Homeopathy for chronic asthma.

BACKGROUND: Homeopathy involves the use, in dilution, of substances which cause symptoms in their undiluted form. It is one of the most widespread forms of complementary medicines and is also used to treat asthma. OBJECTIVES: The objective of this review was to assess the effects of homeopathy in people with chronic stable asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register, the Cochrane Complementary Medicine Field trials register, the Glasgow Homeopathic Hospital database, the Muenchener Modell database and reference lists of articles. SELECTION CRITERIA: Randomised and possibly randomised trials of homeopathy for the treatment of stable chronic asthma, with observation periods of at least one week. DATA COLLECTION AND ANALYSIS: Data extraction was done by one reviewer and checked by the second reviewer. Trial quality was assessed by the reviewers. MAIN RESULTS: Three trials with a total of 154 people were included. These trials were all placebo-controlled and double-blind, but of variable quality. They used three different homeopathic treatments which precluded quantitative pooling of results. The standardised treatments in these trials are unlikely to represent common homeopathic practice, where treatment tends to be individualised. In one trial, severity of symptoms was lessened in the homeopathy group compared to the placebo group. In another trial, lung function measures and medication use showed improvement in the homeopathy group compared to the placebo group. The third trial found improvement in both the homeopathy and placebo groups, but no difference between the groups. REVIEWER'S CONCLUSIONS: There is not enough evidence to reliably assess the possible role of homeopathy in asthma. As well as randomised trials, there is a need for observational data to document the different methods of homeopathic prescribing and how patients respond.

Diagnosing dementia: interrater reliability assessment and accuracy of the NINCDS/ADRDA criteria versus CERAD histopathological criteria for Alzheimer's disease.

We investigated the interrater reliability and accuracy of two independent medical doctors in using NINCDS/ADRDA criteria to classify 82 elderly subjects enrolled in OPTIMA, a longitudinal study investigating dementia. Kappa statistics revealed moderate agreement (0.5) in overall classification of dementia type, and almost perfect agreement (0.9) on the absence or presence of dementia. Combining NINCDS/ADRDA 'possible' and 'probable' Alzheimer's disease (AD) categories produced substantial agreement (0.7). Comparison with CERAD histopathological criteria for AD showed that combining 'possible' and 'probable' AD resulted in a high sensitivity and accuracy, but a low specificity. To increase specificity, the NINCDS/ADRDA 'probable AD' category should be used alone. An important finding was that the accuracy of diagnoses of AD made from the case notes alone was not different from the diagnoses obtained following active involvement with participants.

Relationship between clinical and radiological diagnostic criteria for Alzheimer's disease and the extent of neuropathology as reflected by 'stages': a prospective study.

The distribution of pathology related to Alzheimer's disease (AD) is not uniform throughout the brain. Sites which have a predilection for the development of Alzheimer-type pathology are the limbic regions and neocortical association areas. The changes in these areas of the brain develop gradually, following a well-determined sequence that allows a pathological staging of the disease process. According to the staging hypothesis, the first pathological alterations develop in the transentorhinal and entorhinal regions. The neurofibrillary pathology then spreads into the hippocampus, but not until the final stages does it affect the neocortex. In this study we analyse the relationship between the pathological stages of AD, according ot the staging hypothesis, and the clinical diagnosis in a prospectively assessed patient group. Prediction of any given pathological stage from the clinical diagnosis was found to be poor. This may be partly due to the fact that additional pathologies can alter the clinical picture and severity of dementia in patients who are only in the initial stages of AD. Nevertheless, the NINCDS-ADRDA clinical criteria had a high sensitivity for detection of AD-related pathology: the 'probable AD' category included 22/38 (57.9%) of those in the late isocortical stage, while the 'possible AD' category included 19/23 (82.6%) of those in the limbic stage. Using proposed neuro-imaging protocols for improved identification of patients with AD-related pathology, we largely identified subjects in whom the extent of pathology had spread to the neocortex.

The progression of Alzheimer's disease from limbic regions to the neocortex: clinical, radiological and pathological relationships.

Alzheimer's disease (AD) is characterised by the gradual accumulation of neurofibrillary pathology in selected regions of the brain. Earlier studies indicate that the accumulation of neurofibrillary tangles is associated both with decline in patient's cognitive performance as well as with medial temporal lobe atrophy on CT scans. There are also indications that progression through the pathological stages of AD is associated with decline in cognitive functions. The results of this study indicate that progression of disease, especially beyond the boundaries of the limbic regions, is associated with marked decline in the cognitive performance of patients suffering from AD. However the clinical manifestations of early pathological stages are not so well defined. We also found that the atrophy of the medial temporal lobe on CT scans is related to the progression of pathology. Atrophy is most apparent when the disease reaches its isocortical stages and is not marked in the limbic stages of the disease. The additive effect of pathologies co-existing with AD is apparent in reduced cognitive scores, while the atrophy of limbic structures, as measured on CT scans, seems to be mainly attributable to AD-related pathology.

Diseases of meaning, manifestations of health, and metaphor.

Disease and health are commonly thought of as distinct opposites. We propose a different view in which both may be seen to be facets of healthy functioning, each necessary for the other, each giving rise to the other. Thus, disease may be thought of as a manifestation of health. It is the healthy response of an organism striving to maintain physical, psychologic, and spiritual equilibrium. Disease is not necessarily to be avoided, blocked, or suppressed. Rather, it should be understood to be a process of transformation. The process should therefore be facilitated because it is an integral part of the dynamic equilibrium that we ordinarily think of as health. In many cases, perhaps all, people get ill because there is something going "wrong" in their lives. This could occur in a whole range of ways-relationships, environment, food, or job. Our view, however, is that disease is a meaningful state that can inform health workers how to help patients to heal themselves. In this way, instead of being meaningless, people's problems become diseases of meaning, enabling people to see that things are not necessarily "going wrong" but are, in fact, helping them become stronger, to live more fully and with more understanding. Seen from this perspective, depression; cancer; heart disease; neurodegenerative and autoimmune disease; dementia; and conditions such as community violence, genocide, and the problem of environmental devastation are "diseases of meaning." World Health Organization forecasts make it clear that diseases of meaning will continue well into the next millennium to be the major cause of suffering and death worldwide. To deal with them, the world needs to reformulate the biomolecular paradigm that has been exploited in the last two centuries. It does not address the reasons why these diseases arise, attending mainly to their molecular consequences. A paradigm that includes the importance of meaning must now be given top priority. The concept that diseases are a manifestation of health-a call to a different relationship with ourselves and our environment, both animate and inanimate- is in itself a different approach. Programs for care and education based upon it would have immediate application in medicine, industry, education and ecology. We believe that this model would have far-reaching consequences for the understanding, treatment, and prevention of diseases and behaviors that lead to violence and environmental destruction.

Abnormal function of potassium channels in platelets of patients with Alzheimer's disease.

BACKGROUND: Reports of abnormalities of potassium-channel function in various cultured cells of Alzheimer's disease patients led us to attempt to characterise the pharmacological characteristics of the abnormal channel. METHODS: We studied platelets from 14 patients with Alzheimer-type dementia and 14 non-demented controls matched for age and sex. The effects of specific inhibitors of K+ channels on the efflux of rubidium-86 ions, a radioactive analogue of K+, from the platelets were measured. FINDINGS: Normal platelets contain three types of K+ channel, sensitive to the inhibitory actions of apamin (small-conductance calcium-dependent potassium channels), charybdotoxin (of less specificity, but probably intermediate-conductance calcium-dependent K+ channels), and alpha-dendrotoxin (voltage-sensitive K+ channels). However, 8Rb+ efflux from the platelets of patients with Alzheimer-type dementia was not inhibited by either apamin or charybdotoxin. By contrast, inhibition by alpha-dendrotoxin did occur. INTERPRETATION: Our results suggest that calcium-dependent K+ channels in platelets are selectively impaired in Alzheimer's disease. A similar abnormality in neurons could contribute to the pathophysiology of the disorder.

Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.

BACKGROUND: Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. OBJECTIVE: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. DESIGN: Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. SETTING: Referral population to a hospital clinic between July 1988 and April 1996. MAIN OUTCOME MEASURES: Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. RESULTS: Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. CONCLUSIONS: Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

Comparison of pathological diagnostic criteria for Alzheimer disease.

Because the clinical picture of Alzheimer disease (AD) is often difficult to discriminate from other dementing illnesses, the diagnosis of AD requires neuropathological confirmation. However, for the pathological diagnosis of AD, there are no unanimously accepted criteria. The three currently used sets of pathological criteria (Khachaturian: Khachaturian, Arch Neurol 1985;42:1097-105; Tiemy: Tierney et al., Can J Neurol Sci 1986; 13:424-6; CERAD: Mirra et al., Neurology 1991;41:479-86) for the disease differ from each other considerably. We applied these criteria to the first 43 consecutive subjects (37 demented) with no neuropathology other than AD-type pathology from autopsies after longitudinal prospective clinical study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). The results show that the CERAD category of definite AD corresponds closely with the cases that fulfill Tierney A3 inclusion criteria for AD. The combined CERAD categories of possible, probable, and definite AD correspond closely to cases fulfilling Khachaturian criteria forAD. The influence of a clinical diagnosis of dementia when Khachaturian and CERAD criteria were applied was considerable because between 9.3% and 90.7% of patients would have been categorized differently depending on whether clinical dementia was present or absent.

Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin.

There is evidence consistent with the hypothesis that inflammatory and immune mechanisms are involved in the pathogenesis of Alzheimer disease (AD). We have investigated whether the levels of inflammatory associated proteins in serum or lumbar cerebrospinal fluid (CSF) reflect the progressive cognitive decline and brain atrophy of AD-patients. Levels of interleukin-1beta(IL-1beta), IL-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), the soluble TNF receptors type I and II (sTNFR I and II), and the acute phase protein alpha1-antichymotrypsin (x1-ACT) were determined in paired serum and CSF samples taken yearly over a period of 2-5 years from pathologically confirmed AD patients (n = 8) and normal controls or non-AD subjects with other CNS pathology (n = 9). No significant differences were found between AD subjects and controls in the mean levels of the above mediators. There was also no correlation in either subject group between the levels of these inflammatory mediators in serum or CSF, and the change in cognitive status or the progression of the atrophy of the medial temporal lobe measured by X-ray computed tomography (CT). The concentrations of IL-1beta, IL-6, and TNF-alpha were determined in brain tissue specimens of five to nine different brain regions in six of the AD patients and four of the non-AD subjects. The levels of IL-1beta and IL-6 in the various brain regions were not significantly different in the AD and the non-AD group. However, in AD patients the level of TNF-alpha was significantly lower in the frontal cortex (32%, p = 0.024), the superior temporal gyrus (57%, p = 0.021), and the entorhinal cortex (49%, p = 0.009) compared with non-AD subjects. Low levels of TNF-alpha in the brain areas that showed neuropathology in AD may indicate a dysregulation of the inflammatory process in AD. Despite this finding, this study does not support the use of measurements of any of the inflammatory mediators investigated here as a diagnostic parameter for AD, due the large overlap in the levels of these factors between AD patients and other subjects, and the poor relation to clinical signs of AD.

Accurate prediction of histologically confirmed Alzheimer's disease and the differential diagnosis of dementia: the use of NINCDS-ADRDA and DSM-III-R criteria, SPECT, X-ray CT, and Apo E4 in medial temporal lobe dementias. Oxford Project to Investigate Memory and Aging.

In a prospective study of more than 200 cases of dementia and 119 controls, annual technetium-99m-hexamethyl-propylene amineoxime (99mTC-HMPAO) single-photon emission computed tomography (SPECT) and annual medial temporal lobe (MTL) oriented X-ray computed tomography (CT) have been used to evaluate the diagnostic potential of functional and structural neuroimaging in the differential diagnosis of dementia. Some subjects have had up to 7 annual evaluations. So far, of 151 who have died, 143 (95%) have come to necropsy. Histology is known for 118, of whom 80 had Alzheimer's disease (AD), 24 had other "non-AD" dementias, and 14 controls with no cognitive deficit in life also had no significant central nervous system pathology. To compare the findings in the dementias with the profile of structural and functional imaging in the cognitively normal elderly, scan data from 105 living, elderly controls without cognitive deficit have also been included in the analysis. All clinical diagnoses were according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-III-R) criteria, and all histopathological diagnoses according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Early data from this cohort have suggested that the combination of both MTL atrophy seen on CT with parietotemporal hypoperfusion on SPECT may predict the pathology of AD. The diagnostic sensitivity, specificity, accuracy, and positive and negative predictive values of the NINCDS-ADRDA and DSM-III-R criteria could be assessed in this cohort against the gold standard of histopathology. The diagnostic potential of CT evidence of MTL atrophy alone, SPECT evidence of parietotemporal hypoperfusion alone, and the combination of both of these scan changes in the same individual could then be compared against the diagnostic accuracy of clinical operational criteria in the pathologically confirmed cases. Furthermore, all of these modalities could be compared with the diagnostic accuracy of apolipoprotein E4 (Apo E4) genotyping to predict AD in the histopathologically confirmed cohort. In this population, NINCDS "probable-AD" was 100% specific, 49% sensitive, and 66% accurate; "possible-AD" was only 61% specific, but 93% sensitive and 77% accurate; and the combination of both "probable-AD" and "possible-AD" was 61% specific, 96% sensitive, and 85% accurate. DSM-III-R criteria were 51% sensitive, 97% specific, and 66% accurate. In the same cases and including the 105 living, elderly controls, the diagnostic accuracy of the Oxford Project to Investigate Memory and Aging (OPTIMA) scanning criteria showed CT alone to be 85% sensitive, 78% specific, and 80% accurate; SPECT alone had 89% sensitivity, 80% specificity, and 83% accuracy; and the combination of the two was 80% sensitive, 93% specific, and 88% accurate. The Apo E4 genotype was 74% sensitive but yielded 40% false positives in the histologically confirmed series. The diagnostic accuracy afforded by this method of CT and SPECT used alone is better than that of any established clinical criteria and reveals that the combination of MTL atrophy and parietotemporal hypoperfusion is common in AD, much less common in other dementias, and rare in normal controls. In the NINCDS-ADRDA criteria "possible-AD" cases, the combination of CT and SPECT findings alone were better in all diagnostic indices than the presence of Apo E4 alone in predicting AD. The frequent occurrence of MTL atrophy in AD and also in other "non-AD" dementias later in the course of the disease suggests the concept of medial temporal lobe dementia. This could explain some of the overlap of clinical profiles in the dementias, particularly as the dementia progresses, making clinical differential diagnosis difficult. In this context, the use of SPECT can significantl