Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma

High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m2 melphalan (MEL200), 127 patients with 140 mg/m2 melphalan plus total body irradiation (MEL140 + TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P = 0.003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26-68] compared with 43% (CI 31-54) for MEL140 + TBI and 37% (CI: 18-56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 + TBI groups respectively. These differences were non-significant (P = 0.2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 + TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P = 0.01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.     

Downregulation of antigen-presenting cell functions after administration of mitogenic anti-CD3 monoclonal antibodies in mice

Antibodies against CD3epsilon are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomodulatory properties by inducing T-cell deletion and/or inactivation, their precise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3epsilon antibodies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration process was followed by selective loss of splenic DC, which resulted in a selective inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from anti-CD3epsilon-treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to antigen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3epsilon treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation. APC dysfunction was not observed when nonmitogenic forms of anti-CD3epsilon antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3epsilon monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3epsilon-induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3epsilon antibodies downregulate immune responses.     

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A–induced neuronal growth. VEGF-B–induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B–deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury.Nerves can be damaged either through trauma or disease. Nerves from the peripheral nervous system (PNS) have significantly greater capacity to regenerate and reinnervate their original targets after injury, compared with nerves from the CNS. The successful regeneration of PNS neurons requires a number of intrinsic and extrinsic factors, as well as a permissive microenvironment for axonal regrowth (1). Among the numerous growth factors able to induce nerve regeneration, the family of VEGFs has been implicated as a potent mediator of developmental neurogenesis and adult nerve regeneration (2–4). VEGF-A is a well-characterized and potent angiogenic factor but is also a strong inducer of nerve growth. Several studies have demonstrated that both VEGF-A and -B are expressed during peripheral nerve injury (2, 5). In the setting of injury, VEGF-B plays a role in cell survival, nerve protection, and growth (5, 6). The survival effect of VEGF-B on brain cortical neurons, retinal neurons, and motor neurons in the spinal cord is indicative of its pleiotropic role (5). VEGF-B treatment reduced stroke volume in a middle cerebral artery ligation model and increased survival of retinal ganglion cells in an optic nerve crush injury model (7), and VEGF-B knockout mice suffered severe strokes and exacerbated retinal ganglion cell death in both injury models (7–9). VEGF-B has also been used with promising results in Parkinson’s disease (10) and amyotrophic lateral sclerosis models (11).Given the ability of VEGF-B to regulate both vascular endothelial cells (angiogenesis) as well as axonal growth and survival after injury, it is unclear whether VEGF-B exerts its effects on nerve regeneration through the increase in blood supply or through direct effects on nerve tissue. Indeed, specific studies on its role on peripheral neurons independent of its vascular role are lacking. We have previously reported that VEGF-A can stimulate trigeminal neuronal cell growth and enhance cornea nerve regeneration, resulting in anatomical and functional recovery of peripheral injured nerves independently of its angiogenic effects (12). Here we studied the neuro-regenerative potential of VEGF-B in an avascular model of peripheral nerve injury in mice and the signaling elements involved in the induction of nerve growth. Our results demonstrated tha (i) peripheral nerve regeneration is impaired in mice lacking VEGF-B, (ii) VEGF-B can restore the anatomic and function innervation of target tissues by induction of nerve growth and nerve regeneration, (iii) the effects of VEGF-B are specific for injured nerves and are independent of any vascular effect, and (iv) the effects of VEGF-B on nerve regeneration are distinct from those observed for VEGF-A.     

Chronic fatigue syndrome and personality: A case-control study using the alternative five factor model

Neuroticism is the personality dimension most frequently associated with chronic fatigue syndrome (CFS). Most studies have also shown that CFS patients are less extraverted than non-CFS patients, but results have been inconsistent, possibly because the facets of the extraversion dimension have not been separately analyzed. This study has the following aims: to assess the personality profile of adults with CFS using the Alternative Five-Factor Model (AFFM), which considers Activity and Sociability as two separate factors of Extraversion, and to test the discriminant validity of a measure of the AFFM, the Zuckerman–Kuhlman Personality Questionnaire, in differentiating CFS subjects from normal-range matched controls. The CFS sample consisted of 132 consecutive patients referred for persistent fatigue or pain to the Department of Medicine of a university hospital. These were compared with 132 matched normal population controls. Significantly lower levels of Activity and significantly higher levels of Neuroticism-Anxiety best discriminated CFS patients from controls. The results are consistent with existing data on the relationship between Neuroticism and CFS, and clarify the relationship between Extraversion and CFS by providing new data on the relationship of Activity to CFS.     

Effects of isometric training on the knee extensor moment–angle relationship and vastus lateralis muscle architecture

Purpose

To analyse the muscle adaptations induced by two protocols of isometric training performed at different muscle lengths.

Methods

Twenty-eight subjects were divided into three groups: one (K90) performed isometric training of the knee extensors at long muscle lengths (90° of knee flexion) for 8 weeks, and the second group (K50) at short muscle lengths (50°). The subjects of the third group acted as controls. Isokinetic dynamometry was utilized to analyse the net moment–angle relationship and vastus lateralis muscle thickness at three different locations, and pennation angles and fascicle length at 50 % of thigh length were measured at rest with ultrasonography.

Results

Only subjects from K90 group showed significant increases in isokinetic strength (23.5 %, P < 0.001), while K50 group showed no increases in isokinetic strength: (10 %, P > 0.05). There was a shift in the angle of peak torque of the K90 group to longer muscle lengths (+14.6 %, P = 0.002) with greater increases in isokinetic strength, while the K50 angle shifted to shorter muscle lengths (?7.3 %, P = 0.039). Both training groups showed significant increases in muscle thickness, (K90 9–14 % vs. K50 5–9 %) but only K90 significantly increased their pennation angles (11.7 %, P = 0.038). Fascicle lengths remained unchanged.

Conclusions

Isometric training at specific knee angles led to significant shifts of peak torque in the direction of the training muscle lengths. The greater strength gains and the architectural changes with training at long muscle lengths probably come from a combination of different factors, such as the different mechanical stresses placed upon the muscle–tendon complex.     

Maternal–Fetal Interactions Focus: Toward an understanding of allogeneic conflict in pregnancy and transplantation

Pregnancy is recognized as a spontaneously acquired state of immunological tolerance by the mother to her semi-allogeneic fetus, but it is a major cause of allosensitization in candidates for organ transplantation. This sensitization, assessed by the presence of anti-HLA IgG, contributes to sex disparity in access to transplantation and increases the risk for rejection and graft loss. Understanding this dual tolerance/sensitization conundrum may lead to new strategies for equalizing access to transplantation among sexes and improving transplant outcomes in parous women. Here, we review the clinical evidence that pregnancy results in humoral sensitization and query whether T cell responses are sensitized. Furthermore, we summarize preclinical evidence on the effects of pregnancy on fetus-specific CD4⁺ conventional, regulatory, and CD8⁺ T cells, and humoral responses. We end with a discussion on the impact of the divergent effects that pregnancy has upon alloantigen re-encounter in the context of solid organ transplantation, and how these insights point to a therapeutic roadmap for controlling pregnancy-dependent allosensitization.

IntroductionThe fact that multiple successive pregnancies with the same male partner can be brought to term successfully suggests that the immunological response to a semi-allogeneic fetus is diametrically opposite to the responses elicited by genetically comparable transplanted organs. Peter Medawar in 1953 (Medawar, 1953) discussed this “immunological paradox of pregnancy,” and since then, there have been extensive investigations into how the fetus avoids rejection. A plethora of immune regulatory mechanisms has been uncovered within the uterine environment, including enrichment in regulatory T cells (Tregs), natural killer cells, regulatory macrophages, entrapment of APCs, and chemokine gene silencing of decidual stromal cells (PrabhuDas et al., 2015). Systemic factors that prevent fetal rejection have also been identified, including immune modulation by pregnancy-related hormones and release of tolerogenic placental debris, which may contribute to the preferential systemic expansion of fetus-specific Tregs and acquired dysfunction by conventional T cells (Tconvs) and CD8⁺ T cells. Since the majority of these mechanisms either act locally or only during pregnancy, it was assumed that T cell tolerance would manifest itself only in the context of subsequent pregnancy, and that encounter with the same alloantigens in the context of a solid organ transplant, in the absence of local or systemic pregnancy-induced immunomodulation, would trigger allograft rejection.The emphasis on T cells as the major mediator of allograft rejection and on T cell tolerance as a means to achieve transplantation tolerance parallels the focus on the constraint of T cells in pregnancy. Thus, despite studies in the 1980s by Bell and Billington (Bell and Billington, 1981; Bell and Billington, 1983; Bell and Billington, 1986) that pregnancy can elicit paternal-reactive antibodies, how pregnancy sensitizes B cell responses while maintaining T cell tolerance to the semi-allogeneic fetus has remained an under-investigated topic in preclinical models (PrabhuDas et al., 2015). In contrast and driven by the ease in quantifying HLA-specific antibodies but difficulty in assessing HLA-specific T cell responses, clinical studies in solid organ transplantation have revealed that pregnancy is a highly sensitizing event that results in the production of fetus-reactive anti-HLA antibodies, and the presence of these antibodies limits access to transplantation and contributes to increased risk of transplant rejection. In this review, we focus on the contrasting effects of pregnancy on these two arms of the adaptive immune system, and on how these pregnancy-shaped responses are recalled by alloantigens that are shared between offspring and transplanted allograft.Clinical impact of pregnancy alloimmunization in organ transplantationHumoral sensitizationThe effect of pregnancy on the immune system was first reported by J.J. Rodd in 1959 when he described peripartum women experiencing an increased number of blood transfusion reactions (Van Rood et al., 1958). It was this observation that allowed for the discovery of anti-HLA antibodies from the sera of pregnant women (Van Rood et al., 1958). Anti-HLA antibodies are produced during the first trimester of a pregnancy and increase in titer over the gestational course and with multiple pregnancies (Lee et al., 2011). During the postpartum phase, antibody levels rise in the first 90 d and gradually disappear in 50% of postpartum women over a 1–2 yr period (Cecka, 2010; Masson et al., 2013). Anti-HLA antibody titers following kidney transplantation increase more robustly in patients having had prior pregnancies than in those having received previous transplantation or transfusion, suggestive of robust pregnancy-induced memory B cells (Higgins et al., 2015). Notably, although pregnancy-induced alloantibodies can diminish with time, alloreactive memory T and B cells can persist (Senn et al., 2021). Thus, anti-HLA antibodies and memory B cells induced by semi-allogeneic pregnancies play a pivotal role prior to and after transplantation, especially for multiparous women.Historically, anti-HLA antibody titers were measured by the panel-reactive antibody (PRA) technique through a complement-dependent cytotoxicity assay; however, the major limitation of this method is its inconsistency and lack of HLA specificity. In 2009, the United Network for Organ Sharing implemented measuring sensitization using single HLA-coated beads, an assay that precisely identifies specific HLA antigen targets (Cecka, 2010). A computer algorithm generates a calculated PRA (cPRA) according to the HLA frequencies derived from the donor population with the goal of providing consistently accurate results on the extent of sensitization of transplant candidates and the chances for a highly sensitized candidate to find a compatible organ donor. Around 30% of pregnant women are sensitized when measured via complement-dependent cytotoxicity assay, whereas 50–75% of women were found to be sensitized by pregnancy when the single HLA bead assay was used (Bromberger et al., 2017). Furthermore, a retrospective analysis of the United Network for Organ Sharing registry’s waitlist pool showed that individuals with a cPRA >98% were over-represented by women by ~60% (Redfield et al., 2016). Cumulatively, these data reveal the detrimental impact of pregnancy in women in need of a transplant and the disparity it creates toward identifying a suitable donor organ and having a successful post-transplantation course.Living donor kidney transplantation has better outcomes compared to kidney transplantation from deceased donors (Roodnat et al., 2003). However, 30% fewer women received living donor kidney transplantation as compared with men despite comparable referrals (Bromberger et al., 2017; Roodnat et al., 2003). Pregnancy was identified as a major contributor to this disparity, as postpartum women were increasingly incompatible with their spouse and offspring compared with men (Bromberger et al., 2017). Furthermore, parous women are at a higher risk of being sensitized to unrelated donors sharing an allele of the partner or offspring (Gibney et al., 2006; Vaidya et al., 2006). Child-specific sensitization measured by single-HLA bead assay was detected at the HLA-A/B/C/DR loci in 28–38% of 301 multiparous women analyzed (Honger et al., 2013), with child-specific HLA-B loci being the most sensitizing followed by HLA-A > HLA-DRB1 > HLA-C (Dankers et al., 2003; Honger et al., 2013). Furthermore, by quantifying mother/child mismatches by the number of mismatched HLA eplets, where an eplet is defined as the cluster of amino acids representing the smallest functional unit of structural epitopes on the HLA molecule targeted by B cell receptor and antibodies, the rate of child-specific sensitization increased with the presence of ≥20 mismatched eplets (Honger et al., 2013). These observations are reminiscent of eplet-load mismatch between the organ donor and the recipient predicting de novo anti-HLA antibody production by the host and reduced graft survival, and thus underscories the detrimental effects of pregnancy-induced humoral sensitization (Philogene et al., 2020; Sapir-Pichhadze et al., 2020).T cell sensitizationIn contrast to the abundant evidence that fetus-specific B cell responses are induced during pregnancy and the barrier they pose to transplantation, the effects of pregnancy-induced effector T cell responses on subsequent transplantation are more opaque. Specifically, although it is clear that maternal T cells acquire tolerance to the semi-allogeneic fetus, it is uncertain whether this T cell tolerance extends to subsequent organ allografts sharing antigens with the fetus. Early observations that fetal-derived stem cells can persist in low numbers in the mother’s circulation for as long as 27 yr, a phenomenon termed peripheral fetal microchimerism (Nelson, 1998), prompted the hypothesis that this microchimerism mediates long-term fetus-specific tolerance in mothers and promotes the acceptance of grafts from their offspring (Starzl et al., 1993). However, several studies testing the correlation between donor/recipient kinship and allograft fate have reported comparable outcomes between groups receiving grafts from offspring versus non-offspring (Cohen et al., 2018; Ghafari, 2008; Mahanty et al., 2001). A recent retrospective analysis performed using the Organ Procurement and Transplant Network living donor liver transplant database revealed that 1-, 5- and 10-yr allografts and patient survival was poorer among mothers who received the organ from their offspring as compared with unrelated living donors (Dagan et al., 2020). A major caveat of such studies is the potential pro-rejection effects of pregnancy-sensitized B cells even when pregnancy-induced antibodies have diminished; as a result, the contribution of pregnancy-primed T cells, either pro-rejection or pro-tolerogenic, may be obscured. Indeed, Senn et al. (2021) reported that women with prior pregnancies receiving kidneys from their husband consistently had a higher rate of antibody-mediated rejection compared with women with prior pregnancies receiving kidneys from other living or deceased donors.A limited number of studies have attempted to directly quantify ex vivo donor-specific T cell responses arising during normal human pregnancy using proliferation, cytokine production, or cellular cytotoxicity as readouts. When IL-4 and IFNγ ELISPOT assays were used to quantify PBMC responses from non-pregnant versus pregnant women to paternal or pooled alloantigens, Mjosberg et al. (2007) reported that pregnancy did not result in increased paternal-specific IL-4 or IFNγ responses. Furthermore, removal of Tregs resulted in non-specific increases in IFNγ responses and paternal-specific augmentation in IL-4 production. Collectively, their study suggested an absence of pregnancy-specific sensitization of T cells, while also hinting at postpartum Tregs controlling fetus-specific IL-4 responses and broadly controlling IFNγ responses. Notably, reduced frequencies of circulating FoxP3⁺ Tregs were observed with spontaneous preterm birth, preeclampsia, and recurrent spontaneous miscarriages compared to healthy pregnancies suggesting a more systemic effect of Tregs (Dimova et al., 2011; Inada et al., 2015; Inada et al., 2013; Kisielewicz et al., 2010; Koucky et al., 2014; Mjosberg et al., 2010; Nadkarni et al., 2016; Schober et al., 2012; Tilburgs et al., 2008; Tsuda et al., 2018).Pregnancy-induced Tregs are critical for promoting both primary and secondary pregnancies by suppressing T cell proliferation and cytokine production not only in secondary lymphoid organs but also in the placenta (Salvany-Celades et al., 2019). Expansion of Tregs in the decidual tissue has been prostulated to suppress fetus-specific responses locally (Tilburgs et al., 2008; Erlebacher, 2013). Notably, three different Treg populations have been identified at the maternal–fetal interface: CD25^HIFOXP3⁺, PD1^HIFOXP3⁻IL-10⁺, and TIGIT⁺FOXP3^dim Tregs. Decidual CD25^HIFOXP3⁺ Tregs were able to suppress the proliferation and IFNγ and TNFα production by CD4⁺ and effector CD8⁺ T cells in vitro, whereas decidual PD1^HI Tregs and TIGIT⁺ Tregs inhibited CD4⁺ but not effector CD8⁺ T cells. However, whether pregnancy-induced Tregs are most potent in the decidua or whether they can also dominantly suppress T cell responses to offspring-matched allografts in secondary lymphoid organs is currently unknown.CD8⁺ T cell responses to fetus-specific minor antigens have been more consistently reported to develop during pregnancy compared to CD4⁺ T cell responses (Linscheid and Petroff, 2013). Lissauer et al. (2012) assayed fetal-specific CD8⁺ cytotoxic responses using MHC-peptide dextramer multimers bearing a HY-immunodominant peptide in women pregnant with a male fetus. These CD8⁺ T cells expanded during pregnancy and persisted in the post-natal period in 50–62% of pregnant women. Furthermore, the fetal-specific CD8⁺ T cells retained their ability to proliferate, secrete IFNγ, and lyse target cells. These observations corroborated previous studies (Bouma et al., 1996; James et al., 2003; Mommaas et al., 2002; Piper et al., 2007; Verdijk et al., 2004) and suggested that fetal-specific CD8⁺ T cells expand during pregnancy and persist postpartum. It is tempting to speculate that preservation of fetus-CD8⁺ T cell responses during pregnancy, especially in the decidua, may have been evolutionarily selected to ensure the development of protective immunity for the developing fetus against viral infections, given that the fetus is haplo-identical to the mother, and thus maternal HLA-restricted CD8⁺ responses will recognize virally infected fetal cells (Tilburgs and Strominger, 2013; van Egmond et al., 2016). Indeed, observations that the decidua contains a higher percentage of CD8⁺ T cells and a lower percentage of CD4⁺ T cells compared with the peripheral blood is consistent with this possibility (Tilburgs et al., 2009; van Egmond et al., 2016).Potentially divergent fates of fetus-specific T cell subsets, together with a paucity of studies examining fetus-specific T cell responses in the extended postpartum period, make it difficult to definitively conclude if pregnancy-primed T cells are functionally tolerant or sensitized to fetal antigens presented in the context of a solid organ transplant. The ex vivo quantification of fetus-specific T cell responses is technically challenging and complicated by the increased frequency of pregnancy-induced Tregs (Salvany-Celades et al., 2019). Furthermore, ex vivo observations may not necessarily predict how these cells will behave in vivo after transplantation with organs sharing HLA antigens with the fetus. In vivo studies in postpartum recipients suggest that poorer outcomes are complicated by pregnancy-induced humoral sensitization (

Rapid screening of platelet donors for PlA1 (HPA-1a) alloantigen using a solid-phase microplate immunoassay

PlA1 and PlA2 are alternative platelet-specific alloantigens in the PlA1 system. Sensitization to PlA1 underlies most cases of neonatal alloimmune thrombocytopenia (NAIT) and posttransfusion purpura (PTP) in white populations. A rapid and simple method for large-scale platelet phenotyping is desirable for identifying expectant mothers at risk of allosensitization and for identifying PlA1-negative donors when transfusions are indicated for treatment of NAIT or PTP. We investigated the effectiveness of a solid-phase microplate immunoassay for this purpose. Platelet-rich donor plasmas were tested using the Capture-P(R) kit (Immucor, Norcross, GA). Platelet monolayers in microtiter wells were incubated with anti-PlA1, washed, and exposed to red blood cells (RBCs) precoated with anti-human IgG. Adherence of RBCs in a diffuse pattern across the well surface indicated the attachment of anti-PlA1 to PlA1-positive platelets whereas sedimentation of unattached RBCs into a central pellet indicated the platelets were PlA1-negative. Of 520 donors, 15 (2.88%) tested PlA1-negative, which correlates well with the reported PlA2,2 frequency in whites of 2.25 percent. Results were confirmed by DNA genotyping and/or immunoblotting. This screening technique permits phenotyping donors for PlA1 alloantigen with minimal specialized equipment. Confirmatory testing for PlA2 alloantigen can be reserved for donors that test negative for PlA1.     

Estándares de calidad asistencial para las consultas de enfermería en reumatología

BackgroundNursing clinics in rheumatology (NCR) are organizational models in the field of nursing care. There are various NCR models, but there is no consensus on its operational definition. Our objective is to develop quality standards to define and characterize a NCR.MethodTwo-round Delphi method. The panel consisted of 67 experts: Rheumatologists and nurses of the nursing working group of the Spanish Society of Rheumatology (SSR). The Delphi questionnaire was developed after a literature and experience review from previous SSR projects. The questionnaire consists of 7 sections: general considerations, standards of structure, process, treatment and monitoring, health education, training and research and quality of care. Each item was scored from 1 (least important) to 9 (most important) or by assigning a number (e.g., waiting days). The degree of agreement among the experts was categorized according to the coefficient of variation (CoV) between very high (CoV≤25%) and very low (CoV>100%).ResultsThe second round questionnaire (182 items) was answered by 46 panelists (34 rheumatologists and 12 nurses). A very important agreement was reached on the general standards of structure, process, treatment and monitoring, health education and quality of care. Less agreement was observed on standards related to training time, number of recommended nurses’ research projects and publications.ConclusionThe standards developed in this study would be useful for establishing desirable quality standards of structure and process, and criteria for clinical work, research and teaching that can be used to develop and evaluate the NCRs.     

Supranuclear gaze palsy following extracorporeal surgery with induced hypothermia. Report of two cases

Although up to 5-20% of the patients who underwent surgery with hypothermia and cardiac arrest may present neurological complications, just a few cases of ocularmotor disorders have been described. Acquired supranuclear ocular motor paresis (ASOMP) is a rare disorder characterized by impairment in volitional and reflex saccades and smooth pursuit in one or more directions of gaze with intact extraocular movements in response to vestibular estimulation. We present two cases of acquired supranuclear ocular motor paresis associated with a peculiar gait disorder. Although a partial improvement was observed, both patients continue with ocular motor paresis in vertical direction after one year of evolution. A selective vulnerability of certain brainstem neuronal groups would explain the pathophysiology of these symptoms.