ObjectiveTo examine the association between classes of antidepressants and hyponatremia, and between specific antidepressants and hyponatremia.DesignRetrospective register-based cohort study using nationwide registers from 1998 to 2012.SettingThe North Denmark Region.ParticipantsIn total, 638 352 individuals were included.Primary and secondary outcome measuresPlasma sodium was obtained from the LABKA database. The primary outcome was hyponatremia defined as plasma sodium (p-sodium) below 135 mmol/L and secondary outcome was severe hyponatremia defined as p-sodium below 130 mmol/L. The association between use of specific antidepressants and hyponatremia was analysed using multivariable Poisson regression models.ResultsAn event of hyponatremia occurred in 72 509 individuals and 11.36% (n=6476) of these events happened during treatment with antidepressants. Incidence rate ratios and CIs for the association with hyponatremia in the first p-sodium measured after initiation of treatment were for citalopram 7.8 (CI 7.42 to 8.20); clomipramine 4.93 (CI 2.72 to 8.94); duloxetine 2.05 (CI 1.44 to 292); venlafaxine 2.90 (CI 2.43 to 3.46); mirtazapine 2.95 (CI 2.71 to 3.21); and mianserin 0.90 (CI 0.71 to 1.14).ConclusionsAll antidepressants except mianserin are associated with hyponatremia. The association is strongest with citalopram and lowest with duloxetine, venlafaxine and mirtazapine.

PACAP is found in human skin and is capable of releasing histamine from skin mast cells.

Binding of the plasma proteinase inhibitor inter-␣-trypsin inhibitor (ITI) to hyaluronan is necessary for normal expansion of the cumulus-oocyte complex. Lack of ITI causes severe infertility. Binding of ITI to hyaluronan depends on calcium ions and coupling activity present in follicular fluid (Ødum et al., 2002). The complexes formed by this process contain ITI heavy chains bound to hyaluronan, and bikunin is detached from ITI during the coupling reaction. In the present study, an electrophoretic technique by which hyaluronan-bound ITI is immobilized was used to demonstrate that tumour necrosis factor stimulated gene 6 (TSG-6) is necessary for the coupling reaction. Thus, immunoprecipitation of TSG-6 in human follicular fluid eliminates the coupling reaction and re-addition restores the activity. However, it appears that components other than hyaluronan, ITI, calcium ions and TSG-6 are involved in the coupling reaction, as in vitro incubation of these components does not generate stable complexes between ITI heavy chains and hyaluronan unless some follicular fluid is added. In conclusion, TSG-6 is necessary for the coupling of ITI to hyaluronan, but at least one additional component in follicular fluid is essential.

In vivo binding of human inter-alpha-trypsin inhibitor to hyaluronate was investigated by immunoelectrophoretic techniques. Pathological synovial fluids and follicular fluids both contain high concentrations of soluble hyaluronate. Heavy chain epitopes of inter-alpha-trypsin inhibitor were firmly associated with the hyaluronate in synovial fluid and follicular fluid. The hyaluronate-bound inter-alpha-trypsin inhibitor epitopes did not cross-react immunologically with bikunin. Several hyaluronate-bound inter-alpha-trypsin inhibitor fragments with molecular masses in the range 120,000-30,000 Da were demonstrated by immunoblotting. Heavy chain 1 of inter-alpha-trypsin inhibitor was shown to associate with hyaluronate by amino acid sequence analysis of isolated hyaluronate-bound proteins. These data indicate that in vivo metabolism of inter-alpha-trypsin inhibitor takes place in pathological synovial fluid and in ovarian follicular fluid shortly before ovulation.

In previous studies we have shown that the gene encoding cholecystokinin (CCK) is expressed in spermatogenic cells of several mammalian species. In the present study we show that a gene homologous to the CCK-related hormone, gastrin, is expressed in the human testis. The mRNA hybridizing to a human gastrin cDNA probe in the human testis was of the same size (0.7 kb) as gastrin mRNA in the human antrum. By in situ hybridization the gastrinlike mRNA was localized to seminiferous tubules. Immunocytochemical staining of human testis revealed gastrinlike peptides in the seminiferous tubules primarily at a position corresponding to spermatids and spermatozoa. In ejaculated spermatozoa gastrinlike immunoreactivity was localized to the acrosome. Acrosomal localization could also be shown in spermatids with electron microscopy. Extracts of the human testis contained significant amounts of progastrin, but no bioactive amidated gastrins. In contrast, ejaculated sperm contained mature carboxyamidated gastrin 34 and gastrin 17. The concentration of gastrin in ejaculated human spermatozoa varied considerably between individuals. We suggest that amidated gastrin (in humans) and CCK (in other mammals) are released during the acrosome reaction and that they may be important for fertilization. (J. Clin. Invest. 1990. 86:660-669.) Key words: activation * cholecystokinin. fertilization -neuropeptide -sperm Introduction The gastrointestinal hormones gastrin and cholecystokinin (CCK)' are homologous. They share an identical carboxyl-terminus Gly-Trp-Met-Asp-Phe-NH2, which contains the active site ofboth hormones (1, 2). The active site homology explains the overlapping spectra ofactivity and suggests that gastrin and CCK are derived from a common ancestor (3). This suggestion is supported by analysis of mammalian gastrin and CCK preprohormone structures (4-9) and by the recent detection of an invertebrate hybrid of mammalian gastrin and CCK (10).

Helicobacter pyloni infection is associated with increased meal stimulated gastrin secretion, but the reason for this is unknown. Sequence specific radioimmunoassays were used to measure the concentration of ot-amidated gastrin, the total progastrin product, and somatostatin in biopsy specimens of human antral mucosa. The antral concentrations of ct-amidated gastrin and of total progastrin products were significantly higher in H pyloni infected patients than in those not infected by this organism. In contrast, the antral somatostatin concentration was significantly decreased in infected patients. Progastrin processing, determined by gel chromatography, seemed unaffected by H pyloni infection. The results suggest that the finding of increased gastrin secretion from the antral G cells in H pyloni infected patients may be a result of reduced inhibition of G-cell secretion by somatostatin.

The expression of gastrin/cholecystokinin (CCK) peptides and their precursors was examined in 16 medullary carcinomas of the human thyroid. Measurements with libraries of sequence-specific radioimmunoassays before and after enzymatic cleavage of extracts and chromatographic fractions showed that the carcinomas contained 1.7 pmol carboxyamidated CCK/g tissue (median; range 0.6-21.8 pmol/g), 0.9 pmol glycine-extended precursor/g (median; range less than 0.2-2.3 pmol/g) and 2.3 pmol further COOH-terminal-extended proCCK/g (median; range 0.9-6.2 pmol/g). Neither carboxyamidated gastrins nor any progastrins could be measured. Gel and reverse-phase chromatography revealed only small molecular forms, i.e. greater than 90% of the amidated immunoreactivity eluted like non-sulphated CCK-8 or CCK-7. The results show that human medullary thyroid carcinomas synthesize CCK peptides. The predominance of non-sulphated CCK is unusual. Taken together with earlier observations from dogs and pigs, our results raise the possibility that small non-sulphated CCK peptides modulate thyroid C-cell secretion in an autocrine manner.

Background: We report our results for the systematic recording of all errors in a standard clinical laboratory over a 1-year period. Methods: Recording was performed using a commercial database program. All individuals in the laboratory were allowed to report errors. The testing processes were classified according to function, and errors were classified as pre-analytical, analytical, post-analytical, or service-related, and then further divided into descriptive subgroups. Samples were taken from hospital wards (38.6%), outpatient clinics (25.7%), general practitioners (29.4%), and other hospitals. Results: A total of 1189 errors were reported in 1151 reports during the first year, corresponding to an error rate of 1 error for every 142 patients, or 1 per 1223 tests. The majority of events were due to human errors (82.6%), and only a few (4.3%) were the result of technical errors. Most of the errors (81%) were preanalytical. Of the remainder, 10% were analytical, 8% were post-analytical, and 1% was service-related. Nearly half of the errors (ns550) occurred with samples received from general practitioners or clinical hospital wards. Identification errors were relatively common when non-technicians collected blood samples. Conclusions: Each clinical laboratory should record errors in a structured manner. A relation database is a useful tool for the recording and extraction of data, as the database can be structured to reflect the workflow at each individual laboratory.