Hand grip support for rehabilitation and assistance: from patent to TRL5.

In the last decades, the continuous increase in the number of the vast cohort of chronic patients that constantly need medical assistance and supervision, and the widespread lack of therapist has brought to an increased interest in the role of medical technologies in rehabilitative programs and assistive scenarios. Current clinical evidence in rehabilitation demonstrates that there is an important and increasing demand for innovative therapeutic solutions to recover the hand functions to prevent patients to need assistance in performing daily life activities. This works describes the pathway from patent to TRL5 of a device to support hand grip actions and interaction with daily life objects. E-KIRO is based on the use of electromagnets, which are able to attach/detach interactive objects equipped with a ferromagnetic plate. Five end-users used the device and scored it with excellent usability based on the System Usability Scale.

A Bayesian adaptive dose selection procedure with an overdispersed count endpoint.

Adaptive trial designs can considerably improve upon traditional designs, by modifying design aspects of the ongoing trial, like early stopping, adding, or dropping doses, or changing the sample size. In the present work, we propose a two-stage Bayesian adaptive design for a Phase IIb study aimed at selecting the lowest effective dose for Phase III. In this setting, efficacy has been proved for a high dose in a Phase IIa proof-of-concept study, but the existence of a lower but still effective dose is investigated before the scheduled Phase III starts. In the first stage, we randomize patients to placebo, maximal tolerated dose, and one or more additional doses within the dose range. Based on an interim analysis, we either stop the study for futility or success or continue the study to the second stage, where newly recruited patients are allocated to placebo, some fairly high dose, and one additional dose chosen based on interim data. At the interim analysis, we use the criteria based on the predictive probability of success to decide on whether to stop or to continue the trial and, in the latter case, which dose to select for the second stage. Finally, we will select a dose as lowest effective dose for Phase III either at the end of the first stage or at the end of the second stage. We evaluate the operating characteristics of the procedure via simulations and present the results for several scenarios, comparing the performance of the proposed procedure to those of the non-adaptive design.

An empirical calibration method for an a-Si portal imaging device: applications in pretreatment verification of IMRT.

PURPOSE: A new calibration method for an amorphous silicon (a-Si) electronic portal imaging device (EPID) used for dose measurements in pretreatment verification (field-related) of intensity-modulated radiation therapy (IMRT) with sliding-window technique. The method is independent of data contained in the multileaf collimator (MLC) leaf-motion files and of any calculations made by the treatment planning system (TPS). MATERIALS AND METHODS: Sensitivity of the EPID is dependent on radiation energy. For fluence-modulated fields, different dose/reading calibration factors are associated with each pixel of the image acquired by calculating equivalent areas representing the exact ratio between primary and scatter components. The dose measured in the detector plane was compared with that calculated with TPS by using gamma-analysis. Each calibration factor was compared with that calculated by considering the individual contributions of primary and secondary radiation obtained using the convolution method with analytical kernel for homogeneous media. RESULTS: In 837/854 (98%) of the clinical fields analysed, the proportion of irradiated area in which the gamma-index was <1.0 exceeded 95%. The overall average gamma-index was 0.39. There was good agreement between the dose/reading calibration factors obtained with the empirical algorithm and with the convolution method. CONCLUSIONS: The proposed calibration method is suitable for routine clinical pretreatment verification in IMRT.

Dosimetry in the therapy of metastatic differentiated thyroid cancer administering high 131I activity: the experience of Busto Arsizio Hospital (Italy).

AIM: The purpose of the present work was to evaluate the impact of 131I high activity therapy treatments of metastatic differentiated thyroid cancer (MDTC) in terms of feasibility, tolerance, efficacy, and the impact of dosimetry in order to optimize the process. METHODS: Seventeen MDTC patients underwent 27 treatments with 131I, with activity ranging from 6.2 GBq to 24.1 GBq. Red marrow (RM) peritherapy dosimetry was based on the Standard Operating Procedure of European Association of Nuclear Medicine (EANM SOP), while metastases dosimetry on the guidelines of Italian Association of Physicists in Medicine and Italian Association of Nuclear Medicine. In 12 cases prospective dosimetry was performed too, with the purpose of evaluating the possibility of maximizing the therapeutic activity, complying the 2 Gy red marrow (RM) dose constraint. The absorbed dose to 45 lesions was evaluated. The severity of myelotoxic effects was monitored during the follow-up. RESULTS: Treatments were generally well tolerated, also at the highest RM absorbed doses. RM absorbed doses ranged from 0.49 to 6.67 Gy, lesion doses from 1.1 Gy to 778 Gy. In case of repeated treatments on the same site, in 13 cases on a total of 15, an absorbed dose reduction was observed. RM prospective and peritherapeutic dosimetry differed somewhat: absorbed doses measured during therapy ranged from -7% to +40% with respect to provisional absorbed doses. CONCLUSION: In our experience high activity treatments were well-tolerated. Prospective dosimetry needs further investigation to become sufficiently reliable in order to comply the 2 Gy constraint. Lesions became progressively less iodine-avid in case of repeated treatments, so the "first big-shoot" treatment with the highest safe activity seems to be desirable to obtain the maximum efficacy.

Attention deficit induced by blockade of N-methyl D-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors 2/3.

The hypothesis that attention deficits induced by the hypofunction of N-methyl d-aspartate (NMDA) receptors in the prefrontal cortex (PFC) might be associated with increased glutamate release and changes in the phosphorylation of the cyclic adenosine monophosphate response element-binding protein on serine 133 (p-S(133)CREB) was investigated in this study. Infusion of 50 ng/side 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), a competitive glutamate NMDA receptor antagonist, into the medial prefrontal cortex (mPFC) of rats performing the five-choice serial reaction time (5-CSRT) task, reduced accuracy of visual discrimination (measured by % correct responses) and enhanced impulsivity (measured by the number of premature responses) and compulsivity (measured by the number of perseverative responses). The mGluR2/3 receptor agonist, LY379268, injected s.c. at 0.1 mg/kg, reduced (R)-CPP-induced impairment in attentional functioning (accuracy) and impulsivity but not compulsive perseveration. In parallel studies using microdialysis technique and Western blot analysis we found that (R)-CPP (100 µM) infused in the medial prefrontal cortex increased glutamate efflux whereas injected in the medial prefrontal cortex at a dose causing impairments in attentional performance (50 ng/side) increased p-S(133)CREB in the frontal cortex (FC), decreased it in the caudate-putamen (CPu) and was without effect in the nucleus accumbens (NAC). LY379268 at the dose effective in reducing (R)-CPP-induced behavioral deficit reduced both the (R)-CPP-induced rise in glutamate efflux in the prefrontal cortex and the increase in p-S(133)CREB in the frontal cortex but was without effect on the decrease in p-S(133)CREB in the caudate-putamen. The data provide evidence that enhanced glutamate release and phosphorylation of cAMP response element binding protein (CREB) on serine 133 may be associated to attention deficit and loss of impulse control. Furthermore they suggest that mGluR2/3 agonists have a therapeutic potential for cognitive deficits.

Prospective dosimetry with 99mTc-MDP in metabolic radiotherapy of bone metastases with 153Sm-EDTMP.

PURPOSE: On the basis of the encouraging results achieved in several clinical trials and its proven therapeutic efficacy, (153)Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP) has become widely used to palliate pain from bone metastases. The results reported in the literature have led the product suppliers (QUADRAMET, Schering) to suggest administering a fixed activity per kilogram (37 MBq/kg). However, considering the observed extreme inter-patient variability of skeletal uptake of (153)Sm-EDTMP, a real therapy optimization would require the individualization of the activity to be administered on a dosimetric basis. This should be planned taking into account the generally accepted 2-Gy dose constraint to the haematopoietic red marrow, the critical organ in palliative treatments with beta-emitting, bone-seeking radiopharmaceuticals. METHODS: Seven to 14 days before treatment with (153)Sm-EDTMP, 44 patients underwent (99m)Tc-methylene diphosphonate (MDP) total-body bone scan with two scans (the first within 10 min of injection, the second after 6 h). The percentage bone uptake (Tc(%)) was evaluated as the ratio between total counts at 6 h, adjusted for decay, and total counts at the first scan. Tc(%) was then compared to Sm(%) similarly derived from 10-min and 24-h whole-body scans. Tc(%) and Sm(%) were compared both with and without Brenner's method for soft tissue uptake. RESULTS: The correlation between Tc(%) and Sm(%) was R (2) = 0.81 and R (2) = 0.88 with and without soft tissue correction, respectively. The difference between their average values was statistically significant (Sm(%) = 64.3 +/- 15.2, Tc(%) = 56.2 +/- 16.0; p = 0.017) with soft tissue correction, while was not statistically significant (Sm(%) = 68.2 +/- 15.5, Tc(%) = 66.9 +/- 14.0; p = 0.670) without soft tissue correction. CONCLUSIONS: The rate of retention of (99m)Tc-MDP in bone provides a reliable estimate of the (153)Sm-EDTMP rate of retention. The proposed method can be usefully adopted for prospective dosimetry seeing its extreme simplicity, and it requires no special investment in terms of human or instrumental resources. This allows an optimization of administered (153)Sm-EDTMP activity.

Determinação do limiar de anaerobiose de idosos saudáveis: comparação entre diferentes métodos / Determination of anaerobic threshold in healthy elderly people: comparison between different methods

OBJETIVO: Determinar o limiar de anaerobiose (LA) pelo método ventilatório (visual gráfico), pelos modelos matemáticos, Heteroscedástico e Hinkley, aplicados aos conjuntos de dados de freqüência cardíaca (FC), RMS do sinal mioelétrico (Root Mean Square) e VCO2 e comparar o LA obtido pelos três métodos. METODOLOGIA: Foram estudados 9 idosos ativos (61,4±1,8 anos) durante teste de exercício físico dinâmico contínuo do tipo rampa, em cicloergômetro, com incrementos de potência variando de 10 a 15 Watts/min. Foram coletados os dados de FC batimento a batimento, eletromiografia de superfície do músculo vasto lateral e variáveis ventilatórias respiração a respiração. Após a aplicação dos modelos matemáticos e identificados os pontos de quebra de comportamento, foram registrados neste momento os valores de potência, VO2 e FC, comparados e correlacionados aos obtidos pelo método visual gráfico (padrão ouro). Foi utilizado o teste de Friedman para comparações múltiplas e o teste de correlação de Spearman (nível de significância de 5 por cento). RESULTADOS: Não foram encontradas diferenças significantes, em relação ao padrão ouro, entre os valores de potência, VO2 e FC, no momento do LA identificado pelos diferentes modelos. Foram encontradas correlações significantes entre os valores de FC identificados pelos modelos matemáticos entre os valores de VO2 quando identificados pela freqüência cardíaca e de potência somente quando identificada pelo modelo de Hinkley aplicado aos dados de RMS do sinal mioelétrico. CONCLUSÕES: No grupo estudado, os modelos matemáticos mostraram-se adequados na determinação não-invasiva do LA, sendo que ambos ajustaram-se melhor aos dados de FC, seguido pela VCO2 e RMS.

OBJECTIVE: To determine the anaerobic threshold by the graphic visual ventilatory method and the Hinkley and heteroscedastic mathematical models, applied to heart rate, myoelectric root mean square (RMS) signal and VCO2 datasets, and to compare the anaerobic threshold obtained by the three methods. METHOD: Nine active elderly subjects were studied (aged 61.4 ± 1.8 years) during a ramp-load continuous dynamic physical exercise test on a cycle ergometer, with power ranging from 10 to 15 Watts/min. Beat-to-beat heart rate data, electromyographic data from the surface of the vastus lateralis muscle, and breath-to-breath ventilatory data were collected. After applying mathematical models and identifying the behavioral shift points, these power levels, heart rates and VO2 values were noted and these were compared and correlated with those obtained by the graphic visual model (gold standard). The Friedman test for multiple comparisons and the Spearman correlation test were utilized (significance level: 5 percent). RESULTS: No significant differences were found in relation to the gold standard, between the power levels, VO2 values and heart rates at the anaerobic threshold identified by the different models. Significant correlations were found between the heart rates identified by the mathematical models, between the VO2 values identified by the heart rates, and between power rates only when identified by the Hinkley model applied to myoelectric RMS signal data. CONCLUSION: In this study group, the mathematical models were shown to be adequate for non-invasively determining the anaerobic threshold. Both models worked best on the heart rate data, followed by VCO2 and RMS.

Transient post-traumatic hemidiaphragmatic paralysis in two cats.

A diagnosis of post-traumatic hemidiaphragmatic paralysis was made in two cats. Both cats had a history of trauma and paradoxical inward movement of the abdominal wall at inspiration. Thoracic radiographs were taken at inspiration and expiration. Although the images were suggestive of hemidiaphragmatic paralysis, definitive diagnosis was reached by fluoroscopy in one cat and by ultrasonography in the second. Both cases resolved spontaneously and diaphragmatic function was normal at follow-up.

Fluoxetine increases extracellular dopamine in the prefrontal cortex by a mechanism not dependent on serotonin: a comparison with citalopram.

Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin.

Medullary thyroid carcinomas in transgenic mice expressing a Polyoma carboxyl-terminal truncated middle-T and wild type small-T antigens.

Medullary thyroid carcinoma (MTC) is a rare human tumor affecting the calcitonin-secreting c-cells of the thyroid. Here we report that two independent strains of transgenic mice expressing a Polyomavirus (Py) truncated middle-T antigen (deltaMT), consisting of the amino-terminal 304 amino acids, and the full length Py small-T antigen, developed multifocal bilateral MTCs with 100% penetrance. Occasionally one strain also developed mammary and bone tumors. Furthermore, offspring from both transgenic lines displayed pronounced waviness of the whiskers and fur, previously associated with defective epidermal growth factor receptor signaling. Transgene transcription, driven by the homologous early promoter/enhancer, and the corresponding translation products were detected in tumors and in many other organs which did not develop pathologies. The subcellular distribution of deltaMT and its interactions with the adapter proteins of the SHC family have also been analysed. Our study describes a novel murine model of MTC and provides evidence that the N-terminal 304 amino acid fragment of Py middle-T antigen, possibly in co-operation with small-T antigen, acts as a potent oncogene in c-cells of the thyroid.

Immortalization of neuro-endocrine cells from adrenal tumors arising in SV40 T-transgenic mice.

Pheochromocytomas are adrenal medullary tumors which arise from the transformation of neural crest-derived cells. In the course of studies of mice transgenic for an SV40 T-gene ectopically expressed in the adrenal medulla, we observed the occurrence of large, mainly bilateral tumors in a high proportion of transgenic animals. From these tumors we established immortalized cell lines which grow in vitro at 32 degrees C (the permissive temperature for the tsA58 T-protein encoded by the transgene), but not at 38 C. These cells demonstrate characteristics of both neuronal (160 kd neurofilament) and endocrine (chromogranins) cells. The expression of Mash-1 and ret supports their initial characterization as early bipotential neuro-endocrine progenitors.

Development of an adjuvant-active nonionic block copolymer for use in oil-free subunit vaccines formulations.

Nonionic block copolymers, synthesized from repeating units of oxypropylene and oxyethylene, can be designed so that individual copolymers have unique physical properties with differential levels of adjuvant activity. We have designed high molecular weight block copolymers that spontaneously assemble into 500 nm-3 mum particles when formulated with protein antigens in aqueous solutions at physiological pH. The adjuvant activity of one of these copolymers, termed CRL1005, was compared to selected research adjuvants using ovalbumin (OVA) as the prototype vaccine antigen. Suboptimal doses of OVA were formulated with complete and incomplete. Freund's adjuvant (CFA/IFA), alum Quil-A saponins Ribi Adjuvant System (RAS) or the CRL1005 copolymer and these formulations were used to immunize C57BL/6 mice. The CRL1005 copolymer appeared to be more potent than either Quil-A or alum and comparable to the RAS formulation, based on the numbers of responding mice and the OVA-specific antibody titers. Alum. RAS and Quil-A all augmented the production of IgG1 and IgG2l, similarly whereas only the CFA/IFA boosted IgG2a levels significantly. The effect of adjuvants on relative antibody affinity was more variable with the CRL1005 and CFA/IFA inducing antibodies with the highest affinity scores. This high molecular weight nonionic copolymer is nontoxic in aqueous formulations and should therefore be compatible with a wide variety of protein or polysaccharide vaccine antigens.

[Infant mortality in the transition years: a reflection of the Italian and Spanish experiences]. / La mortalidad infantil en los anos de la transicion: una reflexion desde las experiencias italiana y espanola.

PIP: "The first part of this article deals with the main characteristics of the Italian and Spanish infant mortality transition. Both experiences are placed within the European context and a study of mortality by age and cause of death is carried out. The second part intends to define a framework for the analysis of the different factors involved in the decline of infant mortality." (EXCERPT)^ieng

Development of mammary and cutaneous gland tumors in transgenic mice carrying the RET/PTC1 oncogene.

RET/PTC1 is a chimeric oncogene created by the fusion of the tyrosine kinase domain of RET to the 5'-terminal region of another gene named H4. So far, this oncogene has been found activated only in human papillary thyroid carcinomas. In order to investigate its transforming properties in vivo, we have produced transgenic mice carrying RET/PTC1 under the control of the H4 promoter. The transgene was expressed in several tissues, consistently with the ubiquitous expression of the wild type H4 gene. Mammary adenocarcinomas and, less frequently, hyperplasia of sebaceous glands and rare benign skin tumors, named pilomatrixomas, developed in these mice. The tumors were shown to express the transgene both at the RNA and protein level. These results demonstrate that the transforming ability of the RET/PTC1 oncogene is not restricted to the thyroid epithelium in vivo. Despite its ubiquitous expression, however, RET/PTC1 was able to induce only a limited number of tumor types; specifically mammary epithelium was affected by transgene expression, thus suggesting that RET/PTC1 is able to couple with transforming pathways specific for these glandular cells.

5-HT3 receptor antagonists do not modify cocaine place conditioning or the rise in extracellular dopamine in the nucleus accumbens of rats.

Three 5-HT3 receptor antagonists, MDL 72222, tropisetron, and ondansetron were studied for their ability to modify the conditioned place preference (CPP) induced by 10 mg/kg IP cocaine in rats. MDL 72222 (0.03-3 mg/kg SC) and tropisetron (0.01-0.1 mg/kg SC) administered, respectively, 30 min and 1 h before each conditioning session, did not affect the acquisition of cocaine CPP. Ondansetron (0.01-0.1 mg/kg SC) administered 30 min before each conditioning session or just before testing likewise had no effect. At 0.1 mg/kg SC ondansetron did not modify the increase of extracellular dopamine caused by 10 mg/kg cocaine in the nucleus accumbens. The results suggest that 5-HT3 receptor antagonists have no effect on the rewarding properties of cocaine or on the behaviour elicited by the stimuli previously associated with the drug's action.

Deficits in memory and hippocampal long-term potentiation in mice with reduced calbindin D28K expression.

The influx of calcium into the postsynaptic neuron is likely to be an important event in memory formation. Among the mechanisms that nerve cells may use to alter the time course or size of a spike of intracellular calcium are cytosolic calcium binding or "buffering" proteins. To consider the role in memory formation of one of these proteins, calbindin D28K, which is abundant in many neurons, including the CA1 pyramidal cells of the hippocampus, transgenic mice deficient in calbindin D28K have been created. These mice show selective impairments in spatial learning paradigms and fail to maintain long-term potentiation. These results suggest a role for calbindin D28K protein in temporally extending a neuronal calcium signal, allowing the activation of calcium-dependent intracellular signaling pathways underlying memory function.

[Differences in the growth of four regional populations in Italy, 1750-1911]. / Diferencias en el crecimiento de cuatro poblaciones regionales en Italia, 1750-1911.

PIP: The authors discuss the use of inverse projection to examine population growth in four regions of Italy between 1750 and 1911. Information is included on population and growth rates; life expectancy at birth; crude birth rate; and nuptiality, fertility, and mortality.^ieng

Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum.

GR-113808, a potent and selective 5-HT4 receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 microM GR-113808 did not affect the extracellular concentrations of DA in either region and 100 microM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 microM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 micrograms/0.5 microliter) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 micrograms but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT4 receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.

A novel line of transgenic mice (RSV/LTR-bGH) expressing growth hormone in cardiac and striated muscle.

In order to further investigate the deleterious effects of GH overexpression, we generated a novel line of transgenic mice featuring stable and specific expression of bovine GH in the heart and striated muscle. A DNA construct, containing a region with promoter activity from the Long Terminal Repeat of Rous Sarcoma Virus (RSV-LTR) and the entire structural gene of bovine GH (bGH), was microinjected by standard techniques in male pronuclei of fertilized mice eggs. Transgenic mice expressed bGH mRNA in the heart and striated muscle starting at 5-6 weeks of age. They featured circulating levels of a 22 kDa form of bGH up to 700 ng/ml and enhanced growth starting at 6 weeks of age. No pathologic changes of the myocardium and striated muscle fibers, other than hypertrophy, were noticed, although severe glomerulosclerosis and liver alteration occurred in older mice. Future studies on this new line of transgenic GH mice and integration with the existing data might improve our understanding of the molecular mechanism underlying the detrimental effects of elevated GH levels on various organs and functions.