Dehorning Does Not Alter the Stress Response in Southern White Rhinoceroses (Ceratotherium simum simum) during Transport: A Preliminary Investigation.

Translocation and dehorning are common and important practices for rhinoceros management and conservation. It is not known if dehorning causes a stress response or negatively affects rhinoceroses during transport. Twenty-three subadult wild Southern white rhinoceros (Ceratotherium simum simum) bulls were immobilized and translocated >280 km for population management reasons. Ten animals were dehorned at capture, and 13 animals were transported without dehorning. For transport, five dehorned and six nondehorned rhinoceroses were sedated with azaperone (62.38±9.54 µg/kg) and five dehorned and seven nondehorned rhinoceroses with midazolam (64.61±9.28 µg/kg). Blood samples were collected at capture, start of transport, and after 6 h of transport. Measurements included 10 physiologic variables: hematocrit, total serum protein, creatine kinase (CK), aspartate aminotransferase, gamma-glutamyl transferase (GGT), creatinine, urea, cholesterol, ß-hydroxybutyrate, and glucose; and four stress response variables: cortisol, epinephrine, neutrophil-to-lymphocyte ratio, and leukocyte coping capacity. Using a linear mixed model, CK and GGT were higher in dehorned compared with nondehorned rhinoceroses. There were no significant differences in the other variables between the two groups. The likely cause of these differences is that dehorned animals spent more time in the crate before the start of transport than nondehorned rhinoceroses (3:11±0:54 h vs. 1:12±0:56 h, P<0.001). These results indicate that dehorning does not negatively alter the white rhinoceros' physiologic and stress responses during translocation, supporting its use for antipoaching measures.

The Role for Preperitoneal Pelvic Packing in Low-to-Middle-Income Countries: A 16-Year Experience at a Johannesburg Trauma Unit.

INTRODUCTION: Preperitoneal pelvic packing for early pelvic haemorrhage control reduces mortality. Bleeding noted with pelvis fractures is predominantly due to associated venous complex injuries. More studies are advocating for angiography as first-line therapy for haemodynamic instability in pelvic fractures; however, these facilities are not in abundance in middle- and low-income countries. We hypothesized that PPP improves outcomes under these circumstances. METHODS: Retrospective analysis of data from the patients charts over a period of 16 years from 01 January, 2005 to 31 December, 2020. All patients over the age of 18 years who presented with haemodynamic instability from a pelvic fracture and required PPP were included. The demographics, physiological parameter in emergency department, blood products transfused, morbidity and mortality were analysed. RESULTS: There were 110 patients identified in the study period who underwent pelvic preperitoneal packing for refractory shock or ongoing bleeding. The majority (75.5%) of patients were men (n = 83). The median age was 38 years. The most common mechanism of injury was pedestrian vehicle collision (51%), followed by motor vehicle collisions (27.3%). The median ISS and NISS were 35 and 40, respectively. The median RTS in ED was 4.8(3-6.8). None of our patients rebleed after pack removal and no one needed repacking or adjunct angioembolization in our study group. The in-hospital mortality rate was 43.6% (n = 48) in patients who underwent preperitoneal pelvic packing. The operating room table mortality was 20% (n = 22/110), and the mortality rate of those who survived to ICU transfer was 29.5% (n = 26/88). CONCLUSIONS: Pelvic preperitoneal packing has a role in the acute management of haemodynamically abnormal patients with pelvic fractures in our environment. In the absence of immediate angioembolization, preperitoneal packing can be lifesaving.

Fungal microbiome shifts on avocado fruit associated with a combination of postharvest chemical and physical interventions.

AIM OF THE STUDY: The aim was to characterize the baseline microbial population of the avocado carposphere and understand shifts in community structure from the harvest to ready-to-eat stages. METHODS AND RESULTS: The changes in surface or stem-end (SE) fungal microbiomes at the postharvest stage of avocado fruit were studied using next-generation sequencing of the internal transcribed spacer region. Avocado fructoplane and SE pulp fungal richness differed significantly between postharvest stages with a decline following prochloraz dip treatments. Known postharvest decay-causing genera, Colletotrichum, Fusarium, Alternaria, Epicoccum, Penicillium and Neofusicoccum were detected, with Papiliotrema, Meyerozyma and Aureobasidium confirmed as the most dominant potentially beneficial genera. Postharvest interventions such as prochloraz had a negative non-target effect on the presence of Papiliotrema flavescens on the avocado fructoplane. CONCLUSION: Our findings reveal a core community of beneficial and pathogenic taxa in the avocado fructoplane and further highlight the reduction of pathogenic fungi as a consequence of fungicide use. SIGNIFICANCE AND IMPACT OF THE STUDY: The current study provides important baseline data for further exploration of fungal population shifts in avocado fruit driven by chemical (fungicide) as well as physical (cold storage) interventions.

Forced running-induced rhabdomyolysis in the Sprague-Dawley rat: towards a rodent model of capture myopathy.

Capture myopathy (CM) is a metabolic disease associated with mortality in mass boma captured (MBC) wildlife. The condition is induced by the forced pursuit, capturing, and restraint of wild animals, although its causal biology remains to be confirmed. A core feature of MBC-CM is rhabdomyolysis, which is associated with myoglobinuria and hyperthermia. Towards developing a translational model of CM-associated rhabdomyolysis, we investigated forced treadmill running to induce physical exhaustion and trigger rhabdomyolysis in Sprague Dawley (SD) rats. Twenty-four (24) SD rats (12 per sex) were subjected to treadmill habituation in a speed-tiered approach. Forty-eight hours after the last habituation session, one strenuous exercise (SE) session was performed at 75% of the theoretical VO2MAX (30 m/min) until animals reached physical exhaustion. Core and skin surface temperatures were measured before the SE session and after rats reached exhaustion, after which a 1-h-cumulative urine sample was collected, and the myoglobin content assayed. We show that most SE, but not control-exposed (non-exercise) rats presented with myoglobinuria, while core and surface body temperatures in both male and female rats were significantly higher post-exercise. This pre-clinical model framework shows potential for investigating the pathophysiology of MBC-CM.

Hippocampal monoamine changes in the Flinders sensitive line rat: A case for the possible use of selective α2C-AR-antagonists in stress and anxiety disorders in companion animals.

Non-selective α2-adrenoreceptor (AR) stimulation delivers favourable sedative, analgesic, muscle relaxant and anxiolytic actions in companion animals, but is associated with cardiovascular and respiratory side effects. Anxiety conditions underscore monoamine disturbances amenable to α2-AR modulation. We investigated sub-chronic (14 day s.c.) treatment with the selective α2C-AR antagonist, ORM-10921 (0.03, 0.1, 0.3 mg/kg/d) on hippocampal noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their turnover levels in stress sensitive Flinders Sensitive Line (FSL) rats versus Flinders Resistant Line (FRL) controls, using high performance liquid chromatography. The effects of ORM-10921 were compared to the non-selective α2-AR antagonist, idazoxan (IDAZ; 3 mg/kg/d), and to imipramine (IMI; 15 mg/kg/d), a reference antidepressant in this model. FSL rats displayed significantly reduced 5-HT (p = 0.03) and DA (p = 0.02) levels vs. FRL controls, while NA levels showed a similar trend. ORM-10921 significantly increased NA (all doses p ≤ 0.02), 5-HT (0.1 and 0.3 mg/kg p ≤ 0.03) and DA levels (all doses p ≤ 0.03), which correlated with decreased monoamine turnover. In contrast, IDAZ significantly elevated NA (p < 0.005) and DA (p < 0.004) but not 5-HT levels. IMI also significantly increased 5-HT (p < 0.009), with a tendency to increase NA (p = 0.09) but not DA. ORM-10921 exerts similar albeit broader effects on hippocampal monoamines than IDAZ, explaining earlier established efficacy associated with α2C-AR antagonism in animal models of depression and cognitive dysfunction. These and the current studies encourage application of ORM-10921 in depression in humans, as well as raise the intriguing possibility that selective α2C-AR antagonists may be beneficial in anxiety and stress-related disorders in companion animals. Both warrant further study.

The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment.

The recent outbreak of the corona virus disease (COVID-19) has had major global impact. The relationship between severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection and psychiatric diseases is of great concern, with an evident link between corona virus infections and various central and peripheral nervous system manifestations. Unmitigated neuro-inflammation has been noted to underlie not only the severe respiratory complications of the disease but is also present in a range of neuro-psychiatric illnesses. Several neurological and psychiatric disorders are characterized by immune-inflammatory states, while treatments for these disorders have distinct anti-inflammatory properties and effects. With inflammation being a common contributing factor in SARS-CoV-2, as well as psychiatric disorders, treatment of either condition may affect disease progression of the other or alter response to pharmacological treatment. In this review, we elucidate how viral infections could affect pre-existing psychiatric conditions and how pharmacological treatments of these conditions may affect overall progress and outcome in the treatment of SARS-CoV-2. We address whether any treatment-induced benefits and potential adverse effects may ultimately affect the overall treatment approach, considering the underlying dysregulated neuro-inflammatory processes and potential drug interactions. Finally, we suggest adjunctive treatment options for SARS-CoV-2-associated neuro-psychiatric symptoms.

A Comparison of Hematological, Immunological, and Stress Responses to Capture and Transport in Wild White Rhinoceros Bulls (Ceratotherium simum simum) Supplemented With Azaperone or Midazolam.

Capture and transport are essential procedures for the management and conservation of southern white rhinoceroses (Ceratotherium simum simum), but are associated with stress-induced morbidity and mortality. To improve conservation efforts, it is crucial to understand the pathophysiology of rhinoceros stress responses and investigate drug combinations that could reduce these responses. In this study we measured rhinoceros stress responses to capture and transport by quantifying hematological and immunological changes together with adrenal hormone concentrations. We investigated whether the potent anxiolytic drug midazolam was able to mitigate these responses compared to azaperone, which is more commonly used during rhinoceros transport. Twenty three wild white rhinoceros bulls were transported for 6 h (280 km) within the Kruger National Park for reasons unrelated to this study. Rhinoceroses were immobilized with either etorphine-azaperone (group A, n = 11) or etorphine-midazolam (group M, n = 12) intramuscularly by darting from a helicopter. Azaperone (group A) or midazolam (group M) were re-administered intramuscularly every 2 h during transport. Serial blood samples were collected at capture (TC), the start of transport (T0) and after 6 h of transport (T6). Changes in hematological and immunological variables over time and between groups were compared using general mixed models. Increases in plasma epinephrine and serum cortisol concentrations indicated that rhinoceroses mounted a stress response to capture and transport. Packed cell volume decreased from TC to T6 indicating that stress hemoconcentration occurred at TC. Neutrophils progressively increased and lymphocytes and eosinophils progressively decreased from T0 to T6, resulting in an increase in neutrophil to lymphocyte ratio; a characteristic leukocyte response to circulating glucocorticoids. A reduction in serum iron concentrations may suggest the mounting of an acute phase response. Rhinoceroses experienced a decrease in unsaturated fatty acids and an increase in lipid peroxidation products at capture and toward the end of transport indicating oxidative stress. Midazolam, at the dose used in this study, was not able to mitigate adrenal responses to stress and appeared to directly influence leukocyte responses.

The Design and Evaluation of an l-Dopa-Lazabemide Prodrug for the Treatment of Parkinson's Disease.

l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson's disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa's physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa-lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption. Lazabemide is a monoamine oxidase (MAO)-B inhibitor, a class of compounds that slows the depletion of dopamine stores in Parkinson's disease and elevates dopamine levels produced by exogenously administered l-dopa. l-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect l-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined and included lipophilicity (logD), solubility, passive diffusion permeability, pKa, chemical and metabolic stability as well as cytotoxicity. Although oral and i.p. treatment of mice with the prodrug did not result in enhanced striatal dopamine levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly depressed compared to saline, l-dopa and carbidopa/l-dopa treatment. Based on the results, further preclinical evaluation of the l-dopa-lazabemide prodrug should be undertaken with the aim of discovering prodrugs that may be advanced to the clinical stages of development.

Ozone exposure of Flinders Sensitive Line rats is a rodent translational model of neurobiological oxidative stress with relevance for depression and antidepressant response.

RATIONALE: Major depression has been associated with higher levels of air pollution that in turn leads to neurodegeneration via increased oxidative stress. There is a need for suitable translational animal models to study the role of oxidative stress in depression and antidepressant action. OBJECTIVE: Considering the gene X environment hypothesis of depression, the present study investigated the effect of chronic ozone inhalation on depression and anxiety-related behavior, cognition, and brain markers of oxidative stress in the Flinders Sensitive Line (FSL) rat. In addition, response to the antioxidant melatonin, and the antidepressants desipramine or escitalopram, was assessed. METHODS: Rats were exposed to ozone (0.0 or 0.3 parts per million (ppm)) per inhalation for 4 h daily for a period of 15 days, while simultaneously receiving saline or the above-mentioned drugs. RESULTS: The data indicate that chronic ozone inhalation induced memory impairment, anxiety and depression-like effects, reduced cortical and hippocampal superoxide dismutase and catalase activity, and compromised central monoamine levels similar to that noted in depression. Moreover, the behavioral and neurochemical effects of melatonin, desipramine, and escitalopram were mostly attenuated in the presence of ozone. CONCLUSION: Thus, genetically susceptible individuals exposed to high levels of oxidative stress are at higher risk of developing mood and/or an anxiety disorders, showing greater redox imbalance and altered behavior. These animals are also more resistant to contemporary antidepressant treatment. The presented model provides robust face, construct, and predictive validity, suitable for studying neuronal oxidative stress in depression, antidepressant action and mechanisms to prevent neuronal oxidative stress.

N-Acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats.

Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250 mg/kg/day × 14 days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250 mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250 mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs' therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.

Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine.

Apart from altered dopamine (DA) function, schizophrenia displays mitochondrial and immune-inflammatory abnormalities, evidenced by oxidative stress, altered kynurenine metabolism and cytokine release. N-acetyl cysteine (NAC), an antioxidant and glutamate modulator, is effective in the adjunctive treatment of schizophrenia. Social isolation rearing (SIR) in rats is a valid neurodevelopmental animal model of schizophrenia. This study evaluated whether SIR-induced behavioural deficits may be explained by altered plasma pro- and anti-inflammatory cytokines, kynurenine metabolism, and cortico-striatal DA and mitochondrial function (via adenosine triphosphate (ATP) release), and if clozapine or NAC (alone and in combination) reverses these changes. SIR induced pronounced deficits in social interactive behaviours, object recognition memory, and prepulse inhibition (PPI), while simultaneously increasing striatal but reducing frontal cortical accumulation of ATP as well as DA. SIR increased pro- vs. anti-inflammatory cytokine balance and altered kynurenine metabolism with a decrease in neuroprotective ratio. Clozapine (5mg/kg/day×14days) as well as clozapine+NAC (5mg/kg/day and 150mg/kg/day×14days) reversed these changes, with NAC (150mg/kg/day) alone significantly but partially effective in some parameters. Clozapine+NAC was more effective than clozapine alone in reversing SIR-induced PPI, mitochondrial, immune and DA changes. In conclusion, SIR induces mitochondrial and immune-inflammatory changes that underlie cortico-striatal DA perturbations and subsequent behavioural deficits, and responds to treatment with clozapine or NAC, with an additive effect following combination treatment. The data provides insight into the mechanisms that might underlie the utility of NAC as an adjunctive treatment in schizophrenia.

Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues.

Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.

Psychopharmacology of maternal separation anxiety in vervet monkeys.

Maternal separation in non-human primates has been proposed as a model of early adversity. The symptoms of separation anxiety were studied in vervet monkeys, during the weaning period, when psychotropic medications were administered. The control group received a normal diet and treatment groups received citalopram, reboxetine or lamotrigine in their food daily. Treatment was given for 7 weeks starting 1 month prior to weaning. Behavior was recorded twice weekly for 8 weeks, and was rated for anxiety and depression. Cerebrospinal fluid was collected at the beginning and end of the trial and analyzed for monoamines and metabolites using High Performance Liquid Chromatography. Citalopram pretreatment prevented the reduction of affiliation behavior and reduced stereotypies after weaning, and both citalopram and reboxetine abolished the increase in activity seen in control monkeys after weaning, but no statistically significant differences were found between groups. Citalopram pretreatment also significantly increased noradrenaline and 5-hydroxyindolacetic acid (5-HIAA) levels and reboxetine significantly decreased dopamine levels over time. The 5-HIAA levels of reboxetine and lamotrigine treated monkeys were significantly lower than that of the control group at the end of the trial. Although limited by a small sample size, this study demonstrates the possibility of investigating the psychopharmacology of early adversity in a non-human primate model.