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Highlights • Overall, COVID-19 has had massive impacts on mental health care internationally. • Most mental health systems were under-resourced and under-prepared, both to manage existing clients and to manage new clients. • There were significant differences between sites, depending on the explosivity of COVID-19 and the readiness of the mental health system. • Integrated, community mental health systems exhibited greater adaptability in contrast to services which depended on face-to-face and hospital-based care. • There is an urgent requirement to use the lessons of COVID to drive the next wave of mental health reform, which should prioritise local, community and digital solutions., Aim To summarise commonalities and variations in the mental health response to COVID-19 across different sites and countries, with a view to better understanding key steps not only in crisis management, but for future systemic reform of mental health care. Method We conducted a Rapid Synthesis and Translation Process of lessons learned from an international panel of experts, collecting on the ground experiences of the pandemic as it evolved in real time. Digital conferencing and individual interviews were used to rapidly acquire knowledge on the COVID-19 outbreak across 16 locations in Australia, Denmark, Italy, Spain, Taiwan, the UK, and the USA. Results COVID-19 has had massive impacts on mental health care internationally. Most systems were under-resourced and under-prepared, struggling to manage both existing and new clients. There were significant differences between sites, depending on the explosivity the pandemic and the readiness of the mental health system. Integrated, community mental health systems exhibited greater adaptability in contrast to services which depended on face-to-face and hospital-based care. COVID-19 has demonstrated the need for a new approach to rapid response to crisis in mental health. New decision support system tools are necessary to ensure local decision-makers can effectively respond to the enormous practical challenges posed in these circumstances. Conclusions The process we have undertaken has generated clear lessons for mental health policymakers worldwide, beyond pandemic planning and response to guide next steps in systemic mental health reform. Key here is achieving some balance between national leadership and local context adaptation of evidence.

To develop a new, clinically relevant large animal model of pediatric spinal cord injury (SCI) and compare the clinical and experimental features of pediatric SCI.Infant piglets (3-5 weeks old) underwent contusive SCI by controlled cortical impactor at T7. Severe complete SCI was induced in 6 piglets, defined as SCI with no spontaneous return of sensorimotor function. Eight piglets received incomplete SCI, which was followed by partial recovery. Somatosensory evoked potentials, magnetic resonance imaging, neurobehavioral function, and histopathology were measured during a 28-day survival period.Mean SCI volume (defined as volume of necrotic tissue) was larger after complete compared with incomplete SCI (387 +/- 29 vs 77 +/- 38 mm3, respectively, P0.001). No functional recovery occurred after complete SCI. After incomplete SCI, piglets initially had an absence of lower extremity sensorimotor function, urinary and stool retention, and little to no rectal tone. Sensory responses recovered first (1-2 days after injury), followed by spontaneous voiding, lower extremity motor responses, regular bowel movements, and repetitive flexion-extension of the lower extremities when crawling. No piglet recovered spontaneous walking, although 4 of 8 animals with incomplete injuries were able to bear weight by 28 days. In vivo magnetic resonance imaging was performed safely, yielded high-resolution images of tissue injury, and correlated closely with injury volume seen on histopathology, which included intramedullary hemorrhage, cellular inflammation, necrosis, and apoptosis.Piglets performed well as a reproducible model of traumatic pediatric SCI in a large animal with chronic survival and utilizing multiple outcome measures, including evoked potentials, magnetic resonance imaging, functional outcome scores, and histopathology.

background The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial. methods We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years. results Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71). conclusions Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.

In photoperiodic mammals, seasonal cycles of growth and reproduction are cued by changes in the duration of the nocturnal profile of secretion of the pineal hormone melatonin. To investigate the likely mode of action of this hormone on target tissues, the effect of prolonged treatment with melatonin on the sensitivity of the adenylate cyclase (AC) system was examined in primary cultures of ovine pars tuberalis (PT) cells. When cells were exposed to melatonin (100 pM or 1 microM) for 16 h, and the hormone was then removed by a series of washes, basal production of cAMP was elevated over that observed in cells not treated with melatonin. Moreover, the rate of accumulation of cAMP after stimulation with forskolin (1 microM) was markedly enhanced in cells previously treated with melatonin compared to that in untreated controls. This sensitization by melatonin of the basal and forskolin-stimulated responses developed gradually and was half-maximal after approximately 8 h of exposure. There was no significant difference between the sensitizing effects of the two melatonin concentrations used. Treatment with melatonin for 24 h reduced the total amount of specific [125I]iodomelatonin binding in PT cell membranes by 30-50%. However, over the same period there was no reduction in the ability of a maximal (1 microM) concentration of melatonin to inhibit forskolin-stimulated cAMP production, indicating the presence of an excess capacity of melatonin receptors in cultured PT cells. Nevertheless, treatment with melatonin for 16 h did result in a 10-fold increase in the IC50 for the inhibition by melatonin of forskolin-stimulated cAMP production. The enhancement of cAMP production after prolonged treatment with melatonin was not masked by the inclusion of isobutylmethylxanthine (1 mM) during the subsequent challenge with forskolin, suggesting that sensitization was not due to a reduction in the activity of cAMP-phosphodiesterase. In control cells, aluminium fluoride caused an inhibition of forskolin-stimulated cAMP production. Prolonged treatment with melatonin abolished the inhibitory effect of aluminium fluoride, suggesting that treatment with melatonin caused a shift in the net balance between the G-protein-mediated stimulatory and inhibitory influences on the AC system. The sensitization of AC was not blocked by the inclusion of cycloheximide (10 micrograms/ml) during prolonged exposure to melatonin, suggesting that de novo protein synthesis is not a requirement for this effect of the hormone. These results constitute the first demonstration of an independent action of melatonin on ovine PT cells that is dependent upon the duration of the endocrine stimulus.(ABSTRACT TRUNCATED AT 400 WORDS)

We have developed a piglet model to assess chemotherapy administration directly into the fourth ventricle as a potential treatment for medulloblastoma and other malignant posterior fossa tumors. The objective of this study was to assess safety and pharmacokinetics after methotrexate infusions into the fourth ventricle. Catheters were inserted into the fourth ventricle and lumbar cistern in five piglets. Two milligrams of Methotrexate (MTX) was infused into the fourth ventricle on five consecutive days. Safety was assessed by neurological examination, 4.7 T MRI, and post-mortem pathological analysis. MTX levels in serum and cerebrospinal fluid (CSF) were measured, and area under the concentration-time curve (AUC) was calculated for CSF samples. No neurological deficits were caused by MTX infusions. One piglet died from complications of anesthesia induction for MRI scanning. MRI scans showed accurate catheter placement without signal changes in the brainstem or cerebellum. One piglet had asymptomatic ventriculomegaly. Pathological analysis demonstrated meningitis and choroid plexitis consisting predominantly of CD-3 positive T-lymphocytes in all piglets and a small focal area of subependymal necrosis in one. In all piglets, mean peak MTX level in fourth ventricular CSF exceeded that in lumbar CSF by greater than five-fold. Serum MTX levels were undetectable or negligible. Statistically significant differences between fourth ventricle and lumbar AUC were detected at peaks (P = 0.01) and at all collection time points (P = 0.01) but not at troughs (P = 0.36). MTX can be infused into the fourth ventricle without clinical or radiographic evidence of damage. An inflammatory response without clinical correlate is observed. Significantly higher peak MTX levels are observed in the fourth ventricle than in the lumbar cistern.

Object The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. Methods A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10–18 kg, 2–3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. Results All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 μg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. Conclusions Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.

Background Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets. Methods The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM). Results A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM. Conclusion The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques.

The full-length extracellular domain (ECD) of protein tyrosine phosphatase delta (PTP-delta) functions as a ligand to promote cell adhesion and neurite outgrowth; this ECD contains three immunoglobulin (Ig) repeats and eight fibronectin type III (FN III) repeats. However, it is not known which regions of the ECD regulate its ligand functions. Therefore, we constructed and expressed a fusion protein of the PTP-delta ECD lacking FN III repeats 4-8, and tested this protein for neuronal adhesion and neurite-promoting ability. Compared to the full-length isoform, the truncated ECD was poorer at promoting adhesion, but a more potent promoter of neurite growth. The results suggest that distal FN III repeats of PTP-delta are important in adhesive functions, but dispensable for neurite outgrowth promotion. As the predominant isoform of PTP-delta during neural development (type D) also lacks distal FN III repeats, the functional properties we observe may be relevant to periods of axon extension, suggesting that splice variants of receptor PTPs play distinct roles in neural development.

N-acetyltransferase (NAT) activity in the Harderian glands of intact and gonadectomized male and female Syrian hamsters was evaluated. The exogenous administration of 5 alpha-dihydrotestosterone (DHT) to castrated males and intact females produced an increase in NAT values, which reached the values present in the glands of intact males. The administration of a 5 alpha-reductase inhibitor to intact males led to a decrease in NAT activity, suggesting that testosterone is converted in DHT within the glands. It is concluded that NAT activity in the Syrian hamster Harderian glands is under androgenic control, the active steroid being DHT.

The sensitivity of the Syrian hamster pineal gland to stimulation by isoproterenol is greatly increased in the latter half of the daily dark phase. This increased sensitivity requires a period of dark exposure for up to 6.5 hr. Also, if dark-maintained hamsters are exposed to light in the latter half of the night pineal melatonin levels drop precipitously but can be restimulated by isoproterenol administration. As the interval of light exposure continues, however, the pineal Sensitivity to isoproterenol decreases. 0 1987 Society for Experimental Biology and Medicine. In the rat, the administration of either nor- epinephrine (NE) (especially when preceded by the injection of a NE uptake inhibitor) or isoproterenol, a @-receptor agonist, during the photophase of the 1ight:dark (LD) cycle readily stimulates production of melatonin within the pineal gland (1, 2). On the other hand, the daytime administration of these compounds to the Syrian hamster has no stimulatory ac- tion on pineal melatonin (3-5). It was recently discovered, however, that during the dark phase of the LD cycle the Syrian hamster pi- neal will respond to the catecholamine or its agonist. This was proven using two experi- mental paradigms. First, if isoproterenol is given prior to acute light exposure at night the normal light-associated reduction in pineal melatonin levels is delayed (6). Second, if ei- ther NE (preceded by an uptake inhibitor) or isoproterenol is injected into Syrian hamsters with light-suppressed melatonin levels at night, melatonin production within the pineal gland is increased (7-9). In both of these experi- mental paradigms the hamsters were exposed to 6.5-8 hr of darkness before a positive re- sponse to either NE or its agonists could be evoked. The purpose of the first study in this series was to determine whether this period of dark ~ ~~~

Melatonin synthesis in the pineal gland, which is primarily regulated by the environmental lighting regime, can also be influenced by other factors that elicit modifications in sympathetic tone. The objectives of this study were to determine if forced swimming alters the normal pattern of melatonin production in the pineal gland of the Richardson's ground squirrel (Spermophilus richardsonii). In early June, the squirrels were forced to swim for 10 min during the photophase or during the scotophase. In mid-July squirrels swam only during the scotophase. Animals were sacrificed 15, 30, or 60 min after the onset of swimming. Activities of pineal N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) were assessed by radioenzyme assay, and pineal melatonin content was measured by radioimmunoassay. Daytime swimming elicited no major changes in enzyme activity or pineal melatonin. In June, swimming at night prevented the normal rises in NAT activity and pineal melatonin seen in nonswimming controls. In contrast, the pineals of squirrels that were tested 6 weeks later in mid-July did not appear to be as sensitive to nighttime swimming, as there were only minor differences in both NAT activity and melatonin content compared to controls. These results demonstrate that forced nighttime swimming, unlike several other aversive stimuli, can evoke changes in the normal pattern of pineal melatonin production in this species. Furthermore, the pineal's response to such stimuli may not be stable over the course of the active season.

The presence of type II 5′-deiodinase activity in the Syrian hamster Harderian gland was investigated. This enzyme exhibited an increase of its activity after animals entered the normal dark phase, with maximal activity occurring at 04.00 hr (8 hr after lights off). The nocturnal increase was prevented by maintaining the animals in light during the night. Isoproterenol subcutaneously injected every 2 hr (1.0 mg/kg body wt) from 20.00 hr through 0.400 hr to animals exposed to light during the normal dark period mimicked the effect of darkness, i.e., with this treatment an increase in 5′-deiodinase activity with maximal peak values at 02.00 hr was observed. The results show that 5′-deiodinase activity in the Syrian hamster Harderian gland exhibits a nyctohemeral profile dependent on β-adrenergic activation of the gland.

The activity of N-acetyltransferase (NAT) and the content of melatonin (MEL) in the rat pineal have been shown to be sensitive to several types of stressors. This study was designed to assess the role of the adrenals in mediating the effect of one such stressor, insulin-induced hypoglycemia, on pineal synthetic activity. Intact and bilaterally adrenalectomized (ADX) adult male rats were kept under light:dark cycles of 14:10 (lights on 0600 h) and injected intraperitoneally with 10 IU insulin at 1300 h, and groups (n = 8) were killed 2, 3, or 4 h postinjection. Plasma catecholamines were assayed by means of high performance liquid chromatography and radioimmunoassay was used to assess pineal NAT activity and MEL content. All injected groups were rendered hypoglycemic by insulin administration. Compared to uninjected controls, plasma epinephrine in hypoglycemic intact rats rose after 2 h, whereas epinephrine did not change in hypoglycemic ADX animals. The increase in epinephrine in intact animals was correlated with a rise in NAT activity at 2 h. Moreover, pineal MEL content at 2, 3, and 4 h was significantly greater than control values. In contrast, no changes in pineal biosynthetic function were found in ADX rats. This differential response by intact and ADX rats suggests that an adrenal product (possibly epinephrine) is responsible for mediating the stimulatory effects of acute insulin-induced hypoglycemic stress on the rat pineal.

Female Syrian hamsters were kept in a light (14:10 h light:dark cycle, lights on 0600 h)- and temperature (22 or 30 degrees C)-controlled room; some groups were treated with an afternoon s.c. injection of melatonin (6.25, 12.5, or 25 micrograms/day) for 11 or 14 weeks. The melatonin-induced suppression of the reproductive system in hamsters maintained at 22 degrees C (as measured by vaginal cycles, uterine weights, ovarian histology, and plasma and pituitary prolactin levels) was delayed if hamsters were kept at 30 degrees C. The dose-related depression of thyroxine (T4) after melatonin injections for 14 weeks in 22 degrees C was not seen at 30 degrees C. Rather, the depression of plasma T4 and triiodothyronine (T3) seen at the end of 11 or 14 weeks of exposure to 30 degrees C without melatonin injections (vs. control levels at 22 degrees C) was offset by melatonin injections, raising T4 and T3 particularly at the lower doses. In contrast, there was no consistent effect of higher temperature alone on reproductive variables. The interactive effects of temperature and melatonin on the reproductive and thyroidal systems in female hamsters are apparently complex and probably provide a fine-tuning mechanism for the environmental control of endocrine physiology.

Pineal glands of male Syrian hamsters stimulated in vivo with isoproterenol (ISO) for 4 h before the onset of darkness showed a 4-h advance in the timing of the nighttime increases in both N-acetyltransferase activity and melatonin levels. When ISO (1 mg/kg) was administered every 2 h to animals kept in light during the night, a significant increase in melatonin synthesis was observed after 4-6 h. The results suggest that the Syrian hamster pineal gland can respond in vivo to continuous beta-adrenergic stimulation, but a lag period of 4-6 h is required before there is an increase in melatonin synthesis.

T4 type II ′-deiodinase (′-D II) activity was studied in wild-captured Richardson's ground squirrels. As previously reported for other species, ′-D II activity was detected in frontal cortex, cerebellum, pineal gland, and brown adipose tissue (BAT); in the median eminence the levels of ′-D II activity were undetectable with our methodology. When pineal gland, frontal cortex, and cerebellum nyctohemeral profiles were studied, none of them showed variations. Cold exposure for 4 h led to an increase in the enzymatic activity 10-fold above the basal values for BAT, while in the pineal gland the values were doubled; cold exposure failed to change the ′-D II activity in the frontal cortex. Acute melatonin treatment caused a 7-fold increase in ′-D II activity in BAT, but did not affect enzyme activity in either the pineal gland or frontal cortex. The data indicate that ′-D II in Richardson's ground squirrel shows classical localizations. Additionally, two new regulatory factors of ′-D II are reported, i.e. melat...