Genetic association of low density lipoprotein receptor and Alzheimer's disease

The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) LDLR modulates the homeostasis of cholesterol, which itself appears associated with AD. Therefore, we evaluated whether LDLR haplotypes alter the odds of AD by performing an association study examining three LDLR single nucleotide polymorphisms (SNPs) in 118 AD patients and 133 non-AD subjects. LDLR genotypes were obtained by TaqMan allelic discrimination assays. Although individual LDLR SNPs were not associated with AD, analyses of unambiguous haplotypes suggested the hypothesis that the 211 LDLR haplotype was associated with reduced odds of AD. We then evaluated this hypothesis in a second study cohort, i.e., the Religious Orders Study. These results supported the hypothesis that the 211 LDLR haplotype is associated with reduced odds of AD. Moreover, these data suggested further associations between LDLR variants and AD. Thus, LDLR variants appear significantly associated with AD and merit additional study.     

Hope and spirituality among patients with chronic kidney disease undergoing hemodialysis: a correlational study

Objective

to analyze the relationship between the hope and spirituality of patients with chronic kidney disease undergoing hemodialysis.

Method

this is a cross-sectional, correlational study. The sample was composed of 127 patients of a Renal Replacement Unit. Data were collected through individual interviews guided by the following instruments: participant characterization, Herth Hope Index (HHI), and Pinto Pais-Ribeiro Spirituality Scale (PP-RSS).

Results

the average HHI score was 38.06 (±4.32) while the average PP-RSS score was 3.67 (±0.62) for "beliefs" and 3.21 (±0.53) for "hope/optimism". Spearman''s coefficient indicated there was a moderate positive correlation between the HHI and PP-RSS dimensions of "beliefs" (r=0.430; p<0.001) and "hope/optimism" (r=0.376; p<0.001).

Conclusion

Since a relationship between the sense of hope and spirituality of patients with chronic kidney disease was found, these constructs should be taken into account at the time health professionals deliver care to help patients coping with the disease and treatment.     

The value of CT scanning in radiation therapy treatment planning: a prospective study

We report the results of a prospective study in which we assessed the value of computed tomography (CT) scanning in planning radiation therapy for 77 patients. First, conventional studies were performed, treatment fields were designed and simulated and, where appropriate, computer generated treatment plans drawn up. Then a CT scan was performed to delineate the location of the tumor and adjacent uninvolved tissues. The treatment goals and plans were reevaluated and changed when necessary.Forty of the 77 patients (52 %) had their treatment changed as a result of the CT scan. Of these, four (5 % ) had a change of treatment modality. Thirty-two patients (42%) had changes in the radiotherapy technique because of inadequate tumor coverage (in 24 patients (31 %) part of the tumor was outside one or more of the fields and in the other 8 patients (10 %) the tumor coverage was marginal). Field changes resulting only from considerations of normal tissue coverage were made for 4 of these patients (5%). In total, normal tissue coverage was affected in 36 patients (47%).When the significance of these changes was evaluated, CT scanning was judged to be of major value for 28 of the 77 patients (36%) and of minor value in a further 12 patients (16%).     

Proton radiation as boost therapy for localized prostatic carcinoma.

A 160-MeV proton beam has been modified to irradiate patients with localized tumors by using convention treatment schedules. This proton beam has the physical advantage of megavoltage x-rays of reducing the radiation dose to normal tissues adjacent to the tumor volume. A perineal proton technique used as boost therapy (2,000 to 2,500 rads) was evaluated in the definitive irradiation of 17 patients with localized prostatic carcinoma. This technique allows repeated daily treatment of the carefully defined target volume with a precision of +/- 2 mm. Total dose to the prostatic tumor, but not to the posterior rectum, has been increased by 500 to 700 rads. After 12 to 27 months of observation, no noteworthy rectal reaction has developed in a patient, easily managed urethral strictures have developed in two patients, and all but one are locally controlled.     

The emotional ramifications of unmet need in dementia caregiving

Using a unique measure of unmet need that taps into several dimensions of informal long-term care, the present study included data from 694 informal caregivers of persons suffering from dementia at different times in the caregiving career (e.g., at home, following institutionalization, following the death of the care recipient). Multivariate regression models found that unmet need for either confidante or formal support had key implications for caregivers' emotional distress in each of the care situations. The findings suggest that conceptual models should incorporate unmet need as a viable predictor of caregiving outcomes and that assessment of unmet need may provide guidance in the development of more refined psychosocial and community-based intervention protocols.     

Shared random effects analysis of multi-state Markov models: application to a longitudinal study of transitions to dementia

Multi-state models are appealing tools for analysing data about the progression of a disease over time. In this paper, we consider a multi-state Markov chain with two competing absorbing states: dementia and death and three transient non-demented states: cognitively normal, amnestic mild cognitive impairment (amnestic MCI), and non-amnestic mild cognitive impairment (non-amnestic MCI). The likelihood function for the data is derived and estimates for the effects of the covariates on transitions are determined when the process can be viewed as a polytomous logistic regression model with shared random effects. The presence of a shared random effect not only complicates the formulation of the likelihood but also its evaluation and maximization. Three approaches for maximizing the likelihood are compared using a simulation study; the first method is based on the Gauss-quadrature technique, the second method is based on importance sampling ideas, and the third method is based on an expansion by Taylor series. The best approach is illustrated using a longitudinal study on a cohort of cognitively normal subjects, followed annually for conversion to mild cognitive impairment (MCI) and/or dementia, conducted at the Sanders Brown Center on Aging at the University of Kentucky.     

Radioprotection combined with hypoxic sensitization during radiotherapy of a solid murine tumor

EMT6 tumors were transplanted intramuscularly in the right hind leg of female BALB/c mice and irradiated when they reached a diameter of 6-7 mm. Each mouse received an intraperitoneal injection of WR-2721, misonidazole, or both prior to irradiation, and the dose needed to control half of the tumors at 30 days (TCD50/30) was recorded. WR-2721 offered slight tumor protection, with a dose-modifying factor (DMF) of 1.04-1.15 for radioprotector doses of 150-500 mg/kg. Pretreatment with misonidazole at doses of 300-900 mg/kg yielded tumor sensitization with a DMF of 0.71-0.92. Pretreatment with both WR-2721 and misonidazole gave overall tumor sensitization with a DMF of 0.78-0.97. Possible combinations of sensitizers and protectors, while providing overall tumor sensitization, do not seem to improve the therapeutic ratio over what could be obtained from a sensitizer or protector alone.     

Concurrent and subsequent tumors in the same host: A model to evaluate the host tumor interaction

There is evidence which demonstrates an immune rejection response (IRR) directed against tumor cells in some experimental and human tumors. In the case of FSa-1, a methylcholanthrene-induced fibrosarcoma of the C₃Hf/Sed mouse, the IRR is manifested by a decrease in the dose of radiation expected to control half of the treated tumors (TCD₅₀) and an increase in the number of tumor cells expected to transplant the tumor in half of the transplanted recipients (TD₅₀) in immunized hosts. FSaI was transplanted simultaneously in the right and left legs of male and female C₃Hf/Sed mice and each tumor was given 3750 rad when it measured 8 mm. in diameter (viz the TCD₅₀ value for 8 mm FSaI growing as one isotransplant per animal). The two tumors in any one animal usually responded similarly with either permanent regression or local recurrence after irradiation. In a second experiment, a group of animals received also concurrent tumors. This time an immunogenic FSaI was transplanted in one side and a non immunogenic mammary carcinoma (MDAH-MCaIV) on the opposite side. The tumors were irradiated with TCD₅₀ doses (3750 rad for FSaI and 6500 for the less radioresponsive MCa). The distribution of local control and recurrence was probabilistic; 50% of the animals exhibited one tumor destroyed and one recurring. In a third experimental group mice were subsequently transplanted with FSaI Mice who showed no recurrence after irradiation of their first FSaI showed a stronger tendency to reject the second implantation than those who previously had local recurrence and subsequent amputation. Retransplants were controlled more easily by irradiation in the group that had been successfully treated for the first transplant. These data indicate that within the inbred population of C₃Hf/Sed mice there is a relatively broad distribution of capacities to react effectively against the FSaI challenge. This was not predicted by the delayed hypersensitivity skin reaction (DHSR) to the FSaI antigen.     

Sodium hydrogen-S-(3-amino-2-hydroxypropyl) phosphorothioate (WR-77913): toxicity and bone marrow radioprotection

Experiments have been carried out to compare the toxicity and radioprotective effect of sodium hydrogen-S-(3-amino-2-hydroxypropyl) phosphorothioate (WR-77913) with those of S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721). The drugs were given intraperitoneally to 12 week-old female BALB/c mice 30 minutes before whole body irradiation. Lethality at 30 days was the endpoint used. The drug LD50/30 was 678 mg/kg for WR-2721 and 3574 mg/kg for WR-77913. The LD50/30 for WR-77913 combined with 500 mg/kg of WR-2721 was 3328 mg/kg. The LD50/30 for misonidazole was 380 mg/kg when given in combination with 500 mg/kg of WR-2721 and 801 mg/kg when combined with 2200 mg/kg of WR-77913. Protection of bone marrow by WR-77913 and WR-2721 was comparable at doses close to the maximum tolerable dose (MTD, drug dose lethal to 10% of the animals at 30 days), but WR-77913 gave better protection at 35% of the MTD. These characteristics of low toxicity, non-additive toxicity with WR-2721, less toxicity in combination with misonidazole and adequate bone marrow protection at 25% of the MTD, make WR-77913 a protector worthy of further investigation.     

Preclinical AD Workgroup staging: pathological correlates and potential challenges

The National Institute on Aging Preclinical Alzheimer's disease Workgroup (PADW) has issued a preliminary report with recommendations for classifying preclinical Alzheimer's disease (pAD) according to 3 early disease stages. Here we examine the PADW recommendations in relation to neuropathological features in a large, consecutive series of cognitively intact elderly persons, autopsied within a year after cognitive testing (n = 126 cognitively intact patients with mean age 83.7 years at death). Subjects were grouped based on a hypothetical construct correlating pathological features with PADW stages. Many cognitively intact individuals were classifiable as pAD (53/126 or 43%), as expected based on epidemiological and biomarker studies. Of these, most (48%) were in “stage 3”, which corresponds to amyloid pathology with early neurodegeneration. As with prior studies, our data indicate that the development of neocortical neurofibrillary tangles is the key pathological event that is not observed in pAD cases: Braak stages III or IV pathology are hence not truly a substrate for “intermediate likelihood” that cognitive impairment is due to Alzheimer's disease (AD). We also stress the importance of comorbid non-Alzheimer's disease brain pathologies (hippocampal sclerosis, neocortical alpha-synucleinopathy, cerebrovascular disease, and brains with hippocampal neurofibrillary tangles but no cortical amyloid plaques) that can contribute to the development of cognitive impairment, or which may serve as confounds in the application of the PADW recommendations. While the final recommendations from the PADW working group have not yet been released, this preliminary analysis provides a perspective on those recommendations from a neuropathological point of view.