Examining the role of social vulnerability, neighborhood characteristics, and geospatial patterns of firearm-related injuries and clinical outcomes in Milwaukee county.

BACKGROUND: Previous work has shown socioenvironmental factors can influence firearm injury. Milwaukee County, Wisconsin is a diverse midwestern county with historic disinvestment in marginalized communities yielding stark segregation along racial and ethnic lines. It is also one of the many U.S. counties burdened by surging firearm injuries. The differences among communities within Milwaukee County provides a unique opportunity to explore the intersection of socioenvironmental factors that may affect clinical outcomes and geospatial patterns of firearm injury. METHODS: The trauma registry from the regional adult level 1 trauma center was queried for patients who sustained a firearm-related injury from 2015 to 2022 (N = 2402). The Social Vulnerability Index (SVI) ranking was derived using patient residence addresses to evaluate its association with traumatic injury clinical outcomes (i.e., in-hospital mortality, length of hospital stay, ICU or ventilator treatment, or injury severity score) and risk screening results for alcohol use disorder (AUD), posttraumatic stress disorder (PTSD), and depression. We evaluated hotspots of firearm injury density over time for patient residences and injury locations and distances between locations. A spatially lagged regression model tested the association between firearm injury density and SVI domains, alcohol outlet types, and park coverage. RESULTS: Most firearm injury patients were younger, male, racial or ethnic minorities from disadvantaged neighborhoods (SVI total; M = 0.86, SD = 0.15). SVI was not associated with any clinical outcomes. Of those screened, 12.9% screened positive for AUD and 44.5% screened at risk for PTSD, depression, or both. Hotspot analysis indicated consistent concentrations of firearm injury density. There were no differences in clinical outcomes between those injured inside or outside the home. Census tracts with lower socioeconomic status, greater off-premises and lower on-premises alcohol outlet density were associated with greater firearm injury density. CONCLUSIONS: In Milwaukee County, firearm injury patients are injured in and often return to the same disadvantaged neighborhoods that may hamper recovery. Results replicate and expand previous work and implicate specific socioenvironmental factors for intervention and prevention of firearm injury.

A systematic review on the factors associated with positive experiences in carers of someone with cancer.

The aim of this review was to identify the factors associated with positive experiences in non-professional carers of someone with a cancer diagnosis. A systematic search of the following electronic databases was undertaken: Cochrane Library, CINAHL, PsycINFO, SocINDEX and Medline. Literature was searched using terms relating to cancer, caring and positive experiences. Additional records were identified through a manual search of relevant reference lists. The search included studies published in English from 1990 to June 2015. Two raters were involved in data extraction, quality appraisal, coding, synthesis and analysis. Evolutionary concept analysis was used as a guiding framework in order to focus on attributes associated with positive experiences. Fifty-two articles were included in this review. Analysis identified four overarching attributes: "gender," "personal resources," "finding meaning" and "social context." Despite the challenges associated with caring, this combination of internal and external factors enabled some carers to report positive experiences related to caring. This knowledge may be clinically helpful when designing supportive interventions. Strengths and limitations of these claims are discussed. Systematic review registration number: CRD42014014129.

Mental health nurse prescribing: a difficult pill to swallow?

This paper develops an interpretation of the impact of mental health nurse prescribing in the UK. A constructivist-grounded theory methodology was applied to 13 semi-structured interviews with mental health clinicians and service users. The same interpretivist methodology was applied to the literature. Thirty-two practising UK mental health nurse prescribers gave structured feedback on the coherence of the emergent theory. It was found that the theory describes the process of becoming competent in mental health nurse prescribing. This process highlights possible deficits in non-prescribing mental health nurses. It is recommended that if this is corroborated then structured education in medicines management be introduced into pre- and postregistration mental health nursing in UK. The findings of this research offer a framework. That is, the categories emerging within this research translate easily into learning outcomes which can underpin delivery of a consistent medicine management strategy across all levels of nurse education.

A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts.

Zellweger spectrum disorders (ZSD) are diagnosed by biochemical assay in blood, urine and cultured fibroblasts and PEX gene mutation identification. In most cases studies in fibroblasts corroborate results obtained in body fluids. In 1996 Clayton and colleagues described a 10-year old girl with evidence of a peroxisome disorder, based on elevated bile acid metabolites and phytanate. At the time it was not possible to distinguish whether she had a ZSD or a single peroxisomal protein defect. Studies in our laboratory showed that she also had elevated plasma pipecolate, supporting the former diagnosis. Despite the abnormal metabolites detected in blood (phytanate, bile acid intermediates and pipecolate), analysis of multiple peroxisomal pathways in fibroblasts yielded normal results. In addition, she had a milder clinical phenotype than usually associated with ZSD. Since complementation analysis to determine the gene defect was not possible, we screened this patient following the PEX Gene Screen algorithm (PGS). The PGS provides a template for sequencing PEX gene exons independent of complementation analysis. Two mutations in PEX10 were identified, a frameshift mutation inherited from her father and a de novo missense mutation in a conserved functional domain on the other allele. This case highlights that molecular analysis may be essential to the diagnosis of patients at the milder end of the ZSD spectrum. Furthermore, it supports the concept that some tissues are less affected by certain PEX gene defects than brain and liver.

Quantitative analysis of mental health nurse prescribers in Scotland.

The UK parliament approved legislation expanding prescribing rights for all registered nurses in 2006. Mental health nurses do not appear to be embracing prescribing to the same degree as their colleagues. For example, mental health nurses represent 14% of the UK nursing population, but only 3% nurse prescribing population. In order to explore this disparity, the paper discusses quantitative analysis of the following objectives: (1) describe the impact of nurse prescribing on nurse prescribers in NHS Greater Glasgow and Clyde; and (2) identify differences between mental health nurse prescribers and other nurse prescribers in NHS Greater Glasgow and Clyde. Following online pilot study, a 26-item questionnaire was posted to 668 nurse prescribers in NHS Greater Glasgow and Clyde. A total of 365 questionnaires were returned (55.4%). Significant differences were found between mental health nurse prescribers and others in terms of age, gender, prescribing practice, academic achievement, method of prescribing, workplace, experience and attitude to prescribing. Possible reasons for these differences are suggested and form the basis of further planned research.

Nurse prescribing in mental health.

This article presents a suggested clinical management plan for a community psychiatric nurse who is prescribing for older adults with mental health needs. The scope of the clinical management plan and the attendant professional and legal responsibilities are discussed. An antidepressant medication review is used to illustrate mental health prescribing decisions.

A novel transcriptional repression domain mediates p21(WAF1/CIP1) induction of p300 transactivation.

The transcriptional coactivators p300 and CREB binding protein (CBP) are important regulators of the cell cycle, differentiation, and tumorigenesis. Both p300 and CBP are targeted by viral oncoproteins, are mutated in certain forms of cancer, are phosphorylated in a cell cycle-dependent manner, interact with transcription factors such as p53 and E2F, and can be found complexed with cyclinE-Cdk2 in vivo. Moreover, p300-deficient cells show defects in proliferation. Here we demonstrate that transcriptional activation by both p300 and CBP is stimulated by coexpression of the cyclin-dependent kinase inhibitor p21(WAF/CIP1). Significantly this stimulation is independent of both the inherent histone acetyltransferase (HAT) activity of p300 and CBP and of the previously reported carboxyl-terminal binding site for cyclinE-Cdk2. Rather, we describe a previously uncharacterized transcriptional repression domain (CRD1) within p300. p300 transactivation is stimulated through derepression of CRD1 by p21. Significantly p21 regulation of CRD1 is dependent on the nature of the core promoter. We suggest that CRD1 provides a novel mechanism through which p300 and CBP can switch activities between the promoters of genes that stimulate growth and those that enhance cell cycle arrest.

Cell cycle regulation of the transcriptional coactivators p300 and CREB binding protein.

To respond to changes in its environment, the cell utilizes mechanisms that integrate extracellular signals with specific changes in gene expression. To better understand these critical regulatory mechanisms, research has focused, for the most part, on the identification of sequence-specific DNA-binding proteins, such as the nuclear factor kappaB (NF-kappaB) or activator protein 1 (AP-1) families of transcription factors, that interact with the promoter and enhancer elements of genes induced or repressed during cellular activation. More recently, however, it has become apparent that non-DNA-binding transcriptional coactivators, such as p300 and CREB binding protein (CBP), previously thought to function primarily as "bridging" proteins between DNA-bound transcription factors and the basal transcription complex, play a critical regulatory role as integrators of diverse signalling pathways with the selective induction of gene expression. In this commentary, we shall discuss the implications of a particular aspect of this growing and expanding field: how cell cycle regulation of p300 and CBP impacts our understanding of cellular differentiation, the response to DNA damage, and oncogenesis.

Oxidized low density lipoproteins stimulate galactosyltransferase activity, ras activation, p44 mitogen activated protein kinase and c-fos expression in aortic smooth muscle cells.

Previously, our laboratory has shown that oxidized low density lipoproteins (Ox-LDL) can exert a concentration-dependent stimulation in the proliferation of aortic smooth muscle cells, "a hallmark in the pathogenesis of atherosclerosis" (Chatterjee, S. (1992) Mol. Cell. Biochem., 111, 143-147). Here we report a novel aspect of Ox-LDL-mediated signal transduction. We demonstrate that in aortic smooth muscle cells, Ox-LDL stimulates the activity of a UDP-galactose:glucosylceramide beta1-->4 galactosyltransferase (GalT-2) and phosphorylation/activation of p44 mitogen-activated protein (MAP) kinase (p44 MAPK). The activity of GalT-2 increased about 2-fold within 2.5-5 min of incubation of cells with Ox-LDL (10 microg/ml). After 5 min of incubation of cells with Ox-LDL, but not LDL, there was a 2-fold increase in the activity of p44 MAPK. Phosphoamino acid analysis employing thin layer chromatography revealed that the tyrosine and threonine moieties of p44 MAPK was phosphorylated by Ox-LDL. D-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP; a potent inhibitor of GalT-2) impaired the Ox-LDL mediated induction of p44 MAPK activity and the phosphorylation of tyrosine and threonine residues in p44 MAPK. This phenomenon was bypassed by the simultaneous addition of lactosylceramide. The upstream and downstream parameters in MAP kinase signaling pathways were investigated next. We found that Ox-LDL stimulated (9-fold) the loading of GTP on Ras. Interestingly, Ox-LDL specifically induced c-fos mRNA expression (6.5-fold) in these cells, as compared to the control. Thus, one of the biochemical mechanisms in Ox-LDL mediated induction in the proliferation in aortic smooth muscle cells may involve GalT-2 activation, lactosylceramide production, Ras GTP loading, activation of the kinase cascade, and c-fos expression.

Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells.

Previously, our laboratory reported that lactosylceramide (LacCer) stimulated human aortic smooth muscle cell proliferation via specific activation of p44 mitogen-activated protein kinase (MAPK) in the p21(ras)/Raf-1/MEK2 pathway and induced expression of the transcription factor c-fos downstream to the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free oxygen radicals in LacCer-mediated induction of cell proliferation. Superoxide levels were measured by the lucigenin chemiluminescence method, MAPK activity was measured by immunocomplex kinase assays, and Western blot analysis and c-fos expression were measured by Northern blot assay. We found that LacCer (10 microM) stimulates endogenous superoxide production (7-fold compared with control) in human aortic smooth muscle cells specifically by activating membrane-associated NADPH oxidase, but not NADH or xanthine oxidase. This process was inhibited by an inhibitor of NADPH oxidase, diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate. NAC and DPI both abrogated individual steps in the signaling pathway leading to cell proliferation. For example, the p21(ras).GTP loading, p44 MAPK activity, and induction of transcription factor c-fos all were inhibited by NAC and DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced glutathione (GSH). In contrast, depletion of GSH by L-buthionine (S, R)-sulfoximine up-regulated the above described signaling cascade. In sum, LacCer, by virtue of activating NADPH oxidase, produces superoxide (a redox stress signaling molecule), which mediates cell proliferation via activation of the kinase cascade. Our findings may explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.

Lactosylceramide stimulates Ras-GTP loading, kinases (MEK, Raf), p44 mitogen-activated protein kinase, and c-fos expression in human aortic smooth muscle cells.

Previously, our laboratory has shown that lactosylceramide (LacCer) can serve as a mitogenic agent in the proliferation of aortic smooth muscle cells "a hallmark in the pathogenesis of atherosclerosis" (Chatterjee, S. (1991) Biochem. Biophys. Res. Commun. 181, 554-561). Here we report a novel aspect of LacCer-mediated signal transduction. We demonstrate that LacCer (10 microM) can stimulate the phosphorylation of mitogen-activated protein (MAP) kinase p44MAPK to phosphorylated p44MAPK in aortic smooth muscle cells from rabbit or human origin. Western immunoblot assays and direct measurement of activity in immunoprecipitated MAP kinase revealed that within 5 min of incubation of cells with LacCer there was a 3.5-fold increase in the activity of p44MAPK. This continued up to 10 min of incubation; thereafter, the MAP kinase activity decreased in these cells. Phosphoamino acid analysis revealed that the tyrosine and threonine moieties of p44MAPK was phosphorylated by LacCer. Incubation of cells with ceramide and glucosylceramide did not significantly stimulate p44MAPK activity. Preincubation with tyrphostin (20 microM; a potent and specific inhibitor of tyrosine kinase) markedly inhibited the LacCer mediated stimulation in p44MAPK activity. Next we investigated the upstream and downstream parameters in MAP kinase signaling pathways. We found that lactosylceramide stimulated (7-fold) the loading of GTP on Ras. Concomitantly, LacCer stimulated the phosphorylation of MAP kinase kinases (MEK) and Raf within 2.5 min. Lactosylceramide specifically induced c-fos mRNA expression (3-fold) in these cells as compared to control. In summary, one of the biochemical mechanisms in LacCer mediated induction in the proliferation of aortic smooth muscle cells may involve Ras-GTP loading, activation of the kinase cascade (MEK, Raf, p44MAPK), and c-fos expression.

Animal lectins as self/non-self recognition molecules. Biochemical and genetic approaches to understanding their biological roles and evolution.

In recent years, the significant contributions from molecular research studies on animal lectins have elucidated structural aspects and provided clues not only to their evolution but also to their multiple biological functions. The experimental evidence has suggested that distinct, and probably unrelated, groups of molecules are included under the term "lectin." Within the invertebrate taxa, major groups of lectins can be identified: One group would include lectins that show significant homology to membrane-integrated or soluble vertebrate C-type lectins. The second would include those beta-galactosyl-specific lectins homologous to the S-type vertebrate lectins. The third group would be constituted by lectins that show homology to vertebrate pentraxins that exhibit lectin-like properties, such as C-reactive protein and serum amyloid P. Finally, there are examples that do not exhibit similarities to any of the aforementioned categories. Moreover, the vast majority of invertebrate lectins described so far cannot yet be placed in one or another group because of the lack of information regarding their primary structure. (See Table 1.) Animal lectins do not express a recombinatorial diversity like that of antibodies, but a limited diversity in recognition capabilities would be accomplished by the occurrence of multiple lectins with distinct specificities, the presence of more than one binding site, specific for different carbohydrates in a single molecule, and by certain "flexibility" of the binding sites that would allow the recognition of a range of structurally related carbohydrates. In order to identify the lectins' "natural" ligands, we have investigated the interactions between those proteins and the putative endogenous or exogenous glycosylated substances or cells that may be relevant to their biological function. Results from these studies, together with information on the biochemical properties of invertebrate and vertebrate lectins, including their structural relationships with other vertebrate recognition molecules, are discussed.

Mechanism of action of the Escherichia coli UvrABC nuclease: clues to the damage recognition problem.

During the process of E. coli nucleotide excision repair, DNA damage recognition and processing are achieved by the action of the uvrA, uvrB, and uvrC gene products. The availability of highly purified proteins has lead to a detailed molecular description of E. coli nucleotide excision repair that serves as a model for similar processes in eukaryotes. An interesting aspect of this repair system is the protein complex's ability to work on a vast array of DNA lesions that differ widely in their chemical composition and molecular architecture. Here we propose a model for damage recognition in which the UvrB protein serves as the component that confers enhanced specificity to a preincision complex. We hypothesize that one major determinant for the formation of a stable preincision complex appears to be the disruption of base stacking interactions by DNA lesions.

Initiation of the UvrABC nuclease cleavage reaction. Efficiency of incision is not correlated with UvrA binding affinity.

The incision steps of Escherichia coli nucleotide excision repair are mediated by the UvrABC nuclease complex. We have previously shown that the UvrABC nuclease specifically incises apyrimidinic (AP) sites less efficiently than o-benzylhydroxylamine-modified apyrimidinic (BA) sites. To investigate these differences, quantitative DNase I footprinting titration studies were performed. The UvrA binding isotherms were similar for both the AP site (Kd = 6 x 10(-9) M) and the bulkier BA lesion (Kd = 14 x 10(-9) M), despite the fact that the extent of incision differs for these two lesions. It was also found that the relative binding affinity of the preincision UvrA2B complex to the AP and BA substrates differs significantly with estimated apparent equilibrium dissociation constants (Kd) of 4 x 10(-9) M and 80 x 10(-9) to 120 x 10(-9) M, respectively. These results indicate that incision efficiency does not correlate to UvrA binding affinity, but is a direct result of interactions between the UvrA2B complex and the site of the DNA damage. It is also shown that high UvrA concentrations are inhibitory to the UvrABC nuclease reaction.

Damage repertoire of the Escherichia coli UvrABC nuclease complex includes abasic sites, base-damage analogues, and lesions containing adjacent 5' or 3' nicks.

Using oligonucleotide synthesis, we demonstrate a rapid and efficient method for the construction of DNA duplexes containing defined DNA lesions at specific positions. These DNA lesions include apyrimidinic sites, reduced apyrimidinic sites, and base-damage analogues consisting of O-methyl- or O-benzylhydroxylamine-modified apyrimidinic sites. A 49 base pair DNA duplex containing these lesions was specifically incised by the UvrABC nuclease complex. The incision sites occurred predominantly at the eighth phosphodiester bond 5' and the fifth phosphodiester bond 3' to the lesion. Multiple incisions were observed 3' to the lesion. The extent of DNA incisions was base-damage analogues greater than reduced apyrimidinic sites greater than apyrimidinic sites. Introduction of 3' or 5' nicks at the site of a base-damage analogue by treatment of these substrates with either endonuclease III or endonuclease IV reduced, but did not abolish, subsequent incision by the UvrABC complex, whereas introduction of a 3' nick at an abasic site increased the incision efficiency of the UvrABC complex. These data demonstrate a convergence of base and nucleotide excision repair pathways in the removal of specific base damages.

Distribution of choline acetyltransferase in cerebral and extracerebral cranial arteries of the cat. Its relationship to neurogenic atropine-sensitive dilation.

Choline-acetyltransferase (ChAT) activity was surveyed in segments of cranial arteries--both cerebral and extracerebral--from the cat. High levels were found in pial arteries, both cerebral and cerebellar, and in the arteries to salivary glands, tongue, and nose. Intermediate levels were found in the external and internal maxillary arteries and many of their branches. Enzyme levels in the arteries supplying the head--common carotid, vertebral, and in several systemic arteries and veins and also the lingual vein--were probably not significant. Only those vessels that have higher ChAT contents show capacity for neurogenic vasodilation. The dilation of segments of a number of these arteries, the basilar, middle cerebral, lingual, and internal maxillary, is reduced significantly by atropine (5 X 10(-7) M). ChAT activity did not correlate with vessel norepinephrine content. The data may be interpreted as defining a functional vasodilator system to the head encompassing both cerebral and extracerebral arteries that depends in part on a functional cholinergic link involving a muscarinic receptor. It is separate from the adrenergic outflow. The tissues supplied by vasculature receiving this type of innervation are of ectodermal origin.