Morphogenesis during division and griseofulvin-induced changes of the microtubular cytoskeleton in the parasitic protist,<Emphasis Type="Italic"> Trichomonas vaginalis</Emphasis>

The behavior of microtubular structures during division was followed by immunofluorescence in Trichomonas vaginalis using an anti-alpha-tubulin monoclonal antibody together with nuclear staining by DAPI, allowing us to describe successive mitotic stages. In contrast to recent reports, we showed that: (1) the microtubular axostyle-pelta complex depolymerized during division, (2) the flagella were assembled during mitosis, and (3) the flagellar number was restored in each daughter kinetid before cytokinesis. Observation of griseofulvin-treated T. vaginalis cells revealed that the elongation of the mitotic spindle or paradesmosis was not the main motile force separating the daughter kinetids to opposite poles during division, suggesting the existence of other mechanisms and/or molecules involved in this morphogenetic event. Examination of treated cells re-incubated in fresh medium showed the nucleation of microtubules radiating from the perinuclear area, the origin of which is discussed. Finally, we confirm the effectiveness of griseofulvin against T. vaginalis and propose that this antifungal drug could be a promising antitrichomonal agent.     

Should the cytologic diagnosis of "atypical squamous cells of undetermined significance" be qualified? An assessment including comparison between conventional and liquid-based technologies

BACKGROUND: The diagnosis of atypical squamous cells of undetermined significance (ASCUS) remains an enigma for the treating physician, because it encompasses both benign, reactive, as well as preneoplastic and possibly neoplastic conditions. To address this problem, The Bethesda System recommends qualifying the ASCUS diagnosis. This study analyzes the difference in the follow-up results between the various groups of patients with an ASCUS diagnosis as outlined by the Criteria Committee: favor premalignant (ASCUS-P), favor reactive (ASCUS-R), and unqualified (ASCUS-C). The outcome, based on follow-up biopsies and/or cytologies, for both the conventional Papanicolaou smear (CS) and liquid-based (LB) methodologies is compared. METHODS: The CS and LB biopsies and/or cytologies included 590 patients and 137 patients, respectively, who had an initial diagnosis of ASCUS. The final outcome after subsequent biopsy and cytology within a 1-year period for each methodology was tabulated. Furthermore, the addition of qualifiers for each diagnosis was tabulated for both cytology and biopsy follow-up and compared between CS and LB technologies. RESULTS: For CS, 29 patients (8.6%) were found to have squamous intraepithelial lesions (SIL) on subsequent cytologic smears, and 176 patients (63.7%) had SIL on biopsy follow-up. For LB, these numbers were 17 patients (19.1%) and 56 patients (65.1%), respectively. Regardless of the qualification used in the initial CS biopsy or cytology, over 90% of the subsequent smears resulted in a benign diagnosis. Biopsy outcomes after CS diagnoses of ASCUS-P, ASCUS-R, and ASCUS-C showed SIL in 80%, 53%, and 66% of patients, respectively. For LB diagnoses, subsequent smears detected SIL in 33% of patients with a diagnosis of ASCUS-P, 22% of patients with a diagnosis of ASCUS-R, and 12% of patients with a diagnosis of ASCUS-C. Biopsy outcomes after LB diagnoses of ASCUS-P, ASCUS-R, and ASCUS-C showed SIL in 68%, 64%, and 66% of patients, respectively. CONCLUSIONS: There appears to be no statistically valid benefit from a clinical point of view in qualifying an ASCUS interpretation by either CS or LB, except for CS evaluation of patients with a diagnosis of ASCUS-P.     

Rituximab: review and clinical applications focusing on non-Hodgkin's lymphoma

Rituximab (Rituxan) was the first monoclonal antibody approved for cancer therapy and the first single-agent approved for therapy of lymphoma. When combined with CHOP, rituximab is the only drug that has been shown to improve survival of a subpopulation of patients with diffuse large cell lymphoma during the last three decades. It was approved by the FDA for the treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in 1997. Rituximab is also being studied in many other B-cell malignancies alone and in combination with other agents. Furthermore, it is currently being evaluated in several nonmalignant diseases, such as autoimmune disorders. This review will focus on the role of rituximab in patients with non-Hodgkin's lymphoma.     

Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer

The recent developments of nuclear medicine in oncology have involved numerous investigations of novel specific tumor-targeting radiopharmaceuticals as a major area of interest for both cancer imaging and therapy. The current progress in pharmaceutical nanotechnology field has been exploited in the design of tumor-targeting nanoscale and microscale carriers being able to deliver radionuclides in a selective manner to improve the outcome of cancer diagnosis and treatment. These carriers include chiefly, among others, liposomes, microparticles, nanoparticles, micelles, dendrimers and hydrogels. Furthermore, combining the more recent nuclear imaging multimodalities which provide high sensitivity and anatomical resolution such as PET/CT (positron emission tomography/computed tomography) and SPECT/CT (combined single photon emission computed tomography/computed tomography system) with the use of these specific tumor-targeting carriers constitutes a promising rally which will, hopefully in the near future, allow for earlier tumor detection, better treatment planning and more powerful therapy. In this review, we highlight the use, limitations, advantages and possible improvements of different nano- and microcarriers as potential vehicles for radionuclides delivery in cancer nuclear imaging and radiotherapy.     

Early detection and identification of commonly encountered Candida species from simulated blood cultures by using a real-time PCR-based assay

In a recent study, Candida species in clinical blood samples were detected using a real-time PCR-based method (Maaroufi et al, J Clin Microbiol 2003, 41:3293-3298). For the present study, we evaluated the efficiency of this method as an adjunct to the BACTEC blood culture system to early detection of positivity and negativity of simulated low candidemias. We first established an in vitro correlation between the inoculum of the most frequently encountered Candida species and the time to positivity of these microorganisms. Then, aliquots from blood culture bottles infected with a final average candidal inoculum of 3.18 colony-forming units (CFU)/culture bottle (range, 1 to 6 CFU) were collected at increasing incubation times, and DNA was extracted and submitted to the TaqMan-based PCR assay. To optimize this assay, we evaluated the effect of adding 0.5% bovine serum albumin (BSA) to DNA extracts and found that it decreased the effects of inhibitors. Using specific probes for the tested Candida species, the PCR assay was positive on blood culture aliquots collected from the BACTEC system after a minimum culture turnaround time (TAT) of 3.11 +/- 1.24 hours. Addition of BSA to PCR reaction mixtures improves the TAT (1.84 +/- 0.41 hours). Hence, the combination of DNA "amplification" in the culture bottles by normal growth with an additional DNA amplification by PCR might be a reliable tool facilitating the early diagnosis of low candidemias.     

Joint registration of ultrasound,CT and a shape+pose statistical model of the lumbar spine for guiding anesthesia

Purpose

Facet joint injections and epidural needle insertions are widely used for spine anesthesia. Accurate needle placement is important for effective therapy delivery and avoiding complications arising from damage of soft tissue and nerves. Needle guidance is usually performed by fluoroscopy or palpation, resulting in radiation exposure and multiple needle re-insertions. Several ultrasound (US)-based approaches have been proposed but have not found wide acceptance in clinical routine. This is mainly due to difficulties in interpretation of the complex spinal anatomy in US, which leads to clinicians’ lack of confidence in relying only on information derived from US for needle guidance.

Methods

We introduce a multimodal joint registration technique that takes advantage of easy-to-interpret preprocedure computed topography (CT) scans of the lumbar spine to concurrently register a shape+pose model to the intraprocedure 3D US. Common shape coefficients are assumed between two modalities, while pose coefficients are specific to each modality.

Results

The joint method was evaluated on patient data consisting of ten pairs of US and CT scans of the lumbar spine. It was successfully applied in all cases and yielded an RMS shape error of 2.1 mm compared to the CT ground truth. The joint registration technique was compared to a previously proposed method of statistical model to US registration Rasoulian et al. (Information processing in computer-assisted interventions. Springer, Berlin, pp 51–60, 2013). The joint framework improved registration accuracy to US in 7 out of 17 visible vertebrae, belonging to four patients. In the remaining cases, the two methods were equally accurate.

Conclusion

The joint registration allows visualization and augmentation of important anatomy in both the US and CT domain and improves the registration accuracy in both modalities. Observing the patient-specific model in the CT domain allows the clinicians to assess the local registration accuracy qualitatively, which is likely to increase their confidence in using the US model for deriving needle guidance decisions.

     

Magnetoencephalographic signatures of insular epileptic spikes based on functional connectivity

Failure to recognize insular cortex seizures has recently been identified as a cause of epilepsy surgeries targeting the temporal, parietal, or frontal lobe. Such failures are partly due to the fact that current noninvasive localization techniques fare poorly in recognizing insular epileptic foci. Our group recently demonstrated that magnetoencephalography (MEG) is sensitive to epileptiform spikes generated by the insula. In this study, we assessed the potential of distributed source imaging and functional connectivity analyses to distinguish insular networks underlying the generation of spikes. Nineteen patients with operculo‐insular epilepsy were investigated. Each patient underwent MEG as well as T1‐weighted magnetic resonance imaging (MRI) as part of their standard presurgical evaluation. Cortical sources of MEG spikes were reconstructed with the maximum entropy on the mean algorithm, and their time courses served to analyze source functional connectivity. The results indicate that the anterior and posterior subregions of the insula have specific patterns of functional connectivity mainly involving frontal and parietal regions, respectively. In addition, while their connectivity patterns are qualitatively similar during rest and during spikes, couplings within these networks are much stronger during spikes. These results show that MEG can establish functional connectivity‐based signatures that could help in the diagnosis of different subtypes of insular cortex epilepsy. Hum Brain Mapp 37:3250–3261, 2016. © 2016 Wiley Periodicals, Inc .     

Model based analysis of sleep disordered breathing in congestive heart failure

We employed a computational model of the respiratory control system to examine which of several factors, in isolation and in combination, can contribute to or explain the development of Cheyne-Stokes breathing (CSB). Our approach uses a graphical method for stability analysis similar, in concept, to the phase plane. The results from the computer simulations indicate that a postulated three-fold increase in the chemosensitivity of the central chemoreflex (CCR) loop may, by itself, explain development of CSB. By contrast, a similar increase in the chemosensitivity of the peripheral chemoreflex (PCR) loop cannot, by itself, account for CSB. The analysis reveals that the system is more readily destabilized by increasing the gain of only one chemoreflex loop than by a combined increase in gain of both loops. Reduction in the cardiac output or cardiomegaly decreases the size of the stability region. We conclude that development of CSB is the result of a complex interaction between CCR and PCR loops which may, in turn, interact with decreased cardiac output and cardiomegaly.     

Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice

Anaplastic thyroid carcinoma (ATC) remains one of the most lethal human cancers. We hypothesized that sorafenib, a multikinase inhibitor of the BRaf, vascular endothelial growth factor receptor-2, and platelet-derived growth factor receptor-beta kinase, would decrease tumor growth and angiogenesis in an orthotopic model of ATC. The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined. To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice, sorafenib was given p.o. at 40 or 80 mg/kg daily. Intratumoral effects were studied using immunohistochemical analysis. The effect of sorafenib on survival of the mice was also studied. Sorafenib inhibited the in vitro proliferation of ATC cell lines. Sorafenib also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer. As result, the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved. Sorafenib exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect. The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the BRAF mutational status of thyroid tumors. Given the lack of curative options for patients with ATC, sorafenib warrants further study as a therapeutic agent against ATC.