Thermal tolerance in juvenile King George whiting (Sillaginodes punctata) reduces as fish age and this reduction coincides with migration to deeper colder water.

Heat shock proteins (HSPs) are sensitive and readily produced under thermal stress in many fish species and thus serve as a useful stress bio-indicator. Two experiments were conducted to test the hypothesis that King George whiting (KGW) Sillaginodes punctata approaching sexual maturity exhibits a decrease in HSP production and that exposure to high temperatures provokes HSP production in juvenile whiting. Both adult and juvenile whiting expressed significant increases in HSP69 in response to temperature shocks of 24, 26, 28 and 30 °C. Juvenile whiting had significantly higher HSP69 than adults and expressed more HSP69 at 24 and 26 °C. No mortalities were observed in juvenile fish at 30 °C while 50% of adults suffered mortality at 30 °C. Following exposure of juveniles to 24, 26 and 28 °C, HSP69 was measured at 24, 96 and 168 h. HSP69 peaked at 96 h and returned to the 24h level after 168 h exposure. This study indicates that juveniles can cope with high temperatures better than adults, which offers a partial explanation to fish movement patterns in nature where younger fish inhabit near shore waters and then migrate to deep water towards maturation. Further, this work implies that KGW growth and recruitment can be affected by increasing temperatures due to global warming.

In vitro and in Vivo inhibition of immunoglobulin secretion by the immunosuppressive compound HR325 is reversed by exogenous uridine.

The objective was to demonstrate that the immunosuppressive agent HR325 (an inhibitor of dihydroorotate dehydrogenase, DHODH) inhibits immunoglobulin (Ig) secretion both in vitro and in vivo and that this effect can be reversed with exogenous uridine. In vitro, Ig secretion from mouse splenocytes was induced by lipopolysaccharide (LPS) for 5 days. HR325 inhibited the secretion of IgM and IgG with IC50 values of 2.5 and 2 microm, respectively. Adding uridine (50 microm) increased these values to 70 and 60 microm, respectively. Similarly, the IC50 values of another DHODH inhibitor, brequinar sodium, were also attenuated by uridine from 0.04 to 1 microm for IgM, and 0.012 to 10 microm for IgG. HR325 (and a structural analogue A771726) inhibited LPS-induced kappa light-chain cell surface expression on 70Z/3 cells, a property also reversed by uridine. In vivo, the secondary anti-sheep red blood cell (SRBC) antibody response (unaffected by uridine alone) was inhibited by HR325 and brequinar with respective ID50 values of 38 and 0.6 mg/kg per oral (p.o.). Immunosuppression with HR325 (50 mg/kg) and brequinar (1 mg/kg) was abrogated by uridine. Uridine had no effect on cyclophosphamide-induced (10 mg/kg p.o.) immunosuppression. These data are consistent with the immunosuppressive mechanism of HR325 being the result of pyrimidine depletion in vitro and in vivo.

Dual mechanisms of action of interferon-gamma in potentiating responses to LPS in mice: IL1, TNFalpha and IL6 production in serum and hypothermia.

IFNgamma potentiates the production of serum cytokines and mortality induced by LPS, but these responses do not change in parallel, and the underlying mechanisms are not clear. Pretreatment of mice with 15 microg rrIFNgamma intraperitoneally (IP) resulted in potentiation of LPS-induced serum cytokine production and hypothermia, but these changes depended on the pretreatment time and did not occur in parallel. TNFalpha and IL1beta levels showed peak potentiation after 8-h-IFNgamma pretreatment which may result from a process of sensitization of mechanisms involved in LPS responses. IL6 levels were most markedly potentiated after 3- and 6-h-IFNgamma-pretreatment and hypothermia was markedly potentiated after 0-8 h pretreatments. These effects may result from an additional synergistic action of IFNgamma with other mediators when it is present at significant levels earlier after its injection, given that IFNgamma had little (hypothermia) or no effect (cytokines) alone. The degree of potentiation induced by 18-h-IFNgamma pretreatment was related to the dose of LPS, the maximum response having been increased. Two injections of IFNgamma at 42 and 18 h prior to LPS induced greater increases in TNFalpha and IL1beta production than 18-h pretreatment alone, but not in IL6 production or hypothermia. There may be a maximum level of IL6 production which was surpassed under these conditions. These findings suggest that a balance of sensitizing and synergistic actions of IFNgamma with other mediators such as IL1 and TNFalpha, are the major mechanisms underlying its potentiation of LPS responses in mice.

Selective enhancement of LPS-induced serum TNF-alpha production by carrageenan pretreatment in mice.

1. Bacterial lipopolysaccharide (LPS)-induced increases in serum cytokines (TNF-alpha, IL-1 and IL-6) and hypothermia were studied in mice sensitized by carrageenan pretreatment and compared with mice sensitized with heat-killed P. acnes or IFN-gamma, all given IP at appropriate intervals (24 hr, 7 days and 12-18 hr, respectively) before LPS. 2. In mice with localized peritoneal inflammation induced by carrageenan, peak TNF-alpha levels (1.5-2 h after LPS) were markedly enhanced after both doses of LPS tested (50 and 200 microg/mouse IP). However, IL-1beta levels were not changed and IL-6 levels were decreased only after the higher dose of LPS. Hypothermia showed weak and inconsistent changes in carrageenan-sensitized mice. 3. IL-1beta levels in spleen lysates were higher but paralleled those in the serum, being increased in IFN-gamma-sensitized but not in carrageenan-sensitized mice. The levels of both TNF-alpha and IL-1beta were high in the peritoneum of carrageenan-sensitized mice, suggesting that the increased serum TNF-alpha did not emanate from the peritoneum. 4. In mice sensitized with the other two agents, as expected, the levels of all three cytokines increased, but peak levels were attained at the same times post-LPS (TNF-alpha: 1-1.5 hr; IL-1: 3-4 hr; IL-6: 3-4 hr). In addition, hypothermia was increased with both of these methods of sensitization. 5. The lack of consistent correlation of the levels of cytokines studied, particularly TNF-alpha, with the degree of hypothermia, raises questions as to their causative role in its induction in these models. 6. The mechanisms underlying these models of sensitization are clearly different, and further understanding of these mechanisms would aid in the interpretation of the effects of drugs in the models.

Hypothermia as an indicator of the acute effects of lipopolysaccharides: comparison with serum levels of IL1 beta, IL6 and TNF alpha.

1. Hypothermia was investigated as a parameter indicating the severity of the acute effects of lipopolysaccharides (LPS) in BALB/c mice, and was compared with the induction of serum levels of IL1 beta, TNF alpha and IL6. 2. Hypothermia induced by low doses of LPS (10-50 micrograms/mouse IP LPS E. coli 0111:B4) peaked at 2 hr after LPS and then either plateaued (50 micrograms) or declined. LPS, 100 and 300 mu, induced greater degrees of hypothermia that plateaued or continued to increase with time for 8 hr. Higher doses of LPS induced similar levels of hypothermia until 4 hr but then continued to increase markedly until 8 hr. 3. TNF alpha levels peaked early (1-2 hr) and declined rapidly, IL6 levels peaked at 3 hr and then declined slowly, and IL1 beta levels peaked at 4 hr, declined at lower doses of LPS, plateaued at higher doses and continued to slowly increase at highest doses. 4. The peak levels of the cytokines (IL1 beta up to 4 hr) and hypothermia (4 hr) increased in relation to the dose of LPS and maximum responses were apparently achieved in all cases at 300-1000 micrograms LPS. 5. A similar parallel between hypothermia and induction of cytokines was observed in C57BL6 and OF1 mice, which were good and poor responders to LPS, respectively, and with the more potent Shigella dysenteria LPS in BALB/c mice. 6. In conclusion, hypothermia is a useful parameter for indicating the strength of the acute effects of LPS. Further studies are necessary to determine whether or not the cytokines studied here play a causative role in hypothermia.

Dopamine supersensitivity and hormonal status in puerperal psychosis.

BACKGROUND: We examine the dopamine receptor supersensitivity hypothesis of puerperal psychosis, and explore puerperal changes in the functional sensitivity of this receptor system. METHOD: Dopamine receptor sensitivity was estimated using growth hormone (GH) response to apomorphine challenge following delivery in 37 control women, and 11 deliveries in 10 women at 'high risk' of puerperal psychosis (previous history of puerperal affective or non-puerperal manic psychosis). Tests were on days 4 or 5, 11 or 12 and at six weeks postpartum. RESULTS: Three women developing puerperal psychosis had subsensitive GH responsiveness on day 4. GH response to 67 challenge tests (in control and 'high risk' women) increased between days 4 or 5 and six weeks postpartum (P < 0.05). GH response at six weeks correlated with free thyroxine levels (P < 0.01). CONCLUSIONS: These three cases do not support the stated hypothesis. Hypothalamic dopamine receptor sensitivity increases during the puerperium; thyroxine might influence this.

Clinical clues to the aetiology of puerperal psychosis.

Recent case reports of postpartum psychosis are reviewed, which suggest hypotheses for the aetiology of this disease. The main themes are: The relationship to manic depression. Premenstrual relapse. Prepartum onset. Onset after miscarriage or evacuation of a trophoblastic tumour. Onset after bromocriptine treatment. Attempts to treat this and related psychoses by progesterone. Apomorphine growth hormone challenge tests.

Screening for depression in the medically ill. The future of paper and pencil tests.

Paper and pencil screening tests for depression have never become widely used in the medically ill, despite consensus that a sizeable pool of depression exists in this population. The performance of several self-rating scales in these patients is reviewed, demonstrating that satisfactory screening of depression as defined by standard case criteria can be achieved. It is proposed that it is primarily the absence of clear guidelines for treatment to be used in conjunction with these scales which will make clinicians sceptical of their value. Treatment validation of case criteria is required to demonstrate that screening for depression in medical patients is worthwhile.

Late consolidative radiation therapy in the treatment of limited-stage small cell lung cancer.

Two hundred twenty-three patients were enrolled on this randomized Phase III trial testing the value of late consolidative involved-field radiation therapy in the treatment of limited-stage small cell lung cancer (SCLC). Patients were treated with induction chemotherapy consisting of alternating cycles of procarbazine, vincristine, lomustine, and cyclophosphamide (POCC) and etoposide, doxorubicin, and methotrexate (VAM) for 6 to 9 months. Responding patients were then randomized at 6 or 9 months to chemotherapy alone or to involved-field radiation therapy. All partial and complete responders received prophylactic cranial irradiation. Of the 180 eligible and evaluable patients, 80 (44%) achieved a complete response and 39 (22%) achieved a partial response (overall rate of response, 66%). Actuarial median survival time was 11.6 months, with 16% of patients surviving 2 years and 11% surviving 5 years. Forty-eight patients were randomized to chemotherapy alone (24 patients) versus chemotherapy plus involved-field radiation therapy (24 patients). There were no significant differences in time to progression or survival between those patients receiving or not receiving involved-field radiation therapy. The thorax was the site of first relapse in 58% of patients randomized to chemotherapy alone versus 29% in patients randomized to chemotherapy plus involved-field radiation therapy (P equals 0.042). The major acute toxicity was reversible myelosuppression, and the major late toxicity was chronic central nervous system dysfunction. The authors conclude that the addition of late consolidative radiation therapy to induction chemotherapy in the treatment of limited-stage SCLC is well tolerated and improves local control, but does not improve time to progression or rates of survival.

Folie à deux in Down's syndrome. A case report.

A case of folie à deux in a 29 year-old man with Down's syndrome, whose mother had a paranoid psychosis, is described. Successful treatment of the mother's illness also resulted in full recovery of the son without the need for medication.