Association between Inappropriate End-of-Life Cancer Care and Specialist Palliative Care: A Retrospective Observational Study in Two Acute Care Hospitals.

A substantial number of patients with life-threatening illnesses like cancer receive inappropriate end-of-life care. Improving their quality of end-of-life care is a priority for patients and their families and for public health. To investigate the association between provision, timing, and initial setting of hospital-based specialist palliative care and potentially inappropriate end-of-life care for patients with cancer in two acute care hospitals in the Netherlands, we conducted a retrospective observational study using hospital administrative databases. All adults diagnosed with or treated for cancer in the year preceding their death in 2018 or 2019 were included. The main exposure was hospital-based specialist palliative care initiated >30 days before death. The outcome measures in the last 30 days of life were six quality indicators for inappropriate end-of-life care (≥2 ED-visits, ≥2 hospital admissions, >14 days hospitalization, ICU-admission, chemotherapy, hospital death). We identified 2603 deceased patients, of whom 14% (n = 359) received specialist palliative care >30 days before death (exposure group). Overall, 27% (n = 690) received potentially inappropriate end-of-life care: 19% in the exposure group, versus 28% in the non-exposure group (p < 0.001). The exposure group was 45% less likely to receive potentially inappropriate end-of-life care (AOR 0.55; 95% CI 0.41 to 0.73). Early (>90 days) and late (≤90 and >30 days) initiation of specialist palliative care, as well as outpatient and inpatient initiation, were all associated with less potentially inappropriate end-of-life care (AOR 0.49; 0.62; 0.32; 0.64, respectively). Thus, timely access to hospital-based specialist palliative care is associated with less potentially inappropriate end-of-life care for patients with cancer. The outpatient initiation of specialist palliative care seems to enhance this result.

Linking human Dead end 1 (DND1) variants to male infertility employing zebrafish embryos.

STUDY QUESTION: Is the vertebrate protein Dead end (DND1) a causative factor for human infertility and can novel in vivo assays in zebrafish help in evaluating this? SUMMARY ANSWER: Combining patient genetic data with functional in vivo assays in zebrafish reveals a possible role for DND1 in human male fertility. WHAT IS KNOWN ALREADY: About 7% of the male population is affected by infertility but linking specific gene variants to the disease is challenging. The function of the DND1 protein was shown to be critical for germ cell development in several model organisms but a reliable and cost-effective method for evaluating the activity of the protein in the context of human male infertility is still missing. STUDY DESIGN, SIZE, DURATION: Exome data from 1305 men included in the Male Reproductive Genomics cohort were examined in this study. A total of 1114 of the patients showed severely impaired spermatogenesis but were otherwise healthy. Eighty-five men with intact spermatogenesis were included in the study as controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: We screened the human exome data for rare, stop-gain, frameshift, splice site, as well as missense variants in DND1. The results were validated by Sanger sequencing. Immunohistochemical techniques and, when possible, segregation analyses were performed for patients with identified DND1 variants. The amino acid exchange in the human variant was mimicked at the corresponding site of the zebrafish protein. Using different aspects of germline development in live zebrafish embryos as biological assays, we examined the activity level of these DND1 protein variants. MAIN RESULTS AND THE ROLE OF CHANCE: In human exome sequencing data, we identified four heterozygous variants in DND1 (three missense and one frameshift variant) in five unrelated patients. The function of all of the variants was examined in the zebrafish and one of those was studied in more depth in this model. We demonstrate the use of zebrafish assays as a rapid and effective biological readout for evaluating the possible impact of multiple gene variants on male fertility. This in vivo approach allowed us to assess the direct impact of the variants on germ cell function in the context of the native germline. Focusing on the DND1 gene, we find that zebrafish germ cells, expressing orthologs of DND1 variants identified in infertile men, failed to arrive correctly at the position where the gonad develops and exhibited defects in cell fate maintenance. Importantly, our analysis facilitated the evaluation of single nucleotide variants, whose impact on protein function is difficult to predict, and allowed us to distinguish variants that do not affect the protein's activity from those that strongly reduce it and could thus potentially be the primary cause for the pathological condition. These aberrations in germline development resemble the testicular phenotype of azoospermic patients. LIMITATIONS, REASONS FOR CAUTION: The pipeline we present requires access to zebrafish embryos and to basic imaging equipment. The notion that the activity of the protein in the zebrafish-based assays is relevant for the human homolog is well supported by previous knowledge. Nevertheless, the human protein may differ in some respects from its homologue in zebrafish. Thus, the assay should be considered only one of the parameters used in defining DND1 variants as causative or non-causative for infertility. WIDER IMPLICATIONS OF THE FINDINGS: Using DND1 as an example, we have shown that the approach described in this study, relying on bridging between clinical findings and fundamental cell biology, can help to establish links between novel human disease candidate genes and fertility. In particular, the power of the approach we developed is manifested by the fact that it allows the identification of DND1 variants that arose de novo. The strategy presented here can be applied to different genes in other disease contexts. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the German Research Foundation, Clinical Research Unit, CRU326 'Male Germ Cells'. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Evaluating quality of care at the end of life and setting best practice performance standards: a population-based observational study using linked routinely collected administrative databases.

BACKGROUND: A high percentage of people dying at home, and a low percentage of people being admitted to hospital and dying there are regarded as indicators of appropriate care at the end of life. However, performance standards for these quality indicators are often lacking, which makes it difficult to state whether an indicator score falls between the ranges of good or poor quality care. The aim of this study was to assess quality indicators concerning place of death and hospital care utilization in people with diseases relevant for palliative care, and to establish best practice performance standards based on indicator scores in 31 regions in the Netherlands. METHODS: A retrospective nationwide population-based observational study was conducted, using routinely collected administrative data concerning persons who died in 2017 in the Netherlands with underlying causes relevant for palliative care (N = 109,707). Data from four registries were linked for analysis. Scores on eight quality indicators concerning place of death and hospital care utilization were calculated, and compared across 31 healthcare insurance regions to establish relative benchmarks. RESULTS: On average, 36.4% of the study population died at home (range between regions 30.5%-42.6%) and 20.4% in hospital (range 16.6%-25.5%). Roughly half of the population who received hospital care at any time in the last year of life were found to (also) receive hospital care in the last month of life. In the last month, 32.0% of the study population were admitted to hospital (range 29.4-36.4%), 5.3% to an Intensive Care Unit (range 3.2-6.9%) and 23.9% visited an Emergency Department (range 21.0-27.4%). In the same time period, less than 1% of the study population was resuscitated in hospital or received tube or intravenous feeding in hospital. CONCLUSIONS: The variation between regions points towards opportunities for practice improvement. The best practice performance standards as set in this study serve as ambitious but attainable targets for those regions that currently do not meet the standards. Policymakers, healthcare providers and researchers can use the suggested performance standards to further analyze causes of variance between regions and develop and test interventions that can improve practice.

Development of a national quality framework for palliative care in a mixed generalist and specialist care model: A whole-sector approach and a modified Delphi technique.

In a predominantly biomedical healthcare model focused on cure, providing optimal, person-centred palliative care is challenging. The general public, patients, and healthcare professionals are often unaware of palliative care's benefits. Poor interdisciplinary teamwork and limited communication combined with a lack of early identification of patients with palliative care needs contribute to sub-optimal palliative care provision. We aimed to develop a national quality framework to improve availability and access to high-quality palliative care in a mixed generalist-specialist palliative care model. We hypothesised that a whole-sector approach and a modified Delphi technique would be suitable to reach this aim. Analogous to the international AGREE guideline criteria and employing a whole-sector approach, an expert panel comprising mandated representatives for patients and their families, various healthcare associations, and health insurers answered the main question: 'What are the elements defining high-quality palliative care in the Netherlands?'. For constructing the quality framework, a bottleneck analysis of palliative care provision and a literature review were conducted. Six core documents were used in a modified Delphi technique to build the framework with the expert panel, while stakeholder organisations were involved and informed in round-table discussions. In the entire process, preparing and building relationships took one year and surveying, convening, discussing content, consulting peers, and obtaining final consent from all stakeholders took 18 months. A quality framework, including a glossary of terms, endorsed by organisations representing patients and their families, general practitioners, elderly care physicians, medical specialists, nurses, social workers, psychologists, spiritual caregivers, and health insurers was developed and annexed with a summary for patients and families. We successfully developed a national consensus-based patient-centred quality framework for high-quality palliative care in a mixed generalist-specialist palliative care model. A whole-sector approach and a modified Delphi technique are feasible structures to achieve this aim. The process we reported may guide other countries in their initiatives to enhance palliative care.

Inappropriate end-of-life cancer care in a generalist and specialist palliative care model: a nationwide retrospective population-based observational study.

OBJECTIVES: To evaluate the impact of provision and timing of palliative care (PC) on potentially inappropriate end-of-life care to patients with cancer in a mixed generalist-specialist PC model. METHOD: A retrospective population-based observational study using a national administrative health insurance database. All 43 067 adults in the Netherlands, who were diagnosed with or treated for cancer during the year preceding their death in 2017, were included. Main exposure was either generalist or specialist PC initiated >30 days before death (n=16 967). Outcomes were measured over the last 30 days of life, using quality indicators for potentially inappropriate end-of-life care. RESULTS: In total, 14 504 patients (34%) experienced potentially inappropriate end-of-life care; 2732 were provided with PC >30 days before death (exposure group) and 11 772 received no PC or ≤30 days before death (non-exposure group) (16% vs 45%, p<0.001). Most patients received generalist PC (88%). Patients provided with PC >30 days before death were 5 times less likely to experience potentially inappropriate end-of-life care (adjusted OR (AOR) 0.20; (95% CI 0.15 to 0.26)) than those with no PC or PC in the last 30 days. Both early (>90 days) and late (>30 and≤90 days) PC initiation had lower odds for potentially inappropriate end-of-life care (AOR 0.23 and 0.19, respectively). CONCLUSION: Timely access to PC in a mixed generalist-specialist PC model significantly decreases the likelihood of potentially inappropriate end-of-life care for patients with cancer. Generalist PC can play a substantial role.

Variant PNLDC1, Defective piRNA Processing, and Azoospermia.

BACKGROUND: P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are short (21 to 35 nucleotides in length) and noncoding and are found almost exclusively in germ cells, where they regulate aberrant expression of transposable elements and postmeiotic gene expression. Critical to the processing of piRNAs is the protein poly(A)-specific RNase-like domain containing 1 (PNLDC1), which trims their 3' ends and, when disrupted in mice, causes azoospermia and male infertility. METHODS: We performed exome sequencing on DNA samples from 924 men who had received a diagnosis of nonobstructive azoospermia. Testicular-biopsy samples were analyzed by means of histologic and immunohistochemical tests, in situ hybridization, reverse-transcriptase-quantitative-polymerase-chain-reaction assay, and small-RNA sequencing. RESULTS: Four unrelated men of Middle Eastern descent who had nonobstructive azoospermia were found to carry mutations in PNLDC1: the first patient had a biallelic stop-gain mutation, p.R452Ter (rs200629089; minor allele frequency, 0.00004); the second, a novel biallelic missense variant, p.P84S; the third, two compound heterozygous mutations consisting of p.M259T (rs141903829; minor allele frequency, 0.0007) and p.L35PfsTer3 (rs754159168; minor allele frequency, 0.00004); and the fourth, a novel biallelic canonical splice acceptor site variant, c.607-2A→T. Testicular histologic findings consistently showed error-prone meiosis and spermatogenic arrest with round spermatids of type Sa as the most advanced population of germ cells. Gene and protein expression of PNLDC1, as well as the piRNA-processing proteins PIWIL1, PIWIL4, MYBL1, and TDRKH, were greatly diminished in cells of the testes. Furthermore, the length distribution of piRNAs and the number of pachytene piRNAs was significantly altered in men carrying PNLDC1 mutations. CONCLUSIONS: Our results suggest a direct mechanistic effect of faulty piRNA processing on meiosis and spermatogenesis in men, ultimately leading to male infertility. (Funded by Innovation Fund Denmark and others.).

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility.

Mutations affecting the germline can result in infertility or the generation of germ cell tumors (GCT), highlighting the need to identify and characterize the genes controlling germ cell development. The RNA-binding protein and E3 ubiquitin ligase TRIM71 is essential for embryogenesis, and its expression has been reported in GCT and adult mouse testes. To investigate the role of TRIM71 in mammalian germ cell embryonic development, we generated a germline-specific conditional Trim71 knockout mouse (cKO) using the early primordial germ cell (PGC) marker Nanos3 as a Cre-recombinase driver. cKO mice are infertile, with male mice displaying a Sertoli cell-only (SCO) phenotype which in humans is defined as a specific subtype of non-obstructive azoospermia characterized by the absence of germ cells in the seminiferous tubules. Infertility in male Trim71 cKO mice originates during embryogenesis, as the SCO phenotype was already apparent in neonatal mice. The in vitro differentiation of mouse embryonic stem cells (ESCs) into PGC-like cells (PGCLCs) revealed reduced numbers of PGCLCs in Trim71-deficient cells. Furthermore, TCam-2 cells, a human GCT-derived seminoma cell line which was used as an in vitro model for PGCs, showed proliferation defects upon TRIM71 knockdown. Additionally, in vitro growth competition assays, as well as proliferation assays with wild type and CRISPR/Cas9-generated TRIM71 mutant NCCIT cells showed that TRIM71 also promotes proliferation in this malignant GCT-derived non-seminoma cell line. Importantly, the PGC-specific markers BLIMP1 and NANOS3 were consistently downregulated in Trim71 KO PGCLCs, TRIM71 knockdown TCam-2 cells and TRIM71 mutant NCCIT cells. These data collectively support a role for TRIM71 in PGC development. Last, via exome sequencing analysis, we identified several TRIM71 variants in a cohort of infertile men, including a loss-of-function variant in a patient with an SCO phenotype. Altogether, our work reveals for the first time an association of TRIM71 deficiency with human male infertility, and uncovers further developmental roles for TRIM71 in the germline during mouse embryogenesis.

Olanzapine Versus Haloperidol for Treatment of Delirium in Patients with Advanced Cancer: A Phase III Randomized Clinical Trial.

BACKGROUND: Treatment of delirium often includes haloperidol. Second-generation antipsychotics like olanzapine have emerged as an alternative with possibly fewer side effects. The aim of this multicenter, phase III, randomized clinical trial was to compare the efficacy and tolerability of olanzapine with haloperidol for the treatment of delirium in hospitalized patients with advanced cancer. MATERIALS AND METHODS: Eligible adult patients (≥18 years) with advanced cancer and delirium (Delirium Rating Scale-Revised-98 [DRS-R-98] total score ≥17.75) were randomized 1:1 to receive either haloperidol or olanzapine (age-adjusted, titratable doses). Primary endpoint was delirium response rate (DRR), defined as number of patients with DRS-R-98 severity score <15.25 and ≥4.5 points reduction. Secondary endpoints included time to response (TTR), tolerability, and delirium-related distress. RESULTS: Between January 2011 and June 2016, 98 patients were included in the intention-to-treat analysis. DRR was 45% (95% confidence interval [CI], 31-59) for olanzapine and 57% (95% CI, 43-71) for haloperidol (Δ DRR -12%; odds ratio [OR], 0.61; 95% CI, 0.2-1.4; p = .23). Mean TTR was 4.5 days (95% CI, 3.2-5.9 days) for olanzapine and 2.8 days (95% CI, 1.9-3.7 days; p = .18) for haloperidol. Grade ≥3 treatment-related adverse events occurred in 5 patients (10.2%) and 10 patients (20.4%) in the olanzapine and haloperidol arm, respectively. Distress rates were similar in both groups. The study was terminated early because of futility. CONCLUSION: Delirium treatment with olanzapine in hospitalized patients with advanced cancer did not result in improvement of DRR or TTR compared with haloperidol. Clinical trial identification number. NCT01539733. Dutch Trial Register. NTR2559. IMPLICATIONS FOR PRACTICE: Guidelines recommend that pharmacological interventions for delirium treatment in adults with cancer should be limited to patients who have distressing delirium symptoms. It was suggested that atypical antipsychotics, such as olanzapine, outperform haloperidol in efficacy and safety. However, collective data comparing the efficacy and safety of typical versus atypical antipsychotics in patients with cancer are limited. If targeted and judicious use of antipsychotics is considered for the treatment of delirium in patients with advanced cancer, this study demonstrated that there was no statistically significant difference in response to haloperidol or olanzapine. Olanzapine showed an overall better safety profile compared with haloperidol, although this difference was not statistically significant.

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series.

RESEARCH QUESTION: Congenital bilateral absence of vas deferens (CBAVD) is characterized by 'obstructive azoospermia' in male patients with primary infertility. In the routine clinical workup of infertile men, patients with an absence of vas deferens are screened for CFTR variants. However, current genetic testing panels do not cover all variants, missing some CBAVD cases. Here, CFTR testing was explored by targeted next-generation sequencing (NGS) to improve variant detection. DESIGN: Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup. RESULTS: Cases 1, 2 and 3 presented with CBAVD after which CFTR screening by mutation panel analysis was negative. Case 4 presented with congenital unilateral absence of vas deferens, after which CFTR panel analysis identified a heterozygous p.(Phe508del) variant. Case 5 presented with a palpable vas deferens so CFTR panel analysis was not offered. In all five men, targeted NGS revealed additional pathogenic variants: p.(Arg117Cys) and p.(Arg1158*) (case 1); p.(Asp110His) and p.(Ser945Leu) (case 2); p.(Arg248Thr) and p.(Phe508Cys) (case 3); p.(Gly463Ser) (case 4); p.(Phe508del) (case 4 and 5); and p.(Arg117His) (case 5). CONCLUSIONS: Targeted NGS led to the detection of five infertile men with CFTR variants who would otherwise have remained undiagnosed after routine genetic screening during the fertility workup for azoospermia or severe oligozoospermia. Given the wide availability of affordable targeted NGS, the data suggest that full gene analysis, and not mutation panels, should be considered to screen CFTR in azoospermic men.

Accuracy of the Delirium Observational Screening Scale (DOS) as a screening tool for delirium in patients with advanced cancer.

BACKGROUND: The Delirium Observation Screening Scale (DOS) was developed to facilitate early recognition of delirium by nurses during routine clinical care. It has shown good validity in a variety of patient populations, but has not yet been validated in hospitalized patients with advanced cancer, although the DOS is commonly used in this setting in daily practice. The aim of this study was to evaluate the accuracy of the DOS in hospitalized patients with advanced cancer using the revised version of the Delirium Rating Scale (DRS-R- 98) as the gold standard. METHODS: Patients with advanced cancer admitted to the medical oncology ward were screened for delirium with the DOS and DRS-R-98. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of the DOS were calculated, using a DOS score ≥ 3 as a cut-off for delirium. RESULTS: Ninety-five DOS negative and 98 DOS positive patients were identified. Sensitivity of the DOS, was > 99.9% (95%-CI, 95.8-100.0%), specificity was 99.5% (95%-CI 95.5-99.96%), PPV was 94.6% (95% CI 88.0-97.7), and NPV was > 99.9% (95% CI 96.1-100.0). CONCLUSIONS: The DOS is an accurate screening tool for delirium in patients with advanced cancer. Since it has the benefit of being easily implicated in daily practice, we recommend to educate caregivers to screen patients with advanced cancer by DOS analysis. By early recognition and adequate treatment of this distressing delirium syndrome the quality of life of patients with advanced cancer can be improved. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01539733 (Feb 27, 2012 - retrospectively registered), Netherlands Trial Register NTR2559 (Oct 7, 2010).

Effectiveness of Conservative, Surgical, and Postsurgical Interventions for Trigger Finger, Dupuytren Disease, and De Quervain Disease: A Systematic Review.

OBJECTIVES: To provide an evidence-based overview of the effectiveness of conservative and (post)surgical interventions for trigger finger, Dupuytren disease, and De Quervain disease. DATA SOURCES: Cochrane Library, Physiotherapy Evidence Database, PubMed, Embase, and CINAHL were searched to identify relevant systematic reviews and randomized controlled trials (RCTs). DATA SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results. Two reviews (trigger finger and De Quervain disease) and 37 randomized controlled trials (RCTs) (trigger finger: n=8; Dupuytren disease: n=14, and De Quervain disease: n=15) were included. The trials reported on oral medication (Dupuytren disease), physiotherapy (De Quervain disease), injections and surgical treatment (trigger finger, Dupuytren disease, and De Quervain disease), and other conservative (De Qervain disease) and postsurgical treatment (Dupuytren disease). Moderate evidence was found for the effect of corticosteroid injection on the very short term for trigger finger, De Quervain disease, and for injections with collagenase (30d) when looking at all joints, and no evidence was found when looking at the PIP joint for Dupuytren disease. A thumb splint as additive to a corticosteroid injection seems to be effective (moderate evidence) for De Quervain disease (short term and midterm). For Dupuytren disease, use of a corticosteroid injection within a percutaneous needle aponeurotomy in the midterm and tamoxifen versus a placebo before or after a fasciectomy seems to promising (moderate evidence). We also found moderate evidence for splinting after Dupuytren surgery in the short term. CONCLUSIONS: In recent years, more and more RCTs have been conducted to study treatment of the aforementioned hand disorders. However, more high-quality RCTs are still needed to further stimulate evidence-based practice for patients with trigger finger, Dupuytren disease, and De Quervain disease.

Effectiveness of Surgical and Postsurgical Interventions for Carpal Tunnel Syndrome-A Systematic Review.

OBJECTIVE: To present an evidence-based overview of the effectiveness of surgical and postsurgical interventions for carpal tunnel syndrome (CTS). DATA SOURCES: The Cochrane Library, PubMed, EMBASE, CINAHL, and PEDro were searched for relevant systematic reviews and randomized controlled trials (RCTs) up to April 8, 2016. STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results. Four systematic reviews and 33 RCTs were included. Surgery versus nonsurgical interventions, timing of surgery, and various surgical techniques and postoperative interventions were studied. Corticosteroid injection was more effective than surgery (strong evidence, short-term). Surgery was more effective than splinting or anti-inflammatory drugs plus hand therapy (moderate evidence, midterm and long-term). Manual therapy was more effective than surgical treatment (moderate evidence, short-term and midterm). Within surgery, corticosteroid irrigation of the median nerve before skin closure as additive to CTS release or the direct vision plus tunneling technique was more effective than standard open CTS release (moderate evidence, short-term). Furthermore, short was more effective than long bulky dressings, and a sensory retraining program was more effective than no program after surgery (moderate evidence, short-term). For all other interventions only conflicting, limited, or no evidence was found. CONCLUSIONS: Surgical treatment seems to be more effective than splinting or anti-inflammatory drugs plus hand therapy in the short-term, midterm, and/or long-term to treat CTS. However there is strong evidence that a local corticosteroid injection is more effective than surgery in the short-term, and moderate evidence that manual therapy is more effective than surgery in the short-term and midterm. There is no unequivocal evidence that suggests one surgical treatment is more effective than the other. Postsurgical, a short- (2-3 days) favored a long-duration (9-14 days) bulky dressing and a sensory retraining program seems to be more effective than no program in short-term. More research regarding the optimal timing of surgery for CTS is needed.

[Gliomas: fighting until the end against epilepsy; administration of antiepileptic drugs in the end-of-life phase]. / Gliomen: tot het einde in de aanval tegen epilepsie; toediening anti-epileptica in de laatste levensfase.

In patients with high-grade glioma seizures occur relatively frequently during the end-of-life phase. At some point, the use of oral anti-epileptic drugs is no longer possible due to swallowing difficulties caused by advanced tumour progression. We have established a draft guideline and propose that anti-epileptic drugs be prescribed by alternative routes of administration in the end-of-life phase in glioma patients with known epilepsy who develop swallowing difficulties. Buccal clonazepam would be our drug of first choice as a maintenance treatment in addition to intranasal midazolam for the acute management of seizures. Adequate treatment of epileptic seizures, particularly during the end-of-life phase, can help to maintain quality of life as long as possible in patients with high-grade glioma.

Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL.

Bcl-2 homologues (such as Bcl-x(L)) promote survival in part through sequestration of "activator" BH3-only proteins (such as Puma), preventing them from directly activating Bax. It is thus assumed that inhibition of interactions between activators and Bcl-x(L) is a prerequisite for small molecules to antagonize Bcl-x(L) and induce cell death. The biological properties, described here of a terphenyl-based alpha-helical peptidomimetic inhibitor of Bcl-x(L) attest that displacement of Bax from Bcl-x(L) is also critical. Terphenyl 14 triggers Bax-dependent but Puma-independent cell death, disrupting Bax/Bcl-x(L) interactions without affecting Puma/Bcl-x(L) interactions. In cell-free assays, binding of inactive Bax to Bcl-x(L), followed by its displacement from Bcl-x(L) by terphenyl 14, produces mitochondrially permeabilizing Bax molecules. Moreover, the peptidomimetic kills yeast cells that express Bax and Bcl-x(L), and it uses Bax-binding Bcl-x(L) to induce mammalian cell death. Likewise, ectopic expression of Bax in yeast and mammalian cells enhances sensitivity to another Bcl-x(L) inhibitor, ABT-737, when Bcl-x(L) is present. Thus, the interaction of Bcl-x(L) with Bax paradoxically primes Bax at the same time it keeps Bax activity in check, and displacement of Bax from Bcl-x(L) triggers an apoptotic signal by itself. This mechanism might contribute to the clinical efficiency of Bcl-x(L) inhibitors.

Carpal tunnel syndrome. Part II: effectiveness of surgical treatments--a systematic review.

OBJECTIVE: To present an evidence-based overview of the effectiveness of surgical and postsurgical interventions to treat carpal tunnel syndrome (CTS). DATA SOURCES: The Cochrane Library, PubMed, EMBASE, CINAHL, and PEDro were searched for relevant systematic reviews and randomized controlled trials (RCTs). STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results of the included studies. Two reviews and 25 RCTs were included. Moderate evidence was found in favor of surgical treatment compared with splinting or anti-inflammatory drugs plus hand therapy in the midterm and long term, and for the effectiveness of corticosteroid irrigation of the median nerve before skin closure as additive to carpal tunnel release in the short term. Limited evidence was found in favor of a double-incision technique compared with the standard incision technique. Also, limited evidence was found in favor of a mini-open technique assisted by a Knifelight instrument compared with a standard open release at 19 months of follow-up. However, in the short term and at 30 months of follow-up, no significant differences were found between the mini-open technique assisted by a Knifelight instrument compared with a standard open release. Many studies compared different surgical interventions, but no evidence was found in favor of any one of them. No RCTs explored the optimal timing strategy for surgery. No evidence was found for the efficacy of various presurgical or postsurgical treatment programs, including splinting. CONCLUSIONS: Surgical treatment seems to be more effective than splinting or anti-inflammatory drugs plus hand therapy in the midterm and long term to treat CTS. However, there is no unequivocal evidence that suggests one surgical treatment is more effective than the other. More research is needed to study conservative to surgical treatment in which also should be taken into account the optimal timing of surgery. Future research should also concentrate on optimal presurgical and postsurgical treatment programs.

Effectiveness of interventions of specific complaints of the arm, neck, and/or shoulder: 3 musculoskeletal disorders of the hand. An update.

OBJECTIVES: To provide an evidence-based overview of the effectiveness of conservative and surgical interventions for trigger finger, Dupuytren's, and De Quervain's diseases. DATA SOURCES: The Cochrane Library, PEDro, PubMed, Embase, and CINAHL were searched to identify relevant studies. STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential relevant studies from the title and abstracts of the references retrieved by the literature search. Relevant (Cochrane) reviews and randomized controlled trials (RCTs) were included. DATA EXTRACTION: Two reviewers independently extracted the data and performed a methodologic quality assessment. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results of the included trials. One Cochrane review (trigger finger) and 13 RCTs (trigger finger [6], Dupuytren's [4], De Quervain's [3]) were included. The trials reported on physiotherapy (De Quervain's), steroid injections (trigger finger, De Quervain's), surgical treatment (trigger finger, De Quervain's), and a postsurgical treatment (Dupuytren's). For trigger finger, moderate evidence was found for the effectiveness of steroid injections in the short-term (1-4 wk) but not for long-term outcomes. Limited evidence was found for the effectiveness of staples compared with sutures in skin closure and for intermittent compression after surgery to treat Dupuytren's disease. For other interventions, no evidence was found. CONCLUSIONS: Indications for effectiveness of some interventions for trigger finger, Dupuytren's, and De Quervain's diseases were found. Because only a few RCTs were identified, it is difficult to draw firm conclusions. High-quality RCTs are clearly needed in this field.

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax.

The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins. Antibodies directed against TOM22 or an antisense knockdown of the expression of TOM22 specifically inhibited the association of Bax with mitochondria and prevented Bax-dependent apoptosis. In yeast, a haploid strain for TOM22 exhibited a decreased expression of TOM22 and mitochondrial association of ectopically expressed human Bax. Our data provide a new perspective on the mechanism of association of Bax with mitochondria as it involves a classical import pathway.

On our way to targeted therapy for cachexia in cancer?

PURPOSE OF REVIEW: Cachexia, the occurrence of involuntary weight loss due to loss of adipose tissue and skeletal muscle mass, is among the most common and devastating symptoms in patients with advanced cancer. It is a significant factor contributing to the poor performance status and high mortality rate of these patients, and is a distressing problem for both patients and their families. Despite extensive research in an attempt to better understand the mechanisms involved, progress in the management of cancer cachexia has been slow. RECENT FINDINGS: The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumour-derived factors are known to play a significant role, thereby representing suitable therapeutic targets. Moreover, recent advances in the field of molecular biology have shed light on other mediators involved in the mechanisms leading to muscle wasting, thus increasing potential targets for new therapies. SUMMARY: This review will focus on recent findings in relation to the molecular pathways leading to muscle wasting that have improved our current understanding of cachexia and will direct the future management of cachexia in cancer towards targeted therapies.

Role of cardiolipin on tBid and tBid/Bax synergistic effects on yeast mitochondria.

The apoptotic effector Bid regulates cell death at the level of mitochondria. Under its native state, Bid is a soluble cytosolic protein that undergoes proteolysis and yields a 15 kDa-activated form tBid (truncated Bid). tBid translocates to mitochondria and participates in cytochrome c efflux by a still unclear mechanism, some of them at least mediated by Bax. Using mitochondria isolated from wild-type and cardiolipin (CL)-synthase-less yeast strains, we observed that tBid perturbs mitochondrial bioenergetics by inhibiting state-3 respiration and ATP synthesis and that this effect was strictly dependent on the presence of CL. In a second set of experiments, heterologous coexpression of tBid and Bax in wild-type and CL-less yeast strains showed that (i) tBid binding and the subsequent alteration of mitochondrial bioenergetics increased Bax-induced cytochrome c release and (ii) the absence of CL favors Bax effects independently of the presence of t-Bid. These data support recent views suggesting a dual function of CL in mitochondria-dependent apoptosis.

tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak.

TNFR1/Fas engagement results in the cleavage of cytosolic Bid to truncated Bid (tBid), which translocates to mitochondria. We demonstrate that recombinant tBid induces in vitro immediate destabilization of the mitochondrial bioenergetic homeostasis. These alterations result in mild uncoupling of mitochondrial state-4 respiration, associated with an inhibition the adenosine diphosphate (ADP)-stimulated respiration and phosphorylation rate. tBid disruption of mitochondrial homeostasis was inhibited in mitochondria overexpressing Bcl-2 and Bcl-XL. The inhibition of state-3 respiration is mediated by the reorganization of cardiolipin within the mitochondrial membranes, which indirectly affects the activity of the ADP/ATP translocator. Cardiolipin-deficient yeast mitochondria did not exhibit any respiratory inhibition by tBid, proving the absolute requirement for cardiolipin for tBid binding and activity. In contrast, the wild-type yeast mitochondria underwent a similar inhibition of ADP-stimulated respiration associated with reduced ATP synthesis. These events suggest that mitochondrial lipids rather than proteins are the key determinants of tBid-induced destabilization of mitochondrial bioenergetics.