Reported co-infection deaths are more common in early adulthood and among similar infections.

BACKGROUND: Many people have multiple infections at the same time, but the combined contribution of those infections to disease-related mortality is unknown. Registered causes of death offer a unique opportunity to study associations between multiple infections. METHODS: We analysed over 900,000 death certificates that reported infectious causes of death. We tested whether reports of multiple infections (i.e., co-infections) differed across individuals' age or sex. We also tested whether each pair of infections were reported together more or less often than expected by chance, and whether this co-reporting was associated with the number of biological characteristics they had in common. RESULTS: In England and Wales, and the USA, 10 and 6 % respectively of infection-related deaths involved co-infection. Co-infection was reported reported most often in young adults; 30 % of infection-related deaths among those aged 25-44 from the USA, and 20 % of infection-related deaths among those aged 30-39 from England and Wales, reported multiple infections. The proportion of infection-related deaths involving co-infection declined with age more slowly in males than females, to less than 10 % among those aged >65. Most associated pairs of infections co-occurred more often than expected from their frequency of being reported alone (488/683 [71 %] in the USA, 129/233 [55 %] in England and Wales), and tended to share biological characteristics (taxonomy, transmission mode, tropism or timescale). CONCLUSIONS: Age, sex, and biologically similar infections are associated with death from co-infection, and may help indicate patients at risk of severe co-infection.

Psychiatric consequences of needlestick injury.

BACKGROUND: Needlestick injuries (NSIs) are a common occupational hazard with potential physical health effects, including viral infections such as hepatitis and HIV. Less appreciated are the psychiatric consequences of NSIs, potentially including post-traumatic stress disorder (PTSD) and adjustment disorder (AD). AIMS: To study psychiatric consequences of NSIs by diagnosis, duration and severity of depressive symptoms. METHODS: Case control study from patients referred to a psychiatric trauma clinic diagnosed according to ICD-10 diagnostic research criteria guidelines. The Beck Depression Inventory (BDI) was administered to measure depressive symptomatology and assess differences in depression severity between psychiatric trauma patients who had or had not experienced an NSI, and for relationships between the severity of depression and time since NSI using linear models. RESULTS: There were 17 NSI cases and 125 controls. NSI patients had moderately severe depressive symptoms (mean BDI score 22.7 15), which was similar to 125 non-NSI trauma patients. 13 of these 17 cases had AD and four had PTSD. None contracted infections from their NSI, but most described secondary effects of psychiatric illness on occupational, family and sexual functioning. Severity of depressive symptoms declined with time after NSI, but psychiatric illness lasted 1.78 months longer for every month a NSI patient waited for seronegative test results (P < 0.05). CONCLUSIONS: Enduring psychiatric illness can result from NSIs with a severity similar to other psychiatric trauma. Swift delivery of test results may reduce the duration of depression associated with NSI. Occupational health professionals need to be aware of the psychiatric and physical effects of NSIs.

The hypothermic action of carbachol in the rat brain periaqueductal grey area may involve neurotensin.

Neurotensin (NT) and carbachol both caused hypothermia when injected into the periaqueductal grey area (PAG) of rat brain. Atropine prevented carbachol- but not NT-induced hypothermia. NT-induced hypothermia was unaffected by various neurotransmitter agonists and antagonists in the PAG. Both NT antibodies and thyrotrophin releasing hormone prevented carbachol hypothermia. It is concluded that the hypothermic action of carbachol in the PAG is mediated via endogenous NT.

Effect of thyroid status on the thyrotrophin-releasing hormone-degrading activity of rat serum.

The TRH-degrading activity of rat serum in vitro is five times more potent than that of human serum. In rats, it is significantly reduced in hypothyroidism (thiouracil-induced) and significantly increased in hyperthyroidism (T3 or T4-induced). This suggests a possible role in the regulation of adenohypophysial-thyroid function which is probably, in turn, dependent on thyroid hormone, rather than TSH, levels.

Age-related changes in the degradation of thyrotrophin releasing hormone by human and rat serum.

Changes in the rate of in-vitro degradation of thyrotrophin releasing hormone (TRH) in serum as related to age have been investigated in the rat and man. In rats, no inactivation was found up to the age of 15 days but therafter an age-related increase in inactivation was detected with approximately 75% inactivation in 60 min at 40 days and reaching a maximum of 88-93% inactivation in adult male and female animals. The human serum samples studied (both male and female) showed a similar but less clear-cut pattern of inactivation of TRH compared with that found in the rat. A physiological role for these age-related changes in the degradation of TRH remains to be established but it has been concluded that the changes observed in both rat and man may be associated with growth and development, possibly by facilitating feedback control of thyrotrophin secretion through the degradation of TRH.

Mechanisms of inactivation of hypothalamic regulatory hormones.

The mechanisms of enzymic inactivation of thyrotropin-releasing hormone, luteinizing hormone-releasing hormone and somatostatin, the three fully-characterized hypothalamic regulatory hormones, and the possible physiological significance of the peptidases in neuroendocrine control has been reviewed. Application of the criteria of enzyme location (at the sites of biosynthesis, release, action, elimination and excretion), appropriate biochemical characteristics of the enzymes and changes in enzyme activity in physiological circumstances all suggest that the peptidases can contribute to the mechanisms controlling the hypothalamic hormones' release and actions. Besides their physiological function, the enzymes may also be directly involved in certain pathological conditions. There is evidence to indicate that the enzymes degrading the regulatory hormones may participate in the process of hormone activation as well as inactivation. A continuing investigation of the peptidases may lead to a better understanding of the established endocrine and other putative functions of these hypothalamic polypeptide hormones.

Enzymic inactivation of hypothalamic regulatory hormones.

The considerable expansion in studies on the enzymic inactivation of thyrotrophin-releasing hormone, luteinizing hormone-releasing hormone and somatostatin (growth hormone release-inhibiting hormone) has necessitated a re-evaluation of the peptidase enzymes responsible. Through the use of new methods such as high-performance liquid chromatography and the development of artificial enzyme substrates, it has been possible to clarify the mechanisms of enzyme cleavage of these hypothalamic regulatory hormones and to attempt purification of the peptidases. This has brought about a renewed interest in the physiological significance of the enzymes, as well as their role in biotransformation of the hypothalamic hormones. From such studies, the information gained may be used in the design of agonist and antagonist analogues, as well as providing details of the mechanisms of action of such analogues through their increased stability to enzymic degradation. The characterization of corticotrophin-releasing factor and growth hormone-releasing factor will provide a new field for the application of peptidase inactivation to analogue design. Similarly, future examination of the peptidases inactivating the hypothalamic hormones in certain clinical conditions may give new insight into the significance of the enzymes in pathological conditions. Identification of these enzymes, investigation of their localization, properties and functions and assessment of their contribution to the control of hormone action may yield valuable insight into the physiology and pathology of the hypothalamic regulatory hormones.

Enzymic formation of TRH-OH from TRH by rat hypothalamus.

Specific radioimmunoassays for thyrotrophin-releasing hormone (TRH) and deamido-TRH (TRH-OH) were used to investigate the inactivation of TRH by subcellular fractions from rat hypothalamus. TRH-OH was rapidly formed from TRH by an amidase present only in the supernatant fraction at an optimum pH of 7.38; although TRH was degraded by the particulate fraction, no TRH-OH formation was detected. Of several brain areas investigated, the cortex had the highest rate of TRH-OH production and the pituitary the lowest. Once formed in the supernatant fractions, it was found that TRH-OH was stable and did not undergo further degradation. Formation of TRH-OH from TRH appears to be an important step in the tripeptide's enzymic degradation in the brain, so the combined use of specific radioimmunoassays for TRH and TRH-OH may provide a suitable means for studies of the enzymes involved, since these enzymes may contribute to the mechanisms regulating the secretion and duration of action of TRH.

Hypothalamic inactivation of thyrotrophin-releasing hormone.

Following the demonstration of peptidases in the rat hypothalamus which inactivate thyrotrophin-releasing hormone (TRH), a sensitive and specific radioimmunoassay for the releasing hormone was used to investigate the presence of similar peptidases in the rabbit hypothalamus. TRH was found to be rapidly inactivated by supernatant and particulate hypothalamic fractions, with higher peptidase activity in the supernatant than in the particulate fraction. An optimum pH of 7.3 within physiological limits was obtained for the enzymes in both the fractions examined. The results obtained confirm that the rabbit hypothalamus contains enzymes capable of inactivating TRH, and since it has been found that such peptidases interfere with studies on TRH biosynthesis, it is possible that the peptidases may play a part in controlling the releasing hormone's production. The specificity of the antiserum used in the radioimmunoassay has also suggested that the peptidases may cleave the C-terminal-ProNH2,-NH2 or both from the TRH molecule to cause inactivation.

Body temperature effects of opioids administered into the periaqueductal grey area of rat brain.

The ability of opioids to influence rectal temperature after injection into the periaqueductal grey region (PAG) of rat brain was investigated. Both morphine and beta-endorphin caused a dose-dependent increase in rectal temperature of up to 2 degrees C. By using selective ligands of the subclasses of opiate receptor such as [D-Ala2,D-Leu5]enkephalin for delta-receptors and ethylketocyclazocine, dynorphin(1-17) and dynorphin(1-8) for kappa-receptors, it was possible to show that neither the delta- nor the kappa-opiate receptor was involved in the hyperthermic response. However, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), a mu-receptor ligand, did produce a dose-dependent hyperthermia. The ability of naltrexone, an opiate receptor antagonist, to reverse the hyperthermia induced by beta-endorphin and DAGO suggests that the opioid-stimulated increase in body temperature via the PAG is mediated through the mu-opiate receptor. Since the application of opioids to the PAG produces a hyperthermic response, it is possible that this brain site may have a role in the peptidergic control of body temperature.

Induction of wet-dog shaking in rats by analogues and metabolites of thyrotrophin-releasing hormone (TRH).

The ability of thyrotrophin-releasing hormone (TRH), its metabolites and several analogues to induce wet-dog shaking (WDS) was tested by their injection into the periaqueductal grey region of male rats. TRH and its metabolite deamido-TRH (TRH-OH) both stimulated WDS, though TRH-OH gave a longer duration of response; other TRH metabolites were inactive. Of the TRH analogues studied, RX77368 (pGlu-His-3,3'-dimethyl-ProNH2) was the most potent in this behavioural test system. Both CG3509 and CG3703 were also very active in inducing WDS, as were their deamidated metabolites. The relative stability of the TRH analogues to enzymic degradation in the brain may be related to their enhanced behavioural activity over TRH. The production from these analogues of biologically-active metabolites may also explain the increased activity in stimulating WDS of the parent peptides.

Thyrotrophin-releasing hormone inactivation by human postmortem brain.

The mechanisms of inactivation of thyrotrophin-releasing hormone (TRH) by peptidases in several areas of normal human postmortem brain have been investigated by radioimmunoassay and high-performance liquid chromatography. Of the several brain regions studied, the cerebral cortex (Brodman's area, BA10) had the highest TRH-degrading activity in both subcellular fractions. Deamidated-TRH (TRH-OH) was the only product formed by the soluble fraction whereas the histidyl-proline diketopiperazine, cyclo(His-Pro), and a small amount of TRH-OH were formed by the particulate fraction. Several centrally acting TRH analogues showed varying degrees of resistance to degradation by the peptidases in the two fractions, the most stable analogue being RX77368 (pGlu-His-3,3'-dimethyl(ProNH2]. Areas of human postmortem brain appear to contain two of the enzymes capable of degrading TRH, a proline endopeptidase forming TRH-OH and a pyroglutamyl aminopeptidase forming cyclo(His-Pro). The use of the assay procedures in further studies on the inactivation of TRH by peptidases from brain areas of patients with neurological disorders may provide complementary information on the dynamics of TRH in these disorders. The stability of the centrally acting TRH analogues may prove useful in examining their therapeutic potential.

Mechanisms of brain inactivation of centrally-acting thyrotrophin-releasing hormone (TRH) analogues: a high-performance liquid chromatography study.

High-performance liquid chromatography (HPLC) was used to investigate the degradation in vitro of several centrally-acting analogues of thyrotrophin-releasing hormone (TRH) by two subcellular fractions prepared from different areas of rat brain. Of the seven analogues studied, RX77368 (pGlu-His-(3,3'-dimethyl)-ProNH2) was the most stable analogue, showing only a small amount of degradation by the particulate fraction containing a pyroglutamyl aminopeptidase, whereas the other analogues (RX74355, CG3509, CG3703, [3MeHis]TRH, PGHPA and MK771) showed varying degrees of resistance to degradation by this enzyme and the proline endopeptidase in the soluble fraction. However, TRH was rapidly inactivated to its deamidated form, TRH-OH and the histidyl-proline diketopiperazine by both fractions. The relative stability of these TRH analogues to enzyme action may provide some explanation for their enhanced biological activity in vivo.

Effects of mammalian and avian neurotensins and neurotensin fragments on wet-dog shaking and body temperature in the rat.

The ability of mammalian and avian neurotensins and some neurotensin fragments to reduce wet-dog shaking (WDS) induced by thyrotrophin-releasing hormone (TRH) and to influence rectal temperature was tested after their injection into the periaqueductal grey region of male rats. Both neurotensins inhibited TRH-induced WDS and reduced rectal temperature by 2 degrees C; this latter effect was prevented by prior TRH administration. Of the four neurotensin fragments tested, both (1-8)- and (8-13)-neurotensin reduced WDS but only (8-13)-neurotensin reduced rectal temperature significantly. (1-6)- and (1-11)-neurotensin were without effect in either test system. From the activity of the various peptides, further examples of the mutual antagonism between TRH and neurotensin have been demonstrated. It is suggested that there is a possible role for neurotensin in controlling body temperature via the periaqueductal grey and that this may be one function of neurotensin in avian species; there may also be more than one receptor system binding neurotensin in the brain.

Mechanism of neurotensin degradation by rat brain peptidases.

Neurotensin is degraded by peptidases present in soluble and particulate (25000 x g) fractions of rat hypothalamus, thalamus, cortex and pituitary, the soluble fraction of the hypothalamus having the highest activity. High performance liquid chromatography and amino acid analysis were used to identify the degradation pathway. The main product in both fractions was [1-8]neurotensin and the corresponding C-terminal fragment [9-13]neurotensin was identified. [1-10]Neurotensin was also identified, proportionately more of this peptide being produced by the particulate rather than the soluble fraction. In the presence of dithiothreitol, [1-7]neurotensin and [1-10]neurotensin were major products particularly in the soluble fraction. These results suggest that the main sites of cleavage of neurotensin by rat brain peptidases are the Arg8-Arg9, Pro10-Tyr11 and Pro7-Arg8 bonds.

Mechanism of luteinizing hormone-releasing hormone degradation by subcellular fractions of rat hypothalamus and pituitary.

The pathway of LH-RH degradation by two subcellular fractions (a soluble fraction and a 25 000 X g particulate fraction) of rat hypothalamus, pituitary and cerebral cortex has been studied using high performance liquid chromatography and amino acid analysis to identify the breakdown products. The primary cleavage point in the Tyr5-Gly6 bond giving [1-5] LH-RH and [6-10] LH-RH. In the presence of dithiothreitol, cleavage of LH-RH also occurred at the Pro9-Gly10 bond giving [1-9] LH-RH. The fragment [1-5] LH-RH is further degraded sequentially from the C-terminus and [1-4] LH-RH, [1-3] LH-RH, tyrosine and tryptophan were identified. The other major fragment, [6-10] LH-RH, is rapidly broken down, the only intermediate product positively identified being Arg-Pro.

The effects of opioids in the periaqueductal grey region of rat brain on hind-limb muscle tone.

A mechanical apparatus was used to measure hind limb resistance to flexion in rats injected with opioid peptides in the brain periaqueductal grey region (PAG). (D-Ala2, D-Leu5) enkephalin (delta agonist) and dynorphin1-8 and ethylketocyclazocine (kappa agonists) had no effects on hind limb tone. The mu agonist (D-Ala2, MePhe4, Gly-ol5) enkephalin induced limb rigidity when injected into the PAG. beta-Endorphin caused a dose-related limb rigidity that persisted for up to 2h. beta-Endorphin rigidity was prevented by pretreatment of rats with the serotonin depletor 5,7-dihydroxytryptamine. It is concluded that mu receptors and serotonin mechanisms in the PAG can mediate opiate rigidity.

Further characterization of the substrate specificity of a TRH hydrolysing pyroglutamate aminopeptidase from guinea-pig brain.

In this study the substrate specificity of a pyroglutamate aminopeptidase from synaptosomal membranes of guinea-pig brain was investigated. The enzyme was found to be specific for tripeptides, tripeptide-amides and tetrapeptides which possess the N-terminal sequence Glp-His and as such is specific for Thyrotropin Releasing Hormone or only very closely related peptides. The enzyme was found not to hydrolyse a number of analogues of Thyrotropin Releasing Hormone which have been shown to have therapeutical value in certain neuronal disorders.

The presence of peptidases in the rabbit hypothalamus capable of inactivating luteinizing hormone-releasing hormone.

The presence of peptidases in the rabbit hypothalamus capable of inactivating luteinizing hormone-releasing hormone (LH-RH) was investigated with the use of a sensitive and specific radioimmunoassay for the releasing hormone. Enzymes acting on LH-RH were found in two fractions from rabbit hypothalami, a particulate fraction and a supernatant fraction, which very rapidly inactivated the decapeptide. Peptidase activity in the particulate fraction from male and female rabbits was approximately the same, but the supernatant fraction from female animals had significantly greater peptidase activity than that from male animals. These findings confirm the hypothesis that rabbit hypothalamus contains peptidases which inactivate LH-RH, and give some indication that the enzymes may be involved in the control by the central nervous system of reproductive function.

Age-dependent changes in the inactivation of thyrotrophin-releasing hormone by different areas of rat brain.

Age-dependent changes in the inactivation of thyrotrophin-releasing hormone (TRH) were investigated in two subcellular fractions prepared from hypothalamus, thalamus, cortex and cerebellum of male rats. It was found that, in both supernatant and particulate fractions from the four brain areas, enzyme activity increased to a peak at 10-25 days of age and then decreased gradually until adult levels were reached. The changes in TRH degradation observed may be related to alterations in hypothalamic TRH content with age and to maturation of the tripeptide's putative neurotransmitter/neuromodulator function.