Addressing undernutrition in external assistance: an integrated approach through sectors and aid modalities. Tools and Methods Series: reference document no° 13, September 2011.

doi:10.2783/51319

Attentional blink modulation during sustained and after discrete lead stimuli presented in three sensory modalities

Previous studies found larger attentional modulation of acoustic blinks during task-relevant than during task-irrelevant acoustic or visual, but not tactile, lead stimuli. Moreover, blink modulation was larger overall during acoustic lead stimuli. The present experiment investigated whether these results reflect modality specificity of attentional blink modulation or effects of continuous stimulation. Participants performed a discrimination and counting task with acoustic, visual, or tactile lead stimuli. Stimuli were presented Sustained or consisted of two short discrete stimuli. The sustained condition replicated previous results. In the discrete condition, blinks were larger during task-relevant than during task-irrelevant stimuli in all groups regardless of lead stimulus modality. Thus, previous results that seemed consistent with modality-specific accounts of attentional blink modulation reflect effects of continuous stimulus input.

Timing continuous or discontinuous movements across effectors specified by different pacing modalities and intervals

Sensorimotor synchronization is hypothesized to arise through two different processes, associated with continuous or discontinuous rhythmic movements. This study investigated synchronization of continuous and discontinuous movements to different pacing signals (auditory or visual), pacing interval (500, 650, 800, 950 ms) and across effectors (non-dominant vs. non-dominant hand). The results showed that mean and variability of asynchronization errors were consistently smaller for discontinuous movements compared to continuous movements. Furthermore, both movement types were timed more accurately with auditory pacing compared to visual pacing and were more accurate with the dominant hand. Shortening the pacing interval also improved sensorimotor synchronization accuracy in both continuous and discontinuous movements. These results show the dependency of temporal control of movements on the nature of the motor task, the type and rate of extrinsic sensory information as well as the efficiency of the motor actuators for sensory integration.

Education and training in the use of physical agent modalities by occupational therapists practicing in the physical disabilities area

This study was conducted to examine how occupational therapists (OTs) practicing in the physical disabilities area received their training in the use of physical agent modalities (PAMs); to determine the frequency of PAMs usage by those therapists; and to obtain their opinions regarding the training of OTs and OT students in the administration of PAMs. Three hundred OTs practicing in physical diabilities (n = 194 returned) were surveyed. The most frequently used modalities were hot and cold packs, paraffin, and ultrasound. The least frequently used modalities were transcutaneous electrical stimulation (TENS) and whirlpool. On-the-job training was the most common educational method received by the respondents for PAMs usage. The respondents considered a combination of undergraduate education, fieldwork, continuing education and on-the-job training as the most appropriate educational setting for training in modalities. While few of the respondents received preparation in PAMs during entry-level academic programs, the majority felt that OT students should be trained in PAMs usage as part of their education curriculum. ^

Cancer therapy combining the modalities of hyperthermia and chemotherapy: In vitro cellular response after rapid heat accumulation in the cancer cell

Hyperthermia is usually used at a sub-lethal level in cancer treatment to potentiate the effects of chemotherapy. The purpose of this study is to investigate the role of heating rate in achieving synergistic cell killing by chemotherapy and hyperthermia. For this purpose, in vitro cell culture experiments with a uterine cancer cell line (MES-SA) and its multidrug resistant (MDR) variant MES-SA/Dx5 were conducted. The cytotoxicity, mode of cell death, induction of thermal tolerance and P-gp mediated MDR following the two different modes of heating were studied. Doxorubicin (DOX) was used as the chemotherapy drug. Indocyanine green (ICG), which absorbs near infrared light at 808nm (ideal for tissue penetration), was chosen for achieving rapid rate hyperthermia. A slow rate hyperthermia was provided by a cell culture incubator. The results show that the potentiating effect of hyperthermia to chemotherapy can be maximized by increasing the rate of heating as evident by the results from the cytotoxicity assay. When delivered at the same thermal dose, a rapid increase in temperature from 37°C to 43°C caused more cell membrane damage than gradually heating the cells from 37°C to 43°C and thus allowed for more intracellular accumulation of the chemotherapeutic agents. Different modes of cell death are observed by the two hyperthermia delivery methods. The rapid rate laser-ICG hyperthermia @ 43°C caused cell necrosis whereas the slow rate incubator hyperthermia @ 43°C induced very mild apoptosis. At 43°C a positive correlation between thermal tolerance and the length of hyperthermia exposure is identified. This study shows that by increasing the rate of heating, less thermal dose is needed in order to overcome P-gp mediated MDR.

Angiomatoid fibrous histiocytoma: comparison of fluorescence in situ hybridization and reverse transcription polymerase chain reaction as adjunct diagnostic modalities

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the extremities of children and young adults. Although it has characteristic histologic features of a lymphoid cuff surrounding nodules of ovoid cells with blood-filled cystic cavities, diagnosis is often difficult due to its morphologic heterogeneity and lack of specific immunoprofile. Angiomatoid fibrous histiocytoma is associated with recurrent chromosomal translocations, leading to characteristic EWSR1-CREB1, EWSR1-ATF1, and, rarely, FUS-ATF1 gene fusions; fluorescence in situ hybridization (FISH), detecting EWSR1 or FUS rearrangements, and reverse transcription-polymerase chain reaction (RT-PCR) for EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts have become routine ancillary tools. We present a large comparative series of FISH and RT-PCR for AFH. Seventeen neoplasms (from 16 patients) histologically diagnosed as AFH were assessed for EWSR1 rearrangements or EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts. All 17 were positive for either FISH or RT-PCR or both. Of 16, 14 (87.5%) had detectable EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts by RT-PCR, whereas 13 (76.5%) of 17 had positive EWSR1 rearrangement with FISH. All 13 of 13 non-AFH control neoplasms failed to show EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts, whereas EWSR1 rearrangement was present in 2 of these 13 cases (which were histopathologically myoepithelial neoplasms). This study shows that EWSR1-CREB1 or EWSR1-ATF1 fusions predominate in AFH (supporting previous reports that FUS rearrangement is rare in AFH) and that RT-PCR has a comparable detection rate to FISH for AFH. Importantly, cases of AFH can be missed if RT-PCR is not performed in conjunction with FISH, and RT-PCR has the added advantage of specificity, which is crucial, as EWSR1 rearrangements are present in a variety of neoplasms in the histologic differential diagnosis of AFH, that differ in behavior and treatment.

Boosting the CD4 Count in HIV Infection: Comparative Effects of Highly Active Anti-retroviral therapy (HAART) and Different Modalities of Physical Exercise on Biomarkers of Immunity

A decline in the CD4 count is a common feature in HIV/AIDS, suggesting a compromise in immunity of patients. In response, highly active antiretroviral therapy (HAART) is prescribed to slow-down a diminution in the CD4 count and risk of AIDS-related malignancies. However, exercise may improve both the utility and population of innate immune cell components, and may be beneficial for patients with HIV infection. Comparing the effects of different exercises against HAART, on CD4 count, helps in understanding the role and evidence-based application of exercises to ameliorate immune deficiency.

Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss

We investigated the effect of different exercise modalities on high sensitivity-C reactive protein (hs-CRP) and other inflammatory markers in patients with type 2 diabetes and the metabolic syndrome. Eighty-two patients were randomized into 4 groups: sedentary control (A); receiving counseling to perform low-intensity physical activity (B); performing prescribed and supervised high-intensity aerobic (C) or aerobic + resistance (D) exercise (with the same caloric expenditure) for 12 months. Evaluation of leisure-time physical activity and assessment of physical fitness, cardiovascular risk factors and inflammatory biomarkers was performed at baseline and every 3 months. Volume of physical activity increased and HbA1c decreased in Groups B–D. VO2max, HOMA-IR index, HDL-cholesterol, waist circumference and albuminuria improved in Groups C and D, whereas strength and flexibility improved only in Group D. Levels of hs-CRP decreased in all three exercising groups, but the reduction was significant only in Groups C and D, and particularly in Group D. Changes in VO2max and the exercise modalities were strong predictors of hs-CRP reduction, independent of body weight. Leptin, resistin and interleukin-6 decreased, whereas adiponectin increased in Groups C and D. Interleukin-1β, tumor necrosis factor-α and interferon-γ decreased, whereas anti-inflammatory interleukin-4 and 10 increased only in Group D. In conclusion, physical exercise in type 2 diabetic patients with the metabolic syndrome is associated with a significant reduction of hs-CRP and other inflammatory and insulin resistance biomarkers, independent of weight loss. Long-term high-intensity (preferably mixed) training, in addition to daytime physical activity, is required to obtain a significant anti-inflammatory effect.

Integration of Multiple Simultaneous Stimuli within and between Somatosensory sub-Modalities

Psychological characterisation of the somatosensory system often focusses on minimal units of perception, such as detection, localisation, and magnitude estimation of single events. Research on how multiple simultaneous stimuli are aggregated to create integrated, synthetic experiences is rarer. This thesis aims to shed a light on the mechanisms underlying the integration of multiple simultaneous stimuli, within and between different sub-modalities of the somatosensory system. First, we investigated the ability of healthy individuals to perceive the total intensity of composite somatosensory patterns. We found that the overall intensity of tactile, cold, or warm patterns was systematically overestimated when the multiple simultaneous stimuli had different intensities. Perception of somatosensory totals was biased towards the most salient element in the pattern. Furthermore, we demonstrated that peak-biased aggregation is a genuine perceptual phenomenon which does not rely on the discrimination of the parts, but is rather based on the salience of each stimulus. Next, we studied a classical thermal illusion to assess participants’ ability to localise thermal stimuli delivered on the fingers either in isolation, or in uniform and non-uniform patterns. We found that despite a surprisingly high accuracy in reporting the location of a single stimulus, when participants were presented with non-uniform patterns, their ability to identify the thermal state of a specific finger was completely abolished. Lastly, we investigated the perceptual and neural correlates of thermo-nociceptive interaction during the presentation of multiple thermal stimuli. We found that inhibition of pain by warmth was independent from both the position and the number of thermal stimuli administered. Our results suggest that nonlinear integration of multiple stimuli, within and between somatosensory sub-modalities, may be an efficient way by which the somatosensory system synthesises the complexity of reality, providing an extended and coherent perception of the world, in spite of its deep bandwidth limitations.

New chemical modalities for leishmaniasis drug discovery

Leishmaniasis is one of the major parasitic diseases among neglected tropical diseases with a high rate of morbidity and mortality. Human migration and climate change have spread the disease from limited endemic areas all over the world, also reaching regions in Southern Europe, and causing significant health and economic burden. The currently available treatments are far from ideal due to host toxicity, elevated cost, and increasing rates of drug resistance. Safer and more effective drugs are thus urgently required. Nevertheless, the identification of new chemical entities for leishmaniasis has proven to be incredibly hard and exacerbated by the scarcity of well-validated targets. Trypanothione reductase (TR) represents one robustly validated target in Leishmania that fulfils most of the requirements for a good drug target. However, due to the large and featureless active site, TR is considered extremely challenging and almost undruggable by small molecules. This scenario advocates the development of new chemical entities by unlocking new modalities for leishmaniasis drug discovery. The classical toolbox for drug discovery has enormously expanded in the last decade, and medicinal chemists can now strategize across a variety of new chemical modalities and a vast chemical space, to efficiently modulate challenging targets and provide effective treatments. Beyond others, Targeted p Protein Degradation (TPD) is an emerging strategy that uses small molecules to hijack endogenous proteolysis systems to degrade disease-relevant proteins and thus reduce their abundance in the cell. Based on these considerations, this thesis aimed to develop new strategies for leishmaniasis drug discovery while embracing novel chemical modalities and navigating the chemical space by chasing unprecedented chemotypes. This has been achieved by four complementary projects. We believe that these next-generation chemical modalities for leishmaniasis will play an important role in what was previously thought to be a drug discovery landscape dominated by small molecules.