Rationale
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction and restricted, repetitive behaviors. The unmet medical ...need in ASD is considerable since there is no approved pharmacotherapy for the treatment of these deficits in social communication, interaction, and behavior. Cariprazine, a dopamine D
3
-preferring D
3
/D
2
receptor partial agonist, is already approved for the treatment of schizophrenia and bipolar I disorder in adults; investigation in patients with ASD is warranted.
Objectives
The aim of this study was to investigate the effects of cariprazine, compared with risperidone and aripiprazole, in the rat prenatal valporic acid (VPA) exposure model on behavioral endpoints representing the core and associated symptoms of ASD.
Methods
To induce the ASD model, time-mated Wistar rat dams were treated with VPA during pregnancy. Male offspring were assigned to groups and studied in a behavioral test battery at different ages, employing social play, open field, social approach-avoidance, and social recognition memory tests. Animals were dosed orally, once a day for 8 days, with test compounds (cariprazine, risperidone, aripiprazole) or vehicle before behavioral assessment.
Results
Cariprazine showed dose-dependent efficacy on all behavioral endpoints. In the social play paradigm, only cariprazine was effective. On the remaining behavioral endpoints, including the reversal of hyperactivity, risperidone and aripiprazole displayed similar efficacy to cariprazine.
Conclusions
In the present study, cariprazine effectively reversed core behavioral deficits and hyperactivity present in juvenile and young adult autistic-like rats. These findings indicate that cariprazine may be useful in the treatment of ASD symptoms.
Oesophagectomy remains the only curative intervention for oesophageal cancer, with defined nutritional and health-related quality of life (HR-QOL) consequences. It follows therefore that there is a ...significant risk of decline in physical wellbeing with oesophagectomy however this has been inadequately quantified. This study prospectively examines change in physical functioning and habitual physical activity participation, from pre-surgery through 6-months post-oesophagectomy.
Patients scheduled for oesophagectomy with curative intent were recruited. Key domains of physical functioning including exercise tolerance (six-minute walk test (6MWT)) and muscle strength (hand-grip strength), and habitual physical activity participation, including sedentary behaviour (accelerometry) were measured pre-surgery (T0) and repeated at 1-month (T1) and 6-months (T2) post-surgery. HR-QOL was measured using the EORTC-QOL C30.
Thirty-six participants were studied (mean age 62.4 (8.8) years, n = 26 male, n = 26 transthoracic oesophagectomy). Mean 6MWT distance decreased significantly from T0 to T1 (p = 0.006) and returned to T0 levels between T1 and T2 (p < 0.001). Percentage time spent sedentary increased throughout recovery (p < 0.001) and remained significantly higher at T2 in comparison to T0 (p = 0.003). In contrast, percentage time spent engaged in either light or moderate-to-vigorous intensity activity, all reduced significantly (p < 0.001 for both) and remained significantly lower at T2 in comparison to T0 (p = 0.009 and p = 0.01 respectively). Patients reported deficits in multiple domains of HR-QOL during recovery including global health status (p = 0.04), physical functioning (p < 0.001) and role functioning (p < 0.001). Role functioning remained a clinically important 33-points lower than pre-operative values at T2.
Habitual physical activity participation remains significantly impaired at 6-months post-oesophagectomy. Physical activity is a measurable and modifiable target for physical rehabilitation, which is closely aligned with patient-reported deficits in role functioning. Rehabilitation aimed at optimising physical health in oesophageal cancer survivorship is warranted.
Coral reef ecosystems are exposed to a range of environmental forcings that vary on daily to decadal time scales and across spatial scales spanning from reefs to archipelagos. Environmental ...variability is a major determinant of reef ecosystem structure and function, including coral reef extent and growth rates, and the abundance, diversity, and morphology of reef organisms. Proper characterization of environmental forcings on coral reef ecosystems is critical if we are to understand the dynamics and implications of abiotic-biotic interactions on reef ecosystems. This study combines high-resolution bathymetric information with remotely sensed sea surface temperature, chlorophyll-a and irradiance data, and modeled wave data to quantify environmental forcings on coral reefs. We present a methodological approach to develop spatially constrained, island- and atoll-scale metrics that quantify climatological range limits and anomalous environmental forcings across U.S. Pacific coral reef ecosystems. Our results indicate considerable spatial heterogeneity in climatological ranges and anomalies across 41 islands and atolls, with emergent spatial patterns specific to each environmental forcing. For example, wave energy was greatest at northern latitudes and generally decreased with latitude. In contrast, chlorophyll-a was greatest at reef ecosystems proximate to the equator and northern-most locations, showing little synchrony with latitude. In addition, we find that the reef ecosystems with the highest chlorophyll-a concentrations; Jarvis, Howland, Baker, Palmyra and Kingman are each uninhabited and are characterized by high hard coral cover and large numbers of predatory fishes. Finally, we find that scaling environmental data to the spatial footprint of individual islands and atolls is more likely to capture local environmental forcings, as chlorophyll-a concentrations decreased at relatively short distances (>7 km) from 85% of our study locations. These metrics will help identify reef ecosystems most exposed to environmental stress as well as systems that may be more resistant or resilient to future climate change.
Addressing the hypothesis that anaesthetic-analgesic technique during cancer surgery might influence recurrence or metastatic spread is a research priority. Propofol, which has anti-inflammatory ...properties in vitro, is clinically associated with reduced risk of cancer recurrence compared with sevoflurane anaesthesia in retrospective studies. Amide local anaesthetics, such as lidocaine, have cancer inhibiting effects in vitro. Steroids have anti-inflammatory and immunosuppressive effects and are associated with improved recovery after major non-cancer surgery. We compared the effects of propofol, lidocaine and methylprednisolone on postoperative metastasis in a murine model of breast cancer surgery under sevoflurane anaesthesia. 4T1 tumour cells were introduced into the mammary fat-pad of female BALB/c mice and the resulting tumour resected seven days later under general anaesthesia with sevoflurane. Mice (
= 72) were randomized to four treatment groups: Sevoflurane alone (control); Propofol group received 5 mg.kg
; Lidocaine group received 1.5 mg.kg
followed by 2 mg.kg
.h
infusion; Methylprednisolone group received 30 mg.kg
methylprednisolone. The primary outcome measure was pulmonary metastasis colony count, as assessed by in-vitro proliferation, two weeks post-operatively. This was achieved by treating the post-mortem lung tissue with collagenase IV, straining and culturing for 14 days prior to colony count. Compared with control, lidocaine and propofol each individually reduced pulmonary metastasis colonies; mean (SD) 846 (±581) vs. 88 (±52) vs. 34 (±44) respectively, (
= 0.0001 and
= 0.0001). Methylprednisolone increased lung metastasis, 2555 (±609) vs. 846 (±581),
= 0.0001. Post-operative hepatic metastatic disease and serum interleukin-6 and vascular endothelial growth factor levels were similar in all groups. In conclusion, in a murine model of breast cancer surgery during sevoflurane anaesthesia, propofol and lidocaine each decreased pulmonary metastasis, while methylprednisolone increased it.
During the 1997-98 El Niño, the equatorial Pacific Ocean retained 0.7 × 10$^{15}$ grams of carbon that normally would have been lost to the atmosphere as carbon dioxide. The surface ocean became ...impoverished in plant nutrients, and chlorophyll concentrations were the lowest on record. A dramatic recovery occurred in mid-1998, the system became highly productive, analogous to coastal environments, and carbon dioxide flux out of the ocean was again high. The spatial extent of the phytoplankton bloom that followed recovery from El Niño was the largest ever observed for the equatorial Pacific. These chemical and ecological perturbations were linked to changes in the upwelling of nutrient-enriched waters. The description and explanation of these dynamic changes would not have been possible without an observing system that combines biological, chemical, and physical sensors on moorings with remote sensing of chlorophyll.
Electronic tracking tags have revolutionized our understanding of broad-scale movements and habitat use of highly mobile marine animals, but a large gap in our knowledge still remains for a wide ...range of small species. Here, we report the extraordinary transequatorial postbreeding migrations of a small seabird, the sooty shearwater, obtained with miniature archival tags that log data for estimating position, dive depth, and ambient temperature. Tracks (262 ± 23 days) reveal that shearwaters fly across the entire Pacific Ocean in a figure-eight pattern while traveling 64,037 ± 9,779 km roundtrip, the longest animal migration ever recorded electronically. Each shearwater made a prolonged stopover in one of three discrete regions off Japan, Alaska, or California before returning to New Zealand through a relatively narrow corridor in the central Pacific Ocean. Transit rates as high as 910 ± 186 km·day⁻¹ were recorded, and shearwaters accessed prey resources in both the Northern and Southern Hemisphere's most productive waters from the surface to 68.2 m depth. Our results indicate that sooty shearwaters integrate oceanic resources throughout the Pacific Basin on a yearly scale. Sooty shearwater populations today are declining, and because they operate on a global scale, they may serve as an important indicator of climate change and ocean health.
Highly productive hotspots in the ocean often occur where complex physical forcing mechanisms lead to aggregation of primary and secondary producers. Understanding how hotspots persist, however, ...requires combining knowledge of the spatio-temporal linkages between geomorphology, physical forcing, and biological responses with the physiological requirements and movement of top predators.
Here we integrate remotely sensed oceanography, ship surveys, and satellite telemetry to show how local geomorphology interacts with physical forcing to create a region with locally enhanced upwelling and an adjacent upwelling shadow that promotes retentive circulation, enhanced year-round primary production, and prey aggregation. These conditions provide an area within the upwelling shadow where physiologically optimal water temperatures can be found adjacent to a region of enhanced prey availability, resulting in a foraging hotspot for loggerhead sea turtles (Caretta caretta) off the Baja California peninsula, Mexico.
We have identified the set of conditions that lead to a persistent top predator hotspot, which increases our understanding of how highly migratory species exploit productive regions of the ocean. These results will aid in the development of spatially and environmentally explicit management strategies for marine species of conservation concern.
Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting ...the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative pulmonary metastases. We investigated whether the additional administration of bosutinib (a known Src inhibitor) influences lidocaine’s observed beneficial effect in this in vivo model. Female BALB/c mice (n = 95) were inoculated with 25,000 4T1 cells into the mammary fad pad and after 7 days the resulting tumours were excised under sevoflurane anaesthesia. Experimental animals were randomized to one of four treatments administered intravenously prior to excision: lidocaine, bosutinib, both lidocaine and bosutinib in combination, or saline. Animals were euthanized 14 days post-surgery and lung and liver metastatic colonies were evaluated. Post-mortem serum was analysed for MMP-2 and MMP-9, pro-metastatic enzymes whose expression is influenced by the Src pathway. Lidocaine reduced lung, but not liver metastatic colonies versus sevoflurane alone (p = 0.041), but bosutinib alone had no metastasis-inhibiting effect. When combined with lidocaine, bosutinib reversed the anti-metastatic effect observed with lidocaine on sevoflurane anaesthesia. Only lidocaine alone reduced MMP-2 versus sevoflurane (p = 0.044). Both bosutinib (p = 0.001) and bosutinib/lidocaine combined (p = 0.001) reduced MMP-9 versus sevoflurane, whereas lidocaine alone did not. In a murine surgical breast cancer model, the anti-metastatic effects of lidocaine under sevoflurane anaesthesia are abolished by the Src inhibitor bosutinib, and lidocaine reduces serum MMP-2. These results suggest that lidocaine may act, at least partly, via an inhibitory effect on MMP-2 expression to reduce pulmonary metastasis, but whether this is due to an effect on Src or via another pathway remains unclear.
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