Addressing Intergenerational Inequity in Tobacco-Harm: What Helps Children of Smokers to Remain Nonsmokers?

INTRODUCTION: Children of people who smoke are more likely to take up smoking themselves. In Aotearoa New Zealand (NZ), adolescent smoking declined dramatically between 2000 and 2016 despite limited change in parental smoking, demonstrating that the cycle can be broken. AIMS AND METHODS: This study aimed to identify modifiable factors associated with never smoking in Year 10 students (14-15 years) who had at least one caregiver who smoked. We used data from the Youth Insights Survey (2016 and 2018, pooled, N = 5,422) and identified students with at least one caregiver (mother, father, grandparent, other caregiver) who smoked (N = 2,205). To investigate modifiable factors potentially associated with nonsmoking we used logistic regression with marginally adjusted prevalence estimates. RESULTS: Overall, 41% of students had at least one caregiver who smoked. In this group, the majority (65%) had never smoked themselves. After adjustment, never-smoking was more prevalent among students attending low-deprivation (more affluent) schools (73% had never smoked) compared to high-deprivation schools (44%); students not exposed to others' smoking inside the home (72%) or in cars (70%) in the past week compared to those exposed (59% and 51%, respectively); and students whose parents would be upset if they were caught smoking (68% vs 49% for those whose parents would not be upset), or who had high self-esteem (69% vs 55% for those with low self-esteem). CONCLUSIONS: Modifiable factors independently associated with non-smoking in adolescents with caregiver(s) who smoked were: nonexposure to smoking inside the home and in cars, parental expectations of nonsmoking, and high self-esteem. IMPLICATIONS: Even in countries like NZ with relatively low adult smoking rates, children's exposure to caregiver smoking may be prevalent, particularly in structurally disadvantaged populations. This study suggests that action to promote smokefree homes and cars, build high self-esteem in young people, and communicate expectations of non-smoking are likely to help children of people who smoke to remain nonsmokers. A comprehensive approach that also addresses "upstream" factors (eg, socioeconomic deprivation) and underlying causes of structural inequity (eg, institutional racism) is needed. Such policy and community action may help to break intergenerational cycles of tobacco use and health inequity.

Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling.

The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.

Early-onset smoking and vaping of cannabis: Prevalence, correlates and trends in New Zealand 14-15-year-olds.

INTRODUCTION: Initiating cannabis use at an early age elevates risk of harm. Cannabis vaping is an emerging issue, and it is unknown whether the patterning and correlates of early-onset cannabis vaping differ from those of cannabis smoking. METHODS: We used repeat cross-sectional data from a nationally representative biennial survey (2012-2018) of students aged 14-15 years in New Zealand (N = 11,405), response rate 65% (2012), 64% (2014-2016) and 59% (2018). RESULTS: Between 2012 and 2018 lifetime cannabis use decreased, but regular use (past month, weekly, daily) was stable. Prevalence of past month, weekly and daily use in 2016-2018 (pooled) was 8.6%, 3.4% and 1.5%, respectively. Cannabis vaping was reported by 24% of past month cannabis users. The demographic profile of early-onset cannabis smokers and vapers was similar, with elevated use of both modes among Maori (Indigenous), same- or both-sex attracted students and those in low decile (high-deprivation) schools. Correlates were similar for both modes. Cannabis use was strongly associated with tobacco and alcohol use. The next strongest associations (after adjustment) were exposure to second-hand smoke at home, student income >$50/week and low parental monitoring of whereabouts. Past week social media use, psychological distress and low parental monitoring of spending were also associated with both modes. DISCUSSION AND CONCLUSIONS: Early-onset cannabis use is much higher in structurally disadvantaged groups, and among those who use tobacco and alcohol. Comprehensive multisubstance approaches to prevention are indicated in this age group. Efforts to reduce socio-economic inequity and exposure to other risk factors may reduce cannabis-related harm.

Has increasing internet use due to smartphone uptake contributed to the decline in adolescent smoking?

INTRODUCTION: The emergence of low-cost smartphone technology has coincided with major declines in adolescent smoking and other risk behaviours. This study explores the relationship between internet use and smoking in adolescents and investigates whether rising internet use contributed to the decline in smoking between 2012 and 2018. METHODS: Data were drawn from a nationally representative New Zealand survey of students aged 14-15 (N = 11 299), conducted biennially between 2012 and 2018. We used logistic regression to explore the association between internet use and smoking and test whether increasing time on the internet was associated with declining adolescent smoking over the study period. RESULTS: The proportion of students spending 5+ hours per day online increased from 15% to 35%. Heavy internet use was not a protective factor for smoking at the individual level. In 2016/2018, some types of past week internet use were associated with decreased risk of smoking (e.g. doing schoolwork, finding out about news), some were associated with increased risk (e.g. social media use) and others appeared to have no association with smoking (e.g. gaming, online shopping). The relative risk of smoking was lower in 2018 relative to 2012 (relative risk 0.68, 95% confidence interval 0.51, 0.90, after adjustment for demographic factors). Adding internet use to the model did not help to account for smoking decline. DISCUSSION AND CONCLUSIONS: We found no evidence that increasing time spent on the internet during the 2012-2018 period (during which smartphones became ubiquitous) contributed to the decline in adolescent smoking.

The effects of essential oil mouthrinses with or without alcohol on plaque and gingivitis: a randomized controlled clinical study.

BACKGROUND: The efficacy of several variants of essential oil mouthrinses has been studied extensively. This is the first study to compare the anti-plaque and anti-gingivitis efficacy of two marketed essential oil mouthrinses: one is an alcohol containing mouthrinse and the other one is an alcohol-free mouthrinse. METHODS: This examiner-blind, parallel-group study randomized subjects to three groups: 1) Mechanical Oral Hygiene (MOH) only; 2) MOH plus Alcohol-Containing essential oil Mouthrinse (ACM); 3) MOH plus Alcohol-Free essential oil Mouthrinse (AFM). Primary endpoint was whole-mouth mean Modified Gingival Index (MGI) at six months. Secondary endpoints included whole-mouth mean MGI at one and three months, and whole-mouth mean Plaque Index (PI) and whole-mouth mean Bleeding Index (BI) at one, three and six months. Safety assessments were conducted at all time points. RESULTS: A total of 370 subjects were enrolled; 348 subjects completed the study. After six months, subjects using essential oil mouthrinses with or without alcohol showed significant reduction (p < 0.001) in gingivitis (28.2% and 26.7%, respectively) and significant reduction (p < 0.001) in plaque (37.8% and 37.0%, respectively), compared to those performing MOH only. Significant reductions in MGI, PI, and BI (p < 0.001) were observed at one and three months and also at six months for mean BI. No statistically significant differences were observed for all measured indices between ACM and AFM groups at any time point. Both mouthrinses were well tolerated. CONCLUSIONS: No significant differences were observed in the efficacy of ACM and AFM to reduce plaque and gingivitis, when used in addition to MOH, over six months. TRIAL REGISTRATION: The trial was registered on clinicaltrials.gov on November 30, 2016. The registration number is NCT02980497 .

The allosteric glycogen synthase kinase-3 inhibitor NP12 limits myocardial remodeling and promotes angiogenesis in an acute myocardial infarction model.

A key feature of acute myocardial infarction (AMI) is an alteration in cardiac architecture. Signaling events that result in the inhibition of glycogen synthase kinase-3 (GSK-3)ß represent an adaptive response that might limit the extent of adverse remodeling in the aftermath of AMI. Here, we report that an allosteric inhibitor of GSK-3ß, 4-benzyl-2-(naphthalene-1-yl)-1,2,4-thiadiazolidine-3,5-dione (NP12), lessens the magnitude of adverse myocardial remodeling and promotes angiogenesis. Male and female mice 8-10 weeks old were grouped (six animals in each group) into sham surgery (sham group), left anterior descending (LAD) ligation of the coronary artery followed by intramyocardial PBS injections (control group), and LAD ligation followed by NP12 administration (NP12 group). After 7 and 14 days, the extents of fibrosis and integrity of blood vessels were determined. Intramyocardial administration of NP12 increased phosphorylation of GSK-3ß, reduced fibrosis, and restored diastolic function in the mice that had experienced an AMI. Morphometric analyses revealed increased CD31+ and Ki67+ vascular structures and decreased apoptosis in these mice. NP12 administration mediated proliferation of reparative cells in the AMI hearts. In a time-course analysis, Wnt3a and NP12 stabilized ß-catenin and increased expression of both Nanog and VEGFR2. Moreover, NP12 increased the expression of ß-catenin and Nanog in myocardium from AMI mice. Finally, loss- and gain-of-function experiments indicated that the NP12-mediated benefit is, in part, Nanog-specific. These findings indicate that NP12 reduces fibrosis, reestablishes coronary blood flow, and improves ventricular function following an AMI. We conclude that NP12 might be useful for limiting ventricular remodeling after an AMI.

Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease.

Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.

Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells.

Purpose: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow-derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.Experimental Design: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/GR1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).Results: CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/GR1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.Conclusions: We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model. Clin Cancer Res; 23(12); 3109-19. ©2016 AACR.

Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils.

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRß-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.

The inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach.

In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. (99m)Tc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10(-11)M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), that the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 min to bind more tilmanocept (acting as intracellular "drug compilers" of tilmanocept into non-degraded vesicles), gives serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate (99m)Tc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy.

Collaborating with a social housing provider supports a large cohort study of the health effects of housing conditions.

BACKGROUND: Despite the importance of adequate, un-crowded housing as a prerequisite for good health, few large cohort studies have explored the health effects of housing conditions. The Social Housing Outcomes Worth (SHOW) Study was established to assess the relationship between housing conditions and health, particularly between household crowding and infectious diseases. This paper reports on the methods and feasibility of using a large administrative housing database for epidemiological research and the characteristics of the social housing population. METHODS: This prospective open cohort study was established in 2003 in collaboration with Housing New Zealand Corporation which provides housing for approximately 5% of the population. The Study measures health outcomes using linked anonymised hospitalisation and mortality records provided by the New Zealand Ministry of Health. RESULTS: It was possible to match the majority (96%) of applicant and tenant household members with their National Health Index (NHI) number allowing linkage to anonymised coded data on their hospitalisations and mortality. By December 2011, the study population consisted of 11,196 applicants and 196,612 tenants. Half were less than 21 years of age. About two-thirds identified as Maori or Pacific ethnicity. Household incomes were low. Of tenant households, 44% containing one or more smokers compared with 33% for New Zealand as a whole. Exposure to household crowding, as measured by a deficit of one or more bedrooms, was common for applicants (52%) and tenants (38%) compared with New Zealanders as whole (10%). CONCLUSIONS: This project has shown that an administrative housing database can be used to form a large cohort population and successfully link cohort members to their health records in a way that meets confidentiality and ethical requirements. This study also confirms that social housing tenants are a highly deprived population with relatively low incomes and high levels of exposure to household crowding and environmental tobacco smoke.

Meta-analysis of the effect of an essential oil-containing mouthrinse on gingivitis and plaque.

BACKGROUND: Standard recommendations for oral hygiene practices have focused on mechanical methods (toothbrushing and interdental cleaning). Published evidence indicates antimicrobial mouthrinses provide oral health benefits beyond mechanical methods alone. The purpose of this meta-analysis was to evaluate the combined effectiveness of mechanical methods with essential oil-containing mouthrinses (MMEO) versus mechanical methods (MM) alone in achieving site-specific, healthy gingival tissue and reducing plaque and gingivitis. TYPES OF STUDIES REVIEWED: All industry-sponsored clinical trials investigating the antigingivitis and antiplaque effects of essential oil (EO)-containing mouthrinses conducted from 1980 to 2012 were reviewed; 29 of 32 studies met the inclusion criteria of 6 months or longer duration, randomized, observer-masked, placebo-controlled, and with individual-level site-specific data. By-study treatment effects were estimated through generalized linear models for binary data and analysis of covariance for continuous data, and then combined using standard meta-analysis techniques; heterogeneity was also assessed. RESULTS: Summary odds ratios for a healthy gingival site and for a plaque-free site were, respectively, 5.0 (95% confidence interval [CI], 3.3-7.5) and 7.8 (95% CI, 5.4-11.2) for MMEO participants versus MM participants at 6 months. The summary percentage reductions in whole-mouth mean gingivitis and plaque at 6 months were 16.0 (95% CI, 11.3-20.7) and 27.7 (95% CI, 22.4-32.9), respectively. Responder analyses using aggregate individual-level data showed 44.8% of MMEO participants and 14.4% of MM participants achieved at least 50% healthy sites in their mouths at 6 months. Similarly, 36.9% of MMEO participants and 5.5% of MM participants achieved at least 50% plaque-free sites in their mouths at 6 months. CONCLUSIONS AND PRACTICAL IMPLICATIONS: This is the first meta-analysis to demonstrate the clinically significant, site-specific benefit of adjunctive EO treatment in people within a 6-month period (that is, between dental visits).

Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector.

We described earlier a dual-combination anti-HIV type 1 (HIV-1) lentiviral vector (LVsh5/C46) that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT) mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1) vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC) either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.

Association between serum 25-hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis.

OBJECTIVE: To identify effects of vitamin D status, as defined by circulating 25-hydroxyvitamin D (25-OHD) levels on the annual frequency of pulmonary exacerbations (Pex) and hospitalizations, on standard measures of pulmonary function, and to identify determinants of 25-OHD levels in pediatric patients with cystic fibrosis (CF). HYPOTHESIS: Higher levels of serum 25-OHD would be associated with fewer Pex and hospitalizations, and improved lung function based on pulmonary function tests (PFTs). STUDY DESIGN: Retrospective chart review of 53 pediatric patients from January 2011 to December 2011. Significant relationships were examined using linear and logistic regression analyses. PATIENT SELECTION: Patients ages 5 through 22 years followed at the CF Care Center and Clinic at Yale-New Haven Hospital, New Haven, CT., who had at least four clinic visits and at least one 25-OHD measurement between January 1, 2011 and December 31, 2011. RESULTS: Serum 25-OHD level and gender were strong independent determinants of the annual number of Pex (P < 0.01, with lower 25-OHD level and female gender associated with Pex). There was a significant influence of gender (P < 0.05) and a near-significant influence of serum 25-OHD (P < 0.08) on hospitalization rate. There was no effect of 25-OHD levels on PFTs. Other candidate factors (age, season, gender, pancreatic sufficiency, or severity of genetic mutation) did not significantly effect 25-OHD level. CONCLUSIONS: The annual number of Pex in pediatric CF patients is significantly associated with 25-OHD levels and gender, raising the consideration that maintaining vitamin D sufficiency may lead to decreased incidence of Pex and hospitalizations requiring antibiotic therapy.

Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.

Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4(+) T lymphocytes, and CD34(+) hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.

A case of severe 1,25-dihydroxyvitamin D-mediated hypercalcemia due to a granulomatous disorder.

BACKGROUND: Profound hypercalcemia is usually due to underlying malignancy. CASE: We describe a case of granulomatous myositis presenting with extreme hypercalcemia of 20.1 mg/dl and generalized weakness that did not resolve despite rapid correction of serum calcium. The disease process was unmasked by cholecalciferol supplementation. Initial search for a malignant process yielded no diagnosis, but an elevated 1,25-dihydroxyvitamin D level, in the setting of a suppressed PTH and undetectable PTHrP, pointed to the presence of excessive 1α-hydroxylase activity. METHODS AND RESULTS: Biopsy of the vastus lateralis muscle showed extensive granulomatous myositis. Immunohistochemical staining for 1α-hydroxylase was localized to the multinucleated giant cells and histiocytes. Musculoskeletal magnetic resonance imaging showed involvement of proximal muscle groups of both thighs and upper limbs. CONCLUSION: Measurement of vitamin D metabolites is pivotal in diagnosing 1,25-dihydroxyvitamin D-mediated hypercalcemia. Granulomatous disease can occasionally cause profound hypercalcemia and needs to be considered in the differential diagnosis. 1,25-Dihydroxyvitamin D-mediated hypercalcemia is responsive to glucocorticoid therapy.

The feasibility of real-time in vivo optical detection of blood-brain barrier disruption with indocyanine green.

Osmotic disruption of the blood-brain barrier (BBB) by intraarterial mannitol injection is sometimes required for the delivery of chemotherapeutic drugs to brain tissue. Osmotic disruption is affected by a number of factors, and there is a significant variability in the degree and distribution of BBB disruption in clinical and experimental settings. Brain tissue concentrations of indocyanine green (ICG) can be measured by optical techniques. The aim of this experiment was to determine whether the disruption of the BBB significantly altered the regional pharmacokinetics of ICG. We were able to track in vivo brain tissue concentrations of ICG in 13 New Zealand white rabbits by employing a novel optical approach. Evan's blue was used to assess the distribution of BBB disruption on post mortem examination. BBB disruption by intraarterial mannitol injection was found to be highly variable, and only five of the 13 animals demonstrated the disruption at the site of optical measurements. In these animals, we observed a ninefold increase in ICG concentrations and fourfold increase in the area under the concentration-time curve, compared to those without BBB disruption at the site of measurement. This study shows the feasibility of optical monitoring of BBB disruption with intravenous (IV) ICG injections. Virtual real-time optical monitoring of the BBB disruption could help improve intraarterial delivery of chemotherapeutic drugs.

Parental behaviours, but not parental smoking, influence current smoking and smoking susceptibility among 14 and 15 year-old children.

OBJECTIVE: To explore whether parental behaviours related to smoking socialisation and parenting are associated with smoking susceptibility and current smoking in 14-15 year old students. METHOD: Data were sourced from the New Zealand 2006 Year 10 In-depth Survey, a school-based survey of 3,189 students. Outcome measures were susceptibility to smoking and current smoking. Potential determinants were second-hand smoke exposure in the home, parental smoking, parental anti-smoking expectations, anti-smoking rules, pocket money, monitoring of pocket money expenditure, general rule setting and monitoring, and concern about education. Analysis used logistic regression to adjust for potential confounding factors. RESULTS: Exposure to second-hand smoke and lack of parental anti-smoking expectations were independently associated with smoking susceptibility and current smoking. Parental smoking was not independently associated with current smoking or susceptibility. Receiving pocket money and an absence of monitoring of expenditure were associated with smoking susceptibility and current smoking. Lack of parental rule setting was associated with smoking susceptibility. Findings were similar whether or not one or more parents were smokers. CONCLUSIONS: Not allowing smoking in the home, communicating non-smoking expectations to children, monitoring pocket money, and setting rules to guide behaviour are strategies which are likely to reduce risk of smoking uptake. IMPLICATIONS: The study provides evidence to inform the development of parent-focused interventions to reduce the risk of smoking initiation by children.