Anastomotic esophageal leak due to Taenia saginata following esophagectomy for esophageal cancer

A 50-year-old female with squamous cell carcinoma of the lower third of the esophagus underwent an esophagectomy via laparotomy and right thoracotomy. She developed a major anastomotic leak on the third postoperative day. The chest tube slipped out on the 10th postoperative day and a segment of Taenia saginata tapeworm came out through the tube drain site and was extracted. She was given praziquantel tablets treatment; after which the leakage dropped dramatically and ceased completely after one week. Patients scheduled for esophagectomy who experienced recurrent abdominal pain in areas endemic with a tapeworm need to be screened for taeniasis before surgery.     

Modulation of the expression of Tac antigen (T-cell growth factor response) on human thymocytes

This study shows that anti-Tac antibody does not bind to human thymocytes unless they are activated. Human thymocytes could be induced to express Tac antigen (TCGF receptor) on their cell surface by Concanavalin A. B lymphoblastoid cells or 12-O-tetradecanoylphorbol 13-acetate alone did not induce TCGF receptors, but they did exert a very marked synergistic effect with Concanavalin A. This observation is consistent with our earlier finding that B lymphoblastoid cells secrete a factor which exerts a synergistic effect on the induction of lymphokine secretion by thymocytes and T-cells. The early expression of Tac antigen was independent of thymocyte proliferation. Anti-Tac antibody (10(-3)) inhibited the expression of TCGF receptors and late proliferation of thymocytes. TCGF did not reverse this inhibition nor did it prevent the binding of Tac antibody, but it enhanced the expression of Tac antigen.     

5-(Phenylthio)acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens

Purpose The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the pharmacokinetics and bioavailability of oral uridine. PTAU is a potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is fully absorbed after oral administration with 100% oral bioavailability.Methods Uridine (330, 660 or 1320 mg/kg) and/or PTAU (30, 45, 60, 120, 240 or 480 mg/kg) were orally administered to mice. The plasma levels of uridine, its catabolite uracil, and PTAU were measured using HPLC, and pharmacokinetic analysis was performed.Results Oral PTAU up to 480 mg/kg per day is not toxic to mice. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg has a prolonged plasma half-life of 2–3 h, and peak plasma PTAU concentrations (C_max) of 41, 51, 74, 126 and 161 M with AUCs of 70, 99, 122, 173 and 225 mol h/l, respectively. Coadministration of uridine with PTAU did not have a significant effect on the pharmacokinetic parameters of plasma PTAU at any of the doses tested. Coadministration of PTAU (30, 45, 60 and 120 or 240 mg/kg) with uridine (330, 660 or 1320 mg/kg) elevated the concentration of plasma uridine over that following the same dose of uridine alone, a result of reduced metabolic clearance of uridine as evidenced by decreased plasma exposure (C_max and AUC) to uracil. Plasma uridine was elevated with the increase of uridine dose at each PTAU dose tested and no plateau was reached. Coadministration of PTAU at 30, 45, 60, 120 and 240 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9-, 9.9-, 11.7- and 12.5-fold, respectively, and reduced the AUC of plasma uracil (1227.8 mol h/l) by 5.7-, 6.8-, 8.2-, 6.3-, and 6.9-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.7-, 2.4-, 2.6-, 5.2- and 4.3- fold, and that of 660 mg/kg uridine by 2.3-, 2.7-, 3.3-, 4.6- and 6.7-fold, respectively.Conclusion The excellent pharmacokinetic properties of PTAU, and its extraordinary effectiveness in improving the oral bioavailability of uridine, could be useful to rescue or protect from host toxicities of 5-fluorouracil and various chemotherapeutic pyrimidine analogues used in the treatment of cancer and AIDS, as well as in the management of medical disorders that are remedied by the administration of uridine including CNS disorders (e.g. Huntingtons disease, bipolar disorder), liver diseases, diabetic neuropathy, cardiac damage, various autoimmune diseases, and transplant rejection.     

Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs

Dicationic guanidine, N-alkylguanidine, and reversed amidine derivatives of fused ring systems have been synthesized from their corresponding bis-amines. DNA binding studies suggest that the diguanidines and the N-alkyl diguanidines fluorenes bind in the minor groove in a manner similar to that of the previously reported dicationic carbazole derivatives. The diguanidines and the N-alkyl diguanidines showed promising in vitro activity against both Trypanosoma brucei rhodesiense and Plasmodium falciparum. Promising in vivo biological results were obtained for the dicationic N-isopropylguanidino-9H-fluorene, giving 4/4 cures of the treated animals in the STIB900 animal model for African trypanosomiasis. The N-methyl analogue showed high activity as well. In addition, with the goal of enhancing the oral bioavailability, two novel classes of potential guanidine prodrugs were prepared. The N-alkoxyguanidine derivatives were not effective as prodrugs. In contrast, a number of the carbamates showed promising activity. The value of the carbamate prodrugs was clearly demonstrated by the results, which gave 4/4 cures on oral administration in the STIB900 mouse model.     

6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities

Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents.     

Extra corporal membrane oxygenation in general thoracic surgery: a new single veno-venous cannulation

Extracorporeal membrane oxygenation (ECMO) is used in severe respiratory failure to maintain adequate gas exchange. So far, this technique has not been commonly used in general thoracic surgery. We present a case using ECMO for peri-operative airway management for pulmonary resection, using a novel single-site, internal jugular, veno-venous ECMO cannula.     

Use of anti‐CD20 antibody in the treatment of post‐transplant glomerulonephritis

Damodar A, Mustafa R, Bhatnagar J, Panesar M, Gundroo A, Zachariah M, Blessios G, Tornatore K, Weber‐Shrikant E, Venuto R. Use of anti‐CD20 antibody in the treatment of post‐transplant glomerulonephritis.
Clin Transplant 2011: 25: 375–379. © 2010 John Wiley & Sons A/S. Abstract: Post‐transplant glomerulonephritis (PTGN) accounts for 4–10% of late graft loss. Six consecutive patients who developed PTGN 3–72 months post‐transplant presented to our center with deteriorating kidney function and proteinuria. Three had focal segmental glomerulosclerosis; one had membranoproliferative glomerulonephritis Type 1; one recurrent membranous nephropathy; and one recurrent immunoglobin A nephropathy. All six were treated with an aggressive immunosuppression regimen including rituximab, pulse steriods and/or maximization of mycophenolic acid and calcineurin inhibitor therapy. Four of the six patients received plasma exchange. The patients were followed for a minimum of nine months after treatment. Proteinuria decreased from 7.2 ± 4.4 to 1.4 ± 1.5 g (p = 0.04), while mean estimated glomerular filtration rate was 31.2 ± 13.1 and 42.5 ± 21.7 mL/min (p = 0.07) at nine months. No adverse events were noted. These observations suggest that immune modulating therapy may be of benefit in the treatment of PTGN.     

Complete ophthalmoplegia in Ipilmumab and Nivolumab combination treatment for metastatic melanoma

Ipilimumab and Nivolumab are novel monoclonal antibodies that have recently been used successfully for treatment of metastatic melanoma. Ipilimumab is a human monoclonal antibody against Cytotoxic T Lymphocyte Antigen 4 (CTLA4) receptor, which suppresses T-cell proliferation and stimulates an inflammatory response against cancer cells. Nivolumab is an IgG4 monoclonal antibody against the cytotoxic T lymphocyte associated programmed death 1 receptor (PD-1). Ipilimumab and Nivolumab combination treatment has been shown to induce remission and prolong survival in patients with metastatic melanoma. The side effect profile of these medications has not been well studied. One entity of the side effects reported in the literature is immune-related adverse events (irAEs). There have been few case reports where these events were serious and irreversible. In this case report, we describe a fatal and severe diffuse panmyositis that involved the cardiac, respiratory, and extraocular muscles in a patient with metastatic melanoma secondary to combination treatment with Ipilimumab/Nivolumab.     

Maternal mortality in Syria: causes, contributing factors and preventability

Objectives  To describe the biomedical and other causes of maternal death in Syria and to assess their preventability.
Methods  A reproductive age mortality study (RAMOS) design was used to identify pregnancy related deaths. All deaths among women aged 15–49 reported to the national civil register for 2003 were investigated through home interviews. Verbal autopsies were used to ascertain the cause of death among pregnancy related maternal deaths, and causes and preventability of deaths were assessed by a panel of doctors.
Results  A total of 129 maternal deaths were identified and reviewed. Direct medical causes accounted for 88%, and haemorrhage was the main cause of death (65%). Sixty nine deaths (54%) occurred during labour or delivery. Poor clinical skills and lack of clinical competency were behind 54% of maternal deaths. Ninety one percent of maternal deaths were preventable.
Conclusions  The causes of maternal death in Syria and their contributing factors reflect serious defects in the quality of maternal care that need to be urgently rectified.