Use of insertable cardiac monitors for the detection of atrial fibrillation in patients with cryptogenic stroke in the United States is cost-effective.

Objectives: Atrial fibrillation (AF) is the most common arrhythmia and a major marker of ischemic stroke risk. Early detection is crucial and, once diagnosed, anticoagulation therapy can be initiated to reduce stroke risk. The aim of this study was to assess the cost-effectiveness of employing an insertable cardiac monitor (ICM), BIOMONITOR, for the detection of AF compared to standard of care (SoC) ECG and Holter monitoring in patients with cryptogenic stroke, that is, stroke of unknown origin and where paroxysmal, silent AF is suspected. Materials and methods: A Markov model was developed which consisted of five main health states reflecting the potential lifetime evolution of the AF disease: post cryptogenic stroke (index event), subsequent mild, moderate and severe stroke, and death. Sub-states were included to track a patient's AF diagnostic status and the use of antiplatelet or anticoagulant therapy. AF detection was assumed to result in a treatment switch from aspirin to anticoagulants, except among those with a history of major bleeding. Detection yield and accuracy, clinical actions and treatment effects were derived from the literature and validated by an expert clinician. All relevant costs from a US Medicare perspective were included. Results and conclusions: An ICM-based strategy was associated with a reduction of 37 secondary ischemic strokes per 1000 patients monitored compared with SoC. Total per-patient costs with an ICM were higher (US$90,052 vs. US$85,157) although stroke-related costs were reduced. The use of an ICM was associated with a base-case incremental cost-effectiveness ratio of US$18,487 per life year gained compared with SoC and US$25,098 per quality-adjusted life year gained, below established willingness-to-pay thresholds. The conclusions were found to be robust over a range of input values. From a US Medicare perspective the use of a BIOMONITOR ICM represents a cost-effective diagnostic strategy for patients with cryptogenic stroke and suspected AF.

Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo.

HSP27 form oligomeric structures up to 800 Kda. In cultured cells, the equilibrium between small and large oligomers shifted towards smaller oligomers when phosphorylated on serine residues. To further explore HSP27 structural organization and its repercussion in HSP27 antiapoptotic and tumorigenic properties, we transfected colon cancer REG cells with wild type HSP27 and two mutants in which the phosphorylatable serine residues have been replaced by alanine (to mimic the non phosphorylated protein) or aspartate (to mimic the phosphorylated protein). In growing cells, wild type and alanine mutant formed small and large oligomers and demonstrated antiapoptotic activity while aspartate mutant only formed small multimers and had no antiapoptotic activity. In a cell-free system, only large oligomeric structures interfered with cytochrome c-induced caspase activation, thereby inhibiting apoptosis. The inability of the aspartate mutant to form large oligomers and to protect tumor cells from apoptosis was overcome by growing the cells in vivo, either in syngeneic animals or nude mice. These observations were reproduced by culturing the cells at confluence in vitro. In conclusion (1) large oligomers are the structural organization of HSP27 required for its antiapoptotic activity and (2) cell-cell contacts induce the formation of large oligomers, whatever the status of phosphorylatable serines, thereby increasing cell tumorigenicity.

Cure of colon cancer metastasis in rats with the new lipid A OM 174. Apoptosis of tumor cells and immunization of rats.

The antitumoral effect of the new lipid A OM 174 was investigated in a model of colon cancer in rats. Peritoneal carcinomatosis were induced in BDIX rats by intraperitoneal injection of syngeneic PROb cancer cells. The treatment started 2 weeks later, when rats had macroscopic peritoneal nodules. An antitumoral effect was first obtained with OM 174 intraperitoneally injected, then an intravenous treatment was developed. When injected 15 times intravenously, at the dose of 1 mg/kg, 2 days apart, OM 174 induced the complete regression of tumors and hemorrhagic ascitis in 90% of the tumor-bearing rats, whereas all the untreated rats died of their tumors. To our knowledge, this treatment is the most effective ever applied to macroscopic tumors. Furthermore, the treatment induced the immunization of rats since the reinjection of PROb tumor cells in OM 174-cured rats did not cause the formation of new tumors while injection of another syngenic colon tumor cells did. Only in treated rats tumors were infiltrated with lymphocytes, macrophages and fibroblasts. The treatment did not increase necrosis but generated apoptotic areas. OM 174 was not directly toxic for tumor cells, and thus the observed effect involved the host-mediated antitumor reaction. Therefore we hypothesize that OM 174 therapy induces tumor cell apoptosis, stimulates the phagocytosis of apoptotic bodies and then activates immune system by antigen presentation.

Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors.

Nitric oxide (NO) is generated by a family of isoenzymes named nitric oxide synthases (NOS) which includes a cytokine-inducible form, NOSII. NO is a free radical known to inhibit cell proliferation, to induce apoptosis, and to be a mediator of macrophage cytostatic and cytotoxic effects. We investigated NOS in 40 human breast carcinomas and 8 benign breast lesions. NOSII was localized in tumor cells by immunohistochemistry. NOS activity, measured with the citrulline assay, was detected in 27 of 40 tumors. Neither immunohistologic labeling nor NOS activity was detected in benign samples. NOS labeling and activity were significantly related (p < 0.02). For the first time, a significant negative relationship between NOS activity and tumor cell proliferation (p < 0.002) was found. We also showed that tumors with high NOS activity expressed progesterone receptors (p < 0.04). These results are consistent with the observation of high NOS activity in tumors with low grade (p < 0.05). These in vivo observations were related to in vitro data: cytokines (IL-1beta, IFN-gamma, and TNF-alpha) induced NOSII expression in human MCF-7 breast cancer cells, and NO inhibited their proliferation. Thus, we show herein that tumors with high NOS activity have low proliferation rate and low grade, which correlates with the in vitro observation of the inhibition of proliferation of human breast cancer cells by NO. These results may have future therapeutic implications.

Expression of inducible nitric oxide synthase in tumors in relation with their regression induced by lipid A in rats.

It is well documented that nitric oxide (NO) is an effector molecule of macrophage-mediated tumor cell toxicity in vitro; however, little is known about the role of NO in the antitumor immune response in vivo. We have developed a treatment protocol using lipid A. We have investigated the effects of lipid A on inducible NO synthase (NOS II) expression and evolution inside tumors during the course of treatment. Lipid A (OM-174) treatment induced tumor regression in rats bearing established colon tumors. Furthermore, NO was synthesized and secreted inside the tumors of lipid A-treated rats, as demonstrated by the increase of NOS II mRNA and NOS II content in the tumors, as well as of NOS II activity and NO production. During treatment, NOS II was localized in tumor cells only. Lipid A had no direct effect on tumor cells in vitro, while the combination of interferon gamma (IFN-gamma) plus interleukin-1 beta (IL-1beta) induced production of NO by tumor cells which was cytostatic. The content of IFN-gamma and IL-1beta in tumors was enhanced during lipid A treatment; this is in agreement with an indirect effect of lipid A in vivo via the IFN-gamma and IL-1beta pathways.

Ultrasonography of the infant hip. Part IV: Normal development in the newborn and preterm neonate.

Based on preterm and term infants studied by ultrasonography, and on anatomical sections of various gestational ages the physiological maturation of the hip joint is analysed. Current concepts of a linear growth pattern with an arrest immediately after delivery are confirmed. A more rapid growth and ossification of the acetabular edge than of the femoral head postpartum is suggested. To avoid overtreatment, knowledge of the normal range of development as seen in ultrasonography is mandatory.

Ultrasound of the infant hip. Part 1. Basic principles.

Method and the basic principle of infant hip studies by means of ultrasound are described. It is the purpose of this imaging modality to detect dislocations and dysplasia at an early stage. The visible structures of the hip-joint are shown in histologic-sonographic correlation. Based on the pathomechanics of hip-dysplasia diagnostic criteria for ultrasound studies are developed. Our classification system, in close similarity to Graf, is presented.