Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study.

BACKGROUND: Proteinuria is an important complication in renal transplant recipients. The aim of this prospective study was to evaluate the long-term impact of transplant proteinuria patterns on allograft function and survival. METHODS: We analyzed urinary protein of a cohort of 83 renal transplants with proteinuria ≥0.5 g/d by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radial immunogel diffusion assay. After initial stratification and analysis, the cohort was followed up for 16 yr. The graft outcome and survival were analyzed using Cox regression model to determine their association with different patterns of initial transplant proteinuria. RESULTS: Group with predominantly glomerular (middle- and high-molecular-weight with or without low-molecular-weight) proteinuria (61%) had higher serum creatinine (p < 0.001) than the group with predominantly tubular (low-molecular-weight) proteinuria (39%). The incidences of chronic graft dysfunction and graft loss had increased in the glomerular proteinuria group (p < 0.001, hazard ratio 3.6, 95% confidence interval 1.7-7.5 and p < 0.001, hazard ratio 4.9, 95% confidence interval 1.9-12.1, respectively). Patient death did not differ (p = 0.434, hazard ratio 1.5, 95% confidence interval 0.5-4.5). CONCLUSION: Proteinuria in renal transplants can be differentiated into glomerular and tubular types based on molecular weight. Glomerular proteinuria is associated with significant increase in graft dysfunction and graft loss.

Neurochemistry changes associated with mutations in familial Parkinson's disease.

Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.

Magnetization transfer ratio in Alzheimer disease: comparison with volumetric measurements.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is accompanied by macroscopic atrophy on volumetric MR imaging. A few studies have also demonstrated reduction in magnetization transfer ratio (MTR), suggesting microstructural changes in remaining brain tissue. This study assessed the value of measuring MTR in addition to volumetric MR in differentiating patients with AD from control subjects. MATERIALS AND METHODS: Volumetric T1-weighted images and 3D MTR maps were obtained from 18 patients with AD and 18 age-matched control subjects. Whole-brain (WB) and total hippocampal (Hc) volumes were measured using semiautomated techniques and adjusted for total intracranial volume. Mean MTR was obtained for WB and in the Hc region. Histogram analysis was performed for WB MTR. Among patients, associations between volumetric and MTR parameters and the Mini-Mental State Examination (MMSE) were explored. RESULTS: Patients with AD had significantly reduced WB volume (P<.0001) and mean WB MTR (P=.002) and Hc volume (P<.0001) and Hc mean MTR (P<.0001) compared with control subjects. Histogram analysis of WB MTR revealed significant reduction in the 25th percentile point in patients with AD (P=.03). Both WB volume and mean MTR were independently associated with case-control status after adjusting for the other using linear regression models. However, measuring Hc mean MTR added no statistically significant discriminatory value over and above Hc volume measurement alone. Of all MR imaging parameters, only WB volume was significantly correlated with MMSE (r=0.47, P=.048). CONCLUSIONS: This study demonstrates the independent reduction of WB volume and mean MTR in AD. This suggests that the 2 parameters reflect complementary aspects of the AD pathologic lesion at macrostructural and microstructural levels.

c-Jun regulates the stability and activity of the p53 homologue, p73.

Chemotherapeutic drugs and stress signals activate p73, the structural and functional homologue of p53, both by transcriptional activation and post-translational modifications. However, cisplatin, a DNA damage-inducing chemotherapeutic agent, is thought to regulate p73 only by affecting its stability through mechanisms involving the MLH-1/c-Abl signaling cascade. Here we show that c-Jun, a component of the AP-1 family of transcription factors, contributes to p73 induction by cisplatin. c-jun(-/-) cells are defective in p73 induction, and ectopic c-Jun expression augments p73 levels. c-Jun-mediated accumulation of p73 requires the transactivation activity of c-Jun and occurs in a c-Abl- and Mdm2-independent manner. c-Jun expression increases p73 half-life by preventing it from proteasome-mediated degradation, resulting in the potentiation of p73-mediated transcriptional activity. Moreover, mouse fibroblasts lacking c-Jun are resistant to cisplatin-induced apoptosis, and reintroduction of c-Jun restores p73 activation and sensitivity to cisplatin. Furthermore, p73-mediated apoptosis is abrogated in c-jun(-/-) cells. Together, these findings demonstrate a possible role for c-Jun in regulating p73 function and highlight the importance of the cooperativity between transcription factors in potentiating apoptosis.

An accurate and reproducible scheme for quantification of coronary artery calcification in CT scans.

The coronary artery disease is a major cause of deaths in the western world. One indicator for coronary artery disease (CAD) is coronary artery calcification (CAC). An accurate and reproducible scheme is desired to monitor the progression of patient's coronary calcification in follow-up studies. Traditional approaches for CAC estimation lack to provide accurate and reproducible results. In This work, a new adaptive and stochastic 3D method has been proposed by employing a modified expectation-maximisation (MEM) algorithm. It is less sensitive to partial volume effects, motion effects, slice thickness and low dose. Accuracy of the proposed method was measured by a cardiac CT stationary phantom containing 6 calcium inserts of predetermined size and density that were scanned 90 times using 15 different protocols based on slice thickness and radiation. Reproducibility was measured in 35 patients who were each scanned twice with the patient being repositioned before the second scan. Compared with the Agatston based method, it is shown that the proposed algorithm gives better results in terms of accuracy and reproducibility.

The recent malaria situation in Chittagong, Bangladesh.

This is a retrospective study on 7,005 cases of malaria treated in a base hospital during the period 1998 to 2001. The aim of the study is to analyze the patterns, complications and mortality rates of malaria and its response to standard anti-malarial drugs. Diagnosis of malaria was made from identification of parasites on Giemsa stained thick and thin blood slides among the febrile cases and the clinical (unspecified) malaria was diagnosed as per WHO criteria. Malaria cases accounted for 136.17 per thousand-hospital admissions. Out of 7,005 malaria cases, 54.22% were falciparum, 26.18% were vivax and 12.02% were mixed infections. The most common complications of falciparum malaria were cerebral malaria (2.80%), malarial hepatitis (1.55%), acute pneumonia and/or pulmonary edema (0.22%), acute renal failure (0.13%), algid malaria (0.13%) and black water fever (0.06%). Most of the cases (66.98%) responded (S-response) well to chloroquine. Among the rest, 11.99% required quinine, 9.79% required artemether and 0.08% required both mefloquine and artemether. The total mortality rate was 0.30% but it was 9.25% and 6.17% among complicated malaria and cerebral malaria cases, respectively. Prognosis appeared better on early recognition of complications and initiation of prompt, effective treatment and adequate nursing care. Most mortality was due to complicated falciparum malaria and the emergence of drug resistance.