Alkyl 4-chlorobenzoyloxycarbamates as highly effective nitrogen source reagents for the base-free, intermolecular aminohydroxylation reaction.

Ethyl- (7), benzyl- (8), tert-butyl- (9), and fluorenylmethyl-4-chlorobenzoyloxycarbamates (10) have been prepared as storable and easy-to-prepare nitrogen sources for use in the intermolecular Sharpless aminohydroxylation reaction and its asymmetric variant. These reagents were found to be effective under base-free reaction conditions. The scope and limitations of these methods have been explored using a variety of alkenes, among which, trans-cinnamates, in particular, proved to be good substrates.

Why consider human papillomavirus vaccination in older women?

Preventive human papillomavirus (HPV) L1 vaccines are safe and efficient to prevent infection and lesions of vaccine- specific HPV types in women from 15 to 26 years, but also in older age groups. Clearly, public health funds are to be spent to organize programs for vaccination of young adolescents. Immunobridging studies and clinical trials have shown that HPV vaccines generate significantly higher plasma antibodies than following natural infections in women up to 55 years and prevent up to 90.5% (95% CI 73.7-97.5) vaccine-specific HPV infections and lesions in women aged 24-45 years who are HPV DNA-negative at the time of vaccination. However, data from clinical trials with HPV L1 vaccines in older women (older than 25 years) are still scarce compared to the amount of evidence from trials in women younger than 26 years. Information from large population-based studies indicates that older women remain at risk of infection by high-risk HPV and the risk of persistent high-risk HPV infection is significantly higher than in young women, leading to a higher risk of progressing disease and carcinoma. The natural history of HPV infection remains enigmatic as we do not know if the immune mechanisms that clear the HPV infection offer prolonged protection. On the contrary, some data indicate that seroconversion after a natural infection only partially protects against re-infection. Given the large proportions of adult men and women that change sexual partners, the protective effects of HPV L1 vaccines may offer an extra benefit against HPV-related genital diseases within a much shorter time period than after vaccination of prepubertal adolescents.

'Segmented' crystals solved using synchrotron radiation: (2S,3R,4S,5R)-4-(10,10-dimethyl-3,3-dioxo-3lambda6-thia-4-azatricyclo[5.2.1.0(1,5)]decan-4-ylcarbonyl)-2,6-diphenylperhydropyrrolo[3,4-c]pyrrole-1,3-dione.

The title compound, C(29)H(31)N(3)O(5)S, forms needle-shaped ;segmented' crystals, thereby inhibiting successful single-crystal data collection using conventional laboratory facilities. One crystallite of dimensions 0.15 x 0.03 x 0.01 mm yielded sufficent single-crystal diffraction data on the Australian Synchrotron PX1 beamline. The two independent molecules in the asymmetric unit are nearly superimposable and show only minor conformational deviations from closely related compounds. The molecules pack using one N-H...O hydrogen bond and several phenyl C-H...O(=S), phenyl C-H...O(=C) and methylene C-H...O(=C) hydrogen bonds and weak C-H...pi interactions.

MICA compatibility and immunization in third kidney transplantations.

Significantly lower graft survival has been observed among recipients of a third (G3) compared with a first or second kidney transplantation. Because patients awaiting G3 are largely HLA immunized, they are usually transplanted with a high HLA match. Moreover, their rate of acute rejection episodes is similar to a first or second transplantation. Since major histocompatibility complex class I related chain A (MICA) molecules have been proposed as new targets for antibody recognition, we were interested to type donors and recipients for MICA alleles and to study MICA immunization of these patients. Forty-three pairs of donors and recipients were typed for MICA alleles using Luminex technology (LABtype RSSO). MICA alleles showed strong linkage disequilibrium with the B locus: some 4-digit alleles were preferentially associated with a given MICA allele. A greater frequency of patients with 2 MICA mismatches (MM) was observed among patients with rejection (40%), whereas all the graft losses were observed in patients with 0 or 1 MICA MM. MICA immunization was studied using sera from 52 patients collected on day 0 and after transplantation using a Luminex assay (LABScreen). MICA immunization was less frequent than HLA immunization, and MICA donor-specific antibody (DSA) was equally present in functional and failed grafts. These observations confirmed the potential role of MICA immunization in rejection, whereas the poor graft survival among third transplantations could not be explained by MICA incompatibility or immunization.

(2S,3R,4S,5R)-Diethyl 2-(10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decan-4-ylcarbonyl)-5-phenylpyrrolidine-3,4-dicarboxylate: a novel isomorphous-by-addition compound.

The title compound, C(27)H(36)N(2)O(7)S, (I), is isomorphous by addition with the dimethyl ester analogue [Garner, Dogan, Youngs, Kennedy, Protasiewicz & Zaniewski (2001). Tetrahedron, 57, 71-85], (II), by replacing two methyl ester H atoms with two methyl groups. With the exception of the conformation of one of the ester groups, the molecules are almost superimposable. Likewise, apart from a slightly larger c axis in (I), few differences in the cell packing of (I) and (II) are found, with both dominated by the same C-H...O hydrogen bonds. Full synthetic and spectroscopic details of (I) are given. The molecular synthesis is important as an example of chiral auxiliary-assisted 1,3-dipolar cycloaddition of an azomethine ylid.

L-Enantiomers of transition state analogue inhibitors bound to human purine nucleoside phosphorylase.

Human purine nucleoside phosphorylase (PNP) was crystallized with transition-state analogue inhibitors Immucillin-H and DADMe-Immucillin-H synthesized with ribosyl mimics of l-stereochemistry. The inhibitors demonstrate that major driving forces for tight binding of these analogues are the leaving group interaction and the cationic mimicry of the transition state, even though large geometric changes occur with d-Immucillins and l-Immucillins bound to human PNP.

A practical synthesis of (3R,4R)-N-tert-butoxycarbonyl-4-hydroxymethylpyrrolidin-3-ol.

The title compound (+)-, required for production of transition state analogue inhibitors of enzymes involved in T-cell-dependent disorders, was synthesized in five steps. A 1,3-dipolar cycloaddition of the nitrone formed from formaldehyde and N-benzylhydroxylamine to diethyl maleate gave the racemic cis-isoxazolidine (+/-)-. Reduction of the N-O bond of this compound gave pyrrolidone (+/-)- in excellent yield. A very efficient enzymic resolution of this racemic product led to the title enantiomer (+)-. This route employs only one chromatographic purification.

Syntheses and bio-activities of the L-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases.

(1R)-1-(9-Deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-L-ribitol [(+)-5] and (3S,4S)-1-[(9-deazahypoxanthin-9-yl)methyl]-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-6] are the L-enantiomers of immucillin-H (D-ImmH) and DADMe-immucillin-H (D-DADMe-ImmH), respectively, these D-isomers being high affinity transition state analogue inhibitors of purine nucleoside phosphorylases (PNPases) developed as potential pharmaceuticals against diseases involving irregular activation of T-cells. The C-nucleoside hydrochloride D-ImmH [(-)-5) x HCl], now "Fodosine" is in phase II clinical trials as an anti-T-cell leukaemia agent, while D-DADMe-ImmH is a second generation inhibitor with extreme binding to the target enzyme and has entered the clinic for phase I testing as an anti-psoriasis drug. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the L-nucleoside analogues (+)-5 x HCl and (-)-6, respectively, of D-ImmH and D-DADMe-ImmH, were prepared and their PNPase binding properties were studied. For the synthesis of compound (-)-6 suitable enzyme-based routes to the enantiomerically pure starting material (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-6] and its enantiomer were developed. The L-enantiomers (+)-5 x HCl and (-)-6 bind to the PNPases approximately 5- to 600-times less well than do the D-compounds, but nevertheless remain powerful inhibitors with nanomolar dissociation constants.

The role of the antitragicus muscle in plical folding of the pinna.

BACKGROUND: The antitragicus is one of six intrinsic muscles of the external ear. This study examined the anatomical variations of the muscle and its association with prominent ears. METHODS: Twenty-seven consecutive patients presenting for correction of prominent ears were recruited into the study. In each case, the antihelical fold was assessed preoperatively by a single investigator. A standard anterior cartilage scoring otoplasty was performed, and the presence and quality of the antitragicus muscle were assessed by a second investigator. For statistical analysis, the qualitative assessment of the fold and the muscle was given a numerical value. It was then possible to plot the qualitative assessment of the fold against the muscle, and correlations between muscle and fold were calculated. RESULTS: The presence of the muscle was associated with an absent antihelical fold, whereas a well-defined antihelical fold was associated with an absent muscle (p < 0.0001). CONCLUSIONS: The authors propose that the presence of a well-formed antitragicus muscle, which exerts an anterior pull on the cauda helicis, contributes to the poor development of the antihelical fold.

Significant enhancement of the Stille reaction with a new combination of reagents-copper(I) iodide with cesium fluoride.

The combination of copper(I) iodide and cesium fluoride significantly enhances the Stille reaction. After extensive optimisation, a variety of electronically unfavourable and sterically hindered substrates were coupled in very high yields under mild conditions.

[Clinical practice guidelines of the Spanish Society of Cardiology for pulmonary thromboembolism and hypertension]. / Guías de práctica clínica de la Sociedad Española de Cardiología en tromboembolismo e hipertensión pulmonar.

Primary pulmonary hypertension is a progressive disease. Most affected patients are young and middle-aged women. Etiology is unknown, although a familial and genetic factor is present in up to 6% of cases. Endothelial dysfunction and abnormalities in calcium channels of smooth muscle fibers are the present pathogenetics theories. Diagnostic tests try to exclude secondary causes of pulmonary hypertension and to evaluate its severity. Acute vasodilatory test is vital in the selection of treatment. Oral anticoagulation is indicated in all patients. Lung transplant is performed when medical treatment is unsuccessful. Atrial septostomy is an alternative and palliative treatment for selected cases. Chronic thromboembolic pulmonary hypertension is a special form of secondary pulmonary hypertension, clinically undistinguishable from primary primary hypertension, is of mandatory diagnosis because it can be cured with thromboembolectomy. Pulmonary embolism is common in hospitalised patients. The mortality rate for pulmonary embolism continues to be high: up to 30% in untreated patients. The accurate detection of pulmonary embolism remains difficult, as pulmonary embolism can accompany as well as mimic other cardiopulmonary illnesses. Non-invasive diagnostic tests have poor specificity and sensitivity. The D-dimer level and the spiral CT angiography have also been employed as new alternatives and important tools for precise diagnosis of suspected pulmonary embolism. The standard therapy of pulmonary embolism is intravenous heparin for 5 to 10 days in conjunction with oral anticoagulants posteriorly for 3 to 6 months. The incidence of deep venous thrombosis, pulmonary embolism and death due to pulmonary embolism, can be reduced significantly and shown clear benefits only by adoption of a prophylactic strategy with low-molecular-weight-heparins or dextrans in patients at risk.

[Vegetation analysis and detection of periurban focus of canine piroplasmosis due to Babesia canis in Rhône-Alpes area; ecological basis for map-making]. / Analyse de la végétation et détection des foyers péri-urbains de piroplasmose canine à Babesia canis dans la région Rhône-Alpes; bases écologiques pour une cartographie

Dog piroplasmosis is actually expanding at the periphery of the big cities of the Rhone-Alpes area. The authors present the basis of an epidemiological study and insist upon the interest of vegetation analysis in the detection of the contamination sites.