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Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions.

Several pedigrees have recently been reported in which dominantly inherited familial Alzheimer's disease is associated in some family members with spastic paraparesis and non-neuritic 'cotton wool' plaques. Here we report clinical, genetic and neuropathological findings in two further large pedigrees in which this combination of phenotypes is associated with a deletion of exon 9 of the presenilin-1 (PS-1) gene caused by mutations at the splice acceptor site. In both pedigrees, individuals with paraparesis at presentation had a later than average age at onset of symptoms. In addition, one subject with paraparesis had a much less prominent dementia syndrome than his dementia-affected siblings. As PS-1 mutations are almost always associated with a particularly aggressive form of presenile dementia, these findings suggest the existence of a protective or delaying factor in individuals with spastic paraparesis.

Adult↗

Density gradient centrifugation and glass wool filtration of semen remove spermatozoa with damaged chromatin structure.

The ability of double-layered density gradient centrifugation (DGC) or glass wool filtration (GWF) of semen to remove spermatozoa with damaged chromatin structure was assessed by the flow cytometric sperm chromatin structure assay (SCSA), which measures the susceptibility to sperm nuclear denaturation in situ. Ejaculates from 26 men attending a university-affiliated assisted reproduction laboratory were processed by DGC and GWF. Unprocessed, DGC- and GWF-processed specimens were assessed by the SCSA and by conventional semen parameters. Changes in chromatin structure were compared with conventional semen parameters. Both sperm preparation techniques yielded sperm suspensions with improved sperm chromatin structure as well as motility (%), forward progression (1-4) and viability (%). DGC was superior to GWF in the efficiency of recovering motile, morphologically normal, mature sperm suspensions. However, GWF produced improved chromatin integrity (SDalpha(t)) and viability. Moderate correlations between SCSA and conventional sperm parameters were observed. Nevertheless, the SCSA provides additional information about the biochemical integrity of sperm DNA and may be used in future studies to provide insight into assisted reproduction technology outcomes not explained by conventional sperm parameters.

Cell Separation↗

Cotton wool plaques in non-familial late-onset Alzheimer disease.

Cotton wool plaques (CWP) are large, ball-like plaques lacking dense amyloid cores that displace adjacent structures. They were first described in a Finnish kindred with early-onset Alzheimer disease (AD) with spastic paraparesis due to a presenilin-1 delta9 mutation. We describe a case of sporadic late-onset AD with numerous neocortical CWP as well as severe amyloid angiopathy and marked leukoencephalopathy, compared with 16 cases of late-onset AD with similar degrees of amyloid angiopathy and leukoencephalopathy. The cases were studied with histologic methods and with single and double immunostaining for beta-amyloid (Abeta), paired helical filaments-tau (PHF-tau), neurofilament (NF), glial fibrillary acidic protein (GFAP), HLA-DR, and amyloid precursor protein (APP). We found that CWP were well-circumscribed amyloid deposits infiltrated by ramified microglia and surrounded by dystrophic neurites that were immunopositive for APP, but only weakly for NF and PHF-tau. Abeta1-12 was diffuse throughout the CWP, while Abeta37-42 was peripherally located and Abeta20-40 more centrally located. Two of the 16 late-onset AD cases also had CWP, but they were also admixed with diffuse plaques and plaques with dense amyloid cores. Pyramidal tract degeneration was not a consistent finding or a prominent feature in any case. The results suggest that CWP are not specific for early-onset familial AD with spastic paraparesis.

Age of Onset↗

Pulmonary microembolism associated with massive transfusion: I. Physiologic effects and comparison in vivo of standard and dacron wool (swank) blood transfusion filters in its prevention.

Pulmonary microembolism of microaggregates associated with massive blood transfusion may be a cause of post-traumatic pulmonary embolism. The purpose of this study was to investigate in the dog the influence on certain physiologic parameters of transfusion of blood containing platelet: white blood cell: fibrin (PWF) aggregates and to evaluate the effects of using blood transfusion filters of varying pore sizes during such transfusions. Exchange transfusions of approximately twice blood volume were performed in three groups of animals. Screen filtration pressure measurements verified the presence of large numbers of PWF aggregates in the transfusions. When no transfusion filters or standard commercially available blood transfusion filters of pore size 170 mu were used, experimental animals developed pulmonary hypertension, a decrease in total body 92 consumption, and metabolic acidosis. Interposition of Dacron wool (Swank) blood transfusion filters prevented these changes.

Animals↗

Polymerase chain reaction detection of cytomegalovirus and human immunodeficiency virus-1 in the retina of patients with acquired immune deficiency syndrome with and without cotton-wool spots.

PURPOSE: The authors determine the association, if any, between detection of human cytomegalovirus (CMV) and human immunodeficiency virus (HIV) nucleic acids and retinal lesions in patients with acquired immune deficiency syndrome. METHODS: Postmortem eyes were examined with a dissecting microscope and light microscopy. Retinal cotton-wool spots (CWS) were removed using a clean touch punch biopsy technique. Equivalent amounts of retinal tissue from the posterior pole of the retina not affected by CWS and from the retinal periphery also were studied. Polymerase chain reaction (PCR) detection of retinal cellular DNA (GA3PD gene), human CMV DNA (major immediate early gene), and HIV (gag gene) was performed using ethidium bromide and liquid hybridization detection. RESULTS: Ninety percent of CWS were positive for CMV DNA versus 22% of peripheral retinal biopsies (P < 0.025). Liquid hybridization showed similar results. Analysis of lesions in which results of both tests were positive (ethidium and liquid hybridization) versus lesions in which results of either test were negative also showed a strong association between CWS and CMV, but not HIV nucleic acids (P < 0.02). Studies of HIV showed no association between retinal CWS lesions and HIV nucleic acid; with liquid hybridization HIV, RNA was detected equally at low levels in all areas. CONCLUSION: There is a statistically significant association between the presence of human CMV nucleic acids and retinal CWS detected by PCR. There is a low level presence of HIV in the retinal tissue studied that is only detectable using liquid hybridization techniques and is not associated with a particular area or lesions in the retina; this may represent detection of HIV in blood. The presence of CMV in areas of retinal CWS may have implications for their pathogenesis, but further study is necessary because other explanations are possible.

AIDS-Related Opportunistic Infections↗

Prethymic nylon wool-passed bone marrow cells, substituting for helper T cells, can augment the generation of cytotoxic T lymphocytes from their precursors.

Nylon wool-passed bone marrow (NW-BM) cells treated with anti-Thy.1 monoclonal antibody and complement were added to a mixed lymphocyte culture which contained a limiting number of lymph node cells, as responder cells, and a sufficient number of mitomycin-c-treated allogeneic spleen cells as stimulator cells. NW-BM cells of the same MHC haplotype as responder cells enhanced the generation of allo-specific cytotoxic T lymphocytes (CTL) not only at a relatively high dose (3 x 10(3) cells/well) of responder cells, but also at an extremely dilute dose (1 x 10(3) cells/well). NW-BM cells which had a third-party MHC haplotype, a haplotype different from both responder and stimulator cells, also enhanced the generation of CTL at relatively high doses, but not at low doses, of responder cells. NW-BM cells which had MHC haplotypes identical with those of responder cells induced CTL from helper T cell-depleted responder cells, but NW-BM cells which had the third-party haplotype did not. These results showed that the enhancing effects of NW-BM cells of the same MHC haplotype as responder cells might be due to a specific helper effect and the enhancing effect of NW-BM cells of the third-party haplotype might be due to a nonspecific filler effect, which only conditioned the cultured cells. It was also found that, to exhibit the helper effect, NW-BM cells had to possess MHC class II, but not MHC class I, molecules in common with CTL precursors. This study showed that in the induction of CTL, prethymic NW-BM cells had a capability comparable to that of mature helper T cells.

Animals↗

Thy.1lowCD3- cells sorted from nylon wool-passed bone marrow cells can augment the H-2 identical but not non-identical cytotoxic T lymphocyte precursors in mixed lymphocyte cultures.

Thy.1lowCD3- cells obtained from nylon wool-passed murine bone marrow (NW-BM) cells by cell sorting did not express CD4, CD8, or T cell receptor-alpha/beta and -gamma/delta on their cell surfaces. An extremely limited number of B10.BR (H-2k) responder lymph node (LN) cells were stimulated with B10.D2 (H-2d) stimulator spleen cells in cultures containing the minimum required dose of rat T cell growth factor (TCGF). In these cultures, the generation of cytotoxic T lymphocytes (CTL) was very low. B10.BR Thy.1lowCD3- NW-BM cells, added to these cultures, could augment the CTL generation vigorously, but neither B10 (H-2b) nor B10.D2 cells could. When B10 LN cells were used as responder cells in these cultures, B10 Thy.1lowCD3- NW-BM cells could augment the CTL generation, but neither B10.BR nor B10.D2 cells could. Similar findings were obtained when Lyt-2+ cells or Thy.1+L3T4- (CTL precursor) cells sorted from spleen cells were used as responder cells. Both elements, rat-TCGF and Thy.1low CD3- NW-BM cells, were essential for this augmentation of the CTL generation in this culture system because neither one alone could augment generation, and rat-TCGF could be replaced by Thy.1+ Lyt-2- helper T (Th) cells sorted from spleen cells. These findings showed that NW-BM cells could augment CTL precursors in a self-major histocompatibility complex (self-MHC)-antigen restricted manner, and further that both NW-BM cells and Th cells had different and independent functions to induce CTL.

Animals↗

Removal of leukocytes from whole blood and erythrocyte suspensions by filtration through cotton wool. V. Results after transfusion of 1,820 units of filtered erythrocytes.

1,820 units of leukocyte- and platelet-poor erythrocyte suspensions were prepared by filtration through cotton wool. On the average more than 98% of the leukocytes and 90-95% of the platelets could be removed. The red cell recovery was 96%. 97% of the units given to polytransfused patients did not cause febrile reactions. Serological follow-up of future transplantation recipients indicated that the immunization may be avoided by using erythrocyte suspensions of fresh, filtered blood.

Antibodies↗

Effectiveness of red blood cells filtered through cotton wool to prevent antileukocyte antibody production in multitransfused patients.

The effectiveness of red blood cells made leukocyte-free by filtration through cotton wool to prevent the production of antileukocyte antibodies was evaluated in children suffering from Cooley's anemia. Two studies were performed: study I was carried out prospectively in two groups of non transfused patients, one group treated with leukocyte-free filtered red cells, the other with buffy-coat-free packed red cell units. Different types of antileukocyte antibodies were looked for in both groups and the results were compared. In study II the behavior of pre-existing lymphocytotoxic antibodies found in the serum of children previously transfused with standard or buffy-coat-free packed red cell units was followed after the patients had been passed to a program of transfusion with leukocyte-free filtered red cells. Study I showed that none of the patients transfused with leukocyte-free filtered red cell units have produced antileukocyte antibodies, while these could be found in 2/3 of the patients transfused with buffy-coat-free packed red cell units. Study II showed that the repeated transfusion of leukocyte-free filtered red cells to patients who possessed in their serum preformed lymphocytotoxic antibodies did not cause any increase in the potency or spectrum of these antibodies, but was in fact accompanied in some cases by their decrease or disappearance. It is concluded that filtration through cotton is an easy and inexpensive means of preparing leukocyte-free red blood cells for transfusion capable of preventing (or reducing) the production of antileukocyte antibodies in multitransfused patients.

Antilymphocyte Serum↗

Lymphocyte purification from normal human peripheral blood by filtration through columns of cotton wool.

With a view to simplifying the separation of haemopoietic stem cell concentrates from human peripheral blood, in preparation for their clinical use, the production of lymphocyte concentrates by cotton wool filtration has been investigated. Using the method which is described in detail, highly purified suspensions may be prepared without the selective loss of thymus-independent lymphocytes. Optimal operating conditions are defined. Haemopoietic stem cell concentrates may thereby be harvested, and are shown to be capable of proliferation and differentiation on subsequent culture in vivo.

Cell Separation↗

The incidence of dystocia in fine-wool Merino ewes.

The mean incidence of dystocia in 1,510 fine-wool Merino ewes over a ten-year period was 4.1% of ewes lambing. In the 10 year period, 10% of all neonatal mortality was attributed to dystocia and in only 23% of dystocias was lamb presentation abnormal. The incidence of dystocia was not related to age of ewe. Significantly more ewes experienced dystocia at spring than winter (P less than 0.05) or summer (P less than 0.01) lambings. The mean birth weights of dystocic single and twin born lambs were 4.19 and 3.38 kg respectively. The corresponding birth weights of lambs that did not experience dystocia were 3.69 and 3.00 kg. More ewes experienced dystocia when stocked at 12 or 16 per ha than at 8 per ha (P less than 0.05). Fifty per cent of recorded dystocias occurred in ewes stocked at 16 per ha, 40 per cent at 12 per ha and 10 per cent at 8 per ha. Ewe body weight pre-lambing was not related to the incidence of dystocia but it would appear that weaker ewes are more likely to have a difficult birth than ewes that are stronger and in better condition.

Animals↗

Correlation of natural killer cell activity and clearance of Cryptococcus neoformans from mice after adoptive transfer of splenic nylon wool-nonadherent cells.

Previous reports demonstrate that natural killer (NK) cells inhibit the growth of Cryptococcus neoformans in vitro, but conclusive evidence supporting the effectiveness of NK cells in host resistance to cryptococci is not available. The objective of these studies was to assess the ability of NK cells to clear C. neoformans from the lungs, livers, and spleens of infected mice. CBA/J mice were depleted of NK cells, as well as other natural effector cells, by an intraperitoneal injection of cyclophosphamide (Cy), 240 mg/kg of body weight. One day later, 7.5 X 10(7) nylon wool-nonadherent (NWN) spleen cells, either untreated or treated with anti-asialo GM1 and complement to remove NK cells, were adoptively transferred to Cy-pretreated mice. On day 2 after Cy treatment, the mice were injected intravenously with 2 X 10(4) cryptococci. At 4 and 6 days after Cy treatment, tissues were assayed for NK reactivity, using a 4-h 51Cr-release assay, and for in vivo clearance of cryptococci as reflected by mean log10 CFU per organ. We observed that Cy treatment depleted NK activity against YAC-1 targets and reduced in vivo clearance of C. neoformans from the tissues of infected mice. Additionally, Cy treatment depleted the total lung and spleen cellularity and the total number of peripheral blood lymphocytes when compared with those in normal untreated control mice. Also, spleen weights were significantly decreased in comparison with those of untreated animals 4 days after Cy treatment. Adoptive transfer of untreated NWN spleen cells into Cy-depressed mice restored the NK cell activity which correlated with enhanced clearance of cryptococci from lungs, livers, and spleens. In contrast, treatment of NWN spleen cells with anti-asialo GM1 and complement before adoptive transfer abrogated the ability of these cells to restore NK activity or reduce the numbers of cryptococci present in tissues of infected mice. Taken together, these data indicate that NK cells are the cells effective in diminishing the numbers of cryptococci in tissues of infected mice. Consequently, NK cells may play a role in first-line host resistance against C. neoformans.

Animals↗

The role of axoplasmic transport in the pathogenesis of retinal cotton-wool spots.

Small retinal arterioles in the pig retina were occluded by argon laser photocoagulation and the morphology and topography of the resulting lesions studied by ophthalmoscopy, histology, and electron microscopy. Two days after laser coagulation ischaemic necrosis of the inner retina was observed in the territory of occluded arterioles, and swollen axon terminals packed with cytoplasmic organelles were found in the retinal nerve-fibre layer on the peripheral border of the infarcts and their border nearest to the disc. These swellings gave rise to localised zones of opacification (cotton-wool spots) at the borders of the retinal infarcts, and similar zones developed in relation to the laser burns. Amino-acid uptake and transport in retinal ganglion cells was studied in these animals by autoradiography following an intravitreal injection of tritiated leucine. When 3H-leucine was injected at the same time as laser coagulation and arteriolar occlusion, label became concentrated in the swollen axon-terminals on the peripheral aspect of 2-day-old infarcts but was absent from the terminals on the disc side of infarcts. The accumulation of 3H-leucine and organelles was attributed to interruption of orthograde axoplasmic transport. When 3H-leucine was injected into the vitreous 2 days prior to laser occlusion, label became distributed throughout the axoplasm and then accumulated in swollen axon terminals on both sides of infarcts after a further 2 days. An obstruction to both orthograde and retrograde axoplasmic flow was thus demonstrated. We concluded that cotton-wood spots should be redefined as accumulations of cytoplasmic debris in the retinal nerve-fibre layer caused by obstruction of orthograde or retrograde axoplasmic transport in ganglion cell axons.

Animals↗

A case-control study of lung cancer in a cohort of workers potentially exposed to slag wool fibres.

A cohort of 4841 men were identified as having worked for more than a year at nine slag wool plants. Some of these men were potentially exposed to man made vitreous fibres (MMVF). The vital status of the entire cohort was ascertained to the end of 1989. Of the 504 deaths that occurred between 1970 and 1989, 61 were attributed to lung cancer (cases). Individually matched controls were randomly selected from the remaining deaths. Attempts were made to locate and interview the surviving families of the cases and controls. The families of three lung cancer cases could not be located and no matched controls were found for another three cases. Included in the final analysis were 55 cases and 98 controls. Estimates of individual exposure to MMVF were based on employment records and industrial hygiene surveys. Data on smoking and histories of employment outside the MMVF industry were obtained from telephone interviews and employment records. Relative risks were calculated for cigarette smoking and exposure to MMVF. No increased risk of lung cancer was found associated with exposure to MMVF, and analysis by cumulative fibre exposure did not indicate any trend. As expected, cigarette smoking was found to be responsible for the observed increase in mortality from lung cancer in this group of MMVF workers, and the risk increased with increasing pack-years of cigarette smoking.

Aged↗

Behaviour of sheep-immunoglobulin-bearing and non-immunoglobulin-bearing lymphocytes isolated by nylon wool columns.

The technique of separating lymphocytes on nylon wool columns has been applied to sheep lymphocytes obtained from efferent lymph. The non-immunoglobulin-bearing (sIg-) lymphocytes which pass through the column were MLR-reactive, responsive only to T cell mitogens, and migrated in vivo like T lymphocytes described in rodents. Immunoglobulin-bearing (sIg+) lymphocytes were MLR-non-reactive, responsive to lipopolysaccharide and migrated in vivo like B lymphocytes in rodents. It is considered that the majority of sIg- lymphocytes obtained in this way are T lymphocytes and the majority of sIg+ lymphocytes are B lymphocytes.

Animals↗

Characterization of pig lymphocyte subpopulations by adherence to nylon wool.

The property of adherence to nylon wool was used to separate and characterize pig blood lymphocyte subpopulations. Thymus-dependent null cells proved the least adherent lymphocytes, and B cells, bearing surface Ig or Fc receptor, the most adherent. sIg+ lymphocytes detected by immunofluorescence and by 51Cr release cytotoxicity showed similar frequency and adherence properties. Lymphocytes rosetting with SRBC in PBS or in dextran had similar adherence patterns and showed both non-adherent and adherent components. Lymphocytes bearing major histocompatibility complex (MHC) Ia-like antigens shown by eosin exclusion or 51Cr release cytotoxicity were enriched in the adherent fraction, but also occurred in significant numbers in the non-adherent fraction. Non-adherent Ia+ cells were predominantly sIg- and probably T cells, whereas the adherent Ia+ group included the sIg+ cells and some sIg- cells.

Animals↗

Cotton-wool spots as a sign in leptospirosis (Weil's disease).

A 44-year-old black male presented with fever, myalgia and weakness. He had elevated blood urea nitrogen, creatine phosphokinase and serum glutamic-oxaloacetic transaminase. During the first 6 days of this undiagnosed illness azotemia increased, a pericardial friction rub occurred, and hematuria was present. On the 7th day bilateral subconjunctival hemorrhages, anterior uveitis, and peripapillary cotton-wool spots were noted. This combination of findings suggested leptospirosis, which was subsequently confirmed by specific antibody titers. Therapeutic response was achieved with high-dose systemic steroids.

Adult↗