Pregnancy after transplantation

The National Transplantation Pregnancy Registry (NTPR) was established in 1991 to study the outcomes of pregnancies in female transplant recipients and pregnancies fathered by male transplant recipients. Data from the NTPR have helped to endorse the reassurances from publications of smaller experiences that successful pregnancies are possible in the transplant population. In our last review for this journal (2000), we noted that important future issues would include the reassessment of prepregnancy guidelines, gestational and organ-specific problems, the role of new immunosuppressive drugs, and the long-term effects of pregnancy on both graft and child. Data collected by the NTPR over the last 7 years have addressed these issues, thus providing additional information for health care providers of transplant recipients of childbearing age. There has been some refinement of prepregnancy guidelines, but there is a need for additional data collection so that organ-specific outcomes and risks can further be identified. To date, the outcomes of the children followed have been encouraging, and specific remote effects have not been identified, but continued surveillance is still vital. Of special concern are the new immunosuppressive drugs, specifically for mycophenolate mofetil (CellCept, Roche Laboratories Inc., Nutley, New Jersey), where data reported to the NTPR and through postmarketing surveillance have shown an increased incidence of nonviable outcomes and a specific pattern and increased incidence of malformation in the newborn, which has resulted in a pregnancy category change. Newer information points to an increased need for vigilance among centers and continued monitoring of pregnancy outcomes in this population. As the first reported pregnancy after transplantation occurred in a kidney recipient 50 years ago, in March 1958, this review also highlights the first reported pregnancies in other solid organ recipients.     

L-type calcium channels involvement in aortic smooth muscle contraction as revealed by membrane potential and active force dynamics

Membrane potential (MP) is essential in smooth muscle (SM) contractile activity, mainly by its effect upon L-type Ca2+ channels. We simultaneously recorded SM isometric tension and MP in de-endothelised rat aorta rings and examined their submaximal activation by K+, norepinephrine (NE) or phenylephrine (PHE) and the influence of methoxyverapamil (D600). K+ -induced contraction strictly correlated with depolarization, while faster contractions induced by NE or PHE started and peaked with a less depolarized membrane. D600 completely relaxed K+ or NE contracted rings, time-correlated with full repolarization, but partially relaxed PHE-contracted rings, with partial repolarization, which did not precede relaxation. The observed MP and force dynamics support known mechanisms of action of the drugs used. L-type channels participate in the depolarizing and contractile effect of NE, as opposite to their minor involvement in the effects of PHE.     

Regional mapping of prion proteins in brain.

Scrapie is characterized by the accumulation of a protease-resistant isoform of the prion protein PrPSc. Limited proteolysis and chaotropes were used to map the distribution of PrPSc in cryostat sections of scrapie-infected brain blotted onto nitrocellulose membranes, designated histoblots. Proteolysis was omitted in order to map the cellular isoform of the prion protein (PrPC) in uninfected brains. Compared with immunohistochemistry, histoblots increased the sensitivity for PrPSc detection and showed different patterns of PrPSc accumulation. In Syrian hamsters with Sc237 scrapie, the most intense PrPSc signals occurred in sites with relatively little PrPC, suggesting that aberrant localization of prion protein may be an important feature in the pathogenesis of prion diseases. Immunostaining of PrPSc in white-matter tracts suggested that prions spread along neuroanatomical pathways. PrPSc immunostaining in histoblots was quantitated by densitometry, permitting assessment of the extent of PrPSc accumulation within specific structures. Histoblots were also useful in localizing PrPCJD and beta/A4-amyloid peptide in the brains of patients with Creutzfeldt-Jakob disease and Alzheimer disease, respectively.     

Right pulmonary artery occlusion by an acute dissecting aneurysm of the ascending aorta

We describe the case of a 76-year old female who presented with a Type A aortic dissection requiring repair with an interposition graft and aortic valve replacement. Post-operatively she had clinical features and computerised tomographic images suggestive of a pulmonary embolus and died 24 hours later. The extremely rare finding of intramural thrombus occluding the right pulmonary artery was seen at post mortem.     

Dual energy X-ray absorptiometry of the hand and wrist–a possible technique to assess skeletal maturation: methodology and data in normal youths

Ninety five normal Caucasian subjects (51F, 44 M) aged from 2 to 25 y were measured at the hand and wrist level with a small DXA system (pDEXA™) in order to obtain the normal values of the bone mineral content (BMC), density (BMD) and projected area (A) of carpal (c) and metacarpal (m) bones. BMDc ranged from 0.065 ± 0.007 g/cm to 0.365 ± 0.035 g/cm in females and 0.425 ± 0.040 g/cm in males. It presented a sharp change of increase rate at 15.5 and 17 y of age in girls and boys, respectively. Ac presented the same kind of evolution as BMDc, but had a larger value dispersion. The second metacarpal bone had the highest BMCm value in 85% of females and 90% of males. The sum of BMCmi or Ami values (i = 1–5) and the projected mean density of the 5 metacarpal bones was well correlated with BMCc, Ac and BMDc, respectively ( r > 0.90). A volumetric mineral density, dmi, calculated for each of these bones, approximated to a cylinder, was correlated with age ( r > 0.85).     

MALT lymphoma involving the kidney: a report of 10 cases and review of the literature

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) can arise at any anatomic site, but involvement of the kidney is rare. We describe 10 cases of kidney MALT lymphoma, including 6 localized cases. No predisposing inflammatory conditions were identified, with the possible exception of coexistent renal Actinomyces infection in 1 case. We performed fluorescence in situ hybridization (FISH) using a malt1 break-apart probe in 7 cases. A malt1 gene rearrangement was identified in 1 case (14%). This case was further assessed by FISH using an IgH breakapart probe that showed IgH gene rearrangement. These results are suggestive of the t(14;18) involving malt1 and IgH. Immunostaining for NF-kappaB p65 showed nuclear positivity, consistent with NF-kappaB activation, in 3 of 5 cases assessed. Our results indicate that kidney MALT lymphomas share similarities with MALT lymphomas arising at other sites in that MALT lymphoma-associated translocations and NF-kappaB activation occur in a subset of cases.     

Diabetes in relation to serum levels of polychlorinated biphenyls and chlorinated pesticides in adult Native Americans

BACKGROUND: Recent research suggests that diabetes, a condition whose incidence is increasing, is associated with exposure to polychlorinated biphenyls (PCBs) and chlorinated pesticides. OBJECTIVES: We investigated the potential association between diabetes and serum levels of PCBs, dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), and mirex in a cross-sectional study of an adult Native-American (Mohawk) population. METHODS: Through a standardized questionnaire we collected demographic, medical, and lifestyle information from 352 adults, > or =30 years of age. We collected fasting serum samples that were analyzed for 101 PCB congeners, DDE, HCB, and mirex along with fasting glucose, triglycerides, and cholesterol. Participants who had fasting-glucose values > 125 mg/dL and/or who were taking antidiabetic medication were defined as persons with diabetes. We conducted logistic regression to assess the potential association between organochlorine serum levels and diabetes, while controlling for the potential confounding variables of age, body mass index (BMI), smoking, sex, and serum lipid levels. Organochlorine serum levels were categorized in tertiles, and the lowest tertile was used as the reference category. RESULTS: The prevalence of diabetes was 20.2%. The odds ratio (OR) of having diabetes for participants in the highest tertile of total PCB concentration compared with the lowest tertile was 3.9 (95% confidence interval, 1.5-10.6). The corresponding ORs for DDE and HCB were even higher. Elevated serum mirex was not associated with diabetes. After adjustment for other analytes, the OR for HCB remained significant, whereas ORs for PCBs and DDE remained elevated but not statistically significant. In contrast, after adjustment for other analytes, the OR for mirex became statistically significant and indicated an inverse association. CONCLUSIONS: In this study of adult Native Americans, elevated serum PCBs, DDE, and HCB were positively associated with diabetes after controlling for potential confounders, whereas a negative association was observed for mirex.     

Attempts to restore scrapie prion infectivity after exposure to protein denaturants.

A wealth of experimental evidence argues that infectious prions are composed largely, if not entirely, of the scrapie isoform of the prion protein. We attempted to restore scrapie infectivity after exposure to protein denaturants including urea, chaotropic salts, and SDS. None of the procedures restored infectivity. Dialysis to remove slowly chaotropic ions and urea failed to restore scrapie infectivity. Attempts to create monomers of the scrapie isoform of the prion protein under nondenaturing conditions using a wide variety of detergents have been unsuccessful, to date, except for one report claiming that scrapie infectivity could be recovered from 12% polyacrylamide gels after SDS/PAGE [Brown, P., Liberski, P. P., Wolff, A. & Gajdusek, D. C. (1990) Proc. Natl. Acad. Sci. USA 87, 7240-7244]. We found that < 0.001% of the infectious prion titer could be recovered from the region of a polyacrylamide gel where the denatured proteinase K-resistant core of the scrapie isoform of the prion protein and other 30-kDa proteins migrate. We conclude that under the denaturing conditions used for SDS/PAGE, the scrapie isoform of the prion protein is denatured and little or no renaturation occurs upon injection of fractions eluted from gels into animals for bioassays.     

Silencing of epidermal growth factor,latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma

The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.