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1.
Aust J Rural Health ; 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39283058

ABSTRACT

OBJECTIVE: To identify barriers and facilitators contributing to the successful implementation of the allied health assistant role in private disability practice to better meet population needs. DESIGN: A qualitative case study. SETTING: This study was completed with staff working in private disability practices in a regional context in the Northern Territory. PARTICIPANTS: Eight participants were interviewed, including three allied health assistants, three allied health professionals, and two managers with allied health backgrounds. RESULTS: More barriers were reported than facilitators, with four key themes identified. Financial risk was a barrier when employing allied health assistants. This risk was mediated by providing part-time employment or having allied health assistants in dual roles. Reduced confidence from allied health professionals and assistants to complete delegation work was the second barrier. A facilitator was increasing allied health assistants' task variation, which participants reported increased retention. Finally, a positive working relationship between allied health professionals and assistants facilitates delegation. CONCLUSION: This research offers private disability providers insight into the realities of employing an allied health assistant. It also suggests that formal training programs for both allied health assistants and professionals require increased focus on delegation in the private disability sector. On a government level, a review of the NDIS price guide for allied health assistant rates is needed if private providers are to better meet the requirements for NDIS participants in regional areas.

2.
J Comp Neurol ; 531(13): 1276-1298, 2023 09.
Article in English | MEDLINE | ID: mdl-37279778

ABSTRACT

Nonhuman primates (NHPs) are important to study the pathophysiology of neurodegenerative disease and evaluate therapies targeting the central nervous system (CNS). Understanding the age-associated incidence of natural CNS pathology in a given NHP species is critical to assess the safety of potential treatments for neurodegenerative disorders like Alzheimer's disease (AD). We describe background and age-related neuropathology in the St. Kitts African green monkey (AGM), a recognized translational model for neurodegenerative research, additionally defining the age progression of AD-associated neuropathology in this species. Seventy-one AGM brains were examined, representing age groups of 3-6 years (n = 20), 7-9 years (n = 20), 10-15 years (n = 20), and >15 years (n = 11). A subset of brains (n = 31) was assessed immunohistochemically for AD-related pathology, including expressions of Aß, tau, and GFAP. Age-related microscopic findings included hemosiderosis, spheroid formation, neuronal lipofuscinosis and neuromelanosis, white matter and neuropil vacuolation, astrocytosis, and focal microgliosis. Non-age-related findings included perivascular ceroid-laden macrophages, meningeal melanosis, and vascular mineralization. Immunohistochemistry revealed 4G8-immunopositive Aß plaques and vascular deposits in the prefrontal, frontal, cingulate, and temporal cortices of nine animals over 15 years of age, with associated increase in GFAP expression. In 12 animals, 11 over the age of 10 years, phosphorylated tau CP13-immunoreactive neurons, neuropil, and oligodendrocyte-like cells were seen in the prefrontal, frontal, cingulate, orbital, temporal, and entorhinal cortices as well as the hippocampus; no neurofibrillary tangles were observed. AD-related pathology showed an age-related development in cognitive-associated areas in the AGM, highlighting the value of the AGM as a natural model for these neurodegenerative diseases.


Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Animals , Chlorocebus aethiops , Alzheimer Disease/pathology , tau Proteins/metabolism , Amyloid beta-Peptides , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Brain/metabolism , Aging/pathology
3.
PLoS One ; 16(9): e0248794, 2021.
Article in English | MEDLINE | ID: mdl-34506492

ABSTRACT

Electroencephalography (EEG) likely reflects activity of cortical neurocircuits, making it an insightful estimation for mental health in patients with substance use disorder (SUD). EEG signals are recorded as sinusoidal waves, containing spectral amplitudes across several frequency bands with high spatio-temporal resolution. Prior work on EEG signal analysis has been made mainly at individual electrodes. These signals can be evaluated from advanced aspects, including sub-regional and hemispheric analyses. Due to limitation of computational techniques, few studies in earlier work could conduct data analyses from these aspects. Therefore, EEG in patients with SUD is not fully understood. In the present retrospective study, spectral powers from a data house containing opioid (OUD), methamphetamine/stimulants (MUD), and alcohol use disorder (AUD) were extracted, and then converted into five distinct topographic data (i.e., electrode-based, cortical subregion-based, left-right hemispheric, anterior-posterior based, and total cortex-based analyses). We found that data conversion and reorganization in the topographic way had an impact on EEG spectral powers in patients with OUD significantly different from those with MUD or AUD. Differential changes were observed from multiple perspectives, including individual electrodes, subregions, hemispheres, anterior-posterior cortices, and across the cortex as a whole. Understanding the differential changes in EEG signals may be useful for future work with machine learning and artificial intelligence (AI), not only for diagnostic but also for prognostic purposes in patients with SUD.


Subject(s)
Brain/diagnostic imaging , Electroencephalography/methods , Substance-Related Disorders/diagnostic imaging , Adult , Alcoholism/diagnostic imaging , Alcoholism/physiopathology , Female , Humans , Male , Methamphetamine , Middle Aged , Opioid-Related Disorders/diagnostic imaging , Opioid-Related Disorders/physiopathology , Retrospective Studies , Substance-Related Disorders/physiopathology
4.
Res Dev Disabil ; 114: 103984, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33991930

ABSTRACT

High levels of stress in parents of children with a developmental disability have been extensively documented. These heightened stress levels seem independent of diagnosis and are better explained by the level of challenging behavior of the children. Furthermore, the relationship between stress level and difficult behavior appears reciprocal. The negative impact of stress on parents' skill development, response to difficult behavior, sense of competence, well-being and the child's developmental outcomes have also been thoroughly detailed. The Parent Child Relationally Informed - Early Intervention (PCRI-EI) aims to expand the response repertoires of parents to help address the challenges of parenting a child with a developmental disability, including through reducing parental stress. The current study presents a quasi-experimental assessment of the efficacy of PCRI-EI in reducing stress levels and increasing sense of competency and psychological well-being in a sample of 22 parents of children with a variety of disabilities presenting to a community early childhood development service. Statistically and clinically significant changes in overall stress levels (Parenting Stress Index), psychological well-being (K6) and sense of competence (PSOC) were observed across time.


Subject(s)
Developmental Disabilities , Parents , Child , Child Behavior , Child Development , Child, Preschool , Humans , Parenting , Stress, Psychological
5.
Mar Drugs ; 18(5)2020 May 16.
Article in English | MEDLINE | ID: mdl-32429425

ABSTRACT

This study examined the effects of dietary supplementation with laminarin or chitosan on colonic health in pigs challenged with dextran sodium sulphate (DSS). Weaned pigs were assigned to: (1) a basal diet (n = 22); (2) a basal diet + laminarin (n = 10); and (3) a basal diet + chitosan (n = 10). On d35, the basal group was split, creating four groups: (1) the basal diet (control); (2) the basal diet + DSS; (3) the basal diet + laminarin + DSS; and (4) the basal diet + chitosan + DSS. From d39-42, the pigs were orally challenged with DSS. On d44, colonic tissue/digesta samples were collected. The basal DSS group had reduced growth, higher pathology score and an increased expression of MMP1, IL13 and IL23 compared with the controls (p < 0.05); these parameters were similar between the DSS-challenged groups (p > 0.05). In the basal DSS group, the relative abundance of beneficial taxa including Prevotella and Roseburia were reduced while Escherichia/Shigella were increased, compared with the controls (p < 0.05). The relative abundance of Escherichia/Shigella was reduced and the molar proportions of acetate were increased in the laminarin DSS group compared with the basal DSS group (p < 0.01), suggesting that laminarin has potential to prevent pathogen proliferation and enhance the volatile fatty acid profile in the colon in a porcine model of colitis.


Subject(s)
Chitosan/pharmacology , Colitis/prevention & control , Dietary Supplements , Glucans/pharmacology , Intestinal Mucosa/drug effects , Polysaccharides/pharmacology , Protective Agents/pharmacology , Animals , Chitosan/administration & dosage , Colitis/chemically induced , Dextrans , Disease Models, Animal , Glucans/administration & dosage , Male , Polysaccharides/administration & dosage , Protective Agents/administration & dosage , Random Allocation , Swine
6.
J Pathol ; 251(2): 117-122, 2020 06.
Article in English | MEDLINE | ID: mdl-32297672

ABSTRACT

The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1 flx/flx ) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally, and reproduced successfully. Following Grem1 depletion, the mice became unwell and were euthanised (at 7-13 days). Post-mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy, and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Subject(s)
Bone Marrow Failure Disorders/metabolism , Bone Marrow/metabolism , Epithelial Cells/metabolism , Hematopoietic Stem Cells/metabolism , Intercellular Signaling Peptides and Proteins/deficiency , Intestinal Mucosa/metabolism , Malabsorption Syndromes/metabolism , Animals , Bone Marrow/pathology , Bone Marrow Failure Disorders/genetics , Bone Marrow Failure Disorders/pathology , Cell Lineage , Cell Proliferation , Epithelial Cells/pathology , Hematopoiesis , Hematopoietic Stem Cells/pathology , Intercellular Signaling Peptides and Proteins/genetics , Intestinal Absorption , Intestinal Mucosa/pathology , Malabsorption Syndromes/genetics , Malabsorption Syndromes/pathology , Male , Mice, Knockout , Phenotype , Stem Cell Niche
7.
BMC Pharmacol Toxicol ; 20(1): 47, 2019 08 05.
Article in English | MEDLINE | ID: mdl-31383036

ABSTRACT

BACKGROUND: MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. METHODS: Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. RESULTS: Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. CONCLUSION: Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.


Subject(s)
Environment , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Neurotoxins/toxicity , Serotonin Agents/toxicity , Animals , Brain/drug effects , Brain/metabolism , Dose-Response Relationship, Drug , Male , Neurotoxicity Syndromes/veterinary , Rats , Rats, Sprague-Dawley , Serotonin/metabolism
8.
J Proteomics ; 205: 103421, 2019 08 15.
Article in English | MEDLINE | ID: mdl-31233901

ABSTRACT

Early diagnosis of endometritis in dairy cattle is currently requires invasive techniques and specialist expertise. The goal of this study is to utilize a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without. Blood samples were collected from cows (N = 112) seven days postpartum (DPP). Plasma samples from a cohort of 20 animals with cytological endometritis (n = 10) and without (n = 10) as classified 21 DPP were selected for proteomic analysis. Differential abundances of proteins between the two animal groups were determined using both fold change (≥1.5 fold change) and statistical significance threshold (p < .05). A total of 181 non-redundant proteins were quantified, and 25 proteins were found with differential abundance. These include 4 binding protein alpha and mannose binding lectin 2 involved in immune responses. Differentially abundant proteins between the animals were then processed using PANTHER for gene ontology. Gene ontology included associations with innate immune processes, acute phase responses and immune regulation. A potential marker for disease identified here is the "uncharacterized protein G5E513," a protein previously defined by RNA-transcripts. These proteins may form the basis for endometritis prognosis, the development of which is proceeded by systemic changes in immune function. SIGNIFICANCE: Endometritis is a costly reproductive disease of lactating dairy cows that warrants timely diagnosis. We utilized a gel-free mass-spectrometry based proteomics approach to compare the plasma proteome of dairy cattle with cytological endometritis to those without, for the characterization of changes in the proteomic profile associated with uterine disease postpartum. Furthermore, we compared the plasma proteome of healthy and affected cows in the same physiological status of production to better understand the relationship between changes in expression of circulating proteins and to unravel essential biological mechanisms involved in bovine cytological endometritis.


Subject(s)
Blood Proteins/metabolism , Cattle Diseases/blood , Endometritis/blood , Lactation/metabolism , Proteome/metabolism , Animals , Biomarkers/analysis , Biomarkers/blood , Blood Proteins/analysis , Cattle , Cattle Diseases/metabolism , Cattle Diseases/pathology , Cell Biology , Dairying , Endometritis/metabolism , Endometritis/pathology , Female , Postpartum Period , Proteome/analysis , Puerperal Disorders/blood , Puerperal Disorders/metabolism , Puerperal Disorders/pathology , Puerperal Disorders/veterinary
9.
J Vet Diagn Invest ; 31(3): 343-349, 2019 May.
Article in English | MEDLINE | ID: mdl-30973088

ABSTRACT

Free-roaming chickens on Caribbean islands are important sentinels for local avian diseases and those introduced by birds migrating through the Americas. We studied 81 apparently healthy unvaccinated free-roaming chickens from 9 parishes on St. Kitts, an eastern Caribbean island. Using commercial ELISAs, no chickens had antibodies against avian influenza virus, West Nile virus, or Salmonella Enteritidis, although seropositivity was high to infectious bursal disease virus (86%), infectious bronchitis virus (84%), Mycoplasma (37%), and avian avulavirus 1 (Newcastle disease virus, 31%). Examination of small and large intestinal contents revealed cestodes in 79% and nematodes in 75% of the chickens. Although ectoparasites and endoparasites were common (74% and 79%, respectively), only a few chickens had lesions at postmortem examination, mainly intestinal serosal nodules (12%) and feather loss (6%). Histologic examination of 18 organs from each bird revealed lesions in high percentages of organs, mainly the liver (86%), lung (75%), spleen (60%), small intestine (56%), skin (42%), and kidney (40%). Lesions included degenerative, reactive, inflammatory, and neoplastic, and were not correlated with the serologic status of the chickens except in one case of infectious bursal disease. Microscopically, Paratanaisia bragai was seen in the kidneys of 3 chickens and intestinal coccidiasis in 1 chicken. Pulmonary silicate aggregates were common, were present in intestinal serosal nodules, and were suggestive of environmental exposure.


Subject(s)
Bacterial Infections/veterinary , Chickens , Intestinal Diseases, Parasitic/epidemiology , Intestinal Diseases, Parasitic/veterinary , Poultry Diseases/epidemiology , Virus Diseases/veterinary , Animal Husbandry/methods , Animals , Bacterial Infections/epidemiology , Bacterial Infections/microbiology , Bacterial Infections/pathology , Enzyme-Linked Immunosorbent Assay/veterinary , Female , Intestinal Diseases, Parasitic/microbiology , Intestinal Diseases, Parasitic/pathology , Male , Poultry Diseases/microbiology , Poultry Diseases/parasitology , Poultry Diseases/pathology , Prevalence , Saint Kitts and Nevis/epidemiology , Seroepidemiologic Studies , Virus Diseases/epidemiology , Virus Diseases/pathology , Virus Diseases/virology
10.
Exp Neurol ; 313: 26-36, 2019 03.
Article in English | MEDLINE | ID: mdl-30521789

ABSTRACT

Synthetic cathinones, often marketed as 'bath salts', have been reported to induce an excited delirium syndrome with characteristic symptoms such as paranoid, hallucination and even aggression. 3,4-Methylenedioxypyrovalerone (MDPV), a norepinephrine-dopamine reuptake inhibitor (NDRI), is one of the psychoactive ingredients in bath salts. The present study utilized cortical EEG and brain microdialysis in rats to compare the effects of MDPV (0.25, 1 and 2 mg/kg, i.p.) with the hallucinogenic drugs MK-801 (0.05, 0.1 and 0.5 mg/kg, i.p.) and ketamine (5, 15 and 25 mg/kg, i.p.). Results revealed that MDPV similar to MK-801 and ketamine caused a dose-dependent increase in the cortical EEG synchronization. In addition, all three drugs produced an increase in DA efflux in the prefrontal cortex (FCx). However, there existed difference between the three drugs. In contrast to MDPV, MK-801 and ketamine had only moderate or little effects on DA efflux in the nucleus accumbens (NAcc). Except for ketamine, the effects of MDPV and MK-801 on EEG synchronization were blocked by the D1 receptor antagonist SCH23990 (0.1 mg/kg, i.p.) and D2 receptor antagonist sulpiride (100 mg/kg, i.p.). SCH23990 or sulpiride had no effect on ketamine-induced increases in EEG synchronization. In summary, the present comparative studies suggest that DA in the FCx, but unlikely the NAcc, exerts a critical role in increasing EEG synchronization associated with the excited delirium syndrome. Neural circuits consisting of glutamatergic and GABAergic neurons responsible for the hallucinogenic effect are discussed in the context of hyperdopamine and dysconnection theories for hallucinatory behaviors.


Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Benzodioxoles/pharmacology , Designer Drugs/pharmacology , Dizocilpine Maleate/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Electroencephalography/drug effects , Hallucinogens/pharmacology , Ketamine/pharmacology , Pyrrolidines/pharmacology , Animals , Brain Chemistry/drug effects , Dopamine/metabolism , Dose-Response Relationship, Drug , Electroencephalography Phase Synchronization/drug effects , Male , Rats , Rats, Sprague-Dawley , Synthetic Cathinone
11.
Biointerphases ; 13(5): 051002, 2018 10 16.
Article in English | MEDLINE | ID: mdl-30326703

ABSTRACT

Chronic nonhealing wounds, particularly those complicated by multidrug resistant infections, represent a major health and economic challenge. Plasma treatment promotes wound repair due to its antimicrobial, angiogenic, and cell modulating properties. This study investigated the efficacy of the kINPen Med system in promoting healing and assessed if efficacy was enhanced by adding collagen or hyaluronic acid (HA). Two 6 mm diameter punch biopsy wounds were created on the lumbar spine of Sprague Dawley rats. Based on the results of a pilot study, operating process conditions involving 30 s plasma/day were selected for the pivotal study. In the pivotal study, six groups of rats (n = 28/group) received either control (1), plasma (2), HA (3), plasma and HA (4), collagen (5), or plasma and collagen (6). Wound measurements were obtained on Days 0, 4, 7, and 14. The mean reduction in wound size was significantly higher in all treatment groups compared to controls on Day 4; group 6 performed best. On Day 7, group 6 still performed significantly better compared to groups 1, 2, 3, and 4. Day 14 results were more comparable between groups. Histology (Day 14) revealed epidermal hyperplasia and serocellular crusts. Neutrophilic infiltrates in group 6 were significantly lower compared to group 2. Mononuclear infiltrates were highest in groups 3 and 5, while Langerhans cells were observed in all groups. These results underpin the clinical benefits of the kINPen Med plasma system, particularly when combined with collagen during early inflammatory phases, and support the conduct of future human clinical trials.


Subject(s)
Biological Factors/administration & dosage , Plasma Gases/administration & dosage , Wound Healing , Wounds and Injuries/drug therapy , Animals , Collagen/administration & dosage , Disease Models, Animal , Histocytochemistry , Hyaluronic Acid/administration & dosage , Pilot Projects , Rats, Sprague-Dawley , Treatment Outcome
12.
J Wildl Dis ; 54(4): 881-884, 2018 10.
Article in English | MEDLINE | ID: mdl-29870282

ABSTRACT

We describe histopathologic abnormalities in the kidneys of small Indian mongoose ( Herpestes auropunctatus) on the Caribbean island of Saint Kitts. The lesions observed in moderate to severe cases were suggestive of a chronic nephropathy. Further investigation is needed to explore the magnitude of the problem, potential causes, and predisposing factors.


Subject(s)
Herpestidae , Kidney Diseases/veterinary , Animals , Kidney Diseases/epidemiology , Kidney Diseases/pathology , Prevalence , West Indies/epidemiology
13.
Trop Anim Health Prod ; 50(5): 1171-1173, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29430608

ABSTRACT

Trichomonosis is an endemic disease in cattle that are reared under extensive conditions and bred by natural mating. It causes profound economic losses to the producers by increasing calving interval, increasing embryo losses, and decreasing pregnancy rates. The aim of this study was to determine whether Tritrichomonas foetus infections were absent from cattle in St. Kitts. Using the modified hypergeometric method, preputial samples from bulls (n = 78) were tested using the InPouch™ culture for presence of T. foetus. Results highlighted an absence of trichomoniasis in bulls on St. Kitts with a 95% confidence.


Subject(s)
Cattle Diseases/epidemiology , Protozoan Infections, Animal/epidemiology , Tritrichomonas foetus , Animals , Cattle , Female , Male , Pregnancy , Protozoan Infections , Saint Kitts and Nevis/epidemiology
14.
Article in English | MEDLINE | ID: mdl-31172032

ABSTRACT

In a recreational use of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), some but not all users are stricken with a serious serotonin (5-hydroxytryptamine; 5-HT) syndrome. This raises a question as to whether there exist subpopulations that are more susceptible to MDMA intoxication. The hypothesis was tested with hyperthyroid versus euthyroid rats by measuring changes in body-core temperature (T cor) and 5-HT in the hypothalamus. In the euthyroid rats, injection of MDMA at a recreationally relevant dose had no serious effect on T cor. In contrast, the same dose was sufficient to evoke life-threatening hyperthermia in hyperthyroid rats. Neurochemical studies revealed that there was greater 5-HT efflux in the hyperthyroid than the euthyroid rats. These effects were blocked by pretreatment with M100907, a 5-HT2A receptor antagonist. In summary, our data support the hypothesis that individuals with hyperthyroidism are more susceptible to having a serious serotonin syndrome following MDMA administration.

15.
Sci Rep ; 7: 40717, 2017 01 16.
Article in English | MEDLINE | ID: mdl-28091584

ABSTRACT

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm's canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.


Subject(s)
Anterior Chamber/physiology , Aqueous Humor/metabolism , Endothelium/metabolism , Tight Junctions/metabolism , Animals , Biomarkers , Endothelial Cells/metabolism , Endothelial Cells/ultrastructure , Endothelium/ultrastructure , Gene Expression , Humans , Immunohistochemistry , Mice , Permeability , Primates , RNA Interference , RNA, Small Interfering/genetics , Tight Junctions/ultrastructure
16.
Article in English | MEDLINE | ID: mdl-29732414

ABSTRACT

Ecstasy is a recreational drug containing 3,4-methylenedioxymethamphetamine (MDMA). In the U.S., there are several millions of lifetime users, and millions each year added to the list as new users. Only several thousand every year show signs of severe toxicity and require emergency intervention. The illness is known as serotonin (5-HT) syndrome, which can be mild, moderate or severe. The relationship between mild, moderate and severe syndromes appears to be interchangeable, but the severe syndrome is life-threatening. The serotonergic mechanisms of how the mild or moderate syndrome becomes severe and life-threatening have attracted considerable attention in the last few years as an effort to explore new treatments potentially to manage illness and prevent death of patients. High levels of extracellular 5-HT in the brain produced by large doses of MDMA are not always necessary to cause a severe serotonin syndrome. Additional mechanisms may be more important. Recent research has demonstrated that environmental conditions (i.e., non-drug factors) are more critical in determining the severity of MDMA-induced serotonin syndrome than the drug dose. The purpose of the current article was to review available evidence regarding the effect of non-drug factors on serotonergic extrasynaptic receptor responsivity and the severity of MDMA-induced serotonin syndrome.

17.
J Med Primatol ; 46(1): 9-12, 2017 02.
Article in English | MEDLINE | ID: mdl-27859319

ABSTRACT

BACKGROUND: A uterine neoplasm was observed, as an incidental finding, during post-mortem examination of a 26-year-old female multiparous African green monkey (Chlorocebus aethiops sabaeus). The intramural, expansile, 2 to 3 cm well-demarcated, dark-red, nodular neoplasm was located on the anterior uterine body (corpus) wall. METHODS: The mass was examined by light microscopy and by immunohistochemistry. RESULTS: The mass was confirmed as a cavernous uterine angioleiomyoma (syn. vascular leiomyoma) characterized by abundant intratumoural vasculature lined by Factor VIII-positive endothelial cells and surrounded by smooth muscle actin-positive cell proliferations. CONCLUSION: Angioleiomyoma sharing the characteristics of intramural human cavernous uterine angioleiomyoma should be considered in the differential diagnosis of uterine tumours in non-human primates.


Subject(s)
Angiomyoma/veterinary , Chlorocebus aethiops , Monkey Diseases/diagnosis , Uterine Neoplasms/veterinary , Angiomyoma/diagnosis , Angiomyoma/diagnostic imaging , Animals , Diagnosis, Differential , Female , Immunohistochemistry/veterinary , Monkey Diseases/diagnostic imaging , Uterine Neoplasms/diagnosis , Uterine Neoplasms/diagnostic imaging
18.
J Theor Biol ; 402: 129-43, 2016 08 07.
Article in English | MEDLINE | ID: mdl-27155046

ABSTRACT

Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other. Our method is able to rapidly calculate the evolution of proliferating as well as dead and quiescent cells, and hence a proliferative index, from a given amount and distribution of vascularisation of arbitrary complexity. Applying our model, we found that a heterogeneous vessel distribution provoked a higher proliferative index, suggesting increased malignancy, and increased the amount of dead cells compared to a more static tumour environment when a homogenous vessel distribution was assumed. We subsequently demonstrated that under certain amounts of vascularisation, cell proliferation may even increase when vessel density decreases, followed by a subsequent decrease of proliferation. This effect was due to a trade-off between an increase in compensatory proliferation for replacing dead cells and a decrease of cell population due to lack of oxygen supply in lowly vascularised tumours. Findings were illustrated by an ectopic colorectal cancer mouse xenograft model. Our presented approach can be in the future applied to study the effect of cytostatic, cytotoxic and anti-angiogenic chemotherapy and is ideally suited for translational systems biology, where rapid interaction between theory and experiment is essential.


Subject(s)
Models, Biological , Neoplasms/blood supply , Neoplasms/pathology , Neovascularization, Pathologic/pathology , Animals , Cell Count , Cell Death , Cell Proliferation , HCT116 Cells , Humans , Mice, Inbred BALB C , Mice, Nude , Microvessels/pathology
19.
PLoS One ; 11(5): e0155551, 2016.
Article in English | MEDLINE | ID: mdl-27192423

ABSTRACT

In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP), intracerebroventricular (ICV) and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible reason for the difference in MDMA-elicited serotonin syndrome between systemic and intracranial administrations.


Subject(s)
Brain/drug effects , Brain/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Serotonin Syndrome/etiology , Serotonin Syndrome/metabolism , Animals , Body Temperature , Drug Administration Routes , Male , Microdialysis , Rats , Serotonin/metabolism
20.
JFMS Open Rep ; 2(1): 2055116915626166, 2016.
Article in English | MEDLINE | ID: mdl-28491407

ABSTRACT

CASE SUMMARY: This case describes a young non-pregnant cat that presented with uterine prolapse in association with an unusual diffuse, polypoid, fibrosing perimetritis and parametritis. Following ovariohysterectomy the cat recovered fully. No intra-abdominal complications were seen on ultrasound examination 3 months postsurgery. At the time of writing, the cat remains healthy. RELEVANCE AND NOVEL INFORMATION: Uterine prolapse in the cat is relatively rare and usually associated with the periparturient period. Inflammatory polypoid perimetritis and parametritis have not previously been documented in cats, and in dogs have only been reported in association with the administration of oestrogenic compounds. The polypoid inflammation affecting the uterus and parametrium may have contributed to increased laxity of the uterine ligaments and predisposed to the development of uterine prolapse.

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