Low-dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: lack of vascular normalization.

Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.

Acúmulo de N e P na parte aérea da soja após compactação subsuperficial e aplicação de gesso

Um experimento com soja, utilizando amostra de Latossolo Vermelho-Escuro distrófico textura média, previamente corrigido com 2,5 t ha-1 de calcário dolomítico, foi desenvolvido em casa de vegetação da Escola Superior de Agricultura ''Luiz de Queiroz", Piracicaba (SP), no período de dezembro/1993 a julho/1994, visando avaliar o efeito da compactação subsuperficial e de doses de gesso nos teores de N e de P da parte aérea da soja. Utilizou-se o delineamento em blocos casualizados, com os tratamentos dispostos em fatorial 4 x 4, com quatro repetições, correspondendo à aplicação, na camada superficial, de quatro doses de gesso (zero; 3,25; 6,50 e 9,75 t ha-1) misturadas ao equivalente a 15 t ha-1 de matéria seca de crotalária (MSC) e 2,5 t ha-1 de calcário dolomítico, em quatro níveis de compactação (densidades: 1,32; 1,4 7; 1,62 e 1,77 kg dm-3). Utilizou-se prensa hidráulica no solo do anel central de uma coluna formada pela sobreposição de três anéis de PVC de 15 cm de diâmetro e altura de 5 cm para o anel central e inferior e 12,5 cm para o anel superior . Observou-se que as doses de gesso não tiveram influência no teor de N da parte aérea da soja, quando ocorreu o crescimento radicular em profundidade. Quando a compactação do solo restringiu o crescimento radicular somente à camada superficial, a concentração de N na parte aérea da soja foi maior, quando a dose de gesso estimada era de 5 t ha-1, reduzindo-se para doses maiores do que esta. De maneira geral, a aplicação dos níveis de compactação não alterou os teores de N na parte aérea na presença de gesso, mas levou à redução linear quando o gesso não foi aplicado. Com relação ao fósforo, observou-se que tanto as doses de gesso como os níveis de compactação elevados promoveram aumentos na quantidade de P absorvido pela soja.

Cumulative risk factors for adolescent alcohol misuse and its perceived consequences among 16 to 20 year old adolescents in Switzerland.

AIMS: To assess the cumulative impact of environmental and individual factors associated with adolescent alcohol misuse and their correlation with self-reported consequences of drinking. METHOD: Cross-sectional school-based survey of a nationally representative sample of 7548 post-mandatory school students and apprentices aged 16-20 years, Switzerland 2002. Alcohol misuse defined by frequency of alcohol use, episodes of drunkenness and driving while drunk. RESULTS: Fifteen significant risk factors were identified among both boys, and girls. An individual score of cumulated risk factors was created by adding the risk factors. The association between the score and the likelihood of being engaged in alcohol misuse was highly significant and dose-dependent (p<.001). A significant proportion of adolescents report perceived adverse consequences of their alcohol consumption. A linear trend (p<.001) was found between the score of risk factors and the proportion of respondents reporting problems related to drinking such as diminished school performance, physical hazard, relational problems and current risky sexual behavior. CONCLUSION: Risk factors for adolescent alcohol misuse are cumulative and can be synthesized into an individual score correlated with the likeliness of misuse. A further indication of the validity of this score is its linear relationship with self-reported problems related to drinking.

Cyberhealth serving to support individual intake of medication.

The Internet and new communication technologies are deeply affecting healthcare systems and the provision of care. The purpose of this article is to evaluate the possibility that cyberhealth, via the development of widespread easy access to wireless personal computers, tablets and smartphones, can effectively influence intake of medication and long-term medication adherence, which is a complex, difficult and dynamic behaviour to adopt and to sustain over time. Because of its novelty, the impact of cyberhealth on drug intake has not yet been well explored. Initial results have provided some evidence, but more research is needed to determine the impact of cyberhealth resources on long-term adherence and health outcomes, its user-friendliness and its adequacy in meeting e-patient needs. The purpose of such Internet-based interventions, which provide different levels of customisation, is not to take over the roles of healthcare providers; on the contrary, cyberhealth platforms should reinforce the alliance between healthcare providers and patients by filling time-gaps between visits and allowing patients to upload and/or share feedback material to be used during the visits. This shift, however, is not easily endorsed by healthcare providers, who must master new eHealth skills, but healthcare systems have a unique opportunity to invest in the Internet and to use this powerful tool to design the future of integrated care. Before this can occur, however, important issues must be addressed and resolved, for example ethical considerations, the scientific quality of programmes, reimbursement of activity, data security and the ownership of uploaded data.

Influência de algumas características do solo nos teores de boro disponível

Este trabalho objetivou avaliar a utilização da água quente e CaCl2 5 mmol L-1 como extratores de B disponível, usando forno de microondas como fonte de aquecimento, e estudar a influência de algumas características do solo nos teores de B extraído. A dosagem de B nos extratos foi feita com azometina-H. Executou-se um experimento em casa de vegetação em fatorial completo 17 solos x 6 doses de B (0, 0,15, 0,30, 0,60, 0,90 e 1,50 mg dm-3), com três repetições, em blocos ao acaso, usando o milho como planta-teste. Os solos foram analisados por meio dos dois extratores e os teores de B e a produção de matéria seca da parte aérea foram medidos. Foram feitas análises de regressão e correlação para as diversas variáveis, trabalhando com os dados de todas as doses ou apenas com a dose zero. Verificou-se que os extratores revelaram capacidades semelhantes na determinação do B disponível; o CaCl2 5 mmol L-1 recuperou 8% a mais do B aplicado, em relação à água quente; a elevação dos teores de ferro livre, de argila e de matéria orgânica e dos valores de equivalente de umidade reduziram significativamente a taxa de recuperação do B aplicado, por ambos os extratores. Os teores de B no solo acima de 0,1 mg dm-3 (por CaCl2 5 mmol L-1) e de 7,8 mg kg-1 na planta acarretaram decréscimo da produção de matéria seca.

Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual hsp70 chaperones.

Hsp70 is a central molecular chaperone that passively prevents protein aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and mediate the proper refolding of proteins in the cell. Yet, the molecular mechanism by which the active Hsp70 chaperone functions are achieved remains unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold misfolded structures in aggregated polypeptides, leading to gradual disaggregation. We found that the specific unfolding and disaggregation activities of individual DnaK molecules were optimal for large aggregates but dramatically decreased for small aggregates. The active unfolding of the smallest aggregates, leading to proper global refolding, required the cooperative action of several DnaK molecules per misfolded polypeptide. This finding suggests that the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can recruit random chaperone motions to locally unfold misfolded structures and gradually disentangle stable aggregates into refoldable proteins.

Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.

OBJECTIVE: To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, for the treatment of acute gouty arthritis. METHODS: In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS: Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION: Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

Sedation and analgesia for colonoscopy: patient tolerance, pain, and cardiorespiratory parameters.

BACKGROUND: Colonoscopy is generally performed with the patient sedated and receiving analgesics. However, the benefit of the most often used combination of intravenous midazolam and pethidine on patient tolerance and pain and its cardiorespiratory risk have not been fully defined. METHODS: In this double-blind prospective study, 150 outpatients undergoing routine colonoscopy were randomly assigned to receive either (1) low-dose midazolam (35 micrograms/kg) and pethidine (700 micrograms/kg in 48 patients, 500 micrograms/kg in 102 patients), (2) midazolam and placebo pethidine, or (3) pethidine and placebo midazolam. RESULTS: Tolerance (visual analog scale, 0 to 100 points: 0 = excellent; 100 = unbearable) did not improve significantly more in group 1 compared with group 2 (7 points; 95% confidence interval [-2-17]) and group 3 (2 points; 95% confidence interval [-7-12]). Similarly, pain was not significantly improved in group 1 as compared with the other groups. Male gender (p < 0.001) and shorter duration of the procedure (p = 0.004), but not amnesia, were associated with better patient tolerance and less pain. Patient satisfaction was similar in all groups. Oxygen desaturation and hypotension occurred in 33% and 11%, respectively, with a similar frequency in all three groups. CONCLUSIONS: In this study, the combination of low-dose midazolam and pethidine does not improve patient tolerance and lessen pain during colonoscopy as compared with either drug given alone. When applying low-dose midazolam, oxygen desaturation and hypotension do not occur more often after combined use of both drugs. For the individual patient, sedation and analgesia should be based on the endoscopist's clinical judgement.

Estimativa da capacidade de campo de Latossolos e Neossolos Quartzarênicos pela determinação do equivalente de umidade

A quantidade de água retida no solo determinada pelo equivalente de umidade (EU) aproxima-se da umidade na capacidade de campo (CC), em solos de regiões temperadas, com presença predominante de argilas de atividade alta. Nos solos característicos das regiões tropicais e úmidas, esse critério, que fixa o potencial matricial da CC em -33 kPa, deve ser alterado para potenciais maiores, da ordem de -10 a -6 kPa. O objetivo deste trabalho foi verificar a possibilidade de estimar a CC em Latossolos e Neossolos Quartzarênicos por meio da determinação do EU. Para isso, realizou-se um levantamento bibliográfico em teses defendidas na Universidade Federal de Viçosa a partir de 1968, considerando adequados os dados que incluíam classificação do solo, teor de argila, EU e CC. Foram selecionados oitenta Latossolos e oito Neossolos Quartzarênicos. Os dados analisados resultaram na equação CC = 0,081 + 0,888 EU (R² = 0,910), em que CC e EU são expressos em kg kg-1. O intercepto, diferente de zero e positivo, confirma que a CC ocorre, nestes solos, a potenciais maiores que -33 kPa.

A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins.

OBJECTIVE: To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation. DESIGN: Cohort study. SETTING: Fertility center in a university hospital. PATIENT(S): Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996. INTERVENTION(S): The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999. MAIN OUTCOME MEASURE(S): Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS). RESULT(S): The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS. CONCLUSION(S): The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Efficiency and safety of bilateral contemporaneous pallidal stimulation (deep brain stimulation) in levodopa-responsive patients with Parkinson's disease with severe motor fluctuations: a 2-year follow-up review.

OBJECT: The aim of this study was to evaluate the long-term safety and efficacy of bilateral contemporaneous deep brain stimulation (DBS) in patients who have levodopa-responsive parkinsonism with untreatable motor fluctuations. Bilateral pallidotomy carries a high risk of corticobulbar and cognitive dysfunction. Deep brain stimulation offers new alternatives with major advantages such as reversibility of effects, minimal permanent lesions, and adaptability to individual needs, changes in medication, side effects, and evolution of the disease. METHODS: Patients in whom levodopa-responsive parkinsonism with untreatable severe motor fluctuations has been clinically diagnosed underwent bilateral pallidal magnetic resonance image-guided electrode implantation while receiving a local anesthetic. Pre- and postoperative evaluations at 3-month intervals included Unified Parkinson's Disease Rating Scale (UPDRS) scoring, Hoehn and Yahr staging, 24-hour self-assessments, and neuropsychological examinations. Six patients with a mean age of 55 years (mean 42-67 years), a mean duration of disease of 15.5 years (range 12-21 years), a mean "on/off' Hoehn and Yahr stage score of 3/4.2 (range 3-5), and a mean "off' time of 40% (range 20-50%) underwent bilateral contemporaneous pallidal DBS, with a minimum follow-up period lasting 24 months (range 24-30 months). The mean dose of levodopa in these patients could not be changed significantly after the procedure and pergolide was added after 12 months in five patients because of recurring fluctuations despite adjustments in stimulation parameters. All but two patients had no fluctuations until 9 months. Two of the patients reported barely perceptible fluctuations at 12 months and two at 15 months; however, two patients remain without fluctuations at 2 years. The mean improvements in the UPDRS motor score in the off time and the activities of daily living (ADL) score were more than 50%; the mean off time decreased from 40 to 10%, and the mean dyskinesia and complication of treatment scores were reduced to one-third until pergolide was introduced at 12 months. No significant improvement in "on" scores was observed. A slight worsening after 1 year was observed and three patients developed levodopa- and stimulation-resistant gait ignition failure and minimal fluctuations at 1 year. Side effects, which were controlled by modulation of stimulation, included dysarthria, dystonia, and confusion. CONCLUSIONS: Bilateral pallidal DBS is safe and efficient in patients who have levodopa-responsive parkinsonism with severe fluctuations. Major improvements in motor score, ADL score, and off time persisted beyond 2 years after the operation, but signs of decreased efficacy started to be seen after 12 months.