ABSTRACT
BACKGROUND AND PURPOSE: Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans. EXPERIMENTAL APPROACH: Long-term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short-term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio-marker of the treatment. KEY RESULTS: PTZ has a wide therapeutic window (0.03-3 mg·kg(-1)) that is >10-1000-fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short-term, low, chronic dose regimens of pentylenetetrazole elicited long-lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice. CONCLUSIONS AND IMPLICATIONS: Low doses of pentylenetetrazole were safe, produced long-lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.
Subject(s)
Down Syndrome/drug therapy , GABA-A Receptor Antagonists/therapeutic use , Pentylenetetrazole/therapeutic use , Animals , Behavior, Animal/drug effects , Circadian Rhythm , Cognition/drug effects , Disease Models, Animal , Down Syndrome/physiopathology , Down Syndrome/psychology , Electroencephalography , GABA-A Receptor Antagonists/adverse effects , GABA-A Receptor Antagonists/pharmacology , Hippocampus/anatomy & histology , Hippocampus/drug effects , Male , Memory, Long-Term/drug effects , Mice , Pentylenetetrazole/adverse effects , Pentylenetetrazole/pharmacology , Seizures/chemically induced , Seizures/physiopathologyABSTRACT
The occurrence and fate of surface water and wastewater pathogens (faecal coliforms, Escherichia coli, Giardia lamblia and Cryptosporidium parvum) in two constructed waterways and a pond-based AIT wastewater treatment plant (AIT WWTP) in Pathumthani, Thailand were studied in the context of several biogeochemical factors and in relation to pollutional pressure and seasonal phenomena with a view to proposing potential mechanisms for their removal. More data on pathogen removal in a given local context would provide assurance that some pathogens could serve as suitable indicator organisms and predict removal of different pathogenic microorganisms such as protozoan parasites covered in this study. The enumeration technique for protozoan pathogens was improved in terms of application of emerging novel molecular technologies for the development of a fast but affordable microbiological method. Potential risk of waterborne disease outbreak in pertinent communities was then characterized using established infection probability models and the compiled pathogen occurrence data. Overall, we have addressed several strategic priorities of pathogen research in waste stabilization ponds in developing tropical countries like
Subject(s)
Seasons , Waste Disposal, Fluid/methods , Water Microbiology , Water Purification/methods , Analysis of Variance , Animals , Cryptosporidium/genetics , Genotype , Giardia/genetics , Models, Theoretical , Thailand , Water Pollutants, Chemical/analysisABSTRACT
Trapping of small mammals was conducted at 5 study sites in Kuala Selangor Nature Park (KSNP) from 20-24 June 2005. A total of 11 animals comprising 2 species of rodents, Maxomys whiteheadi and Rattus exulans were caught from 3 sites, i.e from an area of mixed secondary forest and mangrove swamp; an area of mangrove swamp, and from an area of lalang fringing mangrove swamp. From these animals, the following 7 species of ectoparasites were found: Laelaps echidninus, Laelaps nuttalli, Ascoschoengastia indica, Leptotrombidium deliense, Hoplopleura pectinata, Hoplopleura pacifica and Polyplax spinulosa. One of the ectoparasites found, L. deliense is a known vector of scrub typhus and thus may pose potential health risks to visitors to KSNP.
