Interrupted aortic arch in a child with trisomy 5q31.1q35.1 due to a maternal (20;5) balanced insertion

Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities and chromosomal rearrangements. Of the various forms of CHD, aortic arch interruption, a conotruncal heart defect, is relatively uncommon. Here we report a male neonate with aortic arch interruption type B, secundum atrial septal defect, perimembranous ventricular septal defect, patent ductus arteriosus, aortic and subaortic stenosis, and trisomy 5q31.1q35.1 resulting from a maternal balanced insertion (20;5). Chromosomal deletions, including deletion 22q11, have been reported with interrupted aortic arch (IAA); however, to our knowledge this is the first report of a trisomy of distal chromosome 5q associated with aortic arch interruption. Here we compare this child's features to other cases of trisomy 5q31.1q35.1, and review other causes of IAA. We conclude that gene dosage in this chromosomal region likely influences aortic arch development.     

Effects of difluoromethylornithine on proliferation,polyamine content and plating efficiency of cultured human carcinoma cells

Summary We investigated the effects of an irreversible inhibitor of ornithine decarboxylase, difluoromethylornithine (DFMO), on the proliferation, polyamine content, and plating efficiency of five human adenocarcinoma cell lines in vitro. DFMO inhibited the growth of all five lines when added at concentrations between 0.1 and 5.0 mM. The cell lines varied in their sensitivity to DFMO-induced cytostasis, HuTu-80 being most sensitive and HT-29 being most resistant. These differences appeared to be related to the ability of DFMO to prevent continued production of putrescine in the treated cells. Exogenous putrescine (5–50 M) reversed the growth inhibition for all five cell lines when added 48 h after DFMO treatment. The lowest concentration of exogenous putrescine (5 M) only restored intracellular polyamine content of DFMO-treated cells to control levels for the first 24 h after its addition. After that time, spermidine content declined once again to that observed for cells treated with DFMo alone. The higher concentrations of exogenous putrescine restored the content of all three polyamines to control levels for as much as 3 days after its addition, but did not cause a greater increase in cell growth rates that did 5 M putrescine. These data suggest that human adenocarcinoma cell proliferation is dependent on continued polyamine biosynthesis, but that the basal content of intracellular polyamines is greatly in excess of the minimum level required to support cell growth. In the 1.0–5.0 mM concentration range, DFMO treatment for 48 h caused a slight, but statistically significant, reduction in plating efficiency for three of our cell lines, and had no significant effect on the two others.Abbreviations ANOVA analysis of variance - DAH diaminoheptane - DFMO -difluoromethylornithine - DMEM Dulbecco's modified Eagle's medium - FBS fetal bovine serum - ODC ornithine decarboxylase - Pu putrescine - SD standard deviation - Sd spermidine - sp spermine This investigation was supported by PHS grant no CA-32758 awarded by the National Cancer Institute, DHHS, and by a grant from the American Cancer Society, Illinois Division, Inc. (82-6). Additional support was obtained from a Biomedical Research Support grant to Northwestern University Medical School (RR-05370) from the USPHS, NIH and from the Earle M. Bane Biomedical Research Fund     

Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-{[4-(1H-tetrazol-5-ylmethyl)phenoxy]methyl}phenyl]ethanone,as a pharmacologic antagonist of leukotrienes D4 and E4

Summary LY163443,1-[2-hydroxy-3-propyl-4-{[4-(1H-tetrazol-5-ylmethyl)-phenoxy]methyl}phenyl]ethanone, antagonized LTD₄-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE₄ were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC₄ and parenchymal contractions to LTB₄. Furthermore, LY163443.had little to no effect against contractions of isolated smooth muscles to histamine, bradykinin, PGF₂, carbachol, serotonin or U46619. LY163443, given by oral administration to guinea pigs, blocked LTD₄-induced increases in total pulmonary impedance (TPI). Similar responses elicited by histamine or U46619 were unaffected. Increases in TPI in response to i.v. administration of LTC₄ were antagonized by LY163443 given by the same route. Ovalbumin challenge also increased TPI in guinea pigs previously sensitized against this antigen. In such animals, pretreated with pyrilamine, propranolol, and indomethacin, oral administration of LY163443 blocked the increase in TPI caused by ovalbumin. Additionally, LTD₄ given intradermally to guinea pigs caused a vascular leakage which was suppressed by prior oral administration of LY163443. Finally, LY163443 relaxed isolated guinea pig trachea previously contracted with LTD₄, histamine, or carbachol. Relaxation of tissues contracted by these latter two agonists suggested some inherent airway smooth muscle relaxant properties of the molecule. This was further demonstrated by showing some bronchodilator activity in an in vivo setting. Thus, this pharmacologic profile indicates that LY163443, or a member of the same chemical family, warrants consideration as a possible therapeutic agent in the treatment of asthma and in diseases characterized by an overproduction of LTD₄ and LTE₄.Presented in part at the meeting of The Federation of American Societies for Experimental Biology, April 1985, Anaheim, California.     

Effects of DFMO-induced polyamine depletion on human tumor cell sensitivity to antineoplastic DNA-crosslinking drugs

Summary We investigated the effect of pretreatment with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, on the cytocidal responses of four human adenocarcinoma cell lines to two alkylating and crosslinking agents: chlorambucil and N,N,N-triethylenethio-phosphoramide (thiotepa). The cell lines studied included HuTu-80 (duodenum), HT-29 (colon), ME-180 (cervix), and A-427 (lung). A 48- to 72-h pretreatment with DFMO reduced intracellular putrescine and spermidine contents to <10% and <1% of control levels. This treatment also caused a 30%–70% decline in spermine content. Survival of control and DFMO-pretreated cells after treatment with chlorambucil or thiotepa was measured by a plating efficiency assy. For three of the four lines studied, the DFMO-induced partial polyamine depletion significantly protected cells from the lethal effects of chlorambucil. In ME-180 cultures alone, DFMO pretreatment did not alter the cytocidal efficacy of chlorambucil. Addition of exogenous putrescine to cultures of HuTu-80, HT-29, or A-427 24 h after DFMO addition but 24 h before treatment with chlorambucil reversed the polyamine depletion and its protective effects on chlorambucil-induced cell kill. In contrast to the above observations, DFMO and partial polyamine depletion had no effect on cell survival after thiotepa treatment for any of the cell lines investigated.Abbreviations BCNU 1,3-bis (2-chloroethyl)-1-nitrosourea - CENU chloroethylnitrosourea - cis-Pt (II) cis-diamminedichloroplatinum (II) - DFMO difluoromethylornithine - ODC ornithine decarboxylase - PU putrescine - SD spermidine - SP spermine thiotepa - N,N,N triethylenethiophosphoramide This investigation was supported in part by PHS grant no. CA-32758 awarded by the National Cancer Institute, DHHS; by grant no. 82-6 from the American Cancer Society, Ill. Div., Inc.; and by a Biomedical Research Support Grant to Northwestern University Medical School from the US PHS, NIH (RR-05370)     

Promotion of knowledge transfer and retention in year 2 medical students using an online training exercise

Advances in Health Sciences Education - It was recently shown that novice medical students could be trained to demonstrate the speed-to-diagnosis and diagnostic accuracy typical of System-1-type...     

Urgent desensitization in patients bridged to heart transplantation under extracorporeal membrane oxygenation support: A preliminary experience

Antihuman leukocyte antigen (HLA) antibodies restrict the access to cardiac allografts. Desensitization therapy is a major challenge in patients with cardiogenic shock waiting for urgent heart transplantation (HT). We retrospectively reviewed six patients (mean age of 37.5 years [16–70]) who underwent plasmapheresis (PP) under extracorporeal membrane oxygenation (ECMO) before transplant between January 2017 and September 2018. The average duration of follow‐up was 25 months [20–32]. Mean fluorescence intensity (MFI) of HLA‐specific antibodies was reported as follows: score 4 for MFI < 1000, score 6 for 1000 < MFI < 3000 and score 8 for MFI > 3000. The mean duration of ECMO support was 29 days [1–74] and 6.8 [1–29] PP sessions were performed per patient before transplant. The mean number of HLA‐specific antibodies before HT was 9.6 for score 6 [4–13] and 5.8 for score 8 [1–12]. Four patients had major complications after transplantation (2 hemorrhagic shocks, 5 infectious events). Mean MFI reduction rate was 94% [79–100] for Class I and 44.2% for Class II [0–83]. Hospital survival was 100%, and early antibody‐mediated rejection was diagnosed in one patient at 7 days after HT. Plasmapheresis under ECMO support was associated with favorable early outcomes in highly sensitized candidates for urgent heart transplantation.     

An Intelligent System to Enhance the Performance of Brain Tumor Diagnosis from MR Images

Journal of Digital Imaging - In the human body, cancer is caused by aberrant cell proliferation. Brain tumors are created when cells in the human brain proliferate out of control. Brain tumors...     

Acute airway obstruction following placement of a subclavian Hickman catheter

The purpose of this case report is to describe the events, intervention, and aetiology which led to acute airway obstruction in an adult patient after the placement of a Hickman catheter. Airway obstruction secondary to superior vena cava obstruction occurred after placement of a subclavian vein Hickman catheter. This was felt to occur, in part, to a narrowed superior vena cava as evident by subclavian venography. It resulted in emergency oral tracheal intubation to relieve airway obstruction. Shortly after removal of the Hickman catheter, the signs of superior vena cava obstruction syndrome resolved and the patient was extubated without incidence. It is concluded that, although rare, the serious complication of acute airway obstruction can occur after placement of a Hickman catheter.     

The effects of cyclosporin A,tamoxifen, and medroxyprogesterone acetate on the enhancement of Adriamycin cytotoxicity in primary cultures of human breast epithelial cells

Summary Adriamycin (Adr), the single most active agent used in the treatment of breast cancer, may become ineffective as treatment progresses due to the development of multidrug resistant (MDR) tumors. A major mechanism associated with MDR is increased P-glycoprotein (Pgp) expression. This study examined the abilities of the anti-estrogen tamoxifen (TAM) and the progestin medroxyprogesterone acetate (MPA) as well as cyclosporin A (CsA), a known resistance modifier, to enhance the cytotoxic effects of Adr on human breast epithelial cells (HBEC) in primary culture. Pgp and estrogen receptor (ER) expression were determined in each of the cultures by immunocytochemical assays using the monoclonal antibodies C219 and H222 Sp, respectively. The Adr-sensitive, Pgp-, ER+ MCF-7 cell line and the Adr-resistant, Pgp+, ER-MCF7-AdrR cell line were used as controls. Primary cultures were categorized as HBEC from tissues with or without previous chemotherapy. Pgp was detected in 1 of the 15 cell cultures from tissues without previous chemotherapy and in 5 of the 6 cell cultures from tissues previously exposed to chemotherapy. Incubation with either CsA or MPA plus Adr enhanced Adr toxicity in Pgp+ but not Pgp- cell cultures, whereas TAM had no effect on the sensitivity of any of the cultures. Of the 21 primary cultures of HBEC, 3 were ER+. There was no correlation between the enhancement of Adr cytotoxicity and ER status. The data suggest that MPA as well as CsA may be useful as modifying agents in overcoming Pgp-associated multidrug resistance.