Climate change, malaria and neglected tropical diseases: a scoping review.

To explore the effects of climate change on malaria and 20 neglected tropical diseases (NTDs), and potential effect amelioration through mitigation and adaptation, we searched for papers published from January 2010 to October 2023. We descriptively synthesised extracted data. We analysed numbers of papers meeting our inclusion criteria by country and national disease burden, healthcare access and quality index (HAQI), as well as by climate vulnerability score. From 42 693 retrieved records, 1543 full-text papers were assessed. Of 511 papers meeting the inclusion criteria, 185 studied malaria, 181 dengue and chikungunya and 53 leishmaniasis; other NTDs were relatively understudied. Mitigation was considered in 174 papers (34%) and adaption strategies in 24 (5%). Amplitude and direction of effects of climate change on malaria and NTDs are likely to vary by disease and location, be non-linear and evolve over time. Available analyses do not allow confident prediction of the overall global impact of climate change on these diseases. For dengue and chikungunya and the group of non-vector-borne NTDs, the literature privileged consideration of current low-burden countries with a high HAQI. No leishmaniasis papers considered outcomes in East Africa. Comprehensive, collaborative and standardised modelling efforts are needed to better understand how climate change will directly and indirectly affect malaria and NTDs.

Structure-based virtual screening of perfluoroalkyl and polyfluoroalkyl substances (PFASs) as endocrine disruptors of androgen receptor activity using molecular docking and machine learning.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) pose a substantial threat as endocrine disruptors, and thus early identification of those that may interact with steroid hormone receptors, such as the androgen receptor (AR), is critical. In this study we screened 5,206 PFASs from the CompTox database against the different binding sites on the AR using both molecular docking and machine learning techniques. We developed support vector machine models trained on Tox21 data to classify the active and inactive PFASs for AR using different chemical fingerprints as features. The maximum accuracy was 95.01% and Matthew's correlation coefficient (MCC) was 0.76 respectively, based on MACCS fingerprints (MACCSFP). The combination of docking-based screening and machine learning models identified 29 PFASs that have strong potential for activity against the AR and should be considered priority chemicals for biological toxicity testing.

Electroencephalographic delta/alpha frequency activity differentiates psychotic disorders: a study of schizophrenia, bipolar disorder and methamphetamine-induced psychotic disorder.

Electroencephalography (EEG) has been proposed as a neurophysiological biomarker to delineate psychotic disorders. It is known that increased delta and decreased alpha, which are apparent in psychosis, are indicative of inappropriate arousal state, which leads to reduced ability to attend to relevant information. On this premise, we investigated delta/alpha frequency activity, as this ratio of frequency activity may serve as an effective neurophysiological biomarker. The current study investigated differences in delta/alpha frequency activity, in schizophrenia (SCZ), bipolar I disorder with psychotic features and methamphetamine-induced psychosis. One hundred and nine participants, including individuals with SCZ (n = 28), bipolar I disorder with psychotic features (n = 28), methamphetamine-induced psychotic disorder (MPD) (n = 24) and healthy controls (CON, n = 29). Diagnosis was ascertained with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition disorders and current medication was recorded. EEG was undertaken in three testing conditions: resting eyes open, resting eyes closed and during completion of a simple cognitive task (visual continuous performance task). EEG delta/alpha frequency activity was investigated across these conditions. First, delta/alpha frequency activity during resting eyes closed was higher in SCZ and MPD globally, when compared to CON, then lower for bipolar disorder (BPD) than MPD for right hemisphere. Second, delta/alpha frequency activity during resting eyes open was higher in SCZ, BPD and MPD for all electrodes, except left frontal, when compared to CON. Third, delta/alpha frequency activity during the cognitive task was higher in BPD and MPD for all electrodes, except left frontal, when compared to CON. Assessment of EEG delta/alpha frequency activity supports the delineation of underlying neurophysiological mechanisms present in psychotic disorders, which are likely related to dysfunctional thalamo-cortical connectivity. Delta/alpha frequency activity may provide a useful neurophysiological biomarker to delineate psychotic disorders.

Cycle control with an extended-regimen oral contraceptive combining levonorgestrel and ethinyl estradiol that includes continuous low-dose ethinyl estradiol instead of the traditional hormone-free interval.

PURPOSE: To evaluate scheduled and unscheduled bleeding and spotting over 1 year of treatment with 91-day extended-regimen combined oral contraception (COC) providing continuous low-dose ethinyl estradiol (EE) in place of the traditional 7-day hormone-free interval (HFI). PATIENTS AND METHODS: This post hoc analysis of a multicenter, open-label, 1-year, Phase 3 study of extended-regimen COC with 30 µg EE/150 µg levonorgestrel (LNG) for 84 days and EE 10 µg for 7 days included 799 sexually active, adult women who completed at least one 91-day cycle of therapy. Subjects recorded bleeding and spotting episodes daily using electronic diaries. Logistic regression analyses are reported as ORs with 95% CIs. RESULTS: There was a 10% increase (OR =1.102; 95% CI: 1.006-1.206) in the likelihood of reporting no scheduled bleeding for each additional 91-day cycle completed. From the third 91-day cycle, more than one fifth of women reported no scheduled bleeding (third cycle =23% [121/533]; fourth cycle =22% [97/446]). Among women who reported no scheduled bleeding at Cycle 1 (136/758 [18%]), ≥45% showed sustained lack of scheduled bleeding in later cycles. There were increases of 53% (OR =1.531; 95% CI: 1.393-1.683) and 31% (OR =1.307; 95% CI: 1.205-1.418) in the likelihood of reporting 0 to ≤6 days vs >6 days of unscheduled bleeding and spotting, respectively, for each additional 91-day cycle. By Cycle 2, more than 80% of women reported no unscheduled bleeding or ≤6 days of unscheduled bleeding during each 91-day cycle. CONCLUSION: Improved cycle control with decreased bleeding over time was shown during extended-regimen COC with 30 µg EE/150 µg LNG for 84 days and continuous low-dose EE instead of the traditional 7-day HFI. Women considering this regimen should be informed that those who complete at least one 91-day COC cycle will likely experience less bleeding/spotting in future cycles.

Sexual and Contraceptive Behaviors among Adolescents Requesting Emergency Contraception.

STUDY OBJECTIVE AND DESIGN: Unintended pregnancy rates in the United States remain high among adolescents. Emergency contraception (EC) provides the only option for pregnancy prevention after unprotected sex. To better define the population of adolescents who request and use EC pills, we performed a post hoc analysis of an over-the-counter simulation study of EC pills. SETTING: Teen reproductive health clinics in 5 cities. PARTICIPANTS: Adolescents between the ages of 13 and 17 years who requested EC. INTERVENTIONS: Single-tablet levonorgestrel 1.5 mg. MAIN OUTCOME MEASURES: We calculated the correlations between age and baseline sexual and contraceptive behaviors. χ2 Tests were used to compare behaviors of first-time and repeat EC users. RESULTS: Overall, the most commonly reported contraceptive methods ever used were condoms, oral contraceptives, none, and withdrawal; the most common method ever used in each age group was no method for 13- to 14-year-olds and condom for 15-, 16-, and 17-year-olds. The percentage of participants who had never used contraception before requesting EC decreased with age (53% [20/28] of 13- to 14-year-olds vs 15% [10/65] of 17-year-olds). First-time EC users were more likely to report no previous contraceptive use compared with repeat EC users (42% [88/208] vs 10% [13/135]; P < .001). Regardless of age, the most commonly reported reason for requesting EC was nonuse of any contraceptive method (ie, "unprotected sex"). CONCLUSION: Adolescents who requested EC most commonly reported ever-use of contraceptive methods that rely on user adherence or no method at all, with younger adolescents more likely than older adolescents to have used no previous method. The provision of EC presents an opportunity to provide education and access to highly effective, long-term contraceptive methods.

Effect of Extended 30 µg Ethinyl Estradiol with Continuous Low-Dose Ethinyl Estradiol and Cyclic 20 µg Ethinyl Estradiol Oral Contraception on Adolescent Bone Density: A Randomized Trial.

STUDY OBJECTIVE: To compare changes in lumbar spine bone mineral density after 12 months of a 91-day extended regimen or 28-day combined oral contraceptive with those in a healthy reference group not using hormonal contraceptives. DESIGN: Phase 2, multicenter, open-label, randomized, controlled study. SETTING: Forty-five academic centers, clinical research centers, and community practices in the United States. PARTICIPANTS: Eight hundred twenty-nine postmenarcheal adolescent girls aged 12-18 years. INTERVENTIONS: Adolescents were randomly assigned to 91-day levonorgestrel (LNG)/ethinyl estradiol (EE) extended regimen (84 days of LNG 150 µg/EE 30 µg with 7 days of EE 10 µg [LNG/EE extended regimen]) or 28 days of LNG/EE (21 days of LNG 100 µg/EE 20 µg with 7 days of placebo [LNG/EE 21/7]) for 12 months. A reference group not seeking hormonal contraception was also evaluated. MAIN OUTCOME MEASURES: The primary end point was mean percent change in lumbar spine bone mineral density measured using dual-energy x-ray absorptiometry. RESULTS: Of 1361 adolescents randomized/enrolled, 829 were included in the primary analysis. Mean changes in lumbar spine bone mineral density were +2.26% with LNG/EE extended regimen, +1.45% with LNG/EE 21/7, and +2.50% in the reference group. Noninferiority of the LNG/EE extended regimen compared with the reference group was shown. A statistically significant treatment difference was found between LNG/EE 21/7 and the reference group (1.05%; 95% confidence interval, 0.61%-1.49%) but not between LNG/EE extended regimen and the reference group (0.23%; 95% confidence interval, -0.20% to 0.67%). No new safety signals were noted. CONCLUSION: Compared with the reference group, bone accrual was statistically significantly lower among LNG/EE 21/7 users but not among LNG/EE 30-µg extended regimen users. Additional research is needed to clarify the clinical relevance of these findings.

Efficacy and safety of a 21/7-active combined oral contraceptive with continuous low-dose ethinyl estradiol.

OBJECTIVE: Substituting low-dose ethinyl estradiol (EE) for the hormone-free interval in combined oral contraceptives (COCs) may enhance ovarian suppression and improve tolerability. This noncomparative phase 3 study evaluated the efficacy and safety of a 21/7-active COC regimen including 21days of desogestrel (DSG)/EE followed by 7days of EE. STUDY DESIGN: This multicenter, open-label, phase 3, single-arm study enrolled sexually active women aged 18-40years at risk for pregnancy. Women received up to 1year, or 13 consecutive 28-day cycles, of DSG 150mcg/EE 20mcg for 21days and EE 10mcg alone for 7days. Participants kept diaries to record compliance, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index (PI) and life-table approach. Safety and tolerability were assessed primarily through reported adverse events (AEs). RESULTS: A total of 2858 women enrolled and 1680 completed the study. Forty-six pregnancies in 2401 women aged 18-35years occurred after COC initiation and up to 7days after last DSG/EE or EE-only tablet was taken. When cycles in which another contraceptive method was used were excluded, the PI was 2.68 [95% confidence interval (CI), 1.96-3.57]. The cumulative pregnancy rate after 1year of treatment was 2.47% (95% CI, 1.85-3.29) for all users aged 18-35years. When only cycles during which women considered compliant were included, the PI was 2.00 (95% CI, 1.39-2.80). AEs were similar to those seen with other oral contraceptives. CONCLUSIONS: This 21/7-active DSG/EE COC with 7days of low-dose EE was efficacious and well tolerated for pregnancy prevention. IMPLICATIONS STATEMENT: This phase 3 open-label study demonstrated that a 21/7-active COC regimen including 21days of DSG 150mcg/EE 20mcg and 7days of EE 10mcg was efficacious and well tolerated for pregnancy prevention.

Serial insertion of bilateral uncovered metal stents for malignant hilar obstruction using an 8 Fr biliary system: a case series of 17 consecutive patients.

Controversy exists over the need for unilateral versus bilateral stent placement in patients with malignant obstruction at the biliary hilum. Placement of bilateral uncovered self-expanding metal stent (UCSEMS) at this location is technically challenging, and generally associated with lower rates of procedural success. Serial insertion of side-by-side UCSEMS may be especially difficult when simultaneous deployment is not possible using larger stent delivery catheters. In this single-center, retrospective case series of all patients who underwent bilateral placement of uncovered Wallflex(TM) biliary stents between July 2008 and July 2014, we evaluate the feasibility, technical success, and safety of patients undergoing serial insertion of bilateral UCSEMS using the 8 Fr Wallflex(TM) biliary system for malignant hilar obstruction. A total of 17 patients were included. Primary cholangiocarcinoma, Bismuth IV, was the most common diagnosis. Mean procedure time was 54.4 minutes. Overall procedural technical success was achieved in 17/17 patients. Stricture dilation was necessary prior to Wallflex(TM) insertion in 8/17 patients (47.1%). Transpapillary extension of two stents was performed in all patients. There were no cases of stent deployment malfunction, or inability to insert or deploy the 2(nd) stent. Nine of 17 patients (52.9%) required inpatient hospitalization following ERCP; the most common indications were abdominal pain and need for IV antibiotics. There was one case of ERCP-related cholangitis otherwise; there were no other major complications. Bilateral, serial insertion of UCSEMS using the 8 Fr Wallflex(TM) biliary system in malignant hilar obstruction is feasible with an excellent technical success profile. Using this device for side-by-side deployment of UCSEMS appears to be safe in the majority of patients.

Drinking water turbidity and emergency department visits for gastrointestinal illness in New York City, 2002-2009.

BACKGROUND: Studies have examined whether there is a relationship between drinking water turbidity and gastrointestinal (GI) illness indicators, and results have varied possibly due to differences in methods and study settings. OBJECTIVES: As part of a water security improvement project we conducted a retrospective analysis of the relationship between drinking water turbidity and GI illness in New York City (NYC) based on emergency department chief complaint syndromic data that are available in near-real-time. METHODS: We used a Poisson time-series model to estimate the relationship of turbidity measured at distribution system and source water sites to diarrhea emergency department (ED) visits in NYC during 2002-2009. The analysis assessed age groups and was stratified by season and adjusted for sub-seasonal temporal trends, year-to-year variation, ambient temperature, day-of-week, and holidays. RESULTS: Seasonal variation unrelated to turbidity dominated (~90% deviance) the variation of daily diarrhea ED visits, with an additional 0.4% deviance explained with turbidity. Small yet significant multi-day lagged associations were found between NYC turbidity and diarrhea ED visits in the spring only, with approximately 5% excess risk per inter-quartile-range of NYC turbidity peaking at a 6 day lag. This association was strongest among those aged 0-4 years and was explained by the variation in source water turbidity. CONCLUSIONS: Integrated analysis of turbidity and syndromic surveillance data, as part of overall drinking water surveillance, may be useful for enhanced situational awareness of possible risk factors that can contribute to GI illness. Elucidating the causes of turbidity-GI illness associations including seasonal and regional variations would be necessary to further inform surveillance needs.

Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.

OBJECTIVE: This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. STUDY DESIGN: The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. RESULTS: Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17ß-estradiol, follicle-stimulating hormone and luteinizing hormone levels. CONCLUSIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. IMPLICATIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens.

Liver failure after Hydroxycut™ use in a patient with undiagnosed hereditary coproporphyria.

We report the case of a young male presenting with cholestatic liver failure. After an extensive workup, the etiology of the liver failure was determined to be due to hereditary coprophorphyria (HCP). The inciting event was the use of Hydroxycut™, an over-the-counter supplement to promote weight loss that has been reported to cause oxidative liver injury in vulnerable populations. Although HCP is a rare cause of cholestatic liver failure, it is treatable if diagnosed correctly and in a timely manner. In this clinical vignette, we discuss a case that highlights the genetic susceptibility to disease that can be unmasked by environmental exposures. We also review the relevant literature on Hydroxycut™ and how it can affect hepatic function.

Impaired Energy Metabolism and Disturbed Dopamine and Glutamate Signalling in the Striatum and Prefrontal Cortex of the Spontaneously Hypertensive Rat Model of Attention-Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous behavioural disorder that affects 3-15 % of children worldwide. Spontaneously hypertensive rats (SHR) display the major symptoms of ADHD (hyperactivity, impulsivity and poor performance in tasks that require sustained attention) and are widely used to model the disorder. The present study aimed to test the hypothesis that SHR have a diminished capacity to generate ATP required for rapid synchronized neuronal firing, failure of which might lead to disturbances in neurotransmission that could contribute to their ADHD-like behaviour. Duplicate pooled (n = 5) samples of prefrontal cortex and striatum of prepubertal (35-day-old) SHR and Wistar Kyoto (WKY) rats were subjected to iTRAQ labeling and matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). The MS/MS spectra were analyzed with ProteinPilot using the Ratus ratus database. Proteins detected with >95 % confidence were tested. SHR had decreased levels of several proteins involved in energy metabolism, cytoskeletal structure, myelination and neurotransmitter function when compared to WKY. Differences in protein levels between SHR and WKY were similar in prefrontal cortex and striatum, suggesting global changes in cortico-striato-thalamo-cortical circuits.

The neurobiology of methamphetamine induced psychosis.

Chronic methamphetamine abuse commonly leads to psychosis, with positive and cognitive symptoms that are similar to those of schizophrenia. Methamphetamine induced psychosis (MAP) can persist and diagnoses of MAP often change to a diagnosis of schizophrenia over time. Studies in schizophrenia have found much evidence of cortical GABAergic dysfunction. Methamphetamine psychosis is a well studied model for schizophrenia, however there is little research on the effects of methamphetamine on cortical GABAergic function in the model, and the neurobiology of MAP is unknown. This paper reviews the effects of methamphetamine on dopaminergic pathways, with focus on its ability to increase glutamate release in the cortex. Excess cortical glutamate would likely damage GABAergic interneurons, and evidence of this disturbance as a result of methamphetamine treatment will be discussed. We propose that cortical GABAergic interneurons are particularly vulnerable to glutamate overflow as a result of subcellular location of NMDA receptors on interneurons in the cortex. Damage to cortical GABAergic function would lead to dysregulation of cortical signals, resulting in psychosis, and further support MAP as a model for schizophrenia.

Non-pulmonary allergic diseases and inflammatory bowel disease: a qualitative review.

While the etiological underpinnings of inflammatory bowel disease (IBD) are highly complex, it has been noted that both clinical and pathophysiological similarities exist between IBD and both asthma and non-pulmonary allergic phenomena. In this review, several key points on common biomarkers, pathophysiology, clinical manifestations and nutritional and probiotic interventions for both IBD and non-pulmonary allergic diseases are discussed. Histamine and mast cell activity show common behaviors in both IBD and in certain allergic disorders. IgE also represents a key immunoglobulin involved in both IBD and in certain allergic pathologies, though these links require further study. Probiotics remain a critically important intervention for both IBD subtypes as well as multiple allergic phenomena. Linked clinical phenomena, especially sinonasal disease and IBD, are discussed. In addition, nutritional interventions remain an underutilized and promising therapy for modification of both allergic disorders and IBD. Recommending new mothers breastfeed their infants, and increasing the duration of breastfeeding may also help prevent both IBD and allergic diseases, but requires more investigation. While much remains to be discovered, it is clear that non-pulmonary allergic phenomena are connected to IBD in a myriad number of ways and that the discovery of common immunological pathways may usher in an era of vastly improved treatments for patients.

A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens.

Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 µg on days 1 to 84 with EE 20 µg on days 1 to 42, 25 µg on days 43 to 63, 30 µg on days 64 to 84, and 10 µg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration-time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 µg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs.

Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive.

OBJECTIVE: To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days. STUDY DESIGN: This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18-40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs). RESULTS: A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49-4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18-35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%-3.57%) for all users aged 18-35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported. CONCLUSION: This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile.

Activation of lung toll-like receptors does not exacerbate sickness responses to lipopolysaccharide in mice.

Pneumonia represents a leading cause of death. Recently, a novel treatment strategy for pneumonia has involved enhancing the host pulmonary innate immune response by pre-exposure to aerosolized toll-like receptor (TLR)9 and TLR2/6 agonists, known as O/P. O/P inhalation in mice has been demonstrated to stimulate innate lung immunity, and thus increase survival against subsequent pneumonia infection while producing barely detectable increases in systemic cytokines. Here, we examined the safety of O/P treatment when used in mice that are inflamed systemically. Swiss-Webster mice were treated with two doses of aerosolized O/P (1× or 8×) vs phosphate buffered saline (PBS) either immediately before intraperitoneal injection of 0.1mg/kg lipopolysaccharide (LPS) or PBS (equivolume) or 2h after. Sickness responses (reduced body weight, food intake, activity and social interaction) were examined at 2 and 5.5h post-treatment. Immediately following behavioral testing, mice were euthanized, perfused with PBS, and brains, spleens, livers and lungs snap frozen for assessment of pro-inflammatory cytokine mRNAs. While O/P treatment alone increased lung IL-1ß, IFNγ and TNF-α, no such effects were observed in the brain, spleen or liver. Furthermore, there was no evidence that O/P treatment administered before or after LPS had any synergizing effect to potentiate the cytokine response to LPS in any compartment measured. Supportive of these findings were the measures of sickness behaviors that did not show any increased sickness response in O/P-treated mice exposed to LPS, suggestive that the cytokine signal produced in the lungs from O/P inhalation did not propagate to the brain and synergize with LPS-induced neuroinflammation. These findings support the safety of the use of O/P inhalation as a preventative measure against pneumonia and demonstrate a unique ability of the lungs to compartmentalize pulmonary inflammation and limit propagation of the cytokine signal to the brain.

Maternal separation affects dopamine transporter function in the spontaneously hypertensive rat: an in vivo electrochemical study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR) is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT) in ways that distinguish SHR from control rat strains. METHODS: SHR and control Wistar-Kyoto (WKY) rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by in vivo chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function. RESULTS: Consistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k-1) in SHR striatum. Consistent with this observation, the dopamine clearance time (T100) was increased in SHR. These results suggest that the chronic mild stress of maternal separation impaired the function of striatal DAT in SHR. CONCLUSIONS: The present findings suggest that maternal separation failed to alter the behaviour of SHR in the open field and elevated plus maze. However, maternal separation altered the dopaminergic system by decreasing surface expression of DAT and/or the affinity of DAT for dopamine, increasing the time to clear dopamine from the extracellular fluid in the striatum of SHR.