Caffeine analogs: structure-activity relationships at adenosine receptors.

Caffeine and analogs that contain ethyl, propyl, allyl, propargyl and other substituents in place of methyl at 1-, 3- and 7-positions were antagonists at the two major classes (A1 and A2) of adenosine receptors. Potency at both receptors increased as methyls were replaced with larger substituents. Certain analogs with only one of the three methyl groups of caffeine replaced by larger substituents were somewhat selective for A2 receptors. None of the analogs were particularly selective for A1 receptors. The presence of polar entities in the substituent at the 1- or 7-position was poorly tolerated at adenosine receptors. Activity of caffeine analogs at A1 and A2 adenosine receptors in a variety of systems and cell types is presented and summarized.     

Comparing pharmacokinetics of amoxicillin given twice or three times per day to children older than 3 months with pneumonia

For children with ambulatory pneumonia, the World Health Organization (WHO) recommends oral amoxicillin (15 mg/kg of body weight/dose) thrice daily (t.i.d.) or oral cotrimoxazole (4 mg of trimethoprim/kg/dose) twice daily (b.i.d.). The more frequent amoxicillin dosing may lead to compliance problems. To compare the pharmacokinetics and levels of amoxicillin in plasma in the current WHO acute respiratory infection recommendations with the 25-mg/kg/dose b.i.d. regimen, we performed a two-group parallel study of 66 children ages 3 to 59 months with pneumonia. Amoxicillin was given orally at 25 mg/kg/dose b.i.d. or 15 mg/kg/dose t.i.d. Amoxicillin concentrations were determined by high-performance liquid chromatography after the first dose on days 1 and 3. After the first dose on day 1, the mean area under the concentration-time curve (AUC) for amoxicillin after the 25-mg/kg dose was 54.7 versus 24.9 micro g. h/ml after the 15-mg/kg dose. After the first dose on day 3, the mean AUC was 44.1 versus 28.5 micro g. h/ml. All but two children had plasma amoxicillin concentrations above 0.5 micro g/ml for >50% of the dose interval on both days. Six children on day 1 and five children on day 3 had concentrations above 1.0 micro g/ml for <50% of the dose interval. On day 1, 16 of 27 children in the b.i.d. group and 11 of 26 children in the t.i.d. group had concentrations that were above 2.0 micro g/ml for <50% of the dose interval, and on day 3, 18 of 31 children in the b.i.d. group and 8 of 31 children in the t.i.d. group had concentrations that were above 2.0 micro g/ml for <50% of the dose interval. Amoxicillin b.i.d. is a feasible alternative for t.i.d. dosing. To lengthen the time above the MIC at higher concentration levels, a 30- to 40-mg/kg/dose b.i.d. should be considered instead of the 25 mg/kg/dose used in this study.     

Commercial transplants in local Pakistanis from vended kidneys: a socio-economic and outcome study

Donor shortage and absence of transplant law lead to unrelated commercial transplants in Pakistan. We report the socio‐economic and outcome parameters of 126 local recipients of unrelated kidney vendor transplants presenting to our institute between 1997 and 2007. Their outcome was compared with 180 recipients of living‐related donor transplants matched for age, gender and transplant duration as controls. Age of commercial recipients was 35.63 ± 11.57 years with an M:F ratio of 2.4:1. Majority (92%) were transplanted in northern Pakistan paying US$7271 ± 2198. All were educated with 50% being graduates or above and rich earning a monthly salary of US$517 ± 518 with 44% earning >US$500. Comparison of commercial recipients with controls showed high comorbidities 35 (28%) vs. 14 (8%) (P = 0.0001) with diabetes, hepatitis‐C and cardiovascular diseases. Donor age was 29.97 ± 6.16 vs. 32.63 ± 9.3 years (P = 0.035). Biologic agents induction in 101 (80%) vs. 14 (8%) (P = 0.0001), acute rejections in 42 (33%) vs. 31 (17%) (P = 0.005), 1‐year creatinine 1.84 ± 1.28 vs. 1.27 ± 0.4 mg/dl (P = 0.0001), surgical complications 28 (22%) vs. 14 (8%) (P = 0.001), tuberculosis 14 (11%) vs. 6 (6%) (P = 0.007), acute hepatitis 20 (16%) vs. 3 (2%) (P = 0.0001), cytomegalovirus 33 (26%) vs. 21 (11%) (P = 0.001) and recurrent urinary tract infection 35 (28%) vs. 30 (16%) (P = 0.034). Overall 1‐ and 5‐year graft survival was 86% and 45% vs. 94% and 80%, respectively (P = 0.00001). Total deaths were 34 (27%) vs. 12 (6.0%) (P = 0.001). In conclusion, recipients of the vended kidneys are poor candidates, educated, rich and often self‐selecting. Their outcome is poor, which will leave them poorer still and back to dialysis if not death.     

Neurogenic claudication and radiculopathy as delayed presentations of retained spinal bullet

Background contextFirearm injuries to the spine may cause injury to the neurological structures and/or to the spine, including ligaments and bones.PurposePatients usually present with symptoms immediately after injury. However, only a few cases have been reported where a patient is neurologically intact after the initial injury but develops deficits several months or years later. Almost all these cases develop delayed neurological deficit because of bullet migration.Study designCase report.MethodsA discussion, with a relevant review of the literature, the clinical histories, and radiological findings of two patients who experienced delayed neurological symptoms after gunshot wounds to the spine.ResultsOne patient presented after 14 years and the other after 5 months from the day of injury. Both cases are unique in that the delayed symptoms appeared because of formation of a reactive mass around the site of bullet impact. Lack of serial imaging studies is a barrier to the exclusion of bullet migration as an alternate cause of delayed symptoms.ConclusionThese cases illustrate that retained intraspinal bullets can present with delayed neurological findings secondary to reactive changes around the bullet.     

Gesture subtype-dependent left lateralization of praxis planning: an event-related fMRI study

Ideomotor apraxia is a disorder mainly of praxis planning, and the deficit is typically more evident in pantomiming transitive (tool related) than intransitive (communicative) gestures. The goal of the present study was to assess differential hemispheric lateralization of praxis production using event-related functional magnetic resonance imaging. Voxel-based analysis demonstrated significant activations in posterior parietal cortex (PPC) and premotor cortex (PMC) association areas, which were predominantly left hemispheric, regardless of whether planning occurred for right or left hand transitive or intransitive pantomimes. Furthermore, region of interest-based calculation of mean laterality index (LI) revealed a significantly stronger left lateralization in PPC/PMC clusters for planning intransitive (LI = -0.49 + 0.10, mean + standard deviation [SD]) than transitive gestures (-0.37 + 0.08, P = 0.02, paired t-tests) irrespective of the hand involved. This differential left lateralization for planning remained significant in PMC (LI = -0.47 + 0.14 and -0.36 + 0.13, mean + SD, P = 0.04), but not in PPC (-0.56 + 0.11 and -0.45 + 0.12, P = 0.11), when both regions were analyzed separately. In conclusion, the findings point to a left-hemispheric specialization for praxis planning, being more pronounced for intransitive gestures in PMC, possibly due to their communicative nature.