“Pain is Subjective”: A Mixed-Methods Study of Provider Attitudes and Practices Regarding Pain Management in Sickle Cell Disease Across Three Countries

ContextSickle cell disease (SCD), an autosomal recessive blood disorder, affects millions of people worldwide. Approximately 80% of all cases are located in Africa.ObjectivesThis cross-national, interdisciplinary, collaborative study investigated provider attitudes about, and practices for, managing (assessing and treating) SCD pain.MethodsWe conducted 111 quantitative surveys and 52 semistructured interviews with health-care providers caring for adults and/or children with SCD in Cameroon, Jamaica, and the U.S.ResultsApplying Haywood's scale for assessing SCD provider attitudes, the Jamaica site scored lower on “Negative Attitudes” than the Cameroonian and U.S. sites (P = 0.03 and <0.001, respectively). Providers at the U.S. site scored lower on “Positive Attitudes” than other sites (P < 0.001). “Red Flag” scores at the Cameroon sites were lower than at other sites (P < 0.001). Qualitative results across all three sites describe the current practices for SCD pain management, as well as the challenges surrounding management for health providers, including pain subjectivity, patient-provider and parent-provider relationships, resource availability, perceptions of drug-seeking behavior, and adherence. Providers also spontaneously offered solutions to reported challenges.ConclusionOverall, findings reveal that SCD provider attitudes toward their patients differed across sites, yet at all three sites, treating SCD pain is multidimensional.     

Visuotopic organization of corticocortical connections in the visual system of the cat.

It has recently been demonstrated that, in contrast with the retinogeniculocortical projection, the corticocortical connections in the cat present a high degree of convergence and divergence. This suggests that some corticocortical connections link nonvisuotopically corresponding regions. Using fine-grain electrophysiological mapping and anatomical tracing, we have set out to test this possibility by placing a small injection of retrograde tracer in area 17 and by comparing the extent of visual field encoded in the region of area 18 containing labeled cells and that represented in the uptake zone. The results demonstrate that the size of the labeled region on the surface of area 18 is independent of eccentricity and that, despite its anisotrophy, this region of labeling encodes a broadly circular region of visual field that is larger than that encoded in the uptake zone of the tracer in area 17. For example, in the representation of lower visual field, a virtual point in area 17 that encodes a visual field region 4 degrees in diameter receives afferents from a region of area 18 encoding a region 11 degrees wide. Examination of the density of labeled cells in the labeled zone in area 18 reveals that the highest density is observed in a region in visuotopic correspondence with the injection site. However, high labeling density is also occasionally found in patches that do not represent the same visual field region as the injection site. Many receptive fields of neurons recorded in the labeled zone in area 18 only partially overlap or fail to overlap the visual field region encoded by the injection site. The results also demonstrate that the extent of visual field encoded in the labeled zone in area 18 is the same as that represented in the region of intrinsic labeling in area 17. It is suggested that cortical afferents coming from several cortical areas and converging on a column of cells in area 17 cover the same extent of visual field and that this cortical network constitutes the structural basis for the modulatory regions of the receptive field as well as the synchronization of neurons in different cortical areas.     

Ear length and kidney function decline after kidney donation

The preservation of kidney function after kidney donation depends on the kidney reserve – the potential of the remaining kidney to boost their function after loss of the other kidney. In Traditional Chinese Medicine, size and shape of the external ears are examined to evaluate the person's kidney health. We hypothesized that ear size might be a practical yet overlooked marker of kidney reserve. Fifty kidney transplantation donors were participated in this study. The length and width of both ears of all participants were measured during one of the post‐donation visits. Pre‐donation serum creatinine and post‐donation serum creatinine as well as other relevant parameters (age, sex, weight, height, etc.) of the participants were extracted from medical records. The estimated GFR was calculated from serum creatinine, age and sex using the CKD‐EPI equation. Ear length negatively associated with %GFR decline after kidney donation. For every 1 cm increase in ear length, it was associated with 5.7% less GFR decline after kidney donation (95% Confidence Interval 0.2 to 11.3, P = 0.04). Ear width, as well as age, sex, body weight, height, body mass index, and pre‐donation eGFR did not significantly associate with the GFR decline. Our findings support the notion of Traditional Chinese Medicine that ear morphology may be associated with kidney health and suggest that ear length might be a useful predictor of kidney function decline after kidney donation.     

Molecular analysis of erythrocyte invasion in Plasmodium falciparum isolates from Senegal

The human malaria parasite, Plasmodium falciparum, utilizes multiple ligand-receptor interactions for the invasion of human erythrocytes. Members of the reticulocyte binding protein homolog (PfRh) family have been shown to be critical for directing parasites to alternative erythrocyte receptors that define invasion pathways. Recent studies have identified gene amplification, sequence polymorphism, and variant expression of PfRh paralogs as mechanisms underlying discrimination between pathways for invasion. In this study, we find considerable heterogeneity in the invasion profiles of clonal, uncultured P. falciparum parasite isolates from a low-transmission area in Senegal. Molecular analyses revealed minimal variation in protein expression levels of the PfRh ligands, PfRh1, PfRh2a, and PfRh2b, and an absence of gene amplification in these isolates. However, significant sequence polymorphism was found within repeat regions of PfRh1, PfRh2a, and PfRh2b. Furthermore, we identified a large sequence deletion ( approximately 0.58 kb) in the C-terminal region of the PfRh2b gene at a high prevalence in this population. In contrast to findings of earlier studies, we found no associations between specific sequence variants and distinct invasion pathways. Overall these data highlight the importance of region-specific elaborations in PfRh sequence and expression polymorphisms, which has important implications in our understanding of how the malaria parasite responds to polymorphisms in erythrocyte receptors and/or evades the immune system.     

Free radicals and inflammation. Protection of phagocytosine leukocytes by superoxide dismutase.

Isolated human polymorphonuclear leukocytes engaged in phagocytosis liberate superoxide radical and hydrogen peroxide into the surrounding medium. These two chemical species react to produce the hydroxyl radical, which attacks the leukocyte and leads to premature death of the cell. The hydroxyl radical may be scavenged by mannitol, or its formation can be prevented by the addition of superoxide dismutase or catalase to the medium, thereby eliminating the premature death of the cells. This phenomenon may partially explain the observed anti-inflammatory activity of superoxide dismutase.     

Therapeutic Options for Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is the first human malignancy associated with a retroviral infection and occurs in approximately 5 % of the 15 million to 20 million people infected by human T-cell lymphotropic virus 1. In general, ATL is resistant to chemotherapy, and while awaiting new therapeutics, patients commonly face a detrimental progress of the disease and death. The viral oncoprotein Tax is a key player in the cause of ATL and acts by interfering with DNA repair, cell cycle, apoptosis, and proliferative cellular programs. The Shimoyama classification describes four different subtypes (acute, lymphoma, chronic, and smoldering) associated with different outcomes, and that require different treatment strategies tailored to the clinical presentation. In aggressive ATL (acute and lymphoma subtypes), clinical trials, mostly from Japan, have demonstrated that combinations of chemotherapy can induce acceptable response rates, especially in the lymphoma subtype. However, the overall outcome remains extremely poor owing to a high rate of relapse. Similarly, the so-called indolent forms (smoldering and chronic subtypes) have a poor outcome whether they are managed with watching and waiting or treated with chemotherapy. We recently realized a worldwide meta-analysis and showed that the combination of zidovudine and interferon alpha is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. Patients with lymphoma-type ATL still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine and interferon alpha. Allogeneic stem cell transplantation is a promising option but has several barriers. New drugs such as the new antibody anti-CXCR4 show promising results. Prospective trials testing maintenance therapy in order to avoid relapse are warranted when the patient cannot undergo allogeneic stem cell transplantation.     

Evolution of the pfcrt T76 and pfmdr1 Y86 markers and chloroquine susceptibility 8 years after cessation of chloroquine use in Pikine, Senegal

The goal of the present study was to assess the evolution of the in vitro chloroquine resistance and also the prevalence of pfcrt T76 and pfmdr1 Y86 mutations in Pikine from 2000 while chloroquine (CQ) was the first-line treatment of malaria to 2009 when artemisinin-based combination therapies (ACTs) are in use. We genotyped pfcrt K76T and pfmdr1 N86Y polymorphisms by PCR-RFLP and assessed in vitro CQ susceptibility by double-site enzyme-linked pLDH immunodetection (DELI) assay in Plasmodium falciparum isolates collected in Pikine, Senegal. The proportions of the pfcrt T76 allele in the light of the three different treatment policies were 72.4?% before CQ withdrawal (2000 to 2003), 47.2?% while amodiaquine plus Fansidar was the first-line treatment (2004 to 2005), and 59.5?% since the ACT use was implemented (2006 to 2009). The prevalence of pfcrt T76 decreased significantly after CQ was stopped [X (2)?=?6.54, P?=?0.01 (2000-2003 versus 2004-2005)] and then slightly since ACTs have been implemented [X (2)?=?1.12, P?=?0.28 (2000-2003 versus 2006-2009)]. There were no significant differences on the prevalence of pfmdr1 Y86 throughout the three treatment policies. The DELI assay was carried out episodically in 2000 (n?=?36), 2001 (n?=?47), and 2009 (n?=?37). The mean IC(50)s of the isolates to CQ in 2000 versus 2009 and 2001 versus 2009 are significantly different (P?相似文献   

Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats

AIMS: Hypothalamic mitochondrial reactive oxygen species (mROS)-mediated signaling has been recently shown to be involved in the regulation of energy homeostasis. However, the upstream signals that control this mechanism have not yet been determined. Here, we hypothesize that glucose-induced mitochondrial fission plays a significant role in mROS-dependent hypothalamic glucose sensing. RESULTS: Glucose-triggered translocation of the fission protein dynamin-related protein 1 (DRP1) to mitochondria was first investigated in vivo in hypothalamus. Thus, we show that intracarotid glucose injection induces the recruitment of DRP1 to VMH mitochondria in vivo. Then, expression was transiently knocked down by intra-ventromedial hypothalamus (VMH) DRP1 siRNA (siDRP1) injection. 72 h post siRNA injection, brain intracarotid glucose induced insulin secretion, and VMH glucose infusion-induced refeeding decrease were measured, as well as mROS production. The SiDRP1 rats decreased mROS and impaired intracarotid glucose injection-induced insulin secretion. In addition, the VMH glucose infusion-induced refeeding decrease was lost in siDRP1 rats. Finally, mitochondrial function was evaluated by oxygen consumption measurements after DRP1 knock down. Although hypothalamic mitochondrial respiration was not modified in the resting state, substrate-driven respiration was impaired in siDRP1 rats and associated with an alteration of the coupling mechanism. INNOVATION AND CONCLUSION: Collectively, our results suggest that glucose-induced DRP1-dependent mitochondrial fission is an upstream regulator for mROS signaling, and consequently, a key mechanism in hypothalamic glucose sensing. Thus, for the first time, we demonstrate the involvement of DRP1 in physiological regulation of brain glucose-induced insulin secretion and food intake inhibition. Such involvement implies DRP1-dependent mROS production.