Ravulizumab facilitates reduced burden of vascular access, a major benefit in paediatric atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy resulting from dysregulation of the alternative complement pathway, leading to multi-organ dysfunction and chronic kidney disease. Eculizumab is an anti-C5 monoclonal antibody therapy that has significantly improved aHUS disease control and patient outcomes, however it requires fortnightly intravenous dosing. This often necessitates long term central access and a high hospital attendance burden. Ravulizumab is a novel, next-generation anti-C5 monoclonal antibody engineered from eculizumab to reduce endosomal degradation of the antibody, increasing the dosing interval up to 8 weeks. CASE SERIES: In this retrospective case series we present the transition of three children with aHUS from eculizumab to ravulizumab from a single tertiary paediatric nephrology service. All patients underwent genomic and immunological work up for aHUS, with no cause found. After stabilisation with eculizumab, two patients developed macrovascular thrombotic complications associated with indwelling central vascular catheters, ultimately leading to central access failure. All patients were transitioned from eculizumab to ravulizumab without relapse of aHUS. One patient successfully underwent deceased donor kidney transplantation with ravulizumab for complement inhibition. All patients have transitioned to peripheral access for infusions given the reduced frequency of dosing, maintaining good control of aHUS for 2-4 years. CONCLUSION: Ravulizumab permits sufficiently reduced frequency of infusion to allow for administration by peripheral cannulation - removing the risks of long term central vascular access often required to deliver eculizumab to paediatric patients.

The Shifting Epidemiology of Hepatitis A in the World Health Organization Western Pacific Region.

Within the past few decades, improvement in sanitation and economic growth has driven a changing epidemiology of hepatitis A in the Western Pacific Region (WPR) of the World Health Organization (WHO). In this review, we gathered available published information on hepatitis A epidemiology of the countries in the WPR and reviewed the trends reported in the literature from the years 2000 to 2021. Many countries have shifted from high endemicity to low endemicity. Moreover, the administration of the hepatitis A vaccine among children in recent years has shifted disease susceptibility to the older population. Seroprevalence among children has decreased in most countries, while nearly 100% seropositivity is seen in mid adulthood. This is contrary to the epidemiology seen in previous decades when most children achieved immunity by age ten. This also presents a paradox in that better living conditions have caused more vulnerability to the older age groups who are at higher risk for severe disease. Given these trends, we recommend vaccination of vulnerable populations such as the older age groups and inclusion of the hepatitis A vaccine in government immunization programs.

Sex differences in the rodent medial prefrontal cortex - What Do and Don't we know?

The prefrontal cortex, particularly its medial subregions (mPFC), mediates critical functions such as executive control, behavioral inhibition, and memory formation, with relevance for everyday functioning and psychopathology. Despite broad characterization of the mPFC in multiple model organisms, the extent to which mPFC structure and function vary according to an individual's sex is unclear - a knowledge gap that can be attributed to a historical bias for male subjects in neuroscience research. Recent efforts to consider sex as a biological variable in basic science highlight the great need to close this gap. Here we review the knowns and unknowns about how rodents categorized as male or female compare in mPFC neuroanatomy, pharmacology, as well as in aversive, appetitive, and goal- or habit-directed behaviors that recruit the mPFC. We propose that long-standing dogmatic concepts of mPFC structure and function may not remain supported when we move beyond male-only studies, and that empirical challenges to these dogmas are warranted. Additionally, we note some common pitfalls in this work. Most preclinical studies operationalize sex as a binary categorization, and while this approach has furthered the inclusion of non-male rodents it is not as such generalizable to what we know of sex as a multidimensional, dynamic variable. Exploration of sex variability may uncover both sex differences and sex similarities, but care must be taken in their interpretation. Including females in preclinical research needs to go beyond the investigation of sex differences, improving our knowledge of how this brain region and its subregions mediate behavior and health. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

Awareness, availment, and satisfaction on various health services among residents of a rural community in Samar, Philippines: A mixed methods study

Objectives@#This study sought to investigate citizens' awareness, availment, satisfaction, and perceived need for action with health services offered by a rural municipality in Samar, Philippines.@*Methods@#This study utilized an explanatory-sequential research design, involving 150 participants selected through the Kish Grid Method via a multi-stage sampling approach within the community. The Citizen Satisfaction Index System was employed to assess the levels of awareness, utilization, and satisfaction with health services in the municipality.@*Results@#Among the assessed health services, the cohort had low awareness and low availment on services for communicable diseases, basic dental/oral hygiene, and reproductive health. While high awareness was observed for childbirth services, there was low availment on these. The participants showed high awareness and availment for only two services namely, free general consultation and the free medicine program. While high satisfaction was seen among all services that were assessed, the participants also expressed a high perceived need for action to improve their delivery. @*Conclusion@#This study presents a comprehensive view of rural healthcare in Samar, Philippines. Despite high satisfaction rates, gaps persist in the citizen’s awareness and availment due to accessibility, costs, fear, misinformation, and cultural differences. The findings of this study can guide policymakers in identifying gaps in healthcare in rural areas.

Seroprevalence of human adenovirus type 5 neutralizing antibodies in the Philippines.

Human adenovirus (HAdV), particularly the HAdV type 5 (HAdV-5), has been extensively utilized in the development of vector vaccines due to its high immunogenicity, good safety profile, and ease of propagation. However, one of the main challenges in its use is the presence of pre-existing immunity among vaccine recipients. Pre-existing neutralizing antibodies (NAbs) can prevent the uptake of HAdV-5 vectors and reduce vaccine efficacy. Hence, this study investigated the seroprevalence of NAbs against HAdV-5 in urban and rural regions of the Philippines. Luciferase-based neutralization assay was performed on 391 plasma/serum samples. Out of these samples, 346 or 88.5% were positive for HAdV-5 NAbs, and the majority of them (56.8%) had high titers against the virus. Among the regions included in this study, Bicol (Region V) had the highest seroprevalence rate (94.1%). Our findings show that a significant number of adults in the Philippines have pre-existing immunity against HAdV-5. This supports the recommendation that vaccination programs in the country should consider implementing vaccination techniques, such as a prime-boost regimen or addition of booster doses, to address the potential negative effects of pre-existing HAdV-5 immunity in the efficacy of adenoviral vector-based vaccines.

Use of primary health care services and mortality in older patients with type 2 diabetes with or without comorbidities.

OBJECTIVE: This study aimed to examine primary health care (PHC) service utilization and mortality in older patients with type 2 diabetes (T2D) with or without comorbidities. DESIGN AND SETTING: A cohort study in PHC in the city of Vantaa, Finland. Follow-up period was set between the years 2011 and 2018. SUBJECTS: PHC patients aged 60 years or more with a T2D were included. MAIN OUTCOME MEASURES: Service utilization was defined as the number of face-to-face appointments and telephone contacts between a patient and general practitioner (GP) or nurse. The presence of comorbidities was defined using the Charlson Comorbidity Index (CCI). Mortality was assessed using hazard ratio (HR) and standardized mortality ratio (SMR). RESULTS: In total, 11,020 patients were included and followed for 71,596 person years. Mean age of the women and men in the beginning of follow-up were 71 and 69 years, respectively. The patients in the study cohort had a mean of eight appointments per person year to the GPs or nurses. Patients with T2D with comorbidities had more appointments than patients with T2D without comorbidities (incidence rate ratio (IRR) 1.44 [95% CI 1.39-1.49]). Increase in the number of all appointments reduced mortality in patients with T2D with and without comorbidities. Between patients with T2D with comorbidities and patients with T2D without comorbidities, the age and sex adjusted HR for death was 1.50 (95% CI 1.39-1.62). The SMR was higher in patients with T2D with comorbidities (1.83 [95% CI 1.74-1.92]) than in patients with T2D without comorbidities (0.91 [95% CI 0.86-0.96]). CONCLUSIONS: In older patients with T2D, the presence of comorbidities was associated with increased use of PHC services and increased mortality. Increase in the number of appointments was associated with reduced mortality in patients with T2D with or without comorbidities.Key PointsIn older patients with T2D, it has not been studied whether and to what extend multimorbidity affects use of PHC services and mortality.The presence of comorbidities according to the Charlson Comorbidity Index (CCI) was associated with increased use of PHC services.The number of appointments to GPs or nurses was associated with reduced mortality in patients with T2D with or without comorbidities according to the CCI.

[Non-surgical peri-implantitis treatment with or without systemic antibiotics]. / Initiële behandeling van peri-implantitis met of zonder systemische antibiotica.

This study investigated the effect of initial nonsurgical treatment in patients with peri-implantitis with or without prescription of an antibiotic regimen consisting of amoxicillin and metronidazole. For this purpose, patients with peri-implantitis were randomized into a group of initial treatment with antibiotics and a group without antibiotics. They were re-evaluated 12 weeks after treatment. Analyses were performed at the patient level at 1 peri-implant pocket per patient. Both groups showed significant peri-implant pocket depth reductions after initial treatment. Treatment with antibiotics resulted in a higher mean reduction in peri-implant pocket depth than when no antibiotics were used, but this difference did not reach statistical significance. Only 2 implants, 1 in each group, showed a successful outcome of a peri-implant pocket depth ofunder ≤ 5 mm and with an absence of bleeding and pus after probing. Initial treatment with or without antibiotics is ultimately not sufficient to fully treat peri-implantitis; additional surgical procedures will often be required.

Utility of laboratory and immune biomarkers in predicting disease progression and mortality among patients with moderate to severe COVID-19 disease at a Philippine tertiary hospital.

Purpose: This study was performed to determine the clinical biomarkers and cytokines that may be associated with disease progression and in-hospital mortality in a cohort of hospitalized patients with RT-PCR confirmed moderate to severe COVID-19 infection from October 2020 to September 2021, during the first wave of COVID-19 pandemic before the advent of vaccination. Patients and methods: Clinical profile was obtained from the medical records. Laboratory parameters (complete blood count [CBC], albumin, LDH, CRP, ferritin, D-dimer, and procalcitonin) and serum concentrations of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ, IP-10, TNF-α) were measured on Days 0-3, 4-10, 11-14 and beyond Day 14 from the onset of illness. Regression analysis was done to determine the association of the clinical laboratory biomarkers and cytokines with the primary outcomes of disease progression and mortality. ROC curves were generated to determine the predictive performance of the cytokines. Results: We included 400 hospitalized patients with COVID-19 infection, 69% had severe to critical COVID-19 on admission. Disease progression occurred in 139 (35%) patients, while 18% of the total cohort died (73 out of 400). High D-dimer >1 µg/mL (RR 3.5 95%CI 1.83-6.69), elevated LDH >359.5 U/L (RR 1.85 95%CI 1.05-3.25), lymphopenia (RR 1.91 95%CI 1.14-3.19), and hypoalbuminemia (RR 2.67, 95%CI 1.05-6.78) were significantly associated with disease progression. High D-dimer (RR 3.95, 95%CI 1.62-9.61) and high LDH (RR 5.43, 95%CI 2.39-12.37) were also significantly associated with increased risk of in-hospital mortality. Nonsurvivors had significantly higher IP-10 levels at 0 to 3, 4 to 10, and 11 to 14 days from illness onset (p<0.01), IL-6 levels at 0 to 3 days of illness (p=0.03) and IL-18 levels at days 11-14 of illness (p<0.001) compared to survivors. IP-10 had the best predictive performance for disease progression at days 0-3 (AUC 0.81, 95%CI: 0.68-0.95), followed by IL-6 at 11-14 days of illness (AUC 0.67, 95%CI: 0.61-0.73). IP-10 predicted mortality at 11-14 days of illness (AUC 0.77, 95%CI: 0.70-0.84), and IL-6 beyond 14 days of illness (AUC 0.75, 95%CI: 0.68-0.82). Conclusion: Elevated D-dimer, elevated LDH, lymphopenia and hypoalbuminemia are prognostic markers of disease progression. High IP-10 and IL-6 within the 14 days of illness herald disease progression. Additionally, elevated D-dimer and LDH, high IP-10, IL-6 and IL-18 were also associated with mortality. Timely utilization of these biomarkers can guide clinical monitoring and management decisions for COVID-19 patients in the Philippines.

Determinants of Acquisition, Persistence, and Clearance of Oncogenic Cervical Human Papillomavirus Infection in the Philippines Using a Multi-Omics Approach: DEFEAT HPV Study Protocol.

HPV infection is one of the most studied risk factors in cervical cancer-the second most common cancer site and cause of death due to cancer in the Philippines. However, there is a lack of population-based epidemiological data on cervical HPV infection in the Philippines. Local reports on co-infections with other lower genital tract pathogens, commonly reported globally, are also lacking, which emphasizes the need to increase efforts in targeting HPV prevalence, genotype, and distribution. Hence, we aim to determine the molecular epidemiology and natural history of HPV infection among reproductive-age Filipino women using a community-based prospective cohort design. Women from rural and urban centers will be screened until the target sample size of 110 HPV-positive women (55 from rural sites and 55 from urban sites) is reached. Cervical and vaginal swabs will be collected from all screened participants. For HPV-positive patients, HPV genotypes will be determined. One hundred ten healthy controls will be selected from previously screened volunteers. The cases and controls will comprise the multi-omics subset of participants and will be followed up after 6 and 12 months for repeat HPV screening. Metagenomic and metabolomic analyses of the vaginal swabs will also be performed at baseline, after 6 months, and after 12 months. The results of this study will update the prevalence and genotypic distribution of cervical HPV infection among Filipino women, determine whether the current vaccines used for HPV vaccination programs capture the most prevalent high-risk HPV genotypes in the country, and identify vaginal community state types and bacterial taxa associated with the natural history of cervical HPV infection. The results of this study will be used as the basis for developing a biomarker that can help predict the risk of developing persistent cervical HPV infection in Filipino women.

Spatiotemporal analysis of lake chlorophyll-a with combined in situ and satellite data.

We estimated chlorophyll-a (Chl-a) concentration using various combinations of routine sampling, automatic station measurements, and MERIS satellite images. Our study site was the northern part of the large, shallow, mesotrophic Lake Pyhäjärvi located in southwestern Finland. Various combinations of measurements were interpolated spatiotemporally using a data fusion system (DFS) based on an ensemble Kalman filter and smoother algorithms. The estimated concentrations together with corresponding 68% confidence intervals are presented as time series at routine sampling and automated stations, as maps and as mean values over the EU Water Framework Directive monitoring period, to evaluate the efficiency of various monitoring methods. The mean Chl-a calculated with DFS in June-September was 6.5-7.5 µg/l, depending on the observations used as input. At the routine monitoring station where grab samples were used, the average uncertainty (standard deviation, SD) decreased from 2.7 to 1.6 µg/l when EO data were also included in the estimation. At the automatic station, located 0.9 km from the routine monitoring site, the SD was 0.7 µg/l. The SD of spatial mean concentration decreased from 6.7 to 2.9 µg/l when satellite observations were included in June-September, in addition to in situ monitoring data. This demonstrates the high value of the information derived from satellite observations. The conclusion is that the confidence of Chl-a monitoring could be increased by deploying spatially extensive measurements in the form of satellite imaging or transects conducted with flow-through sensors installed on a boat and spatiotemporal interpolation of the multisource data.

Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.

Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

Current Status of Human Papillomavirus Infection and Cervical Cancer in the Philippines.

Cervical cancer is estimated to cause 341,831 deaths each year, with 9 of 10 deaths occurring in developing countries. Over the past decade, there has been a significant increase in cervical cancer incidence among women in the Philippines. Persistent infection with high-risk human papillomavirus (HPV) is the well-established necessary cause of cervical cancer. Based on limited studies conducted in the Philippines, the prevalence of infection with any HPV genotype was 93.8% for cervical squamous cell carcinoma and 90.9% for cervical adenocarcinomas. HPV types 16 and 18 were the most common HPV genotypes among Filipino patients with cervical cancer. On the other hand, the incidence of HPV infection among Filipino women with normal cervices was 9.2%. The World Health Organization has launched a global agenda of eliminating HPV infection by 2030. One of its key milestones is to vaccinate 90% of girls with the HPV vaccine by 15 years. However, the HPV vaccination rate among Filipino women remains to be unsatisfactory. HPV vaccination has only been included in the Philippine Department of Health's community-based National Immunization Program in 2015. Despite these efforts, the Philippines currently ranks last on HPV program coverage among low-middle income countries, with coverage of only 23% of the target female population for the first dose and 5% for the final dose. The principal reason for the non-acceptance of HPV vaccines was the perceived high cost of vaccination. The low utilization of available cervical cancer screening tests such as Pap smear and visual inspection with acetic acid hampered the Philippines' control and prevention of HPV infection and cervical cancer. Among those diagnosed with cervical cancer in the Philippines, only an estimated 50% to 60% receive some form of treatment. To this end, we summarize the burden of HPV infection and cervical cancer on Filipinos and the risk factors associated with the disease. We present the current screening, diagnostics, treatment, and prevention of HPV-related diseases in the Philippines. Lastly, we also propose solutions on how each building block in health systems can be improved to eliminate HPV infection and reduce the burden of cervical cancer in the Philippines.

Exploiting Dependence of Castration-Resistant Prostate Cancer on the Arginine Vasopressin Signaling Axis by Repurposing Vaptans.

Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castration-resistant prostate cancer (CRPC), requiring new treatment options. We previously demonstrated that the G protein-coupled receptor (GPCR) arginine vasopressin receptor type1A (AVPR1A) is expressed in CRPC and promotes castration-resistant growth in vitro and in vivo. AVPR1A is part of a family of GPCR's including arginine vasopressin receptor type 2 (AVPR2). Interrogation of prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is highly correlated with disease progression. Stimulation of AVPR2 with a selective agonist desmopressin promoted CRPC cell proliferation through cAMP/protein kinase A signaling, consistent with AVPR2 coupling to the G protein subunit alpha s. In contrast, blocking AVPR2 with a selective FDA-approved antagonist, tolvaptan, reduced cell growth. In CRPC xenografts, antagonizing AVPR2, AVPR1A, or both significantly reduced CRPC tumor growth as well as decreased on-target markers of tumor burden. Combinatorial use of AVPR1A and AVPR2 antagonists promoted apoptosis synergistically in CRPC cells. Furthermore, we found that castration-resistant cells produced AVP, the endogenous ligand for arginine vasopressin receptors, and knockout of AVP in CRPC cells significantly reduced proliferation suggesting possible AVP autocrine signaling. These data indicate that the AVP/arginine vasopressin receptor signaling axis represents a promising and clinically actionable target for CRPC. IMPLICATIONS: The arginine vasopressin signaling axis in CRPC provides a therapeutic window that is targetable through repurposing safe and effective AVPR1A and AVPR2 antagonists.

Rodent models of stress and dendritic plasticity - Implications for psychopathology.

Stress, as commonplace as it is, is a major environmental risk factor for psychopathology. While this association intuitively, anecdotally, and empirically makes sense, we are still very early in the process of understanding what the neurobiological manifestations of this risk truly are. Seminal work from the past few decades has established structural plasticity in the brain as a potential key mechanism. In this review we discuss evidence linking particularly chronic stress exposure in rodent models to plasticity at the dendrites, like remodeling of dendritic branches and spines, in a range of brain regions. A number of candidate mechanisms that seek to explain how stress influences neuroanatomy at this level have been proposed, utilizing in vivo, ex vivo and in vitro methods. However, a large gap still remains in our knowledge of how such dynamic structural changes ultimately relate to downstream effects such as altered affective and cognitive states relevant for psychopathology. We propose that future work expand our understanding of plasticity of specific stress-related brain circuits and cell-types. We also note that the vast majority of the work has been conducted solely on male rodents. The next big strides in our understanding of the neurobiology of psychopathology will require the inclusion of female subjects, as several studies have suggested both sex divergent and convergent features. By understanding plasticity, we can harness it. The growth of this body of knowledge will inform our efforts to improve the therapeutic options for stress-related psychopathology.

Pneumococcal IgG Antibody Responses to 23vPPV in Healthy Controls Using an Automated ELISA.

Measurement of pre- and post-pneumococcal antibody levels after immunization with the 23-valent capsular polysaccharide pneumococcal vaccine (23vPPV) is indicative of a T-independent antibody response. The World Health Organisation ELISA is considered gold standard yet is labor-intensive and technically difficult to perform. Interpretation criteria defining an adequate response to 23vPPV remain controversial. The diagnostic Immunology Laboratory at The Royal Children's Hospital, Melbourne (RCH), performs an in-house multi-serotype automated ELISA. The primary objective of this study was to verify RCH interpretation criteria for the laboratory's automated ELISA. Forty pneumococcal conjugate vaccine (PCV)-naïve healthy adults aged 18 to 25 years and 22 PCV-primed healthy children aged 2 to 5 years were immunized with 23vPPV. A serum sample was collected immediately prior and 28 to 42 (± 7) days post immunization. Samples were analyzed on the Tecan Freedom Evo 200 ELISA with adequate response defined as post-immunization antibody level of 1.3 µg/mL or fourfold rise from baseline in ≥ 10/15 serotypes in adult participants and ≥ 4/8 serotypes in pediatric participants. Thirty-nine (97.5%) adults and 22 (100%) children achieved an adequate response to 23vPPV. In PCV-naïve adults, serotypes contained within the conjugate vaccines were less immunogenic, with 12 (30%) adults not achieving an adequate antibody response when only PCV serotypes were used for interpretation. Our diagnostic laboratory has verified the interpretation criteria used for an automated multi-serotype pneumococcal ELISA method. Clinical Trial Registration: ANZCTR registration number ACTRN12618000822280.

Marginal zone B cells acquire dendritic cell functions by trogocytosis.

Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II-C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II-C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.

In Vitro Antiviral Activity of Mentha cordifolia Plant Extract in HIV-1 Latently Infected Cells Using an Established Human Cell Line.

Emergence of drug resistance demands new therapeutic strategies against the human immunodeficiency virus (HIV). Currently, there is an increasing research focus on targeting gene expression-the crucial step wherein new viruses and new viral strains are amplified. Moreover, natural products are also being considered as potential candidates for new antivirals. We screened the extract obtained from a Philippine medicinal plant, Mentha cordifolia (Mc). In this study, we demonstrated that Mc ammonium sulfate extract has antiretroviral activity against HIV. HIV-1 latently infected cells (OM10.1) were pretreated with Mc extract and activated with TNFα. In treated cells, viral replication was inhibited in both cell culture supernatant and whole cell lysates. The level of viral production, as measured by the viral p24 protein concentration, was very much inhibited under noncytotoxic concentrations to the similar level without addition of TNFα. Luciferase assays, however, showed that Mc does not inhibit the HIV-1 long terminal repeat-driven gene expression. IκBα degradation and p65 nuclear translocation was also not affected as visualized through Western blot and immunofluorescence. These observations demonstrated that Mc possessed an antiviral component against HIV-1 and warrant further work to explore its target of action at a later step of gene expression. Our study introduces a potential source of a lead compound that targets steps in the HIV life cycle.

Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats.

Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague-Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.

[Periodontitis - infection or inflammation?] / Parodontitis; infectie of ontsteking?

Periodontitis is a complex, multifactorial disease. Multiple factors such as (epi)genetic factors, environmental factors (microbial biofilm), lifestyle (smoking, stress) and general health (diabetes mellitus) contribute to the development of periodontitis. A healthy subgingival microbiome is in balance with its host, is very stable and diverse, and keeps the host healthy. Changes, such as declining oral hygiene, lead to changes in the microbial composition in the subgingival sulcus: anaerobic and protein-degrading microorganisms with pro-inflammatory properties increase in number and disturb the proportions, leading in turn to changes in the subgingival environment and an increase in pro-inflammatory microorganisms. If the first line of the immune system is unable to restore subgingival equilibrium, microorganisms and their products invade the periodontal soft tissues, resulting in activation of osteoclasts and, ultimately, in the destruction of the periodontium and the onset of periodontitis.

[The relation between halitosis and saliva]. / De relatie tussen halitose en speeksel.

Halitosis (bad breath) is caused by a number of volatiles originating, in most cases, in the oral cavity (intra-oral halitosis). These unpleasant smelling gases are volatile sulphur compounds such as hydrogen sulphide, methyl mercaptan and dimethyl sulphide secreted as a result of bacterial metabolism. Bacteria on the tongue dorsum, as well as oral pathologies such as gingivitis and periodontitis, are the main causes of intra-oral halitosis. Saliva has a number of functions that can affect intra-oral halitosis, such as mechanical cleaning, moistening of the oral cavity and antibacterial properties. Very low secretion of saliva (hyposalivation) can affect intra-oral halitosis.