Growing from Our Roots: Strategies for Developing Culturally Grounded Health Promotion Interventions in American Indian,Alaska Native,and Native Hawaiian Communities

Given the paucity of empirically based health promotion interventions designed by and for American Indian, Alaska Native, and Native Hawaiian (i.e., Native) communities, researchers and partnering communities have had to rely on the adaptation of evidence-based interventions (EBIs) designed for non-Native populations, a decidedly sub-optimal approach. Native communities have called for development of Indigenous health promotion programs in which their cultural worldviews and protocols are prioritized in the design, development, testing, and implementation. There is limited information regarding how Native communities and scholars have successfully collaborated to design and implement culturally based prevention efforts “from the ground up.” Drawing on five diverse community-based Native health intervention studies, we describe strategies for designing and implementing culturally grounded models of health promotion developed in partnership with Native communities. Additionally, we highlight indigenist worldviews and protocols that undergird Native health interventions with an emphasis on the incorporation of (1) original instructions, (2) relational restoration, (3) narrative-[em]bodied transformation, and (4) indigenist community-based participatory research (ICBPR) processes. Finally, we demonstrate how culturally grounded interventions can improve population health when they prioritize local Indigenous knowledge and health-positive messages for individual to multi-level community interventions.

     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition

BACKGROUND: A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs. METHODS AND RESULTS: LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors. CONCLUSIONS: This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.     

Epidural analgesia versus intravenous patient-controlled analgesia following minimally invasive pectus excavatum repair: a systematic review and meta-analysis

Background/Purpose

The minimally invasive pectus excavatum repair (MIPER) is a painful procedure. The ideal approach to postoperative analgesia is debated. We performed a systematic review and meta-analysis to assess the efficacy and safety of epidural analgesia compared to intravenous Patient Controlled Analgesia (PCA) following MIPER.

Methods

We searched MEDLINE (1946–2012) and the Cochrane Library (inception–2012) for randomized controlled trials (RCT) and cohort studies comparing epidural analgesia to PCA for postoperative pain management in children following MIPER. We calculated weighted mean differences (WMD) for numeric pain scores and summarized secondary outcomes qualitatively.

Results

Of 699 studies, 3 RCTs and 3 retrospective cohorts met inclusion criteria. Compared to PCA, mean pain scores were modestly lower with epidural immediately (WMD − 1.04, 95% CI − 2.11 to 0.03, p = 0.06), 12 hours (WMD − 1.12; 95% CI − 1.61 to − 0.62, p < 0.001), 24 hours (WMD − 0.51, 95%CI − 1.05 to 0.02, p = 0.06), and 48 hours (WMD − 0.85, 95% CI − 1.62 to − 0.07, p = 0.03) after surgery. We found no statistically significant differences between secondary outcomes.

Conclusions

Epidural analgesia may provide superior pain control but was comparable with PCA for secondary outcomes. Better designed studies are needed. Currently the analgesic technique should be based on patient preference and institutional resources.     

Coincidental diagnosis of tuberculous lymphadenitis: a case report

The aim of this case report was to present a case of multiple calcified tuberculous lymph nodes found on a panoramic radiograph coincidently diagnosed in an endodontic clinic. A detailed discussion on the differential diagnosis of similar such calcification found in the same region is also presented. A 14‐year‐old girl was referred to our department with the complaint of painless swelling in the left side of the lower jaw. Clinical and radiographical examinations were performed, leading to the initial diagnosis of chronic periapical abscess. The patient's medical history was re‐evaluated. Advanced imaging and excisional biopsy were performed in order to confirm the final diagnosis. Regarding the presenting signs and symptoms of bilateral carious mandibular molars, a periapical inflammatory process was considered in the provisional diagnosis. A thorough examination and investigations were suggestive of cervical tuberculous lymphadenitis (scrofula), and the patient underwent excision of the same. The clinician should consider the possibility of chronic granulomatous inflammatory lesions in the differential diagnosis of radiopaque lesions.     

综合性ICU患者监护记录单临床应用的前瞻性研究

目的研究新时期综合ICU患者的临床监护记录单,以保证患者及护士使用过程的便利及安全。方法将我院ICU自2002年使用的“图标式ICU监护记录单”,在原表格的基础上根据综合ICU患者需要多系统监测的特点进行修订,主要以数字和符号表示形式形成新的护理记录表格,并采取对比的方法考证新旧两种表格的效用。结果两种表格各项指标比较：相同人数的护士分别填写两种不同表格所使用的时间分别是新表格平均（66±11）min,旧表格平均（97±10）min,每份表格的分数设为100分,护理质量检查小组检查的结果,新表格平均（97±2）分,旧表格平均（94±2）分,两组时间及分数比较差异有统计学意义（t=10．6263,4．0307;P〈0．01）;新旧表格使用合格率比较差异有统计学意义（90．12％比82．62％,x2=67．49,P〈0．01）。结论新的监护记录单更科学、更全面、简洁、更适合综合ICU不同种类的患者的记录要求,减轻护士工作量,减少记录时间,提高工作效率。     

Molecular basis of multistep voltage activation in plant two-pore channel 1

Voltage-gated ion channels confer excitability to biological membranes, initiating and propagating electrical signals across large distances on short timescales. Membrane excitation requires channels that respond to changes in electric field and couple the transmembrane voltage to gating of a central pore. To address the mechanism of this process in a voltage-gated ion channel, we determined structures of the plant two-pore channel 1 at different stages along its activation coordinate. These high-resolution structures of activation intermediates, when compared with the resting-state structure, portray a mechanism in which the voltage-sensing domain undergoes dilation and in-membrane plane rotation about the gating charge–bearing helix, followed by charge translocation across the charge transfer seal. These structures, in concert with patch-clamp electrophysiology, show that residues in the pore mouth sense inhibitory Ca²⁺ and are allosterically coupled to the voltage sensor. These conformational changes provide insight into the mechanism of voltage-sensor domain activation in which activation occurs vectorially over a series of elementary steps.

Voltage-gated ion channels (VGICs) use voltage-sensing domains (VSDs) to sense changes in electrical potential across biological membranes (1, 2). VSDs are composed of a four-helix bundle, in which one helix carries charged residues that move in response to changes in transmembrane electric field (3, 4). VSDs usually adopt a “resting state” when the membrane is at “resting potential”: ∼ −80 mV for animal and ∼ −150 mV for plant plasma membranes (5). In comparison, much lower resting membrane voltages are set for intracellular endo-membranes: ∼ −30 mV across the plant vacuole (6) and mammalian lysosome (7). As the membrane potential vanishes during depolarization, so does the downward electrostatic force on the cationic side chains causing them to relax toward the outside of the membrane across a hydrophobic constriction site (HCS) or hydrophobic seal (8). This conformational change is conveyed to the central pore, formed by four pore domains in a quasi-fourfold arrangement, which dilates to allow the diffusion of ions down their electrochemical gradients. The exact nature of the conformational change in VSDs has been the subject of decades of biophysical investigation (9–12), though to this date, only a few structural examples exist of voltage sensors in resting or multiple conformations (13–18).Two-pore channels (TPCs) are defined by their two tandem Shaker-like cassette subunits in a single polypeptide chain, which dimerize to form a C2-symmetric channel with four subunits and 24 (4 × 6) transmembrane helices (19–21). There are three TPC channels, TPC1, 2, and 3, each with different voltage or ligand gating and ion selectivity. Among the voltage-gated TPCs (all except lipid-gated TPC2), only the second VSD (VSD2) is electrically active (18, 22–24), while VSD1 is insensitive to voltage changes and is likely static under all changes in potential.In plants, the vacuole comprises up to 90% of the plant cell volume and provides for a dynamic storage organelle that, in addition to metabolites, is a repository for ions including Ca²⁺. TPC1 channels confer excitability to this intracellular organelle (25) and, unlike other TPCs, are calcium regulated: external Ca²⁺ (in the vacuolar lumen) inhibits the channel by binding to multiple luminal sites, while cytosolic Ca²⁺ is required to open the channel by binding to EF hands, although the exact mechanism by which this activation occurs is unknown (22). These electrical properties allowed our group and Youxing Jiang’s group to determine the first structure of an electrically resting VGIC by cocrystallizing the channel with 1 mM Ca²⁺, which maintains the VSD in a resting configuration at 0 mV potential (16, 22).Previously (17), we used a gain-of-function mutant of AtTPC1 with three luminal Ca²⁺-binding acidic residues on VSD2 neutralized (D240N/D454N/E528N) termed AtTPC1_DDE (abbreviated here as DDE) to visualize channel activation at the level of atomic structure, but we were unable to sufficiently resolve details of the electrically active VSD2 due to structural heterogeneity. In addition, the intracellular activation gate remained closed. We now present multiple structures of intermediately activated states of AtTPC1 determined by extensive image processing. In order to visualize such states, we modulated the channel’s luminal Ca²⁺ sensitivity using a well-studied gain-of-function single-point mutant, D454N (fou2), and also the triple mutant DDE for comparison. fou2 is known to desensitize the channel to inhibitory, external (luminal) calcium ions (26, 27). Mutations in D454 and closely related luminal Ca²⁺-binding carboxyls to alanine D240A, D454A, E528A (termed AtTPC1ΔCa_i) were previously shown to effectively attenuate the Ca²⁺-induced shift of the voltage activation threshold of AtTPC1 to depolarizing potentials at high luminal Ca²⁺ (28).The fou2 and DDE mutations lie in the coordination sphere of the inhibitory Ca²⁺ site on the luminal side of the VSD2–pore interface formed by D454, D240, and E528. The D454N mutation in the fou2 channel enhances the defense capacity of plants against fungal or herbivore attack due to increased production of the wounding hormone jasmonate (29). These effects on plant performance and defense are probably due to short circuiting of the vacuolar membrane (26, 27, 30) in which TPC1 has increased open probability at resting potential. Compared to wild-type (WT) TPC1, the activation threshold in the fou2 channel is shifted to more negatively polarized potentials and also has significantly lower sensitivity to inhibitory Ca²⁺ in addition to exhibiting faster activation kinetics than its WT counterpart that was originally named the “slow vacuolar” (SV) channel due to its slow conductance onset (20, 21, 30). Therefore, D454N confers more than just reduced sensitivity to external Ca²⁺ but intrinsic hyperactivity as well. Our structures of these AtTPC1 mutants attempt to explain how the voltage sensor functions during electrical activation and how exactly luminal Ca²⁺ affects this process.