A synthetic strategy to a new class of cycloalkane ring-fused pyridine nucleosides as potential anti HIV agents

Condensation of cyanothioacetamide or cyanoacetamide with sodium salts of 2-formyl-1-cycloalkanones afforded the corresponding cycloalkane ring fused pyridine-2(1H)-thiones and -2-pyridones. The latter compounds served as a key intermediates for the synthesis of a new class of cycloalkane ring fused pyridine glycosides.     

Influence of electrode site and size on variability of magnetic evoked potentials

Successive magnetic evoked potentials (MEPs) concern varying motor neurons. We investigated whether this MEP-specific source of variability depends on electrode site and size. Amplitude variability (standard deviation) was largest over the center of the hypothenar muscles. Latencies were longer at distal and proximal sites than at the center site. Large electrodes (10 cm2) did not decrease this source of amplitude variability compared with EEG electrodes, in contrast to other sources of variability.     

Patterns of allosensitization in allograft recipients: long-term cardiac allograft acceptance is associated with active alloantibody production in conjunction with active inhibition of alloreactive delayed-type hypersensitivity

BACKGROUND: The immunologic characteristics of experimental allograft acceptance remain ill-defined. This study evaluates humoral and cell-mediated immunity in transiently immunosuppressed mice that have accepted cardiac allografts. METHODS: DBA/2-->C57BL/6 heterotopic cardiac allograft recipients were immunosuppressed with either GK1.5 monoclonal antibody or gallium nitrate and monitored for donor-reactive delayed-type hypersensitivity (DTH) assessed by ear challenge and for alloantibody production detected by flow cytometry. RESULTS: Cardiac allograft function continued for >90 days in approximately 50% of GK1.5-treated and 97% of gallium nitrate-treated transplant recipients. All nonsuppressed recipients lost graft function within 7 to 10 days. Among mice that accepted allografts, donor-reactive IgG was produced by about 50% of GK1.5 monoclonal antibody-treated mice and 80% of gallium nitrate-treated mice. None of the these mice exhibited donor-reactive DTH responses, and all could down-regulate third-party DTH responses in a donor alloantigen-dependent manner. This down-regulation is not found in nonsuppressed allograft recipients or in naive mice. Importantly, transfer into SCID mice of splenocytes from mice that accepted allografts, but not naive splenocytes, provided them with a similar ability to accept cardiac allografts, even if the grafts co-expressed third-party alloantigens. CONCLUSIONS: IgG alloantibody production by murine cardiac allograft recipients is not a precise indicator of allosensitization leading to either cardiac allograft rejection or acceptance. However, expression of alloreactive DTH is a reliable indicator of allosensitization leading to acute rejection, and the absence of DTH in association with active DTH down-regulatory mechanisms is a reliable indicator of allograft acceptance in this experimental model. Thus, DTH analysis may hold more promise than alloantibody detection for clinical assessment of posttransplant immune status.     

Peptide-amidating enzymes are expressed in the stellate epithelial cells of the thymic medulla

C-terminal amidation is a post-translational processing step necessary to convey biological activity to a large number of regulatory peptides. In this study we have demonstrated that the peptidyl-glycine alpha-amidating monooxygenase enzyme complex (PAM) responsible for this activity is located in the medullary stellate epithelial cells of the thymus and in cultured epithelial cells bearing a medullary phenotype, using Northern blot, immunocytochemistry, in situ hybridization, and enzyme assays. Immunocytochemical localization revealed a granular pattern in the cytoplasm of the stellate cells, which were also positive for cytokeratins and a B-lymphocyte-associated antigen. The presence of PAM activity in medium conditioned by thymic epithelial cell lines suggests that PAM is a secreted product of these cells. Among the four epithelial cell lines examined, there was a direct correlation between PAM activity and content of oxytocin, an amidated peptide. Taken together, these data provide convincing evidence that thymic epithelial cells have the capacity to generate amidated peptides that may influence T-cell differentiation and suggest that the amidating enzymes could play an important role in the regulation of thymic physiology.     

Venous thromboembolism--incidence and risk factors in Oslo

Over a period of three years, 378 patients with objectively verified venous thromboembolism were treated at Aker University Hospital. Below the age of 60, men and women had about the same incidence of venous thromboembolism, but that age the incidence was significantly higher among men than among women. Incidence increased exponentially with age, from about 1:10,000 at age 20 to about 1:1,000 at age 50. The incidence found here is lower than in earlier Nordic studies. The great majority of the patients (93%) had deep venous thrombosis in the lower extremities, 11% had symptomatic and verified pulmonary embolism, and 1% had their thrombus in an inner organ vein. 23% of patients were previously treated for venous thromboembolism, and 22% had cancer. Seven women were on oral contraception, and 22 used postmenopausal hormone substitution. An obvious temporary precipitating factor was present in 42% of the patients, while 36% had a spontaneous venous thromboembolism. Hereditary thrombophilic disorder was found in 32% of patients below the age of 60.     

HIV disease progression in Australia in the time of combination antiretroviral therapies

OBJECTIVE: To examine the effect of recent developments in antiretroviral therapy on HIV disease progression and survival. DESIGN: Retrospective cohort study. PARTICIPANTS AND SETTING: Two cohorts of people with HIV were defined retrospectively from the records of a large immunology laboratory. The first cohort were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L during 1990, and the second were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L in 1994. MAIN OUTCOME MEASURES: HIV disease progression and survival was determined over a minimum three years of follow-up for each cohort (i.e., 1990-1993; 1994-1997). RESULTS: 346 subjects were included in the analysis (193 subjects from 1990 and 153 from 1994). The relative risk of progression to AIDS in the 1994 cohort compared with the 1990 cohort was 0.57 (95% confidence interval, 0.35-0.91; P = 0.018) and the relative risk of death was 0.20 (95% confidence interval, 0.08-0.49; P < 0.001). CONCLUSIONS: There were 43% fewer AIDS cases and 80% fewer deaths in the time following the increased availability of combination antiretroviral therapy in Australia.     

A seminar/case-based approach to teaching removable partial dentures to predoctoral students

OBJECTIVE: To explore potential long term consequences of second trimester amniocentesis. DESIGN: Children exposed to second trimester amniocentesis have been followed prospectively from birth to school age and compared with children whose mothers declined the test. SETTING: The Hospital for Sick Children, Toronto. SAMPLE: Eighty-six children exposed to amniocentesis and 44 children whose mothers declined the test. INTERVENTIONS: Second trimester amniocentesis for the late maternal age indication. MAIN OUTCOME MEASURES: Standardised tests of intelligence, academic achievement, speech articulation, visual-perceptual-motor ability and fine motor coordination were administered. Parents reported on child behaviour using standardised measures of behaviour problems, social competence, hyperactivity and temperament. Physical growth was also measured, and parents reported on child health. RESULTS: Group differences were not observed. CONCLUSIONS: Second trimester amniocentesis does not appear to compromise child development, behaviour, growth or health.     

Viewing and naming objects: eye movements during noun phrase production

Eye movements have been shown to reflect word recognition and language comprehension processes occurring during reading and auditory language comprehension. The present study examines whether the eye movements speakers make during object naming similarly reflect speech planning processes. In Experiment 1, speakers named object pairs saying, for instance, 'scooter and hat'. The objects were presented as ordinary line drawings or with partly deleted contours and had high or low frequency names. Contour type and frequency both significantly affected the mean naming latencies and the mean time spent looking at the objects. The frequency effects disappeared in Experiment 2, in which the participants categorized the objects instead of naming them. This suggests that the frequency effects of Experiment 1 arose during lexical retrieval. We conclude that eye movements during object naming indeed reflect linguistic planning processes and that the speakers' decision to move their eyes from one object to the next is contingent upon the retrieval of the phonological form of the object names.     

Caries in patients with non-insulin-dependent diabetes mellitus

OBJECTIVE: To describe intratrial differences in hind limb symmetry in healthy dogs at the trot, using noninvasive, computer-assisted, three-dimensional kinematic gait analysis. ANIMALS: 8 clinically normal large-breed adult dogs. PROCEDURE: Dynamic flexion and extension angles and angular velocities were calculated for the coxofemoral, femorotibial, and tarsal joints of dogs at the trot. Temporal and distance variables were computed. Essential Fourier coefficients were used to determine mean flexion and extension curves for all joints and to compare differences in movement between right and left hind limbs. Variances attributable to limb, dog, and trial were determined. RESULTS: Each joint had a characteristic pattern of flexion and extension movement that was used to compare intratrial symmetry of hind limb gait. Significant differences were not detected in temporal or distance variables between the right and left hind limbs. Significant differences were not noted in essential Fourier coefficients used to characterize coxofemoral, femorotibial, and tarsal joint angles and angular velocities, with the exception of the cosine-0 coefficient for coxofemoral angular velocity. Variation in joint angle and angular velocity measurements were attributable to individual dog and trial. Variation attributable to limb was negligible. CONCLUSIONS: Intratrial evaluation of right-left hind limb symmetry, using kinematic gait analysis, indicated objectively that hind limb movement is symmetrical at the trot in healthy large-breed dogs. CLINICAL RELEVANCE: Documentation of hind limb symmetry at the trot will help provide a basis for direct comparison of both hind limbs in future studies evaluating gait and treatment of dogs with musculoskeletal disease.     

The terminal O-acetyltransferase involved in vindoline biosynthesis defines a new class of proteins responsible for coenzyme A-dependent acyl transfer

The gene encoding acetyl CoA:deacetylvindoline 4-O-acetyltransferase (DAT) (EC 2.3.1.107) which catalyzes the last step in vindoline biosynthesis was isolated and characterized. The genomic clone encoded a 50 kDa polypeptide containing the sequences of nine tryptic fragments derived from the purified DAT heterodimer. However, cleavage of DAT protein to yield a heterodimer appears to be an artifact of the protein purification procedure, since the size of the protein (50 kDa) cross-reacting with anti-DAT antibody in seedlings and in leaves of various ages also corresponds to the size of the active recombinant enzyme. Studies with the intact plant and with developing seedlings showed that induction of DAT mRNA, protein accumulation and enzyme activity occurred preferentially in vindoline producing tissues such as leaves and cotyledons of light-treated etiolated seedlings. The ORF of DAT showed significant sequence identity to 19 other plant genes, whose biochemical functions were mostly unknown. The Mr of approximately 50 kDa, a HXXXDG triad, and a DFGWGKP consensus sequence are highly conserved among the 20 plant genes and these criteria may be useful to identify this type of acyltransferase. The involvement of some of these genes in epicuticular wax biosynthesis, fruit-ripening and in benzoyltransfer reactions indicates that the plant kingdom contains a superfamily of multifunctional acyltransferases which operate by a reaction mechanism related to the ancient chloramphenicol O-acetyltransferase and dihydrolipoyl acetyltransferase class of enzymes.