; P < 0.05). Patients with renal dysplasia had a lower incidence of PTE (3 vs 22 percent; P < 0.05) as did those who had been treated with azathioprine (9.4 vs 19 percent; P < 0.05). None of the patients treated with recombinant erythropoietin before transplantation developed PTE during a mean follow-up of 15.1 +/- 4.5 months. The majority of polycythaemic patients had normal erythropoietin levels. These results show that there is an erythropoietin-independent proliferation due to an increased sensitivity of erythroid progenitors or to an erythroid stem cell stimulation by cytokines.

Linear free energy relationship studies of enzyme active site binding: thymidylate synthase.

The requirements for active-site binding of thymidylate synthase from three sources, Lactobacillus casei, murine leukemia L1210, and human lymphoblast (Molt/4F), were investigated by analyzing the binding of a series of 5-(p-substituted phenyl)-2'-deoxyuridylates (N1-substituted 5-aryl-2, 4-dioxopyrimidines) to the enzyme. Multiple regression analysis revealed that an increase in electron density of the heterocyclic ring and hydrophobic substituents enhance affinity. Correlations of biological results with spectral data indicated that higher electron densities at the oxygen atoms are responsible for increase in binding. These results support the presence of both a cationic binding site and a hydrophobic region. In addition, the results revealed an unusual reversal of electronic requirements for binding and catalysis. The formation of the binary complex is enhanced by electron-donating substituents, while the initial catalytic reaction, formation of the covalent ternary complex, is promoted and stabilized by electron-withdrawing substituents.

5-Quinone derivatives of 2'-deoxyuridine 5'-phosphate: inhibition and inactivation of thymidylate synthase, antitumor cell, and antiviral studies.

Both photochemical aromatic substitution and palladium (0)-catalyzed biaryl coupling reactions have been employed in the synthesis of 5-substituted 2'-deoxyuridines. The former procedure was useful in the preparation of the 3,4-dimethyl-2,5-dimethoxyphenyl derivative 12a and the 3,4,6-trimethyl-2,5-dimethoxyphenyl derivative 12b. The latter reaction was efficient in the preparation of the 2-(3-methyl-1,4-dimethoxynaphthyl) derivative 14. These compounds and their nucleotides (20a-c) were converted to the corresponding quinone nucleosides 19a-c and nucleotides 6-8 by an oxidative demethylation reaction using ceric ammonium nitrate and silver(II) oxide, respectively. The kinetics and products of the reaction of the quinone nucleosides 19a,b with methyl thioglycolate showed rapid addition to the quinone ring in the trisubstituted derivative 19a and somewhat slower redox reactions with the tetrasubstituted quinones 19b and 19c. All six nucleotides had high affinity for the title enzyme from Lactobacillus casei with Ki values ranging from 0.59 to 3.6 microM; the most effective compounds were the dimethyl quinone 6 and the naphthoquinone 8. Somewhat higher inhibitory constants were observed with the quinones against the L1210 enzyme. The dimethyl quinone nucleotide 6 showed time-dependent inactivation (kinact = 0.015 s-1) against the L. casei enzyme, a rate saturation effect, and substrate protection in accord with the kinetic expression for an active-site-directed alkylating agent. The apparent second-order rate of this reaction (2.5 X 10(4) M-1 s-1) is one-twentieth the rate (kcat.) of the normal enzymatic reaction leading to product. None of the compound exhibited sufficient activity in the antitumor cell or antiviral assays to warrant further study.

Thiol addition to quinones: model reactions for the inactivation of thymidylate synthase by 5-p-benzoquinonyl-2'-deoxyuridine 5'-phosphate.

The reaction of methyl mercaptoacetate (5) with phenyl-p-benzoquinone (6) or 5-p-benzoquinonyl-3',5'-di-O-acetyl-2'-deoxyuridine (10) resulted in the formation of the three possible adducts to the quinone rings of 6 and 10; an additional product in the reaction with 10 was the unsubstituted hydroquinone (14). Both reactions were found to be solvent dependent; in buffered aqueous acetonitrile the meta and para adducts of 10 were formed in the ratio of 2:1. In ethyl acetate the ortho adduct and the reduction product of 10 were isolated in a ratio of 2:3. The second-order rate constant for the reaction of 5 with 10 in acetonitrile was 0.53 M-1 s-1; the reaction was accelerated by the addition of water. Although the initially proposed mechanism-based enzyme inactivation cannot be excluded, the results of the model reactions support the alternative mechanism, active-site thiol addition to the quinone ring. If this is true the title compound would be classed as an affinity label, not a mechanism-based inhibitor.

Palladium (II)-catalyzed olefin-coupling reactions of kainic acid: effects of substitution on the isopropenyl group on receptor binding.

Two palladium-catalyzed carbon-carbon bond forming reactions were found to be useful for the modification of a protected amino acid derivative containing a sterically hindered isopropenyl group. Arylation of the terminal methylene group of the dimethyl ester of N-(ethoxycarbonyl)kainic acid (3) was accomplished by treatment with an aromatic amine, palladium(II) acetate, and tert-butyl nitrite. Substitution of the allylic methyl group of 3 was accomplished by conversion to the pi-(allyl)palladium complex (5) which, on subsequent treatment with the carbanions of tert-butyl acetoacetate or phenylthioacetone, gave the alkylated products. Both the (Z)- and (E)-3-nitrophenyl derivatives (8a,b) of kainic acid were active in the standard binding assay. Unexpectedly, the cis compound in the nitrophenyl series (8a), which more closely resembles the extended conjugation found in domoic acid, was found to be 20 times less potent than the trans derivative 8b. The latter had one-fifth the receptor-binding affinity of kainic acid.

5-p-benzoquinonyl-2'-deoxyuridine 5'-phosphate: a possible mechanism-based inhibitor of thymidylate synthetase.

The title compound (1), designed as a suicide inhibitor of thymidylate synthetase, can be prepared by silver(II) oxide oxidative demethylation of the corresponding dimethoxyphenyl derivative. Compound 1 shows time-dependent inactivation of thymidylate synthetase (methotrexate-resistant Lactobacillus casei) and saturation kinetics, and the inactivation is responsive to substrate protection. The inactivation is not reversible on prolonged dialysis in attempts to remove the inhibitor. The rate constant for inactivation is 0.065 s-1; the dissociation constant (Ki) was estimated to be 2 microM. The kinetics of this inactivation are compared to inactivation caused by model thiol reagents that do not have affinity for the active site of thymidylate synthetase.

5-Substituted 2'-deoxyuridines: correlation between inhibition of tumor cell growth and inhibition of thymidine kinase and thymidylate synthetase.

A large variety of 5-substituted 2'deoxyuridines (dUrds) and 2'-deoxyuridylates (dUMPs) have been evaluated for their inhibitory effects on the thymidine (dThd) kinase or thymidylate (dTMP) synthetase isolated from mouse leukemia L1210 cells. The most potent inhibitors of dThd kinase were 5-chloro-, 5-bromo- and 5-iodo-dUrd. Their Ki/Km values ranged from 0.57 to 0.82. All dUrd analogs tested showed competitive kinetics with respect to dThd. However, there was little, if any, correlation between the inhibitory effects of the compounds on L1210 cell growth and their inhibitory activities against dThd kinase (r = 0.16). The most potent inhibitors of dTMP synthetase were (in order of decreasing activity): 5-nitro-dUMP greater than 5-formyl-dUMP greater than 5-fluoro-dUMP greater than 5-oxime of 5-formyl-dUMP greater than 5-azidomethyl-dUMP greater than (E)-5-(2-bromovinyl)-dUMP. The ki/Km values for these compounds ranged from 0.001 to 0.665. All dUMP analogs tested showed competitive kinetics with respect to dUMP (if not preincubated with the enzyme at 37 degrees). There was a strong correlation (r = 0.833) between the inhibitory effects of these compounds on L1210 cell growth and their inhibitory activities against dTMP synthetase. Thus, the suppressive action of 5-substituted dUrd derivatives on tumor cell growth would involve prior conversion of the nucleoside analogs to the corresponding 5'-monophosphates followed by an inhibition of dTMP synthetase.

Role of thymidine kinase in the inhibitory activity of 5-substituted-2'-deoxyuridines on the growth of human and murine tumor cell lines.

Twenty-four 5-substituted 2'-deoxyuridines have been evaluated for their inhibitory effects on the growth of three human lymphoblast cell lines (Namalva, RAji and TK- (thymidine kinase deficient) Raji) and these inhibitory effects were compared to those for two murine leukemia cell lines (L1210/0 and L1210/BdUrd). The latter was selected from the parental L1210/0 cell line by its ability to grow at high concentrations of 5-bromo-dUrd and could also be considered as TK-. There was a close correlation between the inhibitory effects of the deoxyuridine analogs on Namalva, Raji and L1210 cells: the correlation coefficient (r) for log ID50 (median inhibitory dose) for L1210 cell growth, on the one hand, and log ID50 for Namalva or Raji cell growth, on the other hand, was 0.902 and 0.929, respectively. There was also a strong correlation (r = 0.936) between the log ID50 values for the two human lymphoblast cell lines. However, there was no significant correlation (r less than 0.40) either between the log ID50 for the TK- Raji cells and the parental TK+ Raji cells, or between the log ID50 for the TK- L1210/BdUrd cells and the parental TK+ L1210/0 cells. We may conclude therefore, that (i) the murine leukemia L1210 cell system is predictive for the growth-inhibitory effects of 5-substituted 2'-deoxyuridines on human lymphoblast cell lines, and (ii) the antitumor cell activity of the 5-substituted 2'-deoxyuridines is, to a large extent, dependent on the thymidine kinase activity of the tumor cells.

N-hydroxymethyl derivatives of nitrogen heterocycles as possible prodrugs I: N-hydroxymethylation of uracils.

Solid samples of 1,3-dihydroxymethyluracil, 3-hydroxymethyl-1-methyluracil, and 1-hydroxymethyl-3-methyluracil were prepared, and their structures were confirmed by spectroscopic analysis. The thermodynamics and kinetics of the formation of N-hydroxymethylated uracils in aqueous formaldehyde solutions also were studied. The equilibrium constants for formation of N-1-hydroxymethyl derivatives were approximately twice those for formation of N-3-hydroxymethyl derivatives, and they were formed more rapidly throughout the pH 3--8 range. Substituents at C-5 of uracil had little effect on the thermodynamics of N-hydroxymethylation. The potential usefulness of N-hydroxymethyl compounds as prodrugs is discussed.