Intranasal fentanyl and inhaled nitrous oxide for fracture reduction: The FAN observational study.

INTRODUCTION: Procedural sedation and analgesia (PSA) are frequently used for fracture reduction in pediatric emergency departments (ED). Combining intranasal (IN) fentanyl with inhalation of nitrous oxide (N2O) allow for short recovery time and obviates painful and time-consuming IV access insertions. METHODS: We performed a bicentric, prospective, observational cohort study. Patients aged 4-18years were included if they received combined PSA with IN fentanyl and N2O for the reduction of mildly/moderately displaced fracture or of dislocation. Facial Pain Scale Revised (FPS-R) and Face, Leg, Activity, Cry, Consolability (FLACC) scores were used to evaluate pain and anxiety before, during and after procedure. University of Michigan Sedation Score (UMSS), adverse events, detailed side effects and satisfaction of patients, parents and medical staff were recorded at discharge. A follow up telephone call was made after 24-72h. RESULTS: 90 patients were included. There was no difference in FPS-R during the procedure (median score 2 versus 2), but the FLACC score was significantly higher as compared to before (median score 4 versus 0, Δ 2, 95% CI 0, 2). Median UMSS was 1 (95% CI 1, 2). We recorded no serious adverse events. Rate of vomiting was 12% (11/84). Satisfaction was high among participants responding to this question 85/88 (97%) of parents, 74/83 (89%) of patients and 82/85 (96%) of physicians would want the same sedation again. CONCLUSION: PSA with IN fentanyl and N2O is effective and safe for the reduction of mildly/moderately displaced fracture or dislocation, and has a high satisfaction rate.

[Ethical aspects of palliative medicine]. / Ethische Aspekte der Palliativmedizin.

BACKGROUND: The aim of palliative medicine is to adequately care for and attend to patients suffering from life-threatening and incurable medical conditions according to their needs. This implies that for these patients it is not a matter of dealing with diseases that can be treated separately but with their existence in the face of their approaching death. OBJECTIVE: This article investigates which ethical questions are currently prioritized for discussion in palliative medicine. METHOD: Review of the current medical and ethical literature and own reflections with a relational ethics approach that puts patient wishes at the centre of attention. RESULTS: Palliative medicine is not a "luxury medicine" but has to be considered as primary care to which every person is entitled. If there is a need for improvement of care, promoting it is an ethical obligation. In this respect the question of a "good death" is extremely complex. The term is connected to the ethics of a good life and includes the dimensions of happiness-suffering as well as meaning-futility; therefore, the best possible treatment of symptoms, most of all pain is just as important as recognizing subjective questions of meaning. Dealing with the wishes of patients, including possible wishes to die, are the starting point for elaborating palliative care measures. It is concerned with finding the right point in time for each patient individually, in their best interests and according to their wishes, at which dying should no longer be held back but for their own benefit the patient should be accompanied and supported during dying. CONCLUSION: In the current construction of palliative medicine, including its normative configuration within the law and medical ethics, the criteria which are essential for the quality of life up to death are being discussed.

Intentions in wishes to die: analysis and a typology--a report of 30 qualitative case studies of terminally ill cancer patients in palliative care.

OBJECTIVE: To investigate the variations in and intentions of wishes to die (WTD) of palliative care cancer patients. METHODS: Thirty terminally ill cancer patients, their caregivers and relatives in a hospice, an oncology palliative care ward of a general hospital, and an outpatient palliative care service. 116 semistructured qualitative interviews analyzed by a combined approach using Grounded Theory and Interpretive Phenomenological Analysis. RESULTS: A WTD is dynamic and interactive. Its subjective phenomenology can be described by three aspects: intentions, motivations, and interactions. In this article, we present a typology of the possible intentions. We identified nine different (ideal) types of intentions that WTD statements might have, other than wishing to live and accepting death. Many WTD statements do not imply a desire to hasten death. The intentions of statements differ according to whether a WTD is related to as imaginary or as an action. Often WTD statements contain several partial wishes, which can be in tension with each other and form a dynamic, sometimes unstable equilibrium. CONCLUSIONS: Terminally ill persons' WTD statements differ in their intention, and deeper knowledge about these differences is ethically relevant.

BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families.

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD).

Homologous repair deficiency (HRD) is present in many cancer types at variable prevalence and can indicate response to platinum-based chemotherapy and PARP inhibition. We developed a tumor classification system based on the loss of function of genes in the homologous recombination repair (HRR) pathway. To this end, somatic and germline alterations in BRCA1/2 and 140 other HRR genes were included and assessed for the impact on gene function. Additionally, information on the allelic hit type and on BRCA1 promoter hypermethylation was included. The HRDsum score including LOH, LST, and TAI was calculated for 8847 tumors of the TCGA cohort starting from genotyping data and for the subcohort of ovarian cancer also starting from WES data. Pan-cancer, deleterious BRCA1/2 alterations were detected in 4% of the tumors, while 18% of the tumors were HRD-positive (HRDsum ≥ 42). Across 33 cancer types, both BRCA1/2 alterations and HRD-positivity were most prevalent in ovarian cancer (20% and 69%). Pan-cancer, tumors with biallelic deleterious alterations in BRCA1/2 were separated strongly from tumors without relevant alterations (AUC = 0.89), while separation for tumors with monoallelic deleterious BRCA1/2 alterations was weak (AUC = 0.53). Tumors with biallelic deleterious alterations in other HHR genes were separated moderately from tumors without relevant alterations (AUC = 0.63), while separation for tumors with such monoallelic alterations was weaker (AUC = 0.57). In ovarian cancer, HRDsum scores calculated from WES data correlated strongly with HRDsum scores calculated from genotyping data (R = 0.87) and were slightly (4%) higher. We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

A 'nonsense' mutation leads to aberrant splicing of hMLH1 in a German hereditary non-polyposis colorectal cancer family.

Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germline mutations in at least four genes encoding integral components of the cellular DNA mismatch repair (MMR) system. The spectrum of genetic alterations encompasses missense- and nonsense mutations, intronic mutations affecting splice donor or acceptor sites as well as small-scale deletions and insertions. We have identified a 'nonsense' mutation that activates a cryptic splice site generating an in frame deletion of the last 17 codons of exon1 of the hMLH1 gene causing HNPCC in a German family. We present a comprehensive genetic analysis of this family that demonstrates important aspects of HNPCC pathogenesis.

Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin.

We have examined 35 epidermal tumors induced in mice of four different strains by chronic exposure to ultraviolet B radiation for the presence of aberrations in the p53 tumor suppressor gene. Polymerase chain reaction products from p53 exons 5 to 8 were screened by single-strand conformation polymorphism analysis and sequencing. Base substitutions were found in seven tumors (20%). All mutations occurred at dipyrimidine sequences; most frequent were C-->T single base and CC-->TT tandem transitions suggesting the involvement of UV radiation in the genesis of the mutations. Three base substitutions were located at codon 148, and all dipyrimidine-derived mutations occurred at sites where the sequence is present in the nontranscribed DNA strand, indicating some site and strand specificity of the ultraviolet B-induced p53 mutations.

[Is informed consent actually possible?]. / Ist ein informed consent wirklich möglich?

In prenatal medicine, the doctrine of informed consent is subject to several restrictions: women are confronted with social expectations to accept screening and tests that entail a pressure to decide. Some authors criticise that the informed consent overstretches the patient, dislocates responsibility to the individual, and, in many cases, is nothing but an empty ritual. The article defends the idea of informed consent. It argues that we need to reinterpret informed consent on the basis of a dialogical principle: the aim is to recognise the subjectivity and vulnerability of the patient in her special situation, which implies a mutual culture of hearing.

Age-related differences in processing visual device and task characteristics when using technical devices.

With aging visual feedback becomes increasingly relevant in action control. Consequently, visual device and task characteristics should more and more affect tool use. Focussing on late working age, the present study aims to investigate age-related differences in processing task irrelevant (display size) and task relevant visual information (task difficulty). Young and middle-aged participants (20-35 and 36-64 years of age, respectively) sat in front of a touch screen with differently sized active touch areas (4″ to 12″) and performed pointing tasks with differing task difficulties (1.8-5 bits). Both display size and age affected pointing performance, but the two variables did not interact and aiming duration moderated both effects. Furthermore, task difficulty affected the pointing durations of middle-aged adults moreso than those of young adults. Again, aiming duration accounted for the variance in the data. The onset of an age-related decline in aiming duration can be clearly located in middle adulthood. Thus, the fine psychomotor ability "aiming" is a moderator and predictor for age-related differences in pointing tasks. The results support a user-specific design for small technical devices with touch interfaces.

When norms normalize: the case of genetic "enhancement".

As the possibility of genetic intervention becomes more concrete, defining and regulating ethically permissible interventions must include a consideration of the implicit as well as explicit consequences. These include the moral implications of defining "enhancement" by reference to a standard of normality. Some authors have called into question the standard ethical concerns about genetic enhancement, but the distinction between enhancing and therapeutic interventions is still structured as relatively unproblematic. However, determining the boundary between therapy and enhancement will have feedback effects on the socially implemented definitions of what counts as normal in human embodiment. Positioning the interface between permissible and nonpermissible interventions at the same place as the boundaries between therapy and enhancement, and between normal and abnormal embodiment, (1) uses biology to justify a moral evaluation, (2) privileges the single standpoint of the genetically canonical person, and (3) enhances the dichotomy between "normal" and "not normal". Assuming that the limit of permissibility along the interventional continuum is coterminous with the definitions of enhancement and of normality, distracts from the work of uncovering the real grounds to setting limits to genetic manipulation.

7,12-Dimethylbenz[a]anthracene-induced mouse keratinocyte malignant transformation independent of Harvey ras activation.

Independent clones of mouse keratinocytes initiated in vitro gave rise to tumor phenotypes typical of mouse skin multistage carcinogenesis and histologically similar to human tumors of the skin, and head and neck. High-molecular-weight genomic DNAs isolated from two 7,12-dimethylbenz[a]anthracene (DMBA)-initiated murine epithelial carcinoma cell lines and one papilloma cell line were examined for transforming activity by transfection into NIH3T3 cells. DNAs from each of these cell lines resulted in the formation of foci morphologically unlike foci containing an activated c-Ha-ras oncogene. Following polymerase chain reaction amplification of the c-Ha-ras gene, Xba I restriction analysis and oligonucleotide differential hybridization did not detect 61st, 12th, or 13th codon mutations. Southern and Northern analysis confirmed that the normal c-Ha-ras gene was not activated by amplification or overexpression. These results provide evidence that 7,12-dimethylbenz[a]anthracene-induced malignant transformation of murine keratinocytes occurred independent of point mutations associated with c-Ha-ras activation. The absence of an activated c-Ha-ras oncogene in these cell lines distinguishes our model from other mouse models of carcinogenesis and may provide a model for functional genetic changes during initiation and progression of human epithelial cancers.

Sampling technique influences the detection of K-ras mutations in normal appearing mucosa of colorectal cancer patients.

Based on three colorectal cancer cell lines with specified K-ras status, a sensitive PCR-RFLP assay was established detecting one K-ras mutant among 106 wild-type cells. Using this assay for tissues of 124 colorectal cancer patients, 59 tumor (46%) and 11 mucosa samples (9%) were found to harbor a K-ras mutation. When using the same scalpel for collecting tumor and mucosa tissues (group A), 18% of the patients had a matching K-ras mutation in both tissues, but this coincidence was seen in 3% of patients only, when separate scalpels were used (group B). Thus we conclude that the sampling technique used for collecting specimens is a major contributor to the detection of K-ras mutations in normal appearing mucosa when a highly sensitive detection technique is used.

The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)--results of an international collaborative study.

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2-5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

Magnetic splitting of valence states in ferromagnetic and antiferromagnetic lanthanide metals

The magnetic splitting of Delta(2) valence states in the heavy lanthanide metals Gd, Tb, Dy, and Ho was studied in epitaxial films by angle-resolved photoemission, revealing an essentially Stoner-like temperature dependence in all cases. It scales linearly with the 4f spin moment, even in the case of the helical antiferromagnet Ho. Such a behavior can be explained by a substantial localization of the corresponding wave function in the c direction. The helical magnetic structure was confirmed for the thin Ho films by in situ resonant magnetic x-ray diffraction.

Comprehensive genetic counseling for families at risk for HNPCC: impact on distress and perceptions.

The aim of the study was to explore distress and health beliefs before and after comprehensive interdisciplinary counseling in families at risk for hereditary non-polyposis colorectal cancer (HNPCC). Results reported here were derived from a consecutive sample of 65 counselees [31 patients with colorectal cancer (CRC) and 34 unaffected at-risk persons] who participated in interdisciplinary counseling provided by human geneticists, surgeons, and psycho-oncologists before genetic testing. Data were collected from self-administered questionnaires before, as well as 4-6 weeks after, counseling. Distress and perceptions specific to HNPCC were assessed at both timepoints using standardized as well as author-derived instruments. Distress declined after counseling, as did worries related to HNPCC. An increase was found in personal belief in control of cancer risk, for instance, in the perceived efficacy of early detection of CRC. We also observed a trend toward greater anticipated ability to cope with a positive gene test after counseling. Changes after counseling were generally more pronounced for persons at risk, as compared to patients with cancer. The decrease in distress was partly attributable to an increase in personal self-confidence. One-third of the sample reported enhanced communication specific to hereditary disease within the family after counseling. A substantial minority, however, said they experienced increased worry and physical symptoms after counseling. Overall, counselees demonstrated less stress and perceived cancer threat as well as enhanced beliefs regarding personal control over cancer, suggesting an overall beneficial impact of comprehensive counseling. Further research is needed to identify those individuals most at risk for increased fear and worry related to HNPCC so that they may be most appropriately counseled.

Differential diagnosis of malignant tumours in the abdominal cavity of rats after intraperitoneal injection of crocidolite or benzo[a]pyrene.

In our investigation (i.p. test), crocidolite and benzo[a]pyrene, both caused a progression from initially reactive, then autonomously transformed proliferation of myofibroblasts and undifferentiated mesenchymal cells to malignant, multidirectionally differentiated (desmin and ED-1 positive) fibro-histiocytic tumours. Immunohistochemically these tumours showed no morphological characteristics (for example co-expression of vimentin and keratin in spindle-shaped tumour cells) of human asbestos-associated malignant mesotheliomas. On the other hand many tumour cells induced by crocidolite and benzo[a]pyrene had an ultrastructural appearance resembling fibroblasts and myofibroblasts. These have been demonstrated in only a few desmoplastic and sarcomatous mesotheliomas in human beings. None of the tumours revealed the typical ultrastructural features of epitheloid or transitional mesotheliomas. Apparently, both carcinogenic substances induce the transformation of undifferentiated pluripotent mesenchymal cells in rat peritoneum, regardless of their localization in the submesothelial compartment or perivascular connective tissue (preferentially after crocidolite application) or in the connective tissue pseudocapsule of major benzo[a]pyrene containing beeswax/tricaprylin depots in the mesometrium and mesenterial fatty tissue. In this way asbestos fibres in this animal experiment do not seem to induce an arrest in differentiation of intermediate or immature mesothelial cells as supposed formerly, but rather affect undifferentiated mesenchyme cells and myofibroblasts. This is an explanation for the immunohistochemical expression of markers of muscular differentiation in these tumour cells, which is known to occur in human malignant fibro-histiocytic tumours. If supplementary immunohistochemical investigations with different keratin antibodies also fail to confirm the mesothelial differentiation of the tumours induced in our i.p. test, the decision to call them "mesotheliomas" should be reconsidered. Further immuno-transmission-electron microscopical investigations with intermediate filament or macrophage antibodies are needed to clarify whether the term malignant "fibrohistiocytic sarcoma", "mesenchymoma" or "mesothelioblastoma" would be more correct from the morphological point of view.

Vaginal birth after cesarean.

Recent studies prompted by the high cesarean birth rates have looked at the issue of vaginal birth after cesarean. The risk of attempting a vaginal birth after cesarean appears to be minimal for selected clients. As more and more obstetricians begin to offer vaginal birth after cesarean to their patients, nurses will need to be fully informed about this option. A review of the pertinent literature relating to vaginal birth after cesarean and nursing implications are presented.

Importance of the lateral view in the evaluation of suspected brain death.

The authors present two cases of clinical brain death that failed to meet the criteria for whole brain death using Tc-99m HMPAO. Conventional anterior cerebral flow studies demonstrated no intracerebral perfusion. Anterior static images also failed to show cerebral activity. However, the lateral images clearly demonstrate cerebellar activity. These cases demonstrate the importance of Tc-99m HMPAO as the agent of choice in evaluating brain death and the necessity of lateral views to meet the criteria for whole brain death. Cerebellar perfusion challenges the present criteria for whole brain death. New criteria must re-evaluate the present technology.

[Retrobulbar optic neuropathy and non-Hodgkin lymphoma]. / Neuropathie optique rétrobulbaire et lymphome malin non hodgkinien.

INTRODUCTION: Non-Hodgkin lymphomas (NHLs) constitute a group of heterogeneous diseases that can arise in lymphatic nodal or extranodal sites. Ocular lymphomas account for 1% of all NHLs. Tumor of the orbit, which can lead to compression of the optic nerve, is the most frequent presentation of the disease. Primary infiltration of the optic nerve and its sheath remains exceptional. OBSERVATION: We report the case of a 51-year-old female patient treated for a NHL. While she was considered to be in remission after four courses of chemotherapy, she presented a right visual loss with hand motion acuity. Her examination revealed a right afferent pupillary defect. Brain MRI emphasized an infiltration of her right optic nerve with no other orbit abnormality. Cerebrospinal fluid analysis showed lymphomatous meningitis. She was then considered to have lymphomatous optic neuropathy (LON). Despite initial improvement of the visual acuity with treatment, the patient died of bone marrow aplasia 6 weeks later. CONCLUSION: LON can be suspected in a painful and sudden visual loss in a context of neoplasia. The diagnosis is confirmed by MRI and cerebrospinal fluid analysis. LON may occur as the sole ocular manifestation of disease recurrence in a patient with systemic NHL, otherwise thought to be in clinical remission.

Practice and carryover effects when using small interaction devices.

The use of interaction devices in modern work often challenges the human motor system, especially when these devices introduce unfamiliar transformations to the user. In this paper we evaluated expert performance and skill differences between experts and novices when using small motion- and force-controlled interaction devices (touchpad and mini-joystick) in an applied text-editing task. Firstly, experts performed better with their familiar input device than with an unfamiliar one. Particularly touchpad experts operating the unfamiliar mini-joystick showed highly asymmetric carryover costs. Results showed that the efficient performance of experts depended on domain-specific skills, which were not transferable. Secondly, with considerable practice (more than observed for simple and short tasks) novices were brought up to higher levels of performance. The motion-transformation between hand and cursor action was easier in understanding and application than the force-transformation. Thus, the touchpad was used more efficiently than the mini-joystick. In conclusion, practice effects found so far are considerably underestimated when it comes to an applied task. The results give reason to develop and implement skill-sensitive training procedures, since the acquisition of domain-specific skills is critical for expert performance. As a consequence, training procedures might be essential for complex applications and/or unfamiliar device transformations.