Comparison of intra-luminal versus intra-tumoural temperature measurements in patients with locally advanced prostate cancer treated with the coaxial TEM system: report of a feasibility study

A study was performed on regional hyperthermia for patients with locally advanced prostate carcinoma. The primary objective was to analyse the thermometry data with an emphasis on the possibility of replacing invasive thermometry by tumour-related intra-luminal thermometry. Fourteen patients were treated with a combination of conformal external beam radiotherapy (70 Gy) and hyperthermia. Hyperthermia was delivered using the Coaxial TEM system, one treatment per week, to a total of five treatments. Thermometry was performed in bladder, urethra, rectum and esophagus. Invasive thermometry in the prostate was carried out during one or two treatments for each patient by placing transperineally a central and a peripheral catheter. Heterogeneous temperature distributions were measured in the prostate. The mean average invasive temperature range was 1.1°C. Due to the temperature heterogeneity and a limited number of thermometry sensors (mean 7, range 2-13), large variability between treatments and patients existed regarding achieved temperatures and dose. The mean invasive T 90 was 40.2 &#45 0.6°C and T 50 was 40.8 &#45 0.6°C. The mean Cum min T 90 >40.5°C per treatment was 22 (range 0-50). Importantly, intra-luminal temperatures did not reliably predict invasively measured temperatures. Invasive thermometry, therefore, remains compulsory to calculate a thermal dose for an individual patient. Changes in temperature during treatment, measured by the urethral sensors, corresponded well with changes in temperature measured by the individual invasive sensors. Similar comparison of rectal temperature changes with intra-prostatic temperature changes was not as predictive. The similarity in temperature changes between the urethral and interstial sites, suggests that urethral temperatures are sufficient for treatment optimization. The SAR profile did not correspond with the temperature profile indicating heterogeneous perfusion. Although regional hyperthermia in combination with external beam radiotherapy for locally advanced prostate carcinoma is clinically feasible, the question on the importance of invasive thermometry remains.     

Vapor condensation with daytime radiative cooling

A radiative vapor condenser sheds heat in the form of infrared radiation and cools itself to below the ambient air temperature to produce liquid water from vapor. This effect has been known for centuries, and is exploited by some insects to survive in dry deserts. Humans have also been using radiative condensation for dew collection. However, all existing radiative vapor condensers must operate during the nighttime. Here, we develop daytime radiative condensers that continue to operate 24 h a day. These daytime radiative condensers can produce water from vapor under direct sunlight, without active consumption of energy. Combined with traditional passive cooling via convection and conduction, radiative cooling can substantially increase the performance of passive vapor condensation, which can be used for passive water extraction and purification technologies.

Energy and clean water are global challenges that are intertwined in an unfavorable way: even in areas where water is abundant, energy may not be available to purify it for human use (1, 2). There has been strong interest in developing passive technologies to purify or harvest water without using fuel or electricity. In this context, passive vapor condensation becomes particularly important because many passive water technologies go through the vapor phase of water in their harvesting or purification processes.Traditional vapor condensation technique is based on convective and conductive heat exchange with ambient environments. This technique is widely used in systems with hot vapors (3–6). However, with ever-increasing emphasis on passive systems, there are many situations in which warm- or even room-temperature vapor needs to be effectively condensed, such as extracting water from atmosphere (7–9) and warm vapor generated from high-efficiency solar evaporation (10). For vapor at such temperatures, most traditional condensers fail. For this reason, there is a clear need for a condensation technique to complement traditional condensers.A different technique is based on radiative vapor condensation. Darkling beetles in the Namib desert (11) use this technique to collect water. Their bodies function as a cooling surface by shedding thermal energy through midinfrared (mid-IR) radiation toward a clear nighttime sky, generating dew from humid air. This mechanism is also used by commercial radiative dew condensers (7–9). However, neither Namib beetle nor existing dew condensers can operate in the daytime (7). Those nighttime radiative condensers are incompatible with many emerging water technologies that require 24 h operation or direct access to sunlight.Recently, Fan et al. showed that passive radiative cooling to subambient temperatures can be realized even during the daytime, by integrating a high-efficiency solar reflector with a high-emissivity thermal emitter in the mid-IR atmospheric transparency window (12). Using this work as a basis, here we demonstrate a daytime radiative condenser. Compared to existing radiative vapor condensers (7–9), our condenser can function even in the presence of sunlight, which is essential for integration into passive water-harvesting systems that mainly operate during daytime.     

Structural basis for p50RhoGAP BCH domain–mediated regulation of Rho inactivation

Spatiotemporal regulation of signaling cascades is crucial for various biological pathways, under the control of a range of scaffolding proteins. The BNIP-2 and Cdc42GAP Homology (BCH) domain is a highly conserved module that targets small GTPases and their regulators. Proteins bearing BCH domains are key for driving cell elongation, retraction, membrane protrusion, and other aspects of active morphogenesis during cell migration, myoblast differentiation, and neuritogenesis. We previously showed that the BCH domain of p50RhoGAP (ARHGAP1) sequesters RhoA from inactivation by its adjacent GAP domain; however, the underlying molecular mechanism for RhoA inactivation by p50RhoGAP remains unknown. Here, we report the crystal structure of the BCH domain of p50RhoGAP Schizosaccharomyces pombe and model the human p50RhoGAP BCH domain to understand its regulatory function using in vitro and cell line studies. We show that the BCH domain adopts an intertwined dimeric structure with asymmetric monomers and harbors a unique RhoA-binding loop and a lipid-binding pocket that anchors prenylated RhoA. Interestingly, the β5-strand of the BCH domain is involved in an intermolecular β-sheet, which is crucial for inhibition of the adjacent GAP domain. A destabilizing mutation in the β5-strand triggers the release of the GAP domain from autoinhibition. This renders p50RhoGAP active, thereby leading to RhoA inactivation and increased self-association of p50RhoGAP molecules via their BCH domains. Our results offer key insight into the concerted spatiotemporal regulation of Rho activity by BCH domain–containing proteins.

Small GTPases are molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state and are primarily involved in cytoskeletal reorganization during cell motility, morphogenesis, and cytokinesis (1, 2). These small GTPases are tightly controlled by activators and inactivators, such as guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), respectively (3, 4), which are multidomain proteins that are themselves regulated through their interactions with other proteins, lipids, secondary messengers, and/or by posttranslational modifications (5–7). Despite our understanding of the mechanisms of action of GTPases, GAPs, and GEFs, little is known about how they are further regulated by other cellular proteins in tightly controlled local environments.The BNIP-2 and Cdc42GAP Homology (BCH) domain has emerged as a highly conserved and versatile scaffold protein domain that targets small GTPases, their GEFs, and GAPs to carry out various cellular processes in a spatial, temporal, and kinetic manner (8–15). BCH domain–containing proteins are classified into a distinct functional subclass of the CRAL_TRIO/Sec14 superfamily, with ∼175 BCH domain–containing proteins (in which 14 of them are in human) present across a range of eukaryotic species (16). Some well-studied BCH domain–containing proteins include BNIP-2, BNIP-H (CAYTAXIN), BNIP-XL, BNIP-Sα, p50RhoGAP (ARHGAP1), and BPGAP1 (ARHGAP8), with evidence to show their involvement in cell elongation, retraction, membrane protrusion, and other aspects of active morphogenesis during cell migration, growth activation and suppression, myoblast differentiation, and neuritogenesis (17–21). Aside from interacting with small GTPases and their regulators, some of these proteins can also associate with other signaling proteins, such as fibroblast growth factor receptor tyrosine kinases, myogenic Cdo receptor, p38-MAP kinase, Mek2/MP1, and metabolic enzymes, such as glutaminase and ATP-citrate lyase (17–26). Despite the functional diversity and versatility of BCH domain–containing proteins, the structure of the BCH domain and its various modes of interaction remain unknown. The BCH domain resembles the Sec14 domain (from the CRAL-TRIO family) (16, 27, 28), a domain with lipid-binding characteristics, which may suggest that the BCH domain could have a similar binding strategy. However, to date, the binding and the role of lipids in BCH domain function remain inconclusive.Of the BCH domain–containing proteins, we have focused on the structure and function of p50RhoGAP. p50RhoGAP comprises an N-terminal BCH domain and a C-terminal GAP domain separated by a proline-rich region. We found that p50RhoGAP contains a noncanonical RhoA-binding motif in its BCH domain and is associated with GAP-mediated cell rounding (13). Further, we showed previously that deletion of the BCH domain dramatically enhanced the activity of the adjacent GAP domain (13); however, the full dynamics of this interaction is unclear. Previously, it has been reported that the BCH and other domains regulate GAP activity in an autoinhibited manner (18, 21, 29, 30) involving the interactions of both the BCH and GAP domains, albeit the mechanism remains to be investigated. It has also been shown that a lipid moiety on Rac1 (a Rho GTPase) is necessary for its inactivation by p50RhoGAP (29, 31), which may imply a role in lipid binding. An understanding of how the BCH domain coordinates with the GAP domain to affect the local activity of RhoA and other GTPases would offer a previously unknown insight into the multifaceted regulation of Rho GTPase inactivation.To understand the BCH domain–mediated regulation of p50RhoGAP and RhoA activities, we have determined the crystal structure of a homologous p50RhoGAP BCH domain from S. pombe for functional interrogation. We show that the BCH domain adopts an intertwined dimeric structure with asymmetric monomers and harbors a unique RhoA-interacting loop and a lipid-binding pocket. Our results show that the lipid-binding region of the BCH domain helps to anchor the prenylation tail of RhoA while the loop interacts directly with RhoA. Moreover, we show that a mutation in the β5-strand releases the autoinhibition of the GAP domain by the BCH domain. This renders the GAP domain active, leading to RhoA inactivation and the associated phenotypic effects in yeast and HeLa cells. The released BCH domain also contributes to enhanced p50RhoGAP–p50RhoGAP interaction. Our findings offer crucial insights into the regulation of Rho signaling by BCH domain–containing proteins.     

成人动脉血气分析标本采集技术的研究进展

本文在文献回顾的基础上对目前成人动脉血气分析采血部位、采血用具、穿刺方法等情况进行归纳分析,旨在为临床护士采集血气分析标本提供参考。     

A phase II study of continuous infusion recombinant human granulocyte- macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.     

北京市新农合大病保险实施效果分析与评价

目的:测算分析北京市新农合大病保险对患者疾病经济负担的减轻作用,对制度实施效果进行评价。方法:按照经济发展水平和大病保险承办方式选取北京市三个区县,再从中选择大病患者较多的2~3个乡镇。通过与大病保险管理者进行访谈,了解其运行现状;对样本乡镇全部大病患者进行问卷调查了解患者主观感受,收到有效问卷497份。利用新农合管理中心信息平台测算患者疾病经济负担。对定量和定性资料分别采用统计分析与主题框架法进行分析。结果:经大病保险报销,三个区县大病患者平均自付费用明显减轻,实际补偿比均有不同程度的提高,但灾难性卫生支出情况无显著改善。结论:应通过提高大病保险起付线与报销比例,拓宽报销目录等举措提高其补偿水平,重点缓解极重患者疾病经济负担。     

Ethnic Background,Socioeconomic Status,and Problem Severity as Dropout Risk Factors in Psychotherapy with Youth

Background

Dropout from child and adolescent psychotherapy is a common phenomenon which can have negative consequences for the individual later in life. It is therefore important to gain insight on dropout risk factors.

Objective

Several potential risk factors [ethnic minority status, a lower socioeconomic status (SES), and higher problem severity] were analyzed in present study. Innovations are that these risk factors were examined for children and adolescents separately, and a distinction was made in termination status between referred patients, dropouts and completers.

Methods

For ethnic majority and minority outpatient children (age 5–11, n = 399) and adolescents (age 12–20, n = 352) problem severity, ethnic background, SES, and treatment termination status (completer, dropout, referral) were specified. Multinomial logistic regression models were used as main method of analysis.

Results

For children, a Moroccan/Turkish ethnicity and higher externalizing scores were risk factors for being referred. For adolescents, a Surinamese/Antillean ethnicity, being female, being older, and lower parental SES occupation levels were risk factors for dropout.

Conclusions

Different dropout risk profiles emerged for children versus adolescents, and for dropouts versus referrals. Also, it depended on the specific ethnic background whether ethnic minority status was a predictor for dropout, and the relationship between SES and termination status differed by whether parental SES occupation or parental SES education were used as SES indicator. Professionals should thus be aware of these potential risk factors for dropout or referral when treating children and adolescents.

     

Liver transplantation for acute liver failure in adults

Acute liver failure is a challenging clinical condition, associated with high morbidity and mortality. In well-selected patients, LT (LT) is the only therapeutic which has been demonstrated to improve patient survival. Clichy and King's College criteria are the two mains scoring systems used to select the patients for liver transplantation. Both models achieve high specificity but remain associated with limited negative predictive value. Several other predictive factors have been evaluated, but none of them have been strongly validated so far. Globally, whole LT appears as the procedure of choice for patients within Clichy and/or King's College criteria. Due to the severity of the disease and its multisystemic consequences, the results of LT for fulminant liver failure remain inferior to those obtained in elective indications. Accord-ing to local conditions, namely expected waiting time before urgent transplantation and surgical expertise, living donor transplantation and auxiliary transplantations appear as valuable alternatives. These techniques have the respective potential advantages to limit the waiting period before transplantation and to avoid the need for lifelong immunosuppression when native liver recovers, but overall results remain inferior to those obtained with whole LT.