John C. Nelson

Emergence of resistance to azithromycin-atovaquone in immunocompromised patients with Babesia microti infection.

BACKGROUND Babesiosis is an emerging tickborne malaria-like infection principally caused by Babesia microti. This infection typically resolves either spontaneously or after administration of a 7-10-day course of azithromycin plus atovaquone or clindamycin plus quinine. Although certain highly immunocompromised patients may respond suboptimally to these drug regimens, unlike the situation with malaria there has been no reported evidence that the cause of treatment failure is infection with drug-resistant strains of B. microti. METHODS Emergence of drug resistance in B. microti was defined as the development of a microbiologic relapse (recurrent parasitemia or a marked increase in parasitemia) in association with both clinical and laboratory abnormalities indicative of active babesiosis in a patient after 28 days of uninterrupted antibabesia drug therapy and while still receiving treatment. RESULTS The clinical case histories of 3 highly immunocompromised patients who received a subcurative course of azithromycin-atovaquone associated with the eventual development of resistance to this drug regimen are described. One of the 3 patients died of complications related to babesiosis. CONCLUSIONS B. microti may become resistant to azithromycin-atovaquone during the treatment of babesiosis with this combined drug regimen in highly immunocompromised patients. Although research is needed to determine the optimal therapy for highly immunocompromised patients with babesiosis, reducing the level of immunosuppression when possible would appear to be a desirable strategy.

Babesiosis in Lower Hudson Valley, New York, USA.

Cases were associated with tick bites and receipt of blood products.

Expression of rat liver heme oxygenase gene during development

We studied the genetic expression during fetal development of heme oxygenase, the rate-limiting enzyme in the oxidation of heme to bilirubin. The transcription of the heme oxygenase gene in livers of fetal and neonatal rats (9 days before birth to 28 days after birth) was examined. Hybridization analyses of total RNA from livers of these animals using cDNA for rat heme oxygenase as the probe revealed a single mRNA species of approximately 18 S in every sample examined. The mRNA level was above the adult level throughout the course of study and reached a maximum 24 h after birth. The high level of heme oxygenase mRNA in fetuses was unaffected when Sn-protoporphyrin, a potent inhibitor of heme oxygenase, was administered to their mothers. On the other hand, the mRNA levels in the mothers treated with this heme analog were substantially increased, possibly by the same mechanism as for the induction by heme. Sn-protoporphyrin potentiates induction of heme oxygenase mRNA in cobalt chloride-pretreated rats, and also acts as a potent inhibitor of heme oxygenase enzyme activities. Our results also indicate that high heme oxygenase levels during fetal maturation are due to an increase in transcription of the gene. Thus, Sn-protoporphyrin which crosses the placenta controls fetal hyperbilirubinemia by direct enzyme inhibition.

Production of thromboplastin (tissue factor) and thrombi by polymor phonuclear neutrophilic leukocytes adhering to vein walls

Abstract Separation of dog femoral and jugular veins from surrounding structures and transient stasis of blood flow for 30 seconds resulted in a lesion characterized by adhesion of neutrophils to the venous endothelium. Neutrophils harvested from this lesion 5 hours later had developed thromboplastic (tissue factor) activity. In immediately removed veins and veins from neutropenic dogs, this lesion did not occur and scrapings of the vein wall did not have thromboplastic activity. In some veins, gross or microscopic thrombosis was seen. It has been reported that neutrophil adhesion to veins also occurs during human surgery. We suggest, therefore, that neutrophils adhering to veins and producing thromboplastin may be a pathogenetic mechanism of deep vein thrombosis in man.

Mesenteric vein thrombosis after laproscopic gastric sleeve procedure.

Laparoscopic procedures for morbid obesity are becoming standard of care. In experienced hands it has very low mortality and morbidity [1]. Thrombosis of mesenteric and portal vein is a rare phenomenon. A few case reports in literature suggest their occurrence after various laparoscopic procedures [2–5]. Our institution is a leading center for obesity surgery and we do over 350 laparoscopic bariatric surgeries each year. We present a case of intraabdominal vein thrombosis after laparoscopic surgery and review of literature [6].

Early protooncogene expression during hemin-induced differentiation of human erythroleukemic cells

In situ hybridization was used to study the effects of hemin on the expression of the oncogenes c-myc, c-fos, and myb, and on the mRNA level of erythroid porphobilinogen deaminase (PBG-D) and alpha-globin in HEL cells during differentiation. The technique was effective in detecting changes in mRNA levels in small numbers of HEL cells. Hemin stimulation of HEL cells results in an early increase in myb and c-myc expression and a decrease in c-fos mRNA, while increased PBG-D and alpha-globin expression is not seen until 8 h after hemin treatment. Blast-like cells display expression of c-myc, alpha-globin and PBG-D, while the more differentiated cells give a positive response to both c-fos and myb. During HEL cell differentiation, the mechanism of hemin stimulation appears to be through the up regulation of myb and c-myc mRNA and down regulation of c-fos. The subsequent expression of PBG-D and alpha-globin may indicate that early increases in protooncogene expression are first required for the normal progression of erythropoiesis to occur.

Ticlopidine-associated thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura is a rare complication of ticlopidine treatment. This syndrome has been reported to occur typically within the first few weeks after the initiation of therapy. The authors describe a case of a 72-year-old woman in whom thrombotic thrombocytopenic purpura developed just 2 days after starting ticlopidine therapy for a new-onset ischemic stroke. The patient responded successfully to plasmapheresis. The authors are reporting this case to emphasize the unpredictable nature of the association between the drug and the disease, which necessitates careful hematologic monitoring.

Evaluation of Temozolomide in Patients with Myelodysplastic Syndrome

In our previous phase I study of temozolomide in patients with acute leukemia, temozolomide was well tolerated and demonstrated significant anti-leukemic activity. The maximum tolerated dose was 200 mg/m2/d for 7 days, repeated approximately every 5-6 weeks. In the current study, we evaluated the same dose of temozolomide in patients with myelodysplastic syndrome. Fourteen patients received 19 courses of temozolomide. The median age was 71 years. In this study, treatment was poorly tolerated with patients requiring admission in 9 of 19 courses. Toxicity included worsening cytopenias, neutropenic fever, and exacerbation of cardiac disease, the latter due to worsening anemia. An unusual finding was the development of leukocytoclastic vasculitis in 4 patients. There were no formal responses to therapy. The current schedule of temozolomide is not efficacious in patients with myelodysplastic syndrome.

Hypersensitivity to plasma exchange in a patient with thrombotic thrombocytopenic purpura.

To a limited extent, thrombotic thrombocytopenic purpura (TTP) in addition to its clinical features is being defined nowadays with laboratory tests such as the assay for the Von Willebrand factor‐cleaving protease (ADAMTS 13) and its antibody. We present a case report of a patient with TTP and idiopathic thrombocytopenic purpura (ITP) who had an elevated inhibitor level after plasma exchange. After instituting plasma exchange, patient improved clinically with a platelet count in the normal range. Subsequently, she developed an elevated ADAMTS antibody titer accompanied by a decline in platelet count despite continued exchange. She was successfully treated with a combination of steroids, rituximab and increased dose plasmapheresis. Based on this experience, we conclude that a drop in platelet count while patient is undergoing plasma exchange especially in an initial episode of TTP needs prompt institution of additional therapy to improve outcomes. This case also brings to attention the possibility of an underlying ITP in a patient with an initial diagnosis of TTP. J. Clin. Apheresis, 2009.

Babesiosis-associated immune thrombocytopenia

Thrombocytopenia is a common feature of babesiosis. The mechanism for thrombocytopenia in babesiosis remains elusive. We report a case of babesiosis with severe new onset immune thrombocytopenia (ITP). In addition to antibiotics treatment for babesiosis, ITP therapy was administered. ITP in the present case was most likely triggered by the babesia infection. The severity of ITP in this case was not proportional to the severity of parasitemia. The neoantigen triggering the autoimmune response in babesiosis requires further characterization.