CYP46: a risk factor for Alzheimer's disease or a coincidence?

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46). Although serum and cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol are altered during the progress of Alzheimer's disease, studies carried out to date in different populations on the association of CYP46 gene polymorphisms and risk of AD have been inconclusive. In this report, we analyzed CYP46 polymorphisms in 215 Polish AD cases and 173 healthy individuals. A fragment of CYP46 intron 2 was amplified by PCR reaction and sequenced. We discovered a new single nucleotide substitution in CYP46 intron 2, but found no difference in particular genotype or allele frequencies between AD patients and controls. However, the GG genotype of the known rs754203 polymorphic site might be a risk factor for AD, especially in APOE varepsilon4 carriers. Interestingly, in AD patients the rs754203 G allele was more frequent in males than in females. However, considering the extreme divergence of results obtained by different authors, a clear connection between the CYP46 gene and AD is questionable.     

Alzheimer's disease: is a vaccine possible?

The cause of Alzheimer''s disease is still unknown, but the disease is distinctivelycharacterized by the accumulation of β-amyloid plaques and neurofibrillary tangles inthe brain. These features have become the primary focus of much of the researchlooking for new treatments for the disease, including immunotherapy and vaccinestargeting β-amyloid in the brain. Adverse effects observed in a clinical trial basedon the β-amyloid protein were attributed to the presence of the target antigen andemphasized the relevance of finding safer antigen candidates for active immunization.For this kind of approach, different vaccine formulations using DNA, peptide, andheterologous prime-boost immunization regimens have been proposed. Promising resultsare expected from different vaccine candidates encompassing B-cell epitopes of theβ-amyloid protein. In addition, recent results indicate that targeting anotherprotein involved in the etiology of the disease has opened new perspectives for theeffective prevention of the illness. Collectively, the evidence indicates that theidea of finding an effective vaccine for the control of Alzheimer''s disease, althoughnot without challenges, is a possibility.     

Are cerebrovascular factors involved in Alzheimer's disease?

Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.     

Atherosclerosis,multiple sclerosis,and Alzheimer's disease: what role for Herpesviridae?

Herpesviridae are ubiquitous, and are commonly involved in well identified diseases as genital herpes, chickenpox and herpes zoster, infectious mononucleosis, exanthem subitum... They are responsible for latent and chronic infections after primary infection. Atherosclerosis, multiple sclerosis, Alzheimer's disease are diseases which are very different, and for which pathogenesis remains unknown. Several authors have hypothesized that Herpesviridae could play a role in such diseases. The present paper reviews arguments not only in favour but also against such hypothesis. Any formal conclusion is impossible, and more extensive studies are warranted.     

Is there a future for vaccination as a treatment for Alzheimer's disease?

Vaccination of APP transgenic mice with Abeta has been shown to prevent amyloid deposits. A clinical trial of Abeta vaccination in Alzheimer's disease (AD) was halted due to serious neurological complications developing in some patients. Such complications were not observed in transgenic mice. Since human APP is not a mouse self-protein, vaccination of mice with Abeta should not produce an autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q poorly recognizes human Abeta so complement activation is much weaker in transgenic mice than in AD. Vaccination will increase complement activation through formation of antigen-antibody complexes. In mice this will enhance phagocytosis. But in AD, where complement is already overactivated, and where the senile plaques are relatively insoluble, this stimulation should increase production of the membrane attack complex, adding to the autodestruction of neurons. The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically.     

Genetic screening for reproductive purposes at school: is it a good strategy?

Thalassemia and Tay-Sachs disease were the first diseases in which the criteria for heterozygote genetic screening were met and successful programs for reproductive purposes were initiated in populations at risk. However, many of the couples first discover the possibility of genetic screening during pregnancy and efforts are made to bring couples to consider screening tests before the first pregnancy. In this context, high school offers a convenient setting and several pilot programs have been very successful. All evaluations of these programs found that education plays a critical role in allowing informed decisions and minimizing the possible harms. While it has been suggested that high school may be the best setting for reproductive screening programs, guidelines of several societies of human genetics recommend the use of carrier screening only in individuals older than 18 years. There are several other problems related to genetic screening programs at school and some are discussed in the review. Our opinion is that school should be a place to provide the tools for decisions by education only; while the option to have the genetic tests later in life or in another setting should be offered to the students as part of the education session. This may allow the students to decide when and where to have a genetic test.     

A safer vaccine for Alzheimer's disease?

Recent reports indicate that amyloid-β (Aβ) vaccine-based therapy for Alzheimer’s disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Aβ1–42 may not be appropriate in humans because it crosses the blood–brain barrier, can seed fibril formation, and is highly fibrillogenic. Aβ1–42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Aβ derivative may be a safer therapeutic approach to impede the progression of Aβ-related histopathology in AD. Although the site of action of the anti-Aβ antibodies has been suggested to be within the brain, peripheral clearance of Aβ may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Aβ compared to brain Aβ. This disruption of the equilibrium between central and peripheral Aβ should then result in efflux of Aβ out of the brain, and subsequent removal of plaques. Aβ therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Aβ derived vaccines should include T_h epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD.     

Glia-related pathomechanisms in Alzheimer's disease: a therapeutic target?

Reactive glial cell properties could contribute to pathomechanisms underlying Alzheimer's disease by favoring oxidative neuronal damage and beta-amyloid toxicity. A critical step is apparently reached when pathological glia activation is no longer restricted to microglia and includes astrocytes. By giving up their differentiated state, astrocytes may lose their physiological negative feed-back control on microglial NO production and even contribute to neurotoxic peroxynitrate formation. Another consequence is the impairment of the astrocyte-maintained extracellular ion homeostasis favoring excitotoxic damage. By the production of apolipoprotein-E, triggered by the microglial cytokine interleukine-1beta, reactive astrocytes could promote the transformation of beta-amyloid into the toxic form. A pharmacologically reinforced cAMP signaling in rat glial cell cultures depressed oxygen radical formation in microglia and their release of TNF-alpha and interleukine-1beta, feed-forward signals which mediate oxidative damage and secondary astrocyte activation. Cyclic AMP also favored differentiation and expression of a mature ion channel pattern in astrocytes improving their glutamate buffering. A deficient cholinergic signaling that increases the risk of pathological APP processing was compensated by an adenosine-mediated reinforcement of the second messenger calcium. A combination therapy with acetylcholine-esterase inhibitors together with adenosine raising pharmaca, therefore, may be used to treat cholinergic deficiency in Alzheimer's disease.     

Induced genome instability as a potential screening test for cancer susceptibility?

The variety of mutations associated with carcinogenesis, along with variations in penetrance and environmental factors, complicate the genetic screening for cancer predisposition. It is proposed here that the detection of inherent genome instability as determined by increased mutagen susceptibility may enhance the identification of populations at risk for cancer. In support for this hypothesis, our analysis reveals a strong association between mutagen-induced chromosomal instability in peripheral blood lymphocytes and the propensity for cancers of oral cavity, pharynx, larynx, and lung. DNA instability in response to a variety of mutagens identifies patients with gastrointestinal, brain, endocrine, breast, skin, and hematologic tumors as well as individuals with cancer family syndromes. Induced genome instability therefore appears to be strongly linked to cancer predisposition, and prospective studies may yield a screening test utilizing a panel of mutagens to better identify populations at risk.     

How early can we predict Alzheimer's disease using computational anatomy?

Computational anatomy with magnetic resonance imaging (MRI) is well established as a noninvasive biomarker of Alzheimer's disease (AD); however, there is less certainty about its dependency on the staging of AD. We use classical group analyses and automated machine learning classification of standard structural MRI scans to investigate AD diagnostic accuracy from the preclinical phase to clinical dementia. Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative were stratified into 4 groups according to the clinical status—(1) AD patients; (2) mild cognitive impairment (MCI) converters; (3) MCI nonconverters; and (4) healthy controls—and submitted to a support vector machine. The obtained classifier was significantly above the chance level (62%) for detecting AD already 4 years before conversion from MCI. Voxel-based univariate tests confirmed the plausibility of our findings detecting a distributed network of hippocampal-temporoparietal atrophy in AD patients. We also identified a subgroup of control subjects with brain structure and cognitive changes highly similar to those observed in AD. Our results indicate that computational anatomy can detect AD substantially earlier than suggested by current models. The demonstrated differential spatial pattern of atrophy between correctly and incorrectly classified AD patients challenges the assumption of a uniform pathophysiological process underlying clinically identified AD.     

Adult genital surgery for intersex: a solution to what problem?

The desirability of routine genital surgery for infants with ambiguous genitalia is increasingly debated. But there is less discussion about intersex adults who choose genital surgery, despite evidence suggesting that the results are often unsatisfactory. This study reports on how six women with intersex conditions decided to have feminizing genital surgery and how they evaluated the outcomes. The initial analysis highlighted a chronological transition from surgery as nondilemmatic to surgery as a serious dilemma; a version of Foucauldian discourse analysis was then used to place the women's experiences in a cultural context. The implications for psychological involvement in services for women with intersex conditions are discussed.     

Genetic screening for pheochromocytoma: should SDHC gene analysis be included?

PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine-secreting chromaffin tumours has been reported to date. We report the case of a 15-year-old girl with hypertension and a norepinephrine-secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.     

Naming ability in patients with mild to moderate Alzheimer's disease: what changes occur with the evolution of the disease?

OBJECTIVES:

Naming deficit is a linguistic symptom that appears in the initial phase of Alzheimer''s disease, but the types of naming errors and the ways in which this deficit changes over the course of the disease are unclear. We analyzed the performance of patients with Alzheimer''s disease on naming tasks during the mild and moderate phases and verified how this linguistic skill deteriorates over the course of the disease.

METHODS:

A reduced version of the Boston Naming Test was administered to 30 patients with mild Alzheimer''s disease, 30 patients with moderate Alzheimer''s disease and 30 healthy controls. Errors were classified as verbal semantic paraphasia, verbal phonemic paraphasia, no response (pure anomia), circumlocution, unrelated verbal paraphasia, visual errors or intrusion errors.

RESULTS:

The patients with moderate Alzheimer''s disease had significantly fewer correct answers than did both the control group and the group with mild Alzheimer''s disease. With regard to the pattern of errors, verbal semantic paraphasia errors were the most frequent errors in all three groups. Additionally, as the disease severity increased, there was an increase in the number of no-response errors (pure anomia). The group with moderate Alzheimer''s disease demonstrated a greater incidence of visual errors and unrelated verbal paraphasias compared with the other two groups and presented a more variable pattern of errors.

CONCLUSIONS:

Performance on nominative tasks worsened as the disease progressed in terms of both the quantity and the type of errors encountered. This result reflects impairment at different levels of linguistic processing.     

Prediction of hypersensitivity to antibiotics: what factors need to be considered?

This review focuses on the epidemiology and different risk factors related to the development of hypersensitivity reactions to antibiotics, with a focus on betalactams and fluoroquinolones, the compounds most frequently involved in these reactions, due to their high level of consumption. The true prevalence of allergic drug reactions is unknown and the corresponding morbidity, mortality and associated economic costs are often underestimated. It is reported that multiple risk factors, related to both the drug and the patient, can modify the clinical expression of immune-mediated drug reactions. These include the chemical properties, molecular weight and administration route of the drug and the age, gender, concomitant diseases and genetic factors of the patient.     

Simple/rapid test devices for anti-HIV screening: do they come up to the mark?

Thirteen simple/rapid test devices (S/RTDs) for the detection of antibodies to HIV 1 and HIV 2 were assessed. Ninety-two specimens in four categories were used and results with the thirteen S/RTDs were compared with those obtained with six currently available commercial laboratory-based anti-HIV 1/2 EIAs. Seven of the 13 S/RTDs scored all 26 blood donors' specimens as unreactive, and 11 correctly identified all the 25 "straightforward" anti-HIV positive specimens. False negative results arose when testing by Uni-Gold HIV and SeroCard HIV, which gave 72 and 68 correct positive observations, respectively, out of 75. No S/RTD detected seroconversion earlier than the most sensitive EIAs, but four S/RTDs performed similarly to most of the EIAs. On the low-titre panel specimens, six S/RTDs were less sensitive than the least sensitive EIA and, in contrast to four of the six EIAs, only one S/RTD was able correctly to identify all the positive specimens. A manufacturing problem was identified that allowed the HIV antigen-sensitised area on the membrane of two SeroCard HIV devices to be misaligned with the device's reading window so that the reaction was almost entirely obscured. As long as small numbers of specimens were involved, most S/RTDs required considerably less time and less equipment than EIAs, but overall they were slightly less sensitive. Their use in various health settings and for confirmatory procedures is discussed.