Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer's disease-nested case-control study.

We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer's disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer's disease. INTRODUCTION: To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer's disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. METHODS: LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005-2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0-30 days' time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. RESULTS: Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77-0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1-3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71-0.83) and hip fracture (aOR 0.68, 95% CI 0.60-0.78). CONCLUSIONS: Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.

Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease-a nested case-control study.

BACKGROUND: Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory. AIM: To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community-dwelling persons with Alzheimer's disease. METHODS: In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N = 4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N = 19 235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30 days before the index date), and cumulative duration of use during 10 years before was investigated with conditional logistic regression. RESULTS: Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (<1 year) (adjusted OR 1.23, 95% CI 1.10-1.37). CONCLUSIONS: The increased risk of hip fracture was evident only in short-term proton pump inhibitor use, but no association was found for long-term or cumulative use. Thus, our findings do not support previous assumptions that long-term proton pump inhibitor use would be associated with an increased risk of hip fractures.

Exposure to soluble nickel in electrolytic nickel refining.

Past and present exposure to nickel was studied in an electrolytic nickel refinery, where an increased incidence of nasal cancer had been reported, using nickel analyses in air, blood and urine. Genotoxic effects were studied using analysis of micronuclei from acridine orange-stained smears from the buccal mucosa of the workers. Workers used respirators or masks in tasks where the exposure was expected to be high. Inside the mask, nickel concentrations were 0.9-2.4 micrograms m-3 in such tasks. In those tasks where masks were not used, nickel concentrations in the breathing zone were 1.3-21 micrograms m-3. Air-borne nickel concentrations (stationary sampling) varied between 230 and 800 micrograms m-3 in 1966-1988 with no systematic change; thereafter lower concentrations (170-460 micrograms m-3) have been observed. After-shift urinary concentrations of nickel were 0.1-2 mumol l-1; they showed no correlation with nickel concentrations in the air. Concentrations of nickel in the urine were still elevated after a 2-4 week vacation. The frequency of micronucleated epithelial cells in the buccal mucosa of nickel refinery workers was not significantly elevated by comparison with referents. No relationship was observed between micronucleus frequencies and levels of nickel in air, urine or blood.

The abdominal diameter index and sudden coronary death in men.

Alternative anthropometric indexes were compared for their ability to discriminate between 35 Atlanta men with sudden coronary death and 81 male controls. With or without adjustments for age, race, and body mass index, the abdominal diameter index (supine sagittal abdominal diameter divided by midthigh circumference) was associated with sudden coronary death more strongly than the waist/hip ratio or waist/thigh ratio of circumferences.

Histiocytoid cardiomyopathy and sudden death.

We present a case of histiocytoid cardiomyopathy resulting in sudden and unexpected death in a 4-month-old infant with Peter's Anomaly and congenital glaucoma. At autopsy, the granular histiocytoid cells that define this entity were found predominantly involving the conduction system, with encasement and partial replacement the His' Bundle. Large aggregates of these cells formed atrioventricular and nodoventricular connections, indicating a possible mechanism for the arrhythmias characteristic of the condition. The striking propensity for involvement of the conduction system in this case lends further support to the view that this disorder represents a developmental anomaly of the Purkinje cell system of the heart.

Hamartomatous malformation of the left ventricle associated with sudden death.

We describe unusual left ventricular cardiac lesions in a 17 year old boy who died suddenly during exertion. These consisted of two grossly evident regions of deficient myocardium, containing cavernous spaces which represented exaggerated intertrabecular regions of the left ventricular cavity. Dense fibro-elastotic tissue was deposited around these spaces along with a variable admixture of mature adipose tissue, fibrous tissue and blood vessels. The etiology of these presumably congenital developmental abnormalities is obscure. The lesions most probably represent a hamartomatous malformation, which is a poorly documented pathological entity.

Murder-suicide in Fulton County, Georgia, 1988-1991. Comparison with a recent report and proposed typology.

Our study of the characteristics of murder-suicide in Fulton County, Georgia is compared with published data, and the usefulness of a proposed typology for classifying murder-suicides is evaluated. Twelve murder-suicides involving 26 decedents occurred in Fulton County (Atlanta), Georgia, during 1988-1991. Similar to national statistics, most offenders were male (100%), there was usually one victim (83%) who was most often female (71%), a spousal or love relationship often existed between the victim and offender (64%), and a firearm was the lethal weapon in almost all incidents (92%). Important differences from published data included a higher incidence of murder-suicide (0.46/100,000), which accounted for a lower proportion of all homicides (1.4%) and a higher proportion of all suicides (3.6%) than is reported nationally, and a lower proportion of white offenders (17%) and higher proportion of male victims (29%). A total of 83% of incidents were intraracial. Murder-suicide in Fulton County was different from national data in ways that might be due to local demographics, the local homicide rate, and the local suicide rate. The proposed typology for classification of murder-suicides is in need of more precise definitions of terminology; further, it does not permit inclusion of some major details that might be useful for study. An alternative classification scheme is offered that enables documentation of more comprehensive information.

Spontaneous coronary artery dissection causing sudden death. Mechanical arterial failure or primary vasculitis?

A previously healthy 36-year-old woman died suddenly, and autopsy examination disclosed dissection of the left anterior descending coronary artery with luminal occlusion. A periadventitial inflammatory infiltrate consisting predominantly of eosinophils and including histiocytic multinucleated giant cells was present. The syndrome of spontaneous coronary artery dissection is a rare but well-described clinicopathologic entity. The pathogenesis and, specifically, the significance of the periarterial inflammation, has been controversial. The findings in our case, as well as in others reported in the literature, suggest a primarily mechanical process inciting a localized inflammatory reaction, rather than a primary vasculitis.

Melioidosis. Forgotten, but not gone!

Melioidosis, infection by the soil bacterium Pseudomonas pseudomallei, has the potential for prolonged latency with recrudescence into an acute, often fulminating, and fatal infection. Although the organism is never found in North America, infection is endemic in areas of southeast Asia, and populations of service personnel exposed during the Vietnam war and southeast Asian immigrants are at risk of severe recrudescent disease. Diagnosis, however, has been missed or delayed because of lack of familiarity with this disease. We present a case of recrudescent melioidosis that illustrates the difficulties encountered in diagnosis and treatment. This case involves a 76-year-old Vietnam veteran who presented with melioidosis of the bone 18 years after exposure to the organism and 10 years after a missed diagnosis of latent pulmonary disease. This case illustrates the protean nature of latent infection and the difficulty of selecting successful antibiotic therapy.

Mortality among sulfide ore miners.

Lung cancer mortality was studied during 1965-1985 in Outokumpu township in North Karelia, where an old copper mine was located. Age-specific lung cancer death rates (1968-1985) were higher among the male population of Outokumpu than among the North Karelian male population of the same age excluding the Outokumpu district (p less than .01). Of all 106 persons who died from lung cancer during 1965-1985 in Outokumpu township, 47 were miners of the old mine, 39 of whom had worked there for at least three years and been heavily exposed to radon daughters and silica dust. The study cohort consisted of 597 miners first employed between 1954 and 1973 by a new copper mine and a zinc mine, and employed there for at least 3 years. The period of follow-up was 1954-1986. The number of person-years was 14,782. The total number of deaths was 102; the expected number was 72.8 based on the general male population and 97.8 based on the mortality of the male population of North Karelia. The excess mortality among miners was due mainly to ischemic heart disease (IHD); 44 were observed, the expected number was 22.1, based on the general male population, and the North Karelian expected number was 31.2 (p less than .05). Of the 44 miners who died from IHD, 20 were drillers or chargers exposed to nitroglycerin in dynamite charges, but also to several simultaneous stress factors including PAHs, noise, vibration, heavy work, accident risk, and working alone. Altogether 16 tumors were observed in the cohort. Ten of these were lung cancers, the expected number being 4.3. Miners who had died from lung cancer were 35-64 years old, and had entered mining work between 1954 and 1960. Five of the ten lung cancer cases came from the zinc mine (1.7 expected). Three of them were conductors of diesel-powered ore trains. The slight excess mortality from lung cancer could be explained by exposure to radon daughters and by the combined effect of silica dust and diesel exhaust gases in the zinc mine.

Differences of T-cell activation by the anti-CD3 antibodies Leu4 and BMA030.

Two anti-CD3 antibodies and their Fab/F(ab')2 fragments were compared with regard to their requirement for secondary signals and generations of intracellular messengers. The anti-CD3 antibody BMA030 was found to require monocyte contact to elicit T-cell mitogenesis. Cross-linking by plastic-bound goat anti-mouse antibodies (panning) failed to activate T cells, even in the presence of recombinant IL-1 or IL-2. In contrast, crosslinking of the anti-CD3 antibody Leu4 or Leu4 fragments was mitogenic in monocyte-free cultures. Measurements of intracellular Ca2+ ([Ca2+]i) and generation of inositol phosphates revealed that binding (+/- panning) of BMA030, Leu4, and their F(ab')2 fragments generated similar amounts of intracellular messengers and thus failed to explain the different responsiveness to passive crosslinking. Since the generation of these messengers was not necessarily followed by proliferation but was always observed when mitogenesis occurred, we conclude that the elevation of [Ca2+]i and the production of inositol phosphates are required but not sufficient to trigger mitogenesis.

T cell reactivity to penicillin: phenotypic analysis of in vitro activated cell subsets.

Patients with penicillin allergy demonstrate a T cell proliferative response after in vitro stimulation with penicillin G (Pen G) and other beta-lactam antibiotics. To understand better penicillin-allergic reactions, T cell subset stimulation with Pen G was studied and compared with other soluble (tetanus toxoid and purified protein derivative [PPD]) and membrane-bound viral (influenza A and Epstein-Barr viruses) antigens. A double fluorescence method for flow cytometry was used to evaluate the activated cells simultaneously by pyronin Y staining of RNA and by indirect immunofluorescence of cell surface T4, T8, or Leu 8 antigens. The antigens used stimulated mainly the T4+ subset (greater than 90%), whereas the number of activated T8 cells was slightly increased only in Pen G- and influenza A-triggered cultures (5% to 15%). Leu 8 antigen was used to analyze more precisely the activated T4+ cells. Pen G and influenza A and Epstein-Barr viruses stimulated both T4+, Leu 8+ (greater than 50% of activated cells, inducers for suppressor cells), and T4+, Leu 8- (helpers for B cells) subsets, whereas PPD activated mainly T4+, Leu 8- subpopulations. These results indicate that penicillin-allergic patients with skin symptoms demonstrate a T cell subset stimulation that resembles more the reaction versus viral antigens (membrane incorporated) than to soluble antigens like PPD. These results suggest that Pen G is presented to T cells like viral proteins and might thus cause allergic reactions resembling skin symptoms observed in viral diseases.

Different effects of IL-2 addition or antibody crosslinking on T-cell subset stimulation by CD3 antibodies.

The effect of exogenous recombinant interleukin-2 (IL-2) or of antibody crosslinking on the activation of human T-cell subsets by IgG2a (OKT3/BMA030), IgG1 (Leu4 and UCHT1), or IgG2b (BMA031) anti-T3 antibodies (CD3) was investigated. In so-called nonresponder cultures as well as in monocyte-depleted cell cultures addition of IL-2 increased the CD3-induced activation and proliferation of T4 and T8 cell subsets. Relatively more T8 than T4 cells were stimulated by antibody binding and IL-2. Crosslinking the cell-bound CD3 antibodies by plastic bound goat anti-mouse antibodies activated both T-cell subsets optimally and increased the IL-2 production of the IgG1-CD3 stimulated cultures. The data show that T cells (T8 greater than T4) can be stimulated by CD3 antibody binding and IL-2, but that crosslinking the cell-bound CD3 antibodies is crucial for optimal T4 cell stimulation and IL-2 production.

Cyclosporine facilitates B-cell membrane immunoglobulin capping.

The immunomodulatory molecule cyclosporine was found to cause an early acceleration of the capping of mouse B-cell membrane immunoglobulin. This was most marked when the capping process was slightly retarded by keeping the cells at 32 degrees. This is a sign that the drug can cause B-cell membrane alterations. At lower drug doses they might not be as easily detected, but are nevertheless sufficient to inhibit the activation of some B cells by membrane immunoglobulin clustering.

Characterization of T8 epitopes by enzymatic digestion, crossblocking, and involvement in cell-mediated lympholysis.

Eleven monoclonal antibodies, directed versus the T8 glycoprotein, were compared using enzyme digestion, phylogenetic comparisons, cross-blocking of antibody binding, and blocking of specific cell-mediated lympholysis (CML). It was found that none of the 11 anti-T8 antibodies tested define the same epitope on the T8 glycoprotein. Some of these antibodies react, however, with closely related structures, as shown by cross-blocking of antibody binding and similar enzyme sensitivity of the epitopes. Moreover, these structural related epitopes show a similar involvement in the effector phase of CML reactions, since the antibodies to these neighboring epitopes inhibit the same CML reactions. Thus, it is possible to apply structural and functional criteria to define "regions" on the T8 glycoprotein, some of which are consistently involved in CML reactions, some never, and some of these regions appear to be involved in specific effector-target cell combinations only.

Interference of cyclosporin with lymphocyte proliferation: effects on mitochondria and lysosomes of cyclosporin-sensitive or -resistant cell clones.

Cyclosporin was previously shown to interfere with--but not to abolish--the increased activities of lysosomes and mitochondria consequent to a mitogenic activation of normal mouse lymphocytes. This was evident from the fluorescence profiles of cell populations after vital staining with euchrysine (giving a lysosomal-specific red fluorescence) and rhodamine-123 (giving a mitochondrial-specific green fluorescence). Fluorescence profiles of the population of cells not exposed to a mitogen were also altered by cyclosporin, with lower lysosomal and mitochondrial fluorescence of these cell populations. In order to find out more precisely what could be the direct effects of cyclosporin on those cellular organelles, our cyclosporin-sensitive (BE7) and cyclosporin-resistant (LB7) lymphoblastoid cell lines were tested and showed clear-cut differences. Only minor effects could be detected for the lysosomal and mitochondrial activities of the resistant cells. On the contrary, cyclosporin caused, in the cells of the sensitive clone BE7, a clear decrease of mitochondrial activity together with an unexpected increase of the red fluorescence of euchrysine. The latter might not correspond to a real increase of the lysosomal activity of such cells. Indeed electron microscopy studies do not show higher numbers of lysosomes; rather they show that numerous vacuoles appear in the cytoplasm of the cyclosporin-treated BE7 cells (but not in the cells of the resistant clone and not in untreated cells of either types).

Interference of cyclosporin with lymphocyte activation maintenance of the cells in a non-cycling phase and with a low intracellular pH.

Cyclosporin can block T cell activation by mitogens as evidenced by inhibition of exogenous thymidine integration into DNA and by blockage of the cells in the G0/G1 phase of the cell cycle. The mitogenic activation sequence shows at least one cyclosporin sensitive step at or prior to the rise of cytoplasmic pH (pHi), which normally occurs after exposure to mitogen and which seems to be a permissive condition for initiation of DNA synthesis (S phase of the cell cycle).

Interference of cyclosporin with lymphocyte activation: blockage of the mitogen-induced increases of lysosomal and mitochondrial activities.

Mouse lymphocytes were activated by a mitogenic dose of concanavalin A and analysed by flow cytometry to monitor the increases of mitochondrial activity (using rhodamine 123 as probe) and of lysosomal activity (using euchrysin [acridine orange] as probe). Cyclosporin A-treated lymphocytes were not capable of responding to concanavalin A in the same way as untreated lymphocytes: both the increased uptakes of rhodamine 123 by mitochondria and of acridine orange by lysosomes were strongly diminished, though not abolished. Cyclosporin may thus interfere at a step of activation prior or concurrent to those early changes of lymphocyte physiology. It looks like that it allows mitogen-activated cells to go through part of the mitochondrial maturation which precedes initiation of nuclear DNA synthesis, after which the cells remain blocked at that incomplete maturation level.

Cytoplasmic lipid droplets as the possible eventual cellular fate of active forms of cyclosporin.

The activity of cyclosporins can be defined with regard to their ability to inhibit the proliferation of susceptible lymphoblastoid cell clones. All active cyclosporins cause the emergence of highly refringent globular bodies, independently of cell susceptibility to cyclosporin. Cyclosporins devoid of proliferation-inhibition capability do not cause such alterations in cell morphology. The use of dansylated active cyclosporins suggests that within a few hours of treatment in vitro, most if not all cyclosporin is contained within those globular bodies. By using cytochemical methods allowing differential staining, we show here that these cyclosporin-containing structures are neither normal mitochondria (shown by use of rhodamine 123) nor normal lysosomes (shown by use of acridine orange under stringent staining conditions) but most probably lipid droplets (shown by use of perylene and various dansylated hydrophobic probes).