All-cause and cause-specific mortality following non-traumatic spinal cord injury: evidence from a population-based cohort study in Switzerland.

STUDY DESIGN: Observational cohort study. OBJECTIVE: To benchmark all-cause and cause-specific mortality following NTSCI to the general population (GP). SETTING: Specialized rehabilitation centers in Switzerland. METHODS: Longitudinal data from the Swiss Spinal Cord Injury (SwiSCI) Medical Record study were probabilistically linked with cause of death (CoD) information from the Swiss National Cohort. Standardized mortality ratios (SMRs) were estimated for all-cause and cause-specific mortality. Competing risk frameworks were used to estimate the probability of death due to specific CoD. RESULTS: One thousand five hundred and one individuals were admitted for first rehabilitation with NTSCI between 1990-2011; CoD information was available for 454 individuals of the 525 individuals that died. Overall, the mortality rate for persons with NTSCI was 1.6 times greater than that of the GP. Deaths due to cardiovascular disease (39.8%), neoplasms (22%), and infection (9.9%) were most often reported. Individuals with an SCI due to a vascular etiology indicated the greatest burden of mortality from infection compared with the GP (SMR 5.4; 95% CI, 3.1 to 9.2). CONCLUSIONS: Cause-specific SMRs varied according to etiology. This supports the need for targeted clinical care and follow-up. Cardiovascular disease, neoplasms, and infection, emerged as main causes of death following NTSCI and should thus be targets for future research and differential clinical management approaches.

Survival after non-traumatic spinal cord injury: evidence from a population-based rehabilitation cohort in Switzerland.

STUDY DESIGN: Observational cohort study. OBJECTIVE: To investigate survival and life expectancy after NTSCI in Switzerland according to etiology. SETTING: Specialized rehabilitation centers in Switzerland. METHODS: Longitudinal data from the Swiss Spinal Cord Injury (SwiSCI) medical records study were used. Adjusted hazard ratios (HRs) and life expectancies were estimated using flexible parametric survival modeling. RESULTS: One thousand four hundred and fifty individuals were admitted to first rehabilitation for NTSCI between 1990 and 2011, contributing 6137 cumulative person-years at risk and 528 deaths. With reference to persons with a degenerative disc disorder, the HR for mortality in individuals with NTSCIs from infections was 1.42 (95% CI 0.99-2.04), while risk in those with NTSCIs from vascular disorders was 1.28 (95% CI 0.97-1.68). Mortality risk was most pronounced in individuals with NTSCIs from malignant neoplasms (HR 6.32, 95% CI 4.79-8.34). Exemplified for males with an attained age of 60 years, a malignant etiology was associated with 1.7 life years remaining (LYR), as compared to 10.1 LYR for non-malignant etiologies. Males with an attained age of 60 years and a degenerative disc etiology were estimated to have 12.9 LYR. CONCLUSIONS: This study contributes an evidence base for risk factors of mortality after NTSCI, reducing a considerable knowledge gap in survival after NTSCI. Survival and life expectancy estimates were highly differential between etiological groups, indicating a need for a heterogeneous clinical approach and dynamic health-care provisions for this growing population.

Differences between Parkinson's and Huntington's diseases and their role for prioritization of stem cell-based treatments.

The problems of allocation of scarce resources and priority setting in health care have so far not been much studied in the context of stem cell-based therapeutic applications. If and when competitive cost effective stem cell-based therapies are available, the problem of priority setting - to whom should stem cellbased therapies be offered and on what grounds - is discussed in this article using the examples of Parkinson's Disease (PD) and Huntington's Disease (HD). The aim of this paper is to examine the presently known differences between PD and HD and analyze the role of these differences for setting priorities of stem cell-based therapeutic applications to treat these diseases. To achieve this aim, we (1) present the theoretical framework used in the analysis; (2) compare PD and HD in terms of health related and non-health related consequences of these diseases for patients, their relatives and third parties; (3) analyze the ethical relevance of observed differences for priority setting given different values and variables; (4) compare PD and HD in terms of social justice related consequences of stem cell-based therapies; and (5) analyze the ethical relevance of these differences for priority setting given different values and variables. We argue that the steps of analysis applied in this paper could be helpful when setting priorities among treatments of other diseases with similar differences as those between PD and HD.

MR imaging findings in flexed abducted supinated (FABS) position and clinical presentation following refixation of distal biceps tendon rupture using bioabsorbable suture anchors.

PURPOSE: To correlate MRI findings after suture anchor repair of distal biceps tendons with symptoms. MATERIALS AND METHODS: 24 men with 25 distal biceps tendon ruptures (one bilateral) treated with suture anchor repair were retrospectively included. Follow-up after a mean of 31 months (range, 12-74) included clinical examination and MRI. The pain level and flexion strength compared to the uninvolved arm were recorded. MRI was performed at 1.5 T obtaining FABS position images (both elbows in 7 patients) and evaluated for artifacts, signal abnormalities, and rerupture by two experienced readers in consensus and blinded to symptoms. Pain and loss of flexion strength>20% were tested against MRI findings as dichotomous data using Fisher's exact chi-square tests (p<0.05). Crosssectional areas of operated and uninvolved tendons were measured and evaluated with the Wilcoxon signed rank test (p<0.05). RESULTS: FABS views enabled good evaluation in 96% of tendons. Rerupture was present in 3 of 25 elbows. Tendinous signal increase was seen in 59% of intact tendons. We found activity-related pain or pain at rest in 32% and a loss of flexion strength in 27 % of these cases. Testing revealed no significant correlation for any of the MRI features with any of the clinical parameters (p>0.05). There was a 2.7-fold mean increase of the tendon cross-sectional area on the repaired side compared to the uninvolved contralateral tendon (p=0.02). CONCLUSION: We found good MRI visualization of postoperative tendons, but no correlation between symptoms and MRI signal abnormalities or rerupture. The increase in caliber of the repaired tendon might promote an impingement in pronation.

Non-equivalent stringency of ethical review in the Baltic States: a sign of a systematic problem in Europe?

We analyse the system of ethical review of human research in the Baltic States by introducing the principle of equivalent stringency of ethical review, that is, research projects imposing equal risks and inconveniences on research participants should be subjected to equally stringent review procedures. We examine several examples of non-equivalence or asymmetry in the system of ethical review of human research: (1) the asymmetry between rather strict regulations of clinical drug trials and relatively weaker regulations of other types of clinical biomedical research and (2) gaps in ethical review in the area of non-biomedical human research where some sensitive research projects are not reviewed by research ethics committees at all. We conclude that non-equivalent stringency of ethical review is at least partly linked to the differences in scope and binding character of various international legal instruments that have been shaping the system of ethical review in the Baltic States. Therefore, the Baltic example could also serve as an object lesson to other European countries which might be experiencing similar problems.

Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide.

BACKGROUND: Exhaled nitric oxide (FENO) is a marker for allergic airway inflammation. We wondered whether in patients with intermittent allergic rhinitis only (i) natural pollen exposure and (ii) artificial pollen exposure by repeated nasal allergen provocations may lead to an elevation of FENO. METHODS: In two prospective studies, we compared the FENO of nonatopic controls with the FENO of nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. Study I: 13 atopic individuals and seven controls had measurements of FENO, blood eosinophils and eosinophilic cationic protein (ECP) before, during and after pollen season. Study II: 16 atopic individuals and 12 controls had nasal allergen provocations on four following days out of pollen season, with daily measurements of FENO before, 2 and 6 h after provocation, and determination of blood eosinophils, ECP and FEV1 at baseline, on days 5 and 10-12. RESULTS: Natural pollen exposure (study I) caused a significant elevation of FENO in allergic individuals. Nasal allergen provocations (study II) did not elicit a statistically significant rise neither of FENO nor of blood eosinophils between baseline and day 5. However, a subgroup of four individuals with a rise of blood eosinophils during nasal allergen provocations showed also a rise of FENO. CONCLUSIONS: We suppose that in allergic rhinitis a concomitant reaction of the bronchial system is dependent on a strong local inflammation leading to a generalized immune stimulation.

Scratch-patch and patch testing in drug allergy--an assessment of specificity.

BACKGROUND: Adverse drug reactions occur frequently in daily practice, but the identification of the eliciting drugs is difficult due to a lack of standardized procedures. The aim of this study was to evaluate and compare scratch-patch and patch tests prospectively with frequently used drugs in persons exposed or not exposed to the drug in order to define a nonirritating concentration. MATERIALS AND METHODS: Altogether, 23 different drugs, mainly antibiotics and analgesics, were evaluated. Any contraindications for patch tests were excluded by a questionnaire. Sixty-one healthy individuals were tested. They were divided into two groups: Group 1 consisted of individuals who hadn't been exposed to the drug; Group 2 was comprised of individuals who had been exposed to the drug, without side effects. Each individual was tested with 10-20 scratch-patch and patch tests. The tests were performed on the upper back. Freshly prepared drug solutions were applied, on one side after scarification of the epidermis, on the other side without. Scratch-patch tests were read at 24 and 48 h, patch tests after 48 and 72 h. In addition, we included 73 individuals with a drug allergy to illustrate that the chosen drug concentrations are able to elicit a positive reaction in truly sensitized individuals. RESULTS: A positive reaction in the non-exposed and nonallergic individuals was considered to be an irritant reaction (IR). In Group 1 (non-exposed individuals), 341 scratch-patch tests were performed, with 22 showing a reaction at the first reading, 3 at the second. Of the 341 patch tests performed in this group, 21 reactions were observed at the first reading, and 7 at the second. In Group 2 (exposed individuals), 141 scratch-patch tests were performed, with 5 IR at the first reading and 1 at the second. Of the 138 patch tests performed in this group, 6 individuals showed an IR at the first, 2 at the second reading. The majority of IR were four drugs, namely cefuroxim, acetylsalicylic acid, propyphenazone/drofenin-HCl, and celecoxib. Lowering the concentration did not reduce the unspecified irritant skin reaction, while a change of the solvent (petrolatum instead of PBS) did reduce the IR. CONCLUSIONS: Our data show concentrations of 23 drugs suitable for scratch-patch or patch tests, as they do not elicit IR. Fourteen of these test preparations elicited a positive reaction in truly sensitized individuals, demonstrating that the test preparation is suitable to identify sensitized persons. Scratch-patch tests are an interesting alternative to patch tests, as they do not elicit more IR than patch tests but can be evaluated earlier. Certain drugs solved in PBS are irritant over a wide dosage range and need to be applied in petrolatum.

Late stent thrombosis in the absence of prior intracoronary brachytherapy.

Late stent thrombosis has not been reported in the absence of prior coronary brachytherapy. We reviewed our experience in 1,855 consecutive patients who received at least one stent and did not receive coronary brachytherapy. Half of all stent thromboses occurred within the first week and nearly 65% (22) occurred within 15 days. The incidence of stent thrombosis within this traditional time frame was 1.2%. An additional 12 patients, however, presented with stent thrombosis between 33 and 270 days post-procedure (mean = 72.9 +/- 23 days). The true incidence of stent thrombosis was therefore 1.8% (34/1,855). There were three bypass operations, one stroke and two deaths in the late stent thrombosis group. Late stent thrombosis is an unusual but serious complication in patients who have not received coronary brachytherapy. Intracoronary radiation may potentiate a phenomenon that already occurs after stent deployment. Prolonged treatment (6-12 months) with anti-platelet agents should be considered after percutaneous intervention with coronary stents.

[Vaginal delivery after two previous cesarean sections]. / Vaginale Entbindung bei Zustand nach zweimaliger Sectio caesarea.

We report on a patient, who, after two previous caesarean sections, normally delivered vaginally without complications. The obstetric approach to, or better, the management of a vaginal delivery after caesarean section, our experience in other vaginal deliveries after previous caesarean section is discussed. This case report shows that, after two previous caesarean sections, the next child can normally be delivered vaginally without complications.

Precise mapping of t(12;14) leiomyoma breakpoint on chromosome 14 between D14S298 and D14S540.

Uterine leiomyoma is a common tumor of smooth muscle cell origin often characterized by the presence of a balanced t(12;14)(q13-15;q24.1) chromosomal translocation. This breakpoint on chromosome 14 had previously been placed between the markers SPTB and D14S77, a region estimated to span 7 cM. In this study we have used a meiotic breakpoint mapping panel to construct a high resolution genetic map of this interval. Markers that mapped within this interval were used to analyze DNA from a somatic cell hybrid containing the t(12;14) translocated chromosome. The results of this analysis localize the t(12;14) breakpoint on chromosome 14 between D14S298 and D14S540, between which no meiotic recombination was detected. This sets the stage for identifying the gene(s) disrupted by the chromosomal translocation by defining the markers that flank the translocation breakpoint.

Mice from a genetically resistant background lacking the interferon gamma receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response.

Mice with homologous disruption of the gene coding for the ligand-binding chain of the interferon (IFN) gamma receptor and derived from a strain genetically resistant to infection with Leishmania major have been used to study further the role of this cytokine in the differentiation of functional CD4+ T cell subsets in vivo and resistance to infection. Wild-type 129/Sv/Ev mice are resistant to infection with this parasite, developing only small lesions, which resolve spontaneously within 6 wk. In contrast, mice lacking the IFN-gamma receptor develop large, progressing lesions. After infection, lymph nodes (LN) and spleens from both wild-type and knockout mice showed an expansion of CD4+ cells producing IFN-gamma as revealed by measuring IFN-gamma in supernatants of specifically stimulated CD4+ T cells, by enumerating IFN-gamma-producing T cells, and by Northern blot analysis of IFN-gamma transcripts. No biologically active interleukin (IL) 4 was detected in supernatants of in vitro-stimulated LN or spleen cells from infected wild-type or deficient mice. Reverse transcription polymerase chain reaction analysis with primers specific for IL-4 showed similar IL-4 message levels in LN from both types of mice. The IL-4 message levels observed were comparable to those found in similarly infected C57BL/6 mice and significantly lower than the levels found in BALB/c mice. Anti-IFN-gamma treatment of both types of mice failed to alter the pattern of cytokines produced after infection. These data show that even in the absence of IFN-gamma receptors, T helper cell (Th) 1-type responses still develop in genetically resistant mice with no evidence for the expansion of Th2 cells.

Physical mapping of the uterine leiomyoma t(12;14)(q13-15;q24.1) breakpoint on chromosome 14 between SPTB and D14S77.

Uterine leiomyoma is the most common tumor of smooth muscle cell origin and is often associated with the recurrent balanced translocation t(12;14)(q13-15;q24). As an initial step toward finding the gene or genes that are interrupted by the translocation breakpoint, a somatic cell hybrid carrying the derivative 14 as the single t(12;14) translocated chromosome was constructed from a leiomyoma cell line with this translocation. Sequence tagged sites (STS) whose locations on the genetic map of chromosome 14 were known were used to map the breakpoint in the translocated chromosomes. The results of this analysis place the translocation breakpoint on the long arm of chromosome 14 between the proximal marker SPTB and the distal marker D14S77, narrowing the chromosomal translocation breakpoint to a region of approximately 7 cM. The identification of flanking markers on chromosome 14 lays the foundation for efforts to clone the breakpoint and to identify the genes involved in the formation of leiomyoma.

Domain-specific reasoning: social contracts, cheating, and perspective change.

What counts as human rationality: reasoning processes that embody content-independent formal theories, such as propositional logic, or reasoning processes that are well designed for solving important adaptive problems? Most theories of human reasoning have been based on content-independent formal rationality, whereas adaptive reasoning, ecological or evolutionary, has been little explored. We elaborate and test an evolutionary approach. Cosmides' (1989) social contract theory, using the Wason selection task. In the first part, we disentangle the theoretical concept of a "social contract" from that of a "cheater-detection algorithm". We demonstrate that the fact that a rule is perceived as a social contract--or a conditional permission or obligation, as Cheng and Holyoak (1985) proposed--is not sufficient to elicit Cosmides' striking results, which we replicated. The crucial issue is not semantic (the meaning of the rule), but pragmatic: whether a person is cued into the perspective of a party who can be cheated. In the second part, we distinguish between social contracts with bilateral and unilateral cheating options. Perspective change in contracts with bilateral cheating options turns P & not-Q responses into not-P & Q responses. The results strongly support social contract theory, contradict availability theory, and cannot be accounted for by pragmatic reasoning schema theory, which lacks the pragmatic concepts of perspectives and cheating detection.

Inhibition of phospholipase A2 by heparin.

Phospholipase A2 (PLA2) is an important enzyme in the regulation of cell behavior. The hydrolysis of phosphatidylcholine in vitro catalyzed by porcine pancreatic PLA2 was inhibited by heparin. Other glycosaminoglycans inhibited PLA2 activity to a significantly lesser extent, with a pattern of inhibition: heparin much greater than chondroitin sulfate (CS)-C greater than CS-A greater than CS-B greater than keratan sulfate. Hyaluronic acid and heparan sulfate caused no inhibition. Heparin's ability to inhibit PLA2 activity did not depend on substrate concentration, but did depend on ionic strength, with inhibition decreasing with increasing ionic strength. Heparin inhibition also varied with pH, being more effective at pH 5-8 than at pH 10. As a consequence, heparin induced a shift of the pH optimum of PLA2 from 7 to 8. Histone IIA and protamine sulfate, heparin-binding proteins, reversed heparin-induced PLA2 inhibition. The concentration of heparin which inhibited PLA2 activity by 50% increased with increasing enzyme concentration. Furthermore, PLA2 bound to heparin-Affigel. The data indicate that the catalytic potential of PLA2 can be regulated by heparin or heparin-like molecules and that inhibition is contingent on the formation of a heparin-PLA2 complex.

Importance of L3T4+ and Lyt-2+ cells in the immunologic control of infection with Mycobacterium bovis strain bacillus Calmette-Guérin in mice. Assessment by elimination of T cell subsets in vivo.

The course of infection after injection of small doses of bacillus Calmette-Guérin (BCG) was studied in mice which were depleted in vivo of T cell subsets by administration of either anti-L3T4 or anti-Lyt-2 mAb. The results presented herein strongly suggest that the L3T4+ subpopulation play a pivotal role in the immunologic control of BCG infection because the depletion of L3T4+ cells led to a dramatic increase in the number of viable bacteria. Depletion of Lyt-2+ cells had no significant effect on the course of infection. These results were confirmed by using adoptive transfer experiments which showed that protective immunity was mediated by L3T4+ cells generated in the spleen as a result of infection. Moreover, T cells capable of controlling the recurrence of BCG multiplication from residual bacteria remaining in organs after the recovery from infection were shown to belong to the L3T4+ subpopulation.

Murine T lymphocyte specificity for African trypanosomes. II. Suppression of the T lymphocyte proliferative response to Trypanosoma brucei by systemic trypanosome infection.

Previously, we described a system allowing the study of murine T cell-dependent proliferative responses to Trypanosoma brucei antigens. It was observed that T. brucei-specific T cells could be demonstrated in the regional lymph nodes of primed mice for only 2 to 3 weeks following priming. The results of the present study indicate that this inability to demonstrate a long-lived memory response is due to an immunosuppressive effect of the resulting T. brucei infection. The exact mechanism of the suppression is not known, and appears to function in the absence of demonstrable suppressor cells. Since the T cell responses are strictly dependent on the presence of macrophages, we have investigated whether the loss in responsiveness is due to a defect in the T cell population, or to a loss of macrophage function. Our results show that T cells taken from mice 3 weeks after priming with T. brucei are unable to mount a proliferative response in the presence of a normal macrophage population, and conversely that macrophages taken 3 weeks after infection with T. brucei are unable to elicit a normal proliferative response using a competent primed T cell population. Thus these results indicate that both populations are affected by the parasite infection.

Murine T lymphocyte specificity for African trypanosomes. I. Induction of a T lymphocyte-dependent proliferative response to Trypanosoma brucei.

A procedure which results in the specific activation of primed murine T lymphocytes was adapted for the study of T lymphocyte activation by the African trypanosome: Trypanosoma brucei. The assay calls for the in vivo priming of lymphocytes by the subcutaneous administration of parasites, followed by the co-cultivation in vitro of cells taken from the regional draining lymph nodes and the parasite. This co-cultivation results in a marked proliferation of lymphoid cells. The proliferation was shown to be specific for the parasite, and to be dependent on the presence of T lymphocytes and macrophages. Both the in vivo priming and the in vitro activation were shown to require the presence of living parasites. Various factors influencing the magnitude of the proliferative response were analysed. Of special interest is the observation that the time interval between in vivo priming and in vitro culture which results in a substantial proliferative response is quite short when compared to that seen with other antigens. Although lymph node cells from mice primed with T. brucei 1 to 2 weeks previously are able to mount a secondary proliferative response upon stimulation with T. brucei, cells taken 3 weeks after priming are unresponsive to an in vitro challenge with T. brucei. This unresponsiveness may be a result of the generalized immunosuppression seen in African trypanosomiasis. Thus, this method offers the potential for the study of specific T cell responsiveness in African trypanosome infections.

Immunoglobulin D as a lymphocyte receptor.

A large proportion of the human peripheral blood lymphocytes of adults and newborns having IgD were found also to have IgM on their membranes and vice versa. A few lymphocytes had one of these classes only. IgD and IgM could be capped independently on the same cell. The possibility that IgD was acquired by a cytophilic process was excluded by the finding that IgD-bearing cells were of one light chain type only, and by the direct demonstration of reappearance of IgD on the lymphocyte membrane during incubation in an IgD-free culture medium. On the basis of these findings, it is proposed that IgD functions as a lymphocyte antigen receptor.