Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor

Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.     

The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus,and their distribution in immature rats

We studied the potential of both stereoisomers of 17-[¹²³I]iodovinyloestradiol (E- andZ-[¹²³I]IVE) and of 11-methoxy-17-[¹²³I]iodovinyloestradiol (E-andZ-[¹²³I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17-[¹²³I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their¹²³I-labelled analogues were studied in immature female rats. All four 17-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE E-IVE. Neither of these 17-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[¹²³I]MIVE being higher than that ofE- andZ-[¹²³I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [¹²³I]MIVE. The uterus-to-blood uptake ratio was higher for^E-[¹²³I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [¹²³I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[¹²³I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.     

Loperamide

In castor oil challenged rats, low doses of loperamide inhibit diarrhea and normalize intestinal propulsion. Unlike other opioids, loperamide is devoid of central opiate-like effects, including blockade of intestinal propulsion, up to the highest subtoxic oral dose. Nevertheless, the antidiarrheal action of loperamide can be considered to be -opiate receptor mediated, only a fewin vitro effects at rather high concentrations being not naloxone-reversible. There is little evidence that interactions with intestinal opiate receptors directly change epithelial cell function. When secretory stimuli increase mucosal tension, however, loperamide may reverse the elevated hydrostatic tissue pressure that opposes normal absorption. This antisecretory effect at the mucosal level is accompanied by motor effects when loperamide reaches the myenteric -opiate receptors. At therapeutic doses for the treatment of acute diarrhea, it is likely that the mucosal effect prevails.     

Four and a half years experience with a vertical flow sterile enclosure

Summary During the use of a vertical flow enclosure of our own design for almost five years, bacteriological studies and the infection rates in different groups of patients have taught us the following:1. In a clean room operating theatre, the use of a respired air exhaust system improves the sterility compared with the use of ordinary masks. In a vertical flow enclosure, the chest, the arms, and the hands of the team are contaminated from respired airborne bacteria if helmets, etc., are not worn.2. In our vertical flow enclosure with almost continuous absolute sterility of the air, the infection rate in primary total hip replacement is very low and less than 1%, including early and late infections. Antibiotics have not been used.In secondary surgery, i.e., total hip replacement in hip joints previously operated upon, the infection rate is markedly higher, probably because of a flare-up of latent infection.Clean room surgery therefore, can only prevent air borne contamination, and no more; but this is very valuable.3. Vertical flow enclosures of the Charnley-Howorth (1975) and Weber et al. (1971) type provide considerable improvement in sterility of the air compared with adaptations of more conventional theatres. We recommend that these facilities be made available for implant surgery. It is also necessary to have a stringent operational policy with cooperation and discipline on the part of all members of the theatre team.

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Résumé Durant l'utilisation, depuis plus de 5 ans, de la serre stérile à flux laminaire vertical que nous avons construite, nous avons pratiqué des études bactériologiques et pu comparer les taux d'infection suivant les groupes de patients.1. Dans une salle d'opération propre, la stérilité est considérablement améliorée par le port de casques possédant un système d'aspiration de l'air expiré, ceci par rapport au port de masques ordinaires. De plus, si l'on ne porte pas le casque dans une serre à flux laminaire vertical, le tronc, les mains et les membres supérieurs de l'équipe chirurgicale sont contaminés par les microbes en suspension dans l'air expiré.2. Dans notre serre où l'air est pratiquement stérile, le taux d'infections précoces et tardives est inférieur à 1% dans les arthroplasties de la hanche, et cela sans utilisation d'antibiotiques.Lors d'interventions dites secondaires, c'est-à-dire dans les cas déjà opérés au préalable, par exemple par ostéotomie, ostéosynthèse, etc., le taux d'infection est plus élevé. On doit probablement en rechercher la cause dans une contamination de la plaie lors de la première intervention, l'infection alors à l'état latent pouvant se réveiller à la faveur d'une nouvelle opération.En opérant dans une serre stérile, on peut donc prévenir la contamination par l'air ambiant, mais pas plus. Cela est cependant déjà très appréciable.3. Comparées aux salles d'opération conventionnelles modernes, les serres stériles à flux laminaire vertical, comme celle de Charnley-Howorth (1975) et Weber-Meierhans (1971), améliorent considérablement la stérilité de l'air. Surtout pour la chirurgie prothétique de la hanche, dont les risques d'infection sont élevés, nous recommandons l'emploi de ce genre d'installation. Mais il est nécessaire que tous les membres de l'équipe chirurgicale adoptent des règles très strictes de discipline.

     

Chloride:phosphate ratio with hypercalcemia secondary to thiazide administration

The chloride:phosphate ratio is of only limited value in aiding the clinician in the differential diagnosis of hypercalcemia. The use of thiazide diuretics may cause hypercalcemia with a chloride:phosphate ratio said to be consistent with a diagnosis of primary hyperparathyroidism. Parathormone assay remains the "gold standard" for definitive diagnosis of hyperparathyroidism.     

An evaluation of interventions designed to stimulate physician reporting of adverse drug events

A frequent complaint among health care professionals about ADE reporting programs is that they never know what happens to the information they took the time and effort to report. In the Mississippi ADE program, physicians appreciated the feedback they were provided--in letter form--indicating the ultimate disposition of the reported information. Also, a regular newsletter summarizing the number and types of reports and the drugs involved was well received. This vehicle was also used to educate physicians about new drugs on the market that warranted closer scrutiny. Reminder posters placed at strategic points around the hospital and periodic inservices on the program are effective in maintaining a level of awareness about the importance of ADE monitoring and its impact on the quality of care.