Based on surrogate assays of peripheral red blood cells, reports state that widely prescribed doses of donepezil hydrochloride provide nearly complete inhibition of cerebral cortical ...acetylcholinesterase activity in the treatment of Alzheimer's disease (AD). To test this, direct positron emission tomography measures of cerebral acetylcholinesterase activity were made in AD patients before and after treatment with donepezil (5 and 10 mg/day) for at least 5 weeks and compared with similar measures in normal controls who were untreated or after acute administration of another AChE inhibitor, physostigmine salicylate (1.5 mg/hr). After physostigmine, acetylcholinesterase inhibition averaged 52% in normal cerebral cortex. After donepezil, cerebral cortical inhibition in AD brain averaged only 27%. Clinical trials of this donepezil dose schedule are not testing the effect of nearly complete cerebral cortical inhibition. Ann Neurol 2000;48:391–395
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Intrathecal morphine sulfate (ITMS) administration was introduced into clinical practice in 1979. Inadequate information exists delineating ITMS respiratory effects in the dosage range most ...frequently employed today. This study evaluated 0.2, 0.4, and 0.6 mg ITMS in male volunteers.
Twenty healthy, young, adult male volunteers received 0.0, 0.2, 0.4, or 0.6 mg preservative-free ITMS in an isobaric solution administered at the L3-L4 interspace in a double-blind randomized fashion. Respiratory function was assessed by finger pulse oximetry (SpO2), respiratory rate, and arterial blood gas analysis via an indwelling arterial catheter and the slope of the ventilatory response to carbon dioxide (VE/CO2). Analgesia was assessed by the effect of ITMS on moderate pain produced by pressure algometry at the tibia. The need for supplemental oxygen, 2 L/min via nasal cannulae, was determined by the failure of verbal and tactile prompts to maintain subjects' SpO2 > or = 85% on more than two occasions. Heart rate, arterial blood pressure, sedation level, pupil size, and the incidence of adverse effects also were documented. All the above measurements were made before and 30 min after ITMS, hourly for 11 h, and then every 2 h for 12 more h.
ITMS produced significant dose-related decreases in SpO2. Mild desaturations (SpO2 > or = 85 and < 90%) occurred in 2 of 5, 3 of 5, and 4 of 5 subjects receiving 0.2, 0.4, and 0.6 mg ITMS, respectively. Moderate to severe desaturations (SpO2 < 85%) occurred in 0 of 5, 2 of 5, and 4 of 5 subjects receiving 0.2, 0.4, and 0.6 mg ITMS, respectively. The need for supplemental oxygen also was significantly related to ITMS dose, with 0 of 5, 1 of 5, and 4 of 5 subjects requiring oxygen after 0.2, 0.4, and 0.6 mg ITMS, respectively. Nasal oxygen administration consistently alleviated hypoxemia. Increases in arterial carbon dioxide tension (PaCO2) and decreases in pH were significantly related to ITMS dose. Peak mean PaCO2s were 42.4, 44.9, and 50.7 mmHg in the 0.2-, 0.4-, and 0.6-mg groups, respectively. These peaks occurred 6.5-7.5 h after ITMS injection. ITMS produced significant dose-related depression of VE/CO2. Maximum mean depressions of VE/CO2 were to 61%, 63%, and 32% of baseline in the 0.2-, 0.4-, and 0.6-mg groups, respectively. These nadirs occurred 3.5-7.5 h after ITMS injection. Some subjects receiving 0.6 mg ITMS experienced profound (< 20% of baseline) and prolonged (< 50% of baseline for up to 20 h) VE/CO2 depression. Magnitude and duration of analgesia after ITMS were dose-related. Changes in heart rate, systolic blood pressure, and respiratory rate were not significantly related to ITMS dose. Hypoxemia was not related to respiratory rate. Although ITMS produced statistically significant dose-related increases in sedation and decreases in pupil size, these changes were small and did not coincide with hypoxemia. ITMS caused dose-related increases in emesis, but the severity of pruritus and urinary retention was unrelated to dose.
ITMS produced dose-related analgesia and respiratory depression in nonsurgical healthy, young, adult male volunteers. Respiratory depression was significant after 0.2 or 0.4 mg and profound and prolonged after 0.6 mg. No clinical signs or symptoms, including respiratory rate, reliably indicated hypoxemia. Pulse oximetry reliably detected hypoxemia after ITMS, and supplemental nasal oxygen (2 L/min) effectively corrected this hypoxemia.
Despite controversial clinicopathological distinctions between Parkinson's disease with dementia (PDD) and Alzheimer's disease (AD), similar patterns of metabolic reduction in the posterior brain ...were reported previously using PET with 18Ffluorodeoxyglucose. The current study was designed to examine more specific regional differences in cerebral glucose metabolism between PDD and AD using accurate and objective brain mapping techniques.
This study included nine normal subjects, nine PDD patients and nine AD patients. PDD and AD groups were matched carefully for age, sex and general dementia severity as measured by Mini-Mental State Examination and Clinical Dementia Rating scales. Each subject underwent 18Ffluorodeoxyglucose-PET and neuropsychological testing. After anatomic standardization of PET image sets and stereotactic data extraction, absolute and normalized cerebral metabolic rates were assessed by region of interest and pixel-by-pixel analyses.
PDD and AD showed global glucose metabolic reduction with similar regional accentuation involving the lateral parietal, lateral temporal and lateral frontal association cortices and posterior cingulate cortex in comparison to normal controls. When comparing between PDD and AD, however, PDD showed greater metabolic reduction in the visual cortex and relatively preserved metabolism in the medial temporal cortex.
Although a common feature of metabolic abnormalities in the posterior brain exists in PDD and AD, the presence of regional metabolic differences suggests different degrees and combinations of disease specific underlying pathological and neurochemical processes.
The impact of the somatic hypermutational machinery was examined by analyzing the frequency and distribution of mutations in nonproductive VHDJH rearrangements obtained from individual human ...peripheral B cells. A strong bias toward nucleotide substitutions within the quadruplet motif RGYW was observed. In addition, there was a comparably increased frequency of mutations of the inverse repeat of RGYW, WRCY. Together, mutations of RGYW / WRCY accounted for 37 % of all nucleotide substitutions. No significant strand polarity of the distribution of mutations was evident when nucleotide substitutions of highly mutated quartets and triplets as well as of their inverse repeats were analyzed. Furthermore, detailed analysis of mutations of specific triplets, such as AGC and TAC provided evidence that they were mutated more frequently when they were included within RGYW and WRCY, respectively. Despite being a target of the mutational machinery, neither RGYW nor WRCY was mutated in the absence of a large number of substitutions of other nucleotides in the same sequence. These results indicate that the mutational machinery targets RGYW sequences for mutations on either DNA strand and do not support the contention that the mutational machinery exhibits DNA strand polarity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Patients with cognitive impairment, particularly as a result of Alzheimer's disease (AD), are at increased risk for falls, but it is unclear how, or if, they differ from normal adults in their ...balance, gait, or ability to clear an obstacle in their path. Using an optoelectronic camera system, we compared body motions and force output at the feet in patients with probable AD (n = 17) with those in healthy older adults (n = 15) while they stood on a force plate or on a beam attached to the force plate that was either stationary or accelerating. Using the same camera system and comparing this AD group with another group of healthy older adults (n = 24), we observed the AD patients during normal walking and while clearing 25- and 152-mm-high obstacles. None of the AD patients had extrapyramidal signs or musculoskeletal impairments. Compared with healthy older adults, normal walking speed was significantly slower in the AD group (p < 0.0001). While clearing either obstacle, the AD patients were significantly slower in their approach (p < 0.0001) and crossing (p < 0.0001) speeds and landed closer to the obstacle after having crossed it (p < 0.02). Moreover, the percent of trials in which a subject made contact with an obstacle was significantly higher in patients with AD (p < 0.005).
Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key ...transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
On 28 May 2009, a 7.3 magnitude earthquake occurred at a depth of 10 km along the boundary between the North American and Caribbean plates, 125 km NNE of La Ceiba, Honduras (USGS 2009). Tremors were ...felt in many neighbouring countries including Belize, El Salvador and Guatemala. The last major earthquake to occur in the region was a 6.6 magnitude quake on 11 July 1999 (MIDAS 2009). The Port Honduras Marine Reserve (414 km2) is in the Gulf of Honduras, ~270 km WSW of the earthquake epicentre. Underwater visual surveys were conducted on SCUBA at 15 sites after the earthquake, covering an area of ~5,000 m2 site1. Of the sites surveyed, seven showed no damage, four showed minimal damage and four were heavily impacted by the earthquake.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
CONTEXT The prevalence of mixed dementia, defined as the coexistence of Alzheimer
disease (AD) and vascular dementia (VaD), is likely to increase as the population
ages. OBJECTIVES To provide an ...overview of the diagnosis, pathophysiology, and interaction
of AD and VaD in mixed dementia, and to provide a systematic literature review
of the current evidence for the pharmacologic therapy of mixed dementia. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION The Cochrane Database of Systematic Reviews was searched using the keyword dementia. MEDLINE was searched for English-language articles
published within the last 10 years using the keywords mixed
dementia, the combination of keywords Alzheimer disease, cerebrovascular disorders, and drug therapy, and the combination of keywords vascular
dementia and drug therapy. EVIDENCE SYNTHESIS Dementia is more likely to be present when vascular and AD lesions coexist,
a situation that is especially common with increasing age. The measured benefits
in clinical trials for the treatment of mixed dementia are best described
as statistically significant differences in cognitive test scores and clinician
and caregiver impressions of change. In these studies, the control groups’
scores typically decline while the treatment groups improve slightly or decline
to a lesser degree over the study period. Nevertheless, even the patients
who experience treatment benefits eventually decline. Cholinesterase inhibitor
(ChI) therapy for mixed dementia shows modest clinical benefits that are similar
to those found for ChI treatment of AD. The N-methyl-D-aspartate (NMDA) antagonist memantine also shows modest clinical
benefits for the treatment of moderate to severe AD and mild to moderate VaD,
but it has not been studied specifically in mixed dementia. The treatment
of cardiovascular risk factors, especially hypertension, may be a more effective
way to protect brain function as primary, secondary, and tertiary prevention
for mixed dementia. CONCLUSIONS Currently available medications provide only modest clinical benefits
once a patient has developed mixed dementia. Cardiovascular risk factor control,
especially for hypertension and hyperlipidemia, as well as other interventions
to prevent recurrent stroke, likely represent important strategies for preventing
or slowing the progression of mixed dementia. Additional research is needed
to define better what individuals and families hope to achieve from dementia
treatment and to determine the most appropriate use of medication to achieve
these goals.
To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP).
The ...cerebral distribution of 11Cflumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and 18Ffluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest.
There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction.
PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.
Animal and human autoradiographic studies have shown increased in vitro binding of the peripheral benzodiazepine binding site antagonist PK 11195 in areas of microgliosis, including the temporal ...association cortex of patients with Alzheimer's disease. To further elucidate the role of cellular inflammation and microgliosis in Alzheimer's disease during life, we used PET and 11CPK 11195, a peripheral benzodiazepine receptor ligand known to bind avidly to microglia.
Eight patients with a diagnosis of probable Alzheimer's disease underwent PET of the brain using 11CPK 11195 and, for comparison, with 18FFDG to determine cerebral glucose metabolism. Uptake of 11CPK 11195 in various brain regions was expressed relative to that in the cerebellum and compared to values determined in one normal elderly subject and in clinically and anatomically unaffected hemispheres of seven patients with small unilateral gliomas.
No increases in peripheral benzodiazepine binding were identified in patients with probable Alzheimer's disease, and binding was lowest in regions that were most hypometabolic.
The peripheral benzodiazepine binding sites associated with microgliosis and cellular inflammation in Alzheimer's disease at postmortem are undetectable by PET using 11CPK 11195 in patients with mild-to-moderate dementia.
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