Building Back Better: Going Big with Emancipatory Sciences.

This commentary argues that precarity and inequity across the life course and aging has accelerated via the COVID-19 pandemic. President Biden's vaccination efforts, $1.9 trillion American Rescue Plan Act, and Build Back Better framework reflect a paradigm shift to restore faith and trust in government that boldly confronts entrenched austerity ideologues. We offer emancipatory sciences as a conceptual framework to analyze and promote social structural change and epic theory development. Emancipatory sciences aim to advance knowledge and the realization of dignity, access, equity, respect, healing, social justice, and social change through individual and collective agency and social institutions. Epic theory development moves beyond isolated incidents as single events and, instead, grasps and advances theory through attempts to change the world itself by demanding attention to inequality, power, and action. Gerontology with an emancipatory science lens offers a framework and vocabulary to understand the individual and collective consequences of the institutional and policy forces that shape aging and generations within and across the life course. It locates an ethical and moral philosophy engaged in the Biden Administration's approach, which proposes redistributing - from bottom-up - material and symbolic resources via family, public, community, and environmental benefits.

Reliability and validity of self-reported questionnaires to measure pain and disability in adults with neck pain and its associated disorders: part 3-a systematic review from the CADRE Collaboration.

PURPOSE: To determine the reliability and validity of self-reported questionnaires to measure pain and disability in adults with grades I-IV neck pain and its associated disorders (NAD). METHODS: We updated the systematic review of the 2000-2010 Bone and Joint Decade Task Force on Neck Pain and its Associated Disorders and systematically searched databases from 2005 to 2017. Independent reviewers screened and critically appraised studies using standardized tools. Evidence from low-risk-of-bias studies was synthesized according to best evidence synthesis principles. Validity studies were ranked according to the Sackett and Haynes classification. RESULTS: We screened 2823 articles, and 26 were eligible for critical appraisal; 18 were low risk of bias. Preliminary evidence suggests that the Neck Disability Index (original and short versions), Whiplash Disability Questionnaire, Neck Pain Driving Index, and ProFitMap-Neck may be valid and reliable to measure disability in patients with NAD. We found preliminary evidence for the validity and reliability of pain measurements including the Body Pain Diagram, Visual Analogue Scale, the Numeric Rating Scale and the Pain-DETECT Questionnaire. CONCLUSION: The evidence supporting the validity and reliability of instruments used to measure pain and disability is preliminary. Further validity studies are needed to confirm the clinical utility of self-reported questionnaires to assess pain and disability in patients with NAD. These slides can be retrieved under Electronic Supplementary Material.

Antibiotic-Induced Rash in Patients With Infectious Mononucleosis.

OBJECTIVE: To provide an extensive review of case reports, epidemiological data, and the underlying mechanism of antibiotic-induced skin rash in patients with concurrent infectious mononucleosis (IM). DATA SOURCES: A MEDLINE literature search inclusive of the dates 1946 to June 2016 was performed using the search terms anti-bacterial agents and infectious mononucleosis. EMBASE (1980 to June 2016) was searched using the terms mononucleosis and antibiotic agent and drug eruption. References of all relevant articles were reviewed for additional citations and information. STUDY SELECTION AND DATA EXTRACTION: We selected English-language, primary literature, review articles, and mechanistic articles that addressed antibiotic-induced skin rash in patients with concurrent IM. We assessed all case reports available for causality utilizing a modified Naranjo nomogram specifically designed for this subject. We assembled the available epidemiological data into tables to identify trends in incidence rates over the years. DATA SYNTHESIS: We identified 17 case reports of antibiotic-associated rash in patients with IM. The median Naranjo score was 6 (range = 1 to 8). The top 3 reported drugs were ampicillin, azithromycin, and amoxicillin. Incidence of this adverse effect was higher in the 1960s (55.6%, 45%, and 33%) than in 2013 (33% and 15%). The mechanism most commonly proposed is a transient virus-mediated immune alteration that sets the stage for loss of antigenic tolerance and the development of a reversible, delayed-type hypersensitivity reaction to the antibiotic. CONCLUSION: A reassessment of the long-held belief of the high incidence (80%-100%) of antibiotic-induced skin rash in patients with IM seems prudent. Additional studies will be necessary to clarify this issue.

Reliability and validity of clinical tests to assess the anatomical integrity of the cervical spine in adults with neck pain and its associated disorders: Part 1-A systematic review from the Cervical Assessment and Diagnosis Research Evaluation (CADRE) Collaboration.

OBJECTIVE: To determine the reliability and validity of clinical tests to assess the anatomical integrity of the cervical spine in adults with neck pain and its associated disorders. METHODS: We updated the systematic review of the 2000-2010 Bone and Joint Decade Task Force on Neck Pain and its Associated Disorders. We also searched the literature to identify studies on the reliability and validity of Doppler velocimetry for the evaluation of cervical arteries. Two independent reviewers screened and critically appraised studies. We conducted a best evidence synthesis of low risk of bias studies and ranked the phases of investigations using the classification proposed by Sackett and Haynes. RESULTS: We screened 9022 articles and critically appraised 8 studies; all 8 studies had low risk of bias (three reliability and five validity Phase II-III studies). Preliminary evidence suggests that the extension-rotation test may be reliable and has adequate validity to rule out pain arising from facet joints. The evidence suggests variable reliability and preliminary validity for the evaluation of cervical radiculopathy including neurological examination (manual motor testing, dermatomal sensory testing, deep tendon reflexes, and pathological reflex testing), Spurling's and the upper limb neurodynamic tests. No evidence was found for doppler velocimetry. CONCLUSIONS: Little evidence exists to support the use of clinical tests to evaluate the anatomical integrity of the cervical spine in adults with neck pain and its associated disorders. We found preliminary evidence to support the use of the extension-rotation test, neurological examination, Spurling's and the upper limb neurodynamic tests.

Design, synthesis and initial characterisation of a radiolabelled [(18)F]pyrimidoindolone probe for detecting activated caspase-3/7.

Evasion of apoptosis is one of the six initially proposed hallmarks of cancer, and as such, a method to detect apoptosis in a tumour would be of considerable interest in both clinical trials of new cancer therapeutics, as well as for routine patient management. Activation of caspase-3/7 is a key biomarker of cellular apoptosis. Herein we describe the design, synthesis and initial characterisation of the first pyrimidoindolone compound for detection of caspase-3/7 activation using positron emission tomography.

Multireader evaluation of lesion conspicuity in small pancreatic adenocarcinomas: complimentary value of iodine material density and low keV simulated monoenergetic images using multiphasic rapid kVp-switching dual energy CT.

OBJECTIVE: Perform multireader analysis of objective and subjective lesion conspicuity for small pancreatic adenocarcinomas using rapid switching dual energy CT (rsDECT). MATERIALS AND METHODS: With IRB approval, 51 abdominal multiphasic rsDECT scans in 46 subjects with small (<3 cm) pancreatic adenocarcinomas were retrospectively reviewed by three independent readers for objective and subjective lesion conspicuity. Measured variables during individual, blinded interpretive sessions of separate low (52) keV, PACS-equivalent (70) keV, and iodine material density (MD) image sets included Hounsfield units (HU) and mg/cc iodine for tumor, nontumoral pancreas, and subcutaneous fat. Objective measures included absolute lesion contrast (LC) and contrast to noise ratios (CNR). Subjective measures included image quality, lesion conspicuity, and reader confidence. Reader agreement was measured with kappa statistic; correlation with truth by Pearson coefficient, CNR with repeated mANOVA; subjective quality measures utilized Tukey-Cramer corrections for multiple testing, p < 0.05 considered significant. RESULTS: Demographics: 26 F, 20 M, mean age 68 years, weight 75 kg, tumor size of 2.3 cm. LC was highest on 52 keV images for all three readers (mean 90.1 HU). Mean CNR for iodine MD images (4.87) was significantly higher than 52 keV (4.13) or 70 keV (3.9). Very high to near-perfect kappa values were observed for all individual measured objective variables but were best for 52 keV images (52 keV 0.89-0.95, 70 keV 0.76-0.83, iodine 0.87-0.92). 70 keV images scored best for subjective image quality; iodine MD images scored best for lesion conspicuity and reader confidence. CONCLUSION: We observed very high reader agreement for independent objective rsDECT image variables and subjective rsDECT image scores in patients with small pancreatic adenocarcinomas. Maximal objective tumor to nontumoral LC was depicted on 52 keV and highest CNR on iodine MD images; readers scored the iodine MD images best for lesion conspicuity and confidence.

Total spinal anaesthesia following obstetric neuraxial blockade: a narrative review.

BACKGROUND: Total spinal anaesthesia (TSA) is an emergency caused by high neuraxial blockade. It is a recognised complication of all neuraxial techniques in obstetric anaesthesia. Its incidence and outcomes have not been evaluated. There is compelling evidence that TSA continues to be a problem in contemporary practice, having the capacity to cause significant morbidity and mortality if not recognised early and promptly treated. This review based on a literature search aims to clarify the epidemiology of TSA, summarise its pathophysiology, and identify risk factors and effective treatments. METHODS: We performed a literature search using PubMed, Web of Science and Google Scholar databases using specified search terms for materials published using search terms. For each case, the type of block, the difficulty of the procedure, the dose of local anaesthetic, positivity of aspiration before and after the event, maternal outcome, Apgar score, onset of symptoms, cardiorespiratory and neurological manifestations, cardiorespiratory support employed, admission to an intensive care unit, cardiac arrest events and duration of mechanical ventilation were extracted. RESULTS: A total of 605 cases were identified, of which 51 were sufficiently detailed for analysis. Although TSA is described after all neuraxial techniques, spinal after epidural was a particular concern in recent reports. Respiratory distress was universal but apnoea was not. The onset of apnoea was variable, ranging from 1 to 180 min. Hypotension was not invariable and occurred in approximately half of cases. Multiple fatalities and neurological injuries were reported, often in under-resourced areas when providers were not skilled in airway management or when recognition and intervention were delayed. In the most recent reports good outcomes were achieved when effective treatments were rapidly provided. CONCLUSIONS: The available literature confirms that TSA remains an active clinical problem and that with prompt recognition and treatment good outcomes can be achieved. This requires anticipation and preparedness in all clinical areas where neuraxial techniques are performed.

Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance.

BACKGROUND: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy. METHODS: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy. RESULTS: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively. CONCLUSION: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.

Biopsychosocial sequelae and recovery trajectories from whiplash injury following a motor vehicle collision.

BACKGROUND CONTEXT: Five out of 10 injured in a motor vehicle collision (MVC) will develop persistent pain and disability. It is unclear if prolonged symptoms are related to peritraumatic pain/disability, psychological distress, muscle fat, lower extremity weakness. PURPOSE: To test if widespread muscle fat infiltration (MFI) was (1) unique to those with poor recovery, (2) present in the peritraumatic stage, (3) related to known risk factors. STUDY DESIGN/SETTING: A cohort study, single-center academic hospital. PATIENT SAMPLES: A total of 97 men and women (age 18-65) presenting to an urban academic emergency medicine department following MVC, but not requiring inpatient hospitalization. PRIMARY OUTCOME MEASURE: Neck disability at 12-months. METHODS: Participants underwent magnetic resonance imaging (MRI) to quantify neck and lower extremity MFI, completed questionnaires on pain/disability and psychological distress (< 1-week, 2-weeks, 3-, and 12-months) and underwent maximum volitional torque testing of their lower extremities (2-weeks, 3-, and 12-months). Percentage score on the Neck Disability Index at 12-months was used for a model of (1) Recovered (0%-8%), (2) Mild (10%-28%), and (3) Moderate/Severe (≥ 30%). This model was adjusted for BMI and age. RESULTS: Significant differences for neck MFI were revealed, with the Recovered group having significantly lower neck MFI than the Mild and Moderate/Severe groups at all time points. The Mild group had significantly more leg MFI at 12-months (p=.02) than the Recovered group. There were no other significant differences at any other time point. Lower extremity torques revealed no group differences. The Traumatic Injury Distress Scale (TIDS) and MFI of the neck at 1-week postinjury significantly predicted NDI score at 12-months. CONCLUSIONS: Higher neck MFI and distress may represent a risk factor though it is unclear whether this is a pre-existing phenotype or result of the trauma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02157038.

Comparative expression of hCG ß-genes in human trophoblast from early and late first-trimester placentas.

Human chorionic gonadotropin (hCG) displays a major role in pregnancy initiation and progression and is involved in trophoblast differentiation and fusion. However, the site and the type of dimeric hCG production during the first trimester of pregnancy is poorly known. At that time, trophoblastic plugs present in the uterine arteries disappear, allowing unrestricted flow of maternal blood to the intervillous space. The consequence is an important modification of the trophoblast environment, including a rise of oxygen levels from about 2.5% before 10 wk of amenorrhea (WA) to ∼8% after 12 WA. Two specific ß-hCG proteins that differ from three amino acids have been described: type 1 (CGB7) and type 2 (CGB3, -5, and -8). Here, we demonstrated in situ and ex vivo on placental villi and in vitro in primary cultures of human cytotrophoblasts that type 1 and 2 ß-hCG RNAs and proteins were expressed by trophoblasts and that these expressions were higher before blood enters in the intervillous space (8-9 vs. 12-14 WA). hCG was immunodetected in villous mononucleated cytotrophoblasts (VCT) and syncytiotrophoblast (ST) at 8-9 WA but only in ST at 12-14 WA. Furthermore, hCG secretion was fourfold higher in VCT cultures from 8-9 WA compared with 12-14 WA. Interestingly, VCT from 8-9 WA placentas were found to exhibit more fusion features. Taken together, we showed that type 1 and type 2 ß-hCG are highly expressed by VCT in the early first trimester, contributing to the high levels of hCG found in maternal serum at this term.

Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder.

A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

Effects of clinical practice environments on clinical teacher and nursing student outcomes.

The purpose of this study was to use a cross-sectional survey design, with an integrated theoretical perspective, to examine clinical teachers' (n = 64) and nursing students' (n = 352) empowerment, teachers' and students' perceptions of teachers' use of empowering teaching behaviors, students' perceptions of nurses' practice behaviors, and students' confidence for practice in acute care settings. In this study, teachers and students were moderately empowered. Teachers reported using a high level of empowering teaching behaviors, which corresponded with students' perceptions of teachers' use of such behaviors. Teachers' empowerment predicted 21% of their use of empowering teaching behaviors. Students reported nurses as using a high level of professional practice behaviors. Students felt confident for professional nursing practice. The findings have implications for practice contexts related to empowering teaching-learning environments and self-efficacy.

The mandala: first-year undergraduate nursing students' learning experiences.

The mandala is a circular art form used by psychologists to access subconscious thought through symbolism and it has recently been adopted by nurse educators as a learning strategy for self-awareness. The lived experiences of six first-year undergraduate nursing students who completed a mandala assignment for emotional learning were explored using hermeneutic phenomenology. Participants experiences diverged from their original expectations that the mandala assignment would allow for a fun and free expression of 'self'. Participants did describe experiences of self-discovery; however, their experiences also resembled those associated with socialization in nursing education. Participants described both self-reflection and critical-reflection while completing the mandala assignment. Nurse educators and researchers can gain insight regarding the use of this assignment as an integrated transformative learning approach for emotional learning.

Nursing students' perceptions of clinical teachers' use of empowering teaching behaviours: instrument psychometrics and application.

The authors present findings of 2nd year nursing students' (N = 352) perceptions of their clinical teachers' use of empowering teaching behaviours (ETB) and to highlight steps undertaken to establish psychometric properties of the Empowering Teaching Behaviours Questionnaire-Student (ETBQ-S). The authors identify a) the process involved in the adoption of the ETBQ-S, b) ETBQ-S validity procedures completed prior to instrument implementation, c) results of nursing students' responses to the ETBQ-S, d) criterion validity, and e) ETBQ-S confirmatory factor analysis findings conducted after study completion. The ETBQ-S reliably measures five facets of empowering actions that clinical teachers can employ with nursing students in practice to enhance their confidence, involve them in decision-making and goal setting, make learning meaningful, and help them to become more autonomous nurses.

Affinity of anti-spike antibodies to three major SARS-CoV-2 variants in recipients of three major vaccines.

Background: Measuring anti-viral antibody affinity in blood plasma or serum is a rational quantitative approach to assess humoral immune response and acquired protection. Three common vaccines against SARS-CoV-2-Comirnaty developed by Pfizer/BioNTech, Spikevax developed by Moderna/NIAID, and Jcovden (previously Janssen COVID-19 Vaccine) developed by Johnson & Johnson/Janssen (J&J)-induce antibodies to a variety of immunogenic epitopes including the epitopes located in the ACE2 receptor-binding domain (RBD) of the spike protein. Blocking RBD with antibodies interferes with the binding of the virus to ACE2 thus protecting against infection. Methods: We perform measurements in the serum of the recipients of Pfizer, Moderna, and J&J vaccines, and we compare the apparent affinities of vaccine-induced antibodies against the RBD of the ancestral SARS-CoV-2 virus and the Delta and Omicron variants. We use our recently published method to determine the apparent affinity of anti-spike protein antibodies directly in human serum. This involves probing antibody-antigen equilibria with a small number of antigen-coated magnetic microparticles and imaging them on a fluorescence microscope. Results: Recipients of two-dose Pfizer and Moderna vaccines, as well as recipients of the single-dose J&J vaccine, develop high-affinity antibodies toward RBD derived from ancestral SARS-CoV-2. Affinities of these antibodies to Delta-RBD are approximately 10 times weaker, and even more drastically reduced (∼1000-fold) toward Omicron-RBD. Conclusions: Vaccine-induced antibodies against ancestral SARS-CoV-2 RBD demonstrate ~10-fold and ~1000-fold weaker affinities toward Delta- and Omicron-RBD, respectively. Our approach offers a direct means for evaluating vaccine-induced adaptive immunity and can be helpful in designing or updating vaccines.

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha.

We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted.

Mutation screening of the 3q29 microdeletion syndrome candidate genes DLG1 and PAK2 in schizophrenia.

Deletion of chromosome 3q29, which is associated with mental retardation and autism, was recently identified as being present in excess or occurring de novo in schizophrenia cases, being present in approximately 1/1,000 cases and 1/40,000 unscreened controls. Of the ∼20 genes in the commonly deleted region two are prominent candidates for involvement in the behavioral features of the microdeletion syndrome: DLG1 and PAK2. We report the result of mutation screening of the entire protein coding sequence of both genes in a sample of 234 unrelated cases and 272 unrelated controls from the UK. We find no evidence for any amino acid changing genetic variants in PAK2. We observe several rare and singleton non-synonymous genetic variations at DLG1, however there is no excess of these variants in cases when compared to controls. Our sample was underpowered to detect very rare or low-penetrance disease relevant alleles in the studied genes. Therefore very rare, low-to-moderate penetrance protein coding mutations or non-coding mutations at DLG1 and/or PAK2, or a nearby gene, may reproduce the behavioral characteristics of the 3q29 microdeletion.

Identification of C-C chemokine receptor 1 (CCR1) as the monocyte hemofiltrate C-C chemokine (HCC)-1 receptor.

Hemofiltrate C-C chemokine (HCC)-1 is a recently cloned C-C chemokine that is structurally similar to macrophage inflammatory protein (MIP)-1alpha. Unlike most chemokines, it is constitutively secreted by tissues and is present at high concentrations in normal human plasma. Also atypical for chemokines, HCC-1 is reported not to be chemotactic for leukocytes. In this paper, we have investigated the chemokine receptor usage and downstream signaling pathways of HCC-1. Cross-desensitization experiments using THP-1 cells suggested that HCC-1 and MIP-1alpha activated the same receptor. Experiments using a panel of cloned chemokine receptors revealed that HCC-1 specifically activated C-C chemokine receptor (CCR)1, but not closely related receptors, including CCR5. HCC-1 competed with MIP-1alpha for binding to CCR1-transfected cells, but with a markedly reduced affinity (IC50 = 93 nM versus 1.3 nM for MIP-1alpha). Similarly, HCC-1 was less potent than MIP-1alpha in inducing inhibition of adenylyl cyclase in CCR1-transfected cells. HCC-1 induced chemotaxis of freshly isolated human monocytes, THP-1 cells, and CCR1-transfected cells, and the optimal concentration for cell migration (100 nM) was approximately 100-fold lower than that of MIP-1alpha (1 nM). These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes.