Anything in modulation?
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
R Hills
Publications and source records attributed to R Hills.
Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease.
We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.
Alzheimer Disease↗
Tau gene mutation K257T causes a tauopathy similar to Pick's disease.
Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. Here we describe a K257T missense mutation in exon 9 of Tau. The proband, a 47-yr-old male, presented with severe personality changes followed by semantic memory loss. A diagnosis of Pick's disease was made. The symptoms progressed until death at age 51. The proband's brain showed a marked frontotemporal atrophy that was most pronounced in the temporal lobes. Numerous tau-immunoreactive Pick bodies were present in the neocortex and the hippocampal formation, as well as in some subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. Diffuse staining for hyperphosphorylated tau was also observed in some nerve cell bodies. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa and 2 very minor bands of 68 and 72 kDa. Upon dephosphorylation, these bands resolved into 6 bands consisting of 3-repeat and 4-repeat tau isoforms, with an overall preponderance of 3-repeat tau. Isolated tau filaments were narrow, irregularly twisted ribbons. Biochemically, recombinant tau proteins with the K257T mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. In addition, the K257T mutation was found to stimulate heparin-induced assembly of 3-repeat tau into filaments. Taken together, the present findings indicate that the K257T mutation in Tau can cause a dementing condition similar to Pick's disease.
Frontal Lobe↗
The messenger RNAs for the N-methyl-D-aspartate receptor subunits show region-specific expression of different subunit composition in the human brain.
The expression of the messenger RNAs encoding N-methyl-D-aspartate receptor subunits in neurologically normal post-mortem human brain was studied by in situ hybridization. In the caudate, putamen and nucleus accumbens strong hybridization signals were observed for N-methyl-D-aspartate R1-1 messenger RNA but much weaker signals for N-methyl-D-aspartate R1-3 and N-methyl-D-aspartate R1-4, N-Methyl-D-aspartate R1-2 was not detectable. N-methyl-D-aspartate R2B was the only N-methyl-D-aspartate R2 subunit detected in these nuclei. In the hippocampus the messenger RNAs for both N-methyl-D-aspartate R1-1 and N-methyl-D-aspartate R1-4 were strongly expressed in the dentate gyrus, CA3-CA1 pyramidal cells, subiculum, entorhinal cortex and perirhinal cortex. Much lower expression was seen for N-methyl-D-aspartate R1-2 and N-methyl-D-aspartate R1-3. The messenger RNAs for both N-methyl-D-aspartate R2A and N-methyl-D-aspartate R2B, but not N-methyl-D-aspartate R2C, subunits were expressed in the hippocampus. In the temporal cortex all N-methyl-D-aspartate RI isoforms were expressed (N-methyl-D-aspartate R1-1 and N-methyl-D-aspartate R1-4 being the most abundant) and N-methyl-D-aspartate R2A and N-methyl-D-aspartate R2B but not N-methyl-D-aspartate R2C were also moderately expressed. In the brain stem N-methyl-D-aspartate R1-4 was strongly expressed in various nuclei including the locus coeruleus, nucleus centralis superior and deep pontine nuclei. Only weak expression was seen for N-methyl-D-aspartate RI-1 and N-methyl-D-aspartate R1-3 but not N-methyl-D-aspartate RI-2; of the N-methyl-D-aspartate R2 subunits only N-methyl-D-aspartate R2C was found to be expressed in these nuclei. In the cerebellum all the N-methyl-D-aspartate I isoforms were expressed (mostly N-methyl-D-aspartate R1-4) in the Purkinje layer which also expressed N-methyl-D-aspartate R2A and N-methyl-D-aspartate R2C. In the molecular layer cells were found expressing N-methyl-D-aspartate R1-4 and N-methyl-D-aspartate R2B and cells in the granule layer were found to express N-methyl-D-aspartate R1-1, N-methyl-D-aspartate R1-3 and N-methyl-D-aspartate R1-4 and N-methyl-D-aspartate R2C only. Preliminary studies indicated that the messenger RNA for the N-methyl-D-aspartate R2D subunit was not expressed in the above areas of brain. These results give the first demonstration of the distribution of N-methyl-D-aspartate receptor subunit messenger RNAs in the human brain. The region-specific expression of subunit combinations suggests a heterogeneity of N-methyl-D-aspartate receptors with diverse physiological/pathophysiological roles and provides a rationale for the development of discriminatory N-methyl-D-aspartate receptor antagonists to target selective neuronal populations.
Aged↗
[Image cytometric DNA analysis in the evaluation of the risk of recurrence after resection of rectal carcinoma].
Prognostically relevant factors derived from re-operative endoluminal US examination or the histopathological work-up of the surgical specimen in carcinoma of the rectum are well known. We investigated the question as to whether the DNA content of tumor cells is an independent influencing factor of prognosis after resection of rectal carcinoma. In 68 patients who underwent resection for rectal carcinoma, in addition to the TNM classification and the usual morphological evaluation, the paraffin-embedded tumor material was de-paraffinized, rehydrated and treated mechanically and enzymatically prior to application to microscope slides. These smears were analysed with the aid of automatic single cell cytometry, and DNA measurements were performed. In contrast to flow cytometry, this technique permits, on the basis of electronic selection criteria, selective analysis of the tumor cells, while artefacts, stroma and inflammatory cells can be excluded. Using DNA cytometry, we were able to differentiate between diploid, polyploid and aneuploid tumors. The best prognosis was associated with a diploid tumor, the poorest with aneuploid tumor. Regression analysis, however, showed that the DNA content of tumor cells is of only secondary significance.
Cytological Techniques↗
Pulmonary collapse during anaesthesia in children with respiratory tract symptoms.
A frequent dilemma facing the anaesthetist is the child with respiratory tract symptoms. The risks of anaesthesia and surgery in these patients have not been clearly established. We present three cases which illustrate a potentially serious complication which may arise. Our patients each had symptoms of cough, but were systemically healthy. Two of the children had absent clinical signs, whilst the third had a normal chest X ray. However, during surgery and anaesthesia each child developed significant pulmonary collapse, associated with desaturation on oximetry.
Anesthesia, General↗
Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease.
The tau protein is a microtubule-associated protein that is normally located in nerve axons. In Alzheimer disease, it is a constituent of paired helical filaments (PHFs), which are the principal fibrous component of the characteristic neurofibrillary tangles. The tau protein, therefore, is abnormally sequestered in an insoluble form in PHFs in the cell body and dendrites in Alzheimer disease. We have used two monoclonal antibodies (mAbs) to selectively measure the levels of normal, soluble tau protein and of PHF-associated tau protein in the brain. mAb 423 binds to PHFs and recognizes a 12-kDa fragment of tau protein released by formic acid treatment of PHFs, but it does not recognize normal tau protein. In contrast, mAb 7.51 recognizes normal tau protein as well as the PHF core-derived tau fragment, but its epitope is concealed in the PHF-bound form. The differential binding properties for these two mAbs have enabled us in this study to quantify insoluble PHF-associated tau protein in the somatodendritic compartment as well as normal soluble tau protein in its predominantly axonal location. Our findings demonstrate that a distinct immunochemical presentation of tau protein recognized by mAb 423, a PHF-specific marker, can be used to quantify neurofibrillary pathology in Alzheimer disease independently of the presence of normal tau proteins.
Alzheimer Disease↗
A second neutralizing epitope of B19 parvovirus implicates the spike region in the immune response.
We used 18 monoclonal antibodies against B19 parvovirus to identify neutralizing epitopes on the viral capsid. Of the 18 antibodies, 9 had in vitro neutralizing activity in a bone marrow colony culture assay. The overlapping polypeptide fragments spanning the B19 structural proteins were produced in a pMAL-c Escherichia coli expression system and used to investigate the binding sites of the neutralizing antibodies. One of the nine neutralizing antibodies reacted with both VP1 and VP2 capsid proteins and a single polypeptide fragment on an immunoblot, identifying a linear neutralizing epitope between amino acids 57 and 77 of the VP2 capsid protein. Eight of nine neutralizing antibodies failed to react with either of the capsid proteins or any polypeptide fragments, despite reactivities with intact virions in a radioimmunoassay, suggesting that additional conformationally dependent neutralizing epitopes exist.
ATP-Binding Cassette Transporters↗
Modified behavior oscillations in diseased plants and its implication to epidemiology and crop loss assessment.
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Agriculture↗
Controlled comparison of short-wave diathermy treatment with osteopathic treatment in non-specific low back pain.
The effectiveness of spinal manipulation carried out by a non-medical qualified osteopath was compared with that of short-wave diathermy (SWD) and a placebo (detuned SWD) in 109 patients with low back pain. More than half the subjects in each of the 3 treatment groups benefited immediately from therapy. Significant improvements were observed in the 3 groups at the end of 2 weeks' treatment, and these were still apparent at 12 weeks. The outcome of treatment was unrelated to the initial severity or duration of pain or to the trend of pain towards deterioration or improvement. It is, therefore, unlikely that the results simply reflect the natural history of low back pain. Benefits obtained with osteopathy and SWD in this study may have been achieved through a placebo effect.
Adult↗
Loss of pigmented dopamine-beta-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type.
Serial sections of human brainstem were used to determine the total number of pigmented cells in locus coeruleus and, by immunohistochemical staining using an antiserum directed against human dopamine-beta-hydroxylase (DBH), the number of DBH-positive cells. In 12 brains from elderly control and dementia subjects there wer not significant differences in the total cell populations determined in the same brain by the two techniques. In 6 patients with senile dementia of Alzheimer's type there was a variable loss (average about 60% reduction) in locus coeruleus cells when compared to controls of similar age. The loss of noradrenergic neurones from locus coeruleus was accompanied by an average reduction of similar magnitude in noradrenaline concentration in temporal cortex, with no change or an increase in dopamine content. There was also a significant reduction in the cholinergic marker choline acetyltransferase in cortex samples from the dementia cases.
Aged↗
Self-administration of medical modalities (SAMM): another method of rehabilitation education.
In order to train patients to carry out home pulmonary care adequately, we developed a hospital-based patient-education program we call Self-Administration of Medical Modalities (SAMM). This teaches patients about their pulmonary disease; about their medications' purposes, side effects and what to do if they occur, possible conflict with other medications, and the medication schedule; about use, care, and cleaning of aerosol inhalation devices and scheduling of aerosol medication treatments; and about chest physical therapy if it is indicated. Nurses, respiratory therapists, and physical therapists in the hospital teach and reinforce these concepts and evaluate the patient's progress in learning. The patient advances through three levels of competency. At Level I he is responsible only for keeping track of his medication and treatment schedules. At Level II the patient initiates requests for medication and treatments on schedule, takes them under supervision, and makes a written record of having done so. At Level III the patient's medications are kept at his bedside, he prepares and takes the medications himself, takes treatments himself, and he keeps written records. At this level the program simulates home conditions as much as possible. Patients have reported that they liked administering their own medications and treatments and that the SAMM Program was helpful in preparing them for self-care at home.
California↗
Protease susceptibility of human A influenza virus polypeptides.
The proteolytic susceptibility of polypeptides of four antigenically distinct subtypes of influenza a virus strains of human origin was studied. The extent of degradation of polypeptide molecules of strains A/PR/8/34 (H0N1) (PR), A/FM/1/47 (H1N1), A/Singapore/1/57 (H2N2) and A/Hong Kong/8/68 (H3N2), assessed by densitometry of gels after sodium dodecylsulfate polyacrylamide gel electrophoresis was variable by treatment with trypsin. Also, sequential treatment of PR strain initially with phospholipase D followed by proteases of different specificities suggested differences in susceptibility of surface and internal polypeptide molecules. The significance of these results is discussed.
Animals↗
Determining patient education needs.
Patients will learn more readily if you teach them what they want to know, in a way suited to their style of learning. The current emphasis in education is on the learner: What is that learner like? What are his or her beliefs, values, attitudes, and behaviors? What is his or her level of knowledge? You need to know all these things--and more--when you embark on a program of patient education. This article offers a step-by-step guide in determining your patients' educational needs.
Attitude to Health↗