This study considers three questions: 1. What are the Canadian public’s prioritization preferences for new government spending on a range of public health-related goods outside the scope of the country’s national system of health insurance? 2. How homogenous or heterogeneous is the Canadian public in terms of these preferences? 3. What factors are predictive of the Canadian public’s preferences for new government spending? Data were collected in 2008 from a national random sample of Canadian adults through a telephone interview survey (n =1,005). Respondents were asked to rank five spending priorities in terms of their preference for new government spending. Bivariate and multivariable logistic regression analyses were conducted. As a first priority, Canadian adults prefer spending on child care (26.2%), followed by pharmacare (23.1%), dental care (20.8%), home care (17.2%), and vision care (12.7%). Sociodemographic characteristics predict spending preferences, based on the social position and needs of respondents. Policy leaders need to give fair consideration to public preferences in priority setting approaches in order to ensure that public health-related goods are distributed in a manner that best suits population needs.

The anti-atherogenic cytokine, TGF-β, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-β remain poorly understood. In this study we examine the effect of TGF-β on macrophage cholesterol homeostasis and delineate the role of Smads-2 and ‐3 during this process. Western blot analysis showed that TGF-β induces a rapid phosphorylation-dependent activation of Smad-2 and ‐3 in THP-1 and primary human monocyte-derived macrophages. Small interfering RNA-mediated knockdown of Smad-2/3 expression showed that the TGF-β-mediated regulation of key genes implicated in the uptake of modified low density lipoproteins and the efflux of cholesterol from foam cells was Smad-dependent. Additionally, through the use of virally delivered Smad-2 and/or Smad-3 short hairpin RNA, we demonstrate that TGF-β inhibits the uptake of modified LDL by macrophages through a Smad-dependent mechanism and that the TGF-β-mediated regulation of CD36, lipoprotein lipase and scavenger receptor-A gene expression was dependent on Smad-2. These studies reveal a crucial role for Smad signaling, particularly Smad-2, in the inhibition of foam cell formation by TGF-β through the regulation of expression of key genes involved in the control of macrophage cholesterol homeostasis.

Highlights

► Anti-atherogenic cytokine TGF-β inhibits macrophage foam cell formation. ► The role of Smads in the control of macrophage cholesterol homeostasis was studied. ► Smads were found to play a key role in the TGF-β-mediated uptake of modified LDL. ► A dominant role of Smad2 was identified in the regulation of gene expression. ► The TGF-β-Smad axis may represent a powerful anti-foam cell therapeutic target.

A major event in mammalian male sex determination is the induction of the testis determining factor Sry and its downstream gene Sox9. The current study provides one of the first genome wide analyses of the downstream gene binding targets for SRY and SOX9 to help elucidate the molecular control of Sertoli cell differentiation and testis development. A modified ChIP-Chip analysis using a comparative hybridization was used to identify 71 direct downstream binding targets for SRY and 109 binding targets for SOX9. Interestingly, only 5 gene targets overlapped between SRY and SOX9. In addition to the direct response element binding gene targets, a large number of atypical binding gene targets were identified for both SRY and SOX9. Bioinformatic analysis of the downstream binding targets identified gene networks and cellular pathways potentially involved in the induction of Sertoli cell differentiation and testis development. The specific DNA sequence binding site motifs for both SRY and SOX9 were identified. Observations provide insights into the molecular control of male gonadal sex determination.

Objective

Weight gain and growth in early life may influence adult pro-inflammatory and pro-thrombotic cardiovascular risk factors.

Methods

Follow-up of a birth cohort in New Delhi, India, whose weight and height were measured 6-monthly until age 21 years. BMI at birth, during infancy (2 years), childhood (11 years) and adulthood (26-32 years) and BMI gain between these ages were analyzed in 886 men and 640 women in relation to adult fibrinogen, high-sensitivity C-reactive protein (hsCRP) and plasminogen activator inhibitor (PAI-1) concentrations.

Results

All the pro-inflammatory/pro-thrombotic risk factors were higher in participants with higher adiposity. In women, BMI at birth and age 2 years was inversely related to fibrinogen (p=0.002 and 0.05) and, after adjusting for adult adiposity, to hsCRP (p=0.02 and 0.009). After adjusting for adult adiposity, BMI at 2 years was inversely related to hsCRP and PAI-1 concentrations (p<0.001 and p=0.02) in men. BMI gain between 2-11 years and/or 11 years to adulthood was positively associated with fibrinogen and hsCRP in women and with hsCRP and PAI-1 in men.

Conclusions

Thinness at birth or during infancy, and accelerated BMI gain during childhood/adolescence are associated with a pro-inflammatory/pro-thrombotic state in adult life. An altered inflammatory state could be one link between small newborn/infant size and adult cardiovascular disease. Associations between pro-inflammatory markers and childhood/adolescent BMI gain are probably mediated through adult adiposity.

Neurotrophin 3 (Ntf3) is expressed in Sertoli cells and acts as a chemo-attractant for cell migration from the mesonephros into the developing testis, a process critical to the early morphological events of testis cord formation. The male sex-determining gene Sry initiates the process of testicular development. Sox9 is a key regulator of male sex determination and is directly regulated by SRY. Information on other downstream target genes of SRY is limited. The current study demonstrates an interaction of SRY with the Ntf3 promoter both in vitro and in vivo. The Ntf3 promoter in both rat and mouse contains at least one putative SRY binding site in the −0.6 kb promoter region. In a luciferase reporter assay system, both SRY and SOX9 stimulated the Ntf3 promoter in vitro through an interaction with this SRY-binding motif. In an immunoprecipitation-based pull-down assay, recombinant SRY protein bound the Ntf3 promoter fragment containing an intact SRY binding site, whereas the same protein did not interact with the fragment containing a mutated SRY motif. Specific antibodies against SRY were used in a chromatin immunoprecipitation (ChIP) assay of embryonic testis and were found to precipitate the Ntf3 promoter region. The SRY ChIP assay confirmed the direct interaction between SRY and the Ntf3 promoter in vivo during male sex determination. Observations suggest that SRY physically interacts with the Ntf3 promoter during male sex determination to coordinate cell migration in the testis to form testis cords.

SRY directly regulates the Ntf3 promoter in vitro and in vivo during male sex determination.

BACKGROUND

The risk of type 2 diabetes mellitus is increased in people who have low birth weights and who subsequently become obese as adults. Whether their obesity originates in childhood and, if so, at what age are unknown. Understanding the origin of obesity may be especially important in developing countries, where type 2 diabetes is rapidly increasing yet public health messages still focus on reducing childhood “undernutrition.”

METHODS

We evaluated glucose tolerance and plasma insulin concentrations in 1492 men and women 26 to 32 years of age who had been measured at birth and at intervals of three to six months throughout infancy, childhood, and adolescence in a prospective, population-based study.

RESULTS

The prevalence of impaired glucose tolerance was 10.8 percent, and that of diabetes was 4.4 percent. Subjects with impaired glucose tolerance or diabetes typically had a low body-mass index up to the age of two years, followed by an early adiposity rebound (the age after infancy when body mass starts to rise) and an accelerated increase in body-mass index until adulthood. However, despite an increase in body-mass index between the ages of 2 and 12 years, none of these subjects were obese at the age of 12 years. The odds ratio for disease associated with an increase in the body-mass index of 1 SD from 2 to 12 years of age was 1.36 (95 percent confidence interval, 1.18 to 1.57; P<0.001).

CONCLUSIONS

There is an association between thinness in infancy and the presence of impaired glucose tolerance or diabetes in young adulthood. Crossing into higher categories of body-mass index after the age of two years is also associated with these disorders.

Objective

To report the successful outcome of a rare optic pit-associated maculopathy with an outer retinal hole following 23 G vitrectomy, internal limiting membrane (ILM) peeling and fluid-gas exchange without additional endolaser.

Method

Interventional case report.

Results

This case report documents a 56-year-old male patient with complaints of progressive diminution of vision in the right eye more than in the left eye due to an optic disc pit with an outer retinal hole and a cataract. Optical coherence tomography confirmed the presence of an outer retinal hole. The case report shows the successful outcome of a rare optic pit-associated maculopathy with an outer retinal hole and a cataract following phacoemulsification with 23 G vitrectomy, ILM peeling and fluid-gas exchange without additional endolaser.

Objective

To study the relationship between lipid peroxidation of spermatozoa and changes in functional intergrity of human spermatozoa membrane in male subjects.

Materials and Methods

Sixty eight male partners of infertile couples were included in the study. Status of oxidative stress was assessed by determining malondialdehyde (MDA) in seminal plasma. Functinal intergrity of sperm membrance was tested subjecting the sperm to hypo-osmotic test (HOS). The seminal plasma MDA levels were compared with seminogram parameters as well as with the results of HOS test using Pearson’s coefficient of correlation (r) and significance of coefficient of correlation calculated from the table.

Result

A significant but weak negative correlation was observed between seminal plasma MDA level and sperm concentration (r=−0.33,p<0.05), sperm motility (r=−0.37,p<0.05), sperm morphology (r=−0.37,p<0.05), and percentage of HOS positive spermatozoa (r=−0.33,p<0.05). Percentages of HOS positive spermatozoa also exhibited a significant but weak negative relationship with sperm concentration (r=−0.47,p<0.01), sperm motility (r=−0.48,p<0.01), sperm morphology (r=−0.49,p<0.01).

Conclusion

Lipid peroxidation of spermatozoa is likely to affect the functional intergrity of the spermatozoa membrane.

The present study has been undertaken to apply the concept of nanoparticulate mucopenetrating drug delivery system for complete eradication of Helicobacter pylori (H. pylori), colonised deep into the gastric mucosal lining. Most of the existing drug delivery systems have failed on account of either improper mucoadhesion or mucopenetration and no dosage form with dual activity of adhesion and penetration has been designed till date for treating H. pylori induced disorders. In the present study, novel chitosan-alginate polyelectrolyte complex (CS-ALG PEC) nanoparticles of amoxicillin have been designed and optimized for various variables such as pH and mixing ratio of polymers, concentrations of polymers, drug and surfactant, using 33 Box-Behnken design. Various studies like particle size, surface charge, percent drug entrapment, in-vitro mucoadhesion and in-vivo mucopenetration of nanoparticles on rat models were conducted. The optimised FITC labelled CS-ALG PEC nanoparticles have shown comparative low in-vitro mucoadhesion with respect to plain chitosan nanoparticles, but excellent mucopenetration and localization as observed with increased fluorescence in gastric mucosa continuously over 6 hours, which clinically can help in eradication of H. pylori.

Background:

Treatment of plantar warts caused by human papilloma virus (HPV) strain types 1, 2 and 4 is often difficult and a challenging problem. Various therapeutic modalities available for treating this problem have not been uniformly successful.

Purpose:

The purpose of present study is to evaluate the efficacy of adapalene applied locally with occlusion in plantar warts.

Materials and Methods:

A total of 10 patient with 118 plantar warts were included in an open study. All were treated by applying adapalene gel 0.1% after paring of warts if needed followed by occlusive dressing with polythene paper in each patient. The effects of the treatment were evaluated every week till the clearance of all warts.

Findings:

Adapalene was used in 10 patient having 118 plantar warts. All the warts cleared in 39±15.07 days. There was no side effects like scar formation, irritation, erythema or infection with adapalene.

Conclusion:

Adapalene clears the plantar warts faster compared to other modalities available.

Limitation:

Need trial with large number of patients.

Bone marrow aspirations and bone marrow biopsies are important diagnostic procedures. A comparative study of both the procedures done simultaneously was retrospectively reviewed in 160 cases where the clinical history is correlated with BMA and BMB results. The advantage of each method is analyzed. Correlation of our findings with that given in the literature is done to give a guideline for both techniques. We have found that 61.25% of the cases showed a positive correlation between bone marrow aspiration and bone marrow biopsy. However, we found that tuberculous granulomas and Hodgkin disease involvement of the marrow were detected better in bone marrow biopsies. The advantage of both the procedures done together provided more material and enabled us to study the cytomorphology of the cells, with the pattern of distribution of the cells depending on the cases. However, when both the procedures are done simultaneously, a proper technique is required so as to yield good diagnostic material.

The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex determining factor SRY as the basic-helix-loop-helix (bHLH) transcription factor TCF21. SRY was found to bind to the Tcf21 promoter and activate gene expression. Mutagenesis of SRY/SOX9 response elements in the Tcf21 promoter eliminated the actions of SRY. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation. TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes. Therefore, SRY acts directly on the Tcf21 promoter to in part initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development.

Atherosclerosis is an inflammatory disorder of the vasculature that is orchestrated by the action of cytokines. Macrophages play a prominent role in all stages of this disease, including foam cell formation, production of reactive oxygen species, modulation of the inflammatory response and the regulation of the stability of atherosclerotic plaques. The role of the matrix metalloproteinase family in the control of plaque stability is well established. A disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) family has been implicated in several diseases and the expression of ADAMTS-4 in macrophages of atherosclerotic lesions has suggested a potential role for this protease in atherosclerosis. However, the action of cytokines on the expression of ADAMTS-4 in macrophages is poorly understood. We have investigated here the effect of transforming growth factor-β (TGF-β) on ADAMTS-4 expression in macrophages along with the regulatory mechanisms underlying its actions. Consistent with the anti-atherogenic role of TGF-β, this cytokine decreased the expression of ADAMTS-4 mRNA and protein in human macrophages. Transient transfection assays showed that the −100 to +10 promoter region contained the minimal TGF-β response elements. Small-interfering RNA-mediated knockdown revealed a critical role for Smads, p38 mitogen-activated protein kinase and c-Jun in the action of TGF-β on ADAMTS-4 mRNA expression. These studies show for the first time that TGF-β inhibits the expression of ADAMTS-4 in human macrophages and identifies the signalling pathways underlying this response. The inhibition of macrophage ADAMTS-4 expression is likely to contribute to the anti-atherogenic, plaque stabilisation action of TGF-β.

Liver X receptors (LXRs) are ligand-dependent transcription factors that are activated by metabolites of cholesterol, oxysterols, and a number of synthetic agonists. LXRs play potent anti-atherogenic roles in part by stimulating the efflux of cholesterol from macrophage foam cells. The LXR-induced expression of ATP-binding cassette transporter (ABC)-A1 and Apolipoprotein E (ApoE) in macrophages is essential for the stimulation of cholesterol efflux and the prevention of atherosclerotic development. Unfortunately, the signaling pathways underlying such regulation are poorly understood and were therefore investigated in human macrophages. The expression of ApoE and ABCA1 induced by synthetic or natural LXR ligands [TO901317, GW3965, and 22-(R)-hydroxycholesterol (22-(R)-HC), respectively] was attenuated by inhibitors of c-Jun N-terminal kinase (JNK) (curcumin and SP600125) and phosphoinositide 3-kinase (PI3K) (LY294002). Similar results were obtained with ABCG1 and LXR-α, two other LXR target genes. LXR agonists activated several components of the JNK pathway (SEK1, JNK and c-Jun) along with AKT, a downstream target for PI3K. In addition, dominant negative mutants of JNK and PI3K pathways inhibited the LXR-agonists-induced activity of the ABCA1 and LXR-α gene promoters in transfected cells. LXR agonists also induced the binding of activator protein-1 (AP-1), a key transcription factor family regulated by JNK, to recognition sequences present in the regulatory regions of the ApoE and ABCA1 genes. These studies reveal a novel role for JNK and PI3K/AKT signaling in the LXR-regulated expression in macrophages of several key genes implicated in atherosclerosis.

Joy Lawn and colleagues used a systematic process developed by the Child Health Nutrition Research Initiative (CHNRI) to define and rank research options to reduce mortality from intrapartum-related neonatal deaths (birth asphyxia) by the year 2015.

TNF-like protein 1A (TL1A), a TNF superfamily cytokine that binds to death receptor 3 (DR3), is highly expressed in macrophage foam cell-rich regions of atherosclerotic plaques, although its role in foam cell formation has yet to be elucidated. We investigated whether TL1A can directly stimulate macrophage foam cell formation in both THP-1 and primary human monocyte-derived macrophages with the underlying mechanisms involved. We demonstrated that TL1A promotes foam cell formation in human macrophages in vitro by increasing both acetylated and oxidized low-density lipoprotein uptake, by enhancing intracellular total and esterified cholesterol levels and reducing cholesterol efflux. This imbalance in cholesterol homeostasis is orchestrated by TL1A-mediated changes in the mRNA and protein expression of several genes implicated in the uptake and efflux of cholesterol, such as scavenger receptor A and ATP-binding cassette transporter A1. Furthermore, through the use of virally delivered DR3 short-hairpin RNA and bone marrow-derived macrophages from DR3 knockout mice, we demonstrate that DR3 can regulate foam cell formation and contributes significantly to the action of TL1A in this process in vitro. We show, for the first time, a novel proatherogenic role for both TL1A and DR3 that implicates this pathway as a target for the therapeutic intervention of atherosclerosis.

BACKGROUND

Although most procedures in the endoscopy clinic are elective, emergency add-on cases in hospital-based endoscopy clinics are common, frequently consuming a great deal of time and resources relative to elective endoscopy procedures.

OBJECTIVE

To determine which specific factors correlate with the high volume of add-on emergency cases in a tertiary care, hospital-based endoscopy unit.

METHODS

A retrospective chart review of all gastrointestinal add-on, and electively booked cases of esophagastroduodenoscopy (EGD), colonoscopy (C) and flexible sigmoidoscopy (FS) procedures from September 2006, to May 2007 was conducted. The day of the week, month, type of procedure and physician were recorded. Emergency add-on procedures performed during the weekends were not assessed. These cases were then compared with elective cases during a similar time frame to determine differences in the aspects of add-on cases versus those that were elective.

RESULTS

Seven hundred twenty-one add-on cases were reviewed (mean patient age 57.4 years; 46% women) and compared with 736 elective cases (mean age 56 years; 49% women; P not significant). Of the add-on cases, 377 (52%) were EGD, 216 C (30%) and 105 (15%) were FS, with 23 combined procedures (3.2%) versus 202 (27%) EGD, 442 (60%) C and 74 (10%) FS in the elective group. Add-on cases were more likely to be EGDs than elective cases (OR 2.7; 95% CI 1.8 to 4.3; P<0.0001) and less likely to be Cs (OR 0.24; 95% CI 0.15 to 0.38; P<0.0001). There were significantly more add-on cases on Mondays (OR 1.7; 95% CI 1.0 to 2.28; P>0.03). Conversely, there were significantly fewer procedures added on Fridays (OR 0.31; 95% CI 0.16 to 0.57; P=0.0001). There were statistically fewer add-on cases in September compared with the other months that were evaluated (OR 0.31; 95% CI 0.11 to 0.78; P=0.0006).

CONCLUSION

With the present system of performing only emergency cases on the weekend, Monday tends to have more add-on cases. Consistent with the fact that upper gastrointestinal bleeding is the most common emergency condition, EGD is more common in add-on cases than with elective cases. Although speculative, the reasons for Friday having fewer add-on cases may be the result of a change of physician on call that day; consequently, most cases may be performed earlier in the week. For unknown reasons, fewer cases tend to be added on in September than in the other months evaluated. These data demonstrate that even in the same institution with similar patients, variability in the number of add-on cases likely is a result of many additional factors governing add-on cases, which require appropriate resource planning to ensure adequate allocation of services to ensure ideal patient care.

This study evaluated the extent of oxidative stress by measuring malondialdehyde and ascorbic acid in the seminal plasma of human subjects with different fertility potential. Semen samples from 148 subjects were evaluated (48 normozoospermics, 34 oligoasthenoteratozoospermics, 34 asthenoteratozoospermics and 32 azoospermics). malondialdehyde level was found to be significantly higher in the abnormal groups (oligoasthenoterato and asthenoterato-zoospermics) than normozoospermics (P < 0.01). Negative correlation was also found between malondialdehyde level, sperm concentration, sperm motility and sperm morphology. Level of ascorbic acid was found to be significantly higher in normozoospermics than other abnormal groups (P < 0.01). It was found to be correlated positively with all seminogram parameters and negatively with malondialdehyde level. The study revealed that, excess lipid peroxidation reflected by high malondialdehyde level with reduced ascorbic acid in human seminal plasma is associated with poor semen quality where as ascorbic acid content has positive correlation with fertility potential.

Background

Our earlier work in the ultrasonograpy of localized scleroderma (LS) suggests that altered levels of echogenicity and vascularity can be associated with disease activity. Utrasound is clinically benign and readily available, but can be limited by operator dependence. We present our efforts to standardize image acquisition and interpretation of pediatric LS to better evaluate the correlation between specific sonographic findings and disease activity.

Methods

Several meetings have been held among our multi-center group (LOCUS) to work towards standardizing sonographic technique and image interpretation. Demonstration and experience in image acquisition were conducted at workshop meetings. Following meetings in 2007, an ultrasound measure was developed to standardize evaluation of differences in echogenicity and vascularity. Based upon our initial observations, we have labeled this an ultrasound disease activity measure. This preliminary measure was subsequently evaluated on over 180 scans of pediatric LS lesions. This review suggested that scoring levels should be expanded to better capture the range of observed differences. The revised levels and their definitions were formulated at a February 2009 workshop meeting. We have also developed assessments for scoring changes in tissue thickness and lesion size to better determine if these parameters aid evaluation of disease state.

Results

We have standardized our protocol for acquiring ultrasound images of pediatric LS lesions. A wide range of sonographic differences has been seen in the dermis, hypodermis, and deep tissue layers of active lesions. Preliminary ultrasound assessments have been generated. The disease activity measure scores for altered levels of echogenicity and vascularity in the lesion, and other assessments score for differences in lesion tissue layer thickness and changes in lesion size.

Conclusions

We describe the range of sonographic differences found in pediatric LS, and present our efforts to standardize ultrasound acquisition and image interpretation for this disease. We present ultrasound measures that may aid evaluation of disease state. These assessments should be considered a work in progress, whose purpose is to facilitate further study in this area. More studies are needed to assess their validity and reliability.

Objectives

To assess whether serial measurements of childhood body mass index (BMI) give clinically useful predictions of the risk of developing adult metabolic syndrome and impaired glucose tolerance or type 2 diabetes.

Design/setting

Follow-up of a community-based birth cohort in Delhi, India.

Participants

1,492 men and women aged 26-32 years whose BMI was recorded 6-monthly throughout childhood.

Main outcome measures

The predictive value of childhood BMI for adult metabolic syndrome (MS) defined using waist circumference, blood pressure and fasting glucose, triglyceride and HDL-cholesterol concentrations, and impaired glucose tolerance (IGT) and diabetes (DM) diagnosed by oral glucose tolerance tests.

Results

Twenty-five percent of subjects had MS and 15% had IGT/DM. Both outcomes were associated with greater childhood BMI gain (MS: OR 1.63 [95% CI 1.44 to 1.85]; IGT/DM: 1.39 [1.20 to 1.60] per unit increase in within-cohort BMI SD-score between 5-14 years). Best predictions of adult disease were obtained using a combined test comprising i) any increase in BMI SD-score between 5-14 years and ii) a BMI SD-score >0 at 14 years (MS: sensitivity 45%, specificity 78%; IGT/DM: 37%, 73%). Likelihood ratios were low (MS: 1.4-2.0; IGT/DM: 1.2-1.4). A single high BMI measurement at 14 years (overweight or obese, International Obesity Task Force criteria) was highly specific but insensitive (MS: sensitivity 7%, specificity 97%; IGT/DM: 8%, 97%). Charts for plotting BMI SD-scores through childhood were produced.

Conclusions

Serial measurements of childhood BMI give useful predictions of adult risk and could guide advice to children and parents on preventing later disease.