Animal models of bipolar mania: The past, present and future.

Bipolar disorder (BD) is the sixth leading cause of disability in the world according to the World Health Organization and affects nearly six million (∼2.5% of the population) adults in the United State alone each year. BD is primarily characterized by mood cycling of depressive (e.g., helplessness, reduced energy and activity, and anhedonia) and manic (e.g., increased energy and hyperactivity, reduced need for sleep, impulsivity, reduced anxiety and depression), episodes. The following review describes several animal models of bipolar mania with a focus on more recent findings using genetically modified mice, including several with the potential of investigating the mechanisms underlying 'mood' cycling (or behavioral switching in rodents). We discuss whether each of these models satisfy criteria of validity (i.e., face, predictive, and construct), while highlighting their strengths and limitations. Animal models are helping to address critical questions related to pathophysiology of bipolar mania, in an effort to more clearly define necessary targets of first-line medications, lithium and valproic acid, and to discover novel mechanisms with the hope of developing more effective therapeutics. Future studies will leverage new technologies and strategies for integrating animal and human data to reveal important insights into the etiology, pathophysiology, and treatment of BD.

Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study.

BACKGROUND: The optimal timing to start androgen deprivation therapy (ADT) in prostate cancer patients with rising prostate-specific antigen (PSA) as the only sign of relapse is unknown. METHODS: We identified men with prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) study who would have been eligible (⩽ cT3aN0M0, primary radical prostatectomy or radiotherapy, PSA relapse as the only evidence of recurrence) for a randomised trial comparing 'immediate' versus 'deferred' ADT initiation. We emulated such trial by assigning patients to the 'immediate' strategy if they initiated ADT within 3 months of PSA relapse and to the 'deferred' strategy if they initiated ADT when they presented with metastasis, symptoms or a short PSA doubling time. We censored patients when they deviated from the assigned strategy and adjusted for this censoring via inverse probability weighting. RESULTS: Of 2096 eligible patients (median age 69, interquartile range 63-75 years), 88% were white, 35% had a Gleason score ⩾ 7, 69% were treated with radical prostatectomy and 31% received radiotherapy only as primary treatment. The mean time from primary treatment to PSA relapse was 37.4 (standard deviation [SD] 34.2) months. Mean follow-up from primary treatment was 91.4 (SD 48.4) months. The adjusted mortality hazard ratio for immediate versus deferred ADT was 0.91 (95% confidence interval (CI), 0.52-1.60), which would be translated into a similar 5-year survival (difference between groups: -2.0% (95% CI: -10.0 to 5.9%). CONCLUSION: Our analysis suggests that prostate cancer patients undergoing immediate ADT initiation within three months after PSA-only relapse had similar survival to those who deferred ADT initiation within 3 months after clinical progression.

The effects of cardiopulmonary bypass on thyroid function in infants weighing less than five kilograms.

Triiodothyronine is an important regulator of cellular metabolism and may have potential use as an inotropic agent. The aim of this study was to determine the effects of cardiopulmonary bypass on thyroid function in infants weighing less than 5 kg. Serial measurements of triiodothyronine, thyroxine, and thyroid-stimulating hormone were made in 10 infants and corrected for the effects of hemodilution. We demonstrated a fall in triiodothyronine and thyroxine levels, with some recovery after 3 to 6 hours. An additional decrease then occurred, reaching a trough at 48 hours (representing a fall of 78% for triiodothyronine and 57% for thyroxine) before hormone levels returned to normal at 5 to 7 days. Thyroid-stimulating hormone concentrations increased and decreased, predating and complementing exactly the changes in triiodothyronine and thyroxine. These results are quantitatively and, for thyroid-stimulating hormone, qualitatively different from those previously reported in adults. In two patients who died, however, and in one who had a particularly difficult postoperative course, no increase in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations was found after a trough had been reached at 48 to 72 hours, which suggests abnormal function at the hypothalamopituitary level.

Fucosidosis in a native-born Briton.

This investigation reports the biochemical findings in a native-born Briton suffering from the adult form of fucosidosis. Alpha-L-fucosidase, alpha-L-iduronidase, and beta-D-galactosidase were studied in cultured fibroblast and leucocytes from the patient with fucosidosis, her maternal grandfather, and several normal controls. A complete lack of alpha-L-fucosidase activity was found in the patient's fibroblasts and leucocytes while the grandfather exhibited a heterozygous level of alpha-L-fucosidase activity in his leucocytes. Excessive excretion of what is very likely to be a fucose-containing sphingolipid was demonstrated in the patient's urine by thin-layer chromatography. Compared with five isoenzyme forms of alpha-L-fucosidase activity in normal leucocytes, cellulose acetate electrophoresis of the patient's leucocytes produced evidence of a single band of slight activity associated with one of the isoenzymes. This residual activity probably accounts for the survival of such patients into adolescence and beyond.

Sudden unexplained death in infancy and hyperimmunization.

Serum immunoglobulin concentrations, predominantly IgM, were raised in 72% of 39 sudden infant death cases, consistent with a state of prolonged or repeated antigenic stimulation.Anti-antibody was found in cases of sudden death significantly more frequently than in ill but living control infants. It is suggested that anti-antibody might participate in fatal anaphylaxis in such cases.

Hypomagnesaemic tetany.

Hypomagnesaemic tetany (hypomagnesaemic tetany with secondary hypocalcaemia) is a rare inherited form of hypomagnesaemia. Initial reports involved affected males only; however, affected females have also been reported. The case of a child with hypomagnesaemic tetany is described, the biochemical and genetic aspects of this condition are reviewed and the importance of the assessment of renal magnesium excretion in patients presenting with hypomagnesaemia is highlighted.

Transcutaneous iodine absorption in infants undergoing cardiac operation.

Povidone-iodine is an effective antiseptic, but its topical use has been associated with a number of adverse reactions in burn patients and in neonates as a result of transcutaneous absorption. In particular, high plasma iodine concentrations are known to cause renal failure, metabolic acidosis, and thyroid suppression. Because of the permeable nature of the skin in small infants and the large areas cleaned before cardiac operations, it is possible that significant transcutaneous iodine absorption might occur in this situation. We have studied 17 infants, less than 3 months of age, who were undergoing closed cardiac or thoracic procedures. After povidone-iodine skin preparation in 15 (covering 20% to 30% of body surface area), plasma total iodine concentrations rose fourfold (range, 160% to 1,440%). This increase was significantly different from the preoperative level at 6, 12, 18, and 24 hours. There was no increase in plasma iodine concentration in 2 patients who were not exposed to povidone-iodine or any other iodine-containing compound. We discuss the implications for a topical antisepsis policy in infants.

Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms.

BACKGROUND: Cardiopulmonary bypass induces a systemic inflammatory response. This study investigated, in a pediatric population, cytokine-induced responses and their potential modification by intraoperative steroid administration. METHODS: Markers of the acute-phase response were measured perioperatively in 24 children weighing less than 10 kg undergoing cardiac operations. Those having operations with cardiopulmonary bypass were randomized to receive either no steroid (group I, n = 8) or 10 mg/kg methylprednisolone in the pump prime (group II, n = 10); patients undergoing nonbypass procedures were controls (group III, n = 6). RESULTS: In all groups, plasma interleukin-6 level was elevated (p < 0.01) above baseline throughout the post-operative period, peaking earlier in group I. Levels of C-reactive protein peaked at 48 hours, and postoperative core temperature was raised in all groups. Levels of interleukin-6 from 2 to 6 hours and C-reactive protein at 24 hours postoperatively were greater (p < 0.05) in group I than in group II. Maximum interleukin-6 level, C-reactive protein level, and temperature were all significantly greater in group I than in group III. Maximum interleukin-6 level correlated with maximum C-reactive protein level in group I only (rs = 0.76; p < 0.05) and showed no association with temperature. Duration of bypass did not correlate with levels of interleukin-6. CONCLUSIONS: This study demonstrated a marked acute-phase response to operation; the greater response to procedures with cardiopulmonary bypass was abrogated by intraoperative steroid administration. The importance of interleukin-6 as an inducer of acute phase proteins after bypass is supported by its association with C-reactive protein levels, but other factors must be important in the induction of pyrexia.

Microprocessor assisted handling of oestrogen receptor assays.

The use of an Apple II microcomputer equipped with a light-pen for interactive analysis of steroid receptor data is described. Processing times have been reduced to less than 5 minutes per patient from around 45-60 minutes by the manual method. Graphical outputs using full and part data sets with derived results are printed for subsequent verification by the Consultant Medical Biochemist. Data processing backlogs have been completely eliminated by this system. The program has, of course, general applicability to any analyses producing a linear correlation between the x and y parameters, and its use in oestrogen receptor analysis is detailed principally because of a considerable and increasing demand for such assays in our department.

A new sensitive microassay for the measurement of erythrocyte glycogen.

Conventional ethanol precipitation of sub-microgram amounts of glycogen leads to low yields (less than 50%). Quantitative recoveries of 90% were attained, however, when the isolation temperature was raised to 50 degrees C and ethanol was replaced by the less polar propan-2-ol. This improvement enabled development of an erythrocyte assay for glycogen which was both sensitive (0.1 microgram glycogen) and required only 1 ml of whole blood. 26 paediatric specimens were analysed and a reference range of values from undetected to 78 micrograms glycogen/g haemoglobin (Hb) was obtained.

Assessment of the AmnioStat-FLM immunoagglutination test for phosphatidylglycerol in amniotic fluid.

One hundred and eight amniotic fluids were assayed by the AmnioStat-FLM (A-FLM) immunological agglutination test for phosphatidylglycerol (PG) and simultaneously measured enzymatically for PG content. Of 52 amniotic fluids found to be PG negative by the A-FLM method, all had enzymatic PG concentrations less than or equal to 1.5 mumol/l. Conversely, of 56 amniotic fluids judged to be either PG positive or weak positive, all but five had enzymatic PG concentrations greater than 1.5 mumol/l. The sensitivity of the A-FLM assay employed clinically for predicting foetal lung maturity was 89% and the specificity was 100%. The overall predictive accuracy of the test could be improved by providing controls at lower, more appropriate PG concentrations. Ninety-one fluids analysed by the A-FLM kit were subsequently tested for the presence of PG by two-dimensional thin-layer chromatography (2D TLC). A 94%-concordance between the methods was found.

Quantitative determination of phosphatidylglycerol in amniotic fluid by enzymatic assay.

Phosphatidylglycerol (PG) was extracted from 54 human amniotic fluids for the assessment of fetal lung maturity. The PG values were derived from an enzymatic assay involving initial conversion of PG to glycerol by phospholipase C and alkaline phosphatase with subsequent analysis of the glycerol formed. This method proved to be reliable when compared with a method for two-dimensional thin layer chromatographic (2D TLC) analysis of amniotic fluid phospholipids. The results revealed that in all but one of 27 amniotic fluids in which no PG was detected by 2D TLC, enzymatic PG concentrations were less than or equal to 1.5 mumol/l and out of these, from 10 newborn infants delivered within 72 h of sampling, 4 developed respiratory distress syndrome (RDS). Conversely, in all but one of 27 amniotic fluids found to contain PG by 2D TLC, enzymatic PG concentrations were greater than 1.5 mumol/l and except for one subject from non-identical twins, no infants developed RDS.

Combined enzymatic assay of phosphatidylglycerol and phosphatidylcholine in amniotic fluid.

We present here a combined, quantitative enzymatic procedure for determining amniotic fluid phosphatidylglycerol and phosphatidylcholine and relate these findings to the assessment of fetal lung maturity. Under the assay conditions described phospholipase C specifically hydrolyses phosphatidylglycerol (PG) and phosphatidylcholine (PC) but not sphingomyelin, precluding the need for removal of sphingomyelin prior to analysis. Solvent extraction of the phospholipids from the amniotic fluid is, however, employed to avoid spurious elevation of PG and PC results by endogenous glycerol and choline. Of 45 amniocentesis fluids examined, 28 yielded detectable PG concentrations (greater than 0.5 mumol/l) and all but three of these exhibited PC concentrations in excess of 10 mumol/l. One case of respiratory distress occurred in an infant of 29 wk gestation with severe intrauterine growth retardation. Of the remaining 17 fluids in which PG was undetected enzymatically (less than or equal to 0.5 mumol/l), 14 also contained PC concentrations less than or equal to 10 mumol/l and all six cases of true respiratory distress syndrome came from within this sub-group. Strong correlations between the PC concentration and the lecithin:sphingomyelin ratio, r = 0.85 (p less than 0.001) and the PC and PG concentrations, r = 0.96 (p less than 0.001) were also found.

Direct gas chromatographic assay of urinary medium-chain fatty acylcarnitines by their thermal decomposition.

We report a gas chromatographic assay for urinary medium-chain acylcarnitines which employs their property of thermal lability, and by circumventing the need for specialised mass spectroscopy is suitable for routine laboratory use. The method produces readily interpreted, uncomplicated chromatograms and has proved to be both sufficiently sensitive and specific to enable detection of octanoylcarnitine in a symptomatic individual with medium-chain CoA dehydrogenase deficiency and in two asymptomatic siblings following administration of a carnitine load.

Renal vein renin measurement and arteriography in the investigation and management of severe childhood hypertension.

Forty-two children aged one to sixteen years with persistent and severe hypertension were investigated by renal vein renin measurements. There were no serious complications in the 49 procedures performed and technical failure occurred on three occasions. Arteriography was performed in 35. Asymmetrical renin release was found in 22 patients and of these 15 underwent surgery. This was successful in 12 patients (80%) who became normotensive. Ten had unilateral disease (100% cure rate) but only 2 (40%) with bilateral disease became normotensive. Renal vein renin studies combined with arteriography have a useful role in the investigation and management of childhood hypertension.

HPLC of phospholipids in biological fluids -- application to amniotic fluid for the prediction of fetal lung maturity.

Because of both the advantage of speed compared with thin layer chromatography (TLC) and the dearth of high pressure liquid chromatography (HPLC) methods for phospholipid separation, it was decided to investigate the use of HPLC with a differential refractometer as detector for the separation and quantitation of amniotic fluid phospholipids required for the prediction of fetal lung maturity. A method was devised which gave results which compared well with those from TLC both in terms of quantitation and predictive value. Despite this, the method was found to lack sufficient reliability for application to the routine clinical assessment of fetal lung maturity. The method does, however, offer a good alternative to two dimensional TLC with phosphate analysis in research work involving quantitation of phosphatidyl inositol, phosphatidyl glycerol and particularly lecithin.

Neonatal endothelin-1 concentrations in term infants.

Endothelin-1 concentrations were studied in 30 term infants during the first week of life using a radioimmunoassay kit. A neonatal reference range was established (7.5-25.7 pmol/l). No significant relation with age, sex, gestation, or birth weight was found.

Infant cerebellar gray and white matter fatty acids in relation to age and diet.

There is little evidence as to the fatty acid composition of the cerebellum in infancy and it remains uncertain whether milk diet can influence its composition. We therefore examined cerebellar gray and white matter of infants less than 6 month old who had died unexpectedly. The fatty acid content of 33 gray and 21 white matter specimens from infants born at term and 6 gray and 5 white matter specimens from preterm infants was assessed by gas chromatographic/mass spectrometric analysis. Infants were grouped according to whether they had received human or manufactured formula milk. Whereas cerebellar cortex docosahexaenoic acid (DHA, 22:6n-3) concentrations were significantly lower (P<0.01) in the formula-fed than breast-fed infants, no differences existed between the term (n = 10) and preterm (n = 5) Synthetic Milk Adapted [corrected] (SMA) formula-fed infants. Cerebellar white matter DHA concentrations were similarly lower (P<0.01) in the SMA formula-fed infants (n = 8) than in an age-matched breast-fed group. Low concentrations of cerebellar white matter lignoceric (24:0) and nervonic acid (24:1n-9) in two 7-wk-old preterm infants appeared to correlate with postgestational rather than chronological age. Dietary long-chain polyunsaturated fatty acids, particularly DHA, are probably essential for normal development of the infant cerebellum.

Measurement of urinary medium chain acyl glycines by gas chromatography--negative ion chemical ionization mass spectrometry.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism, which is difficult to diagnose, partly because of its unpredictable clinical presentation. A specific diagnostic marker is an increased excretion of certain medium chain acyl glycines. A sensitive and specific method has been developed for the extraction, derivatization, identification and quantitation of urinary medium chain acyl glycines by gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICIMS). The following series of standard acyl glycines has been synthesized and characterized: hexanoyl, octanoyl, 3-phenylpropionyl and suberyl and their respective isotopomers (using 13C2-glycine; for use as internal standards). The range of excretion of these compounds in normal subjects has been established using this method and increased excretion of acyl glycines, particularly hexanoyl, 3-phenylpropionyl and suberyl was successfully demonstrated in three MCAD deficient subjects from one family.

Alloxan therapy for nesidioblastosis.

Two patients with nesidioblastosis presented to the Royal Hospital for Sick Children in Glasgow and developed recurrent hypoglycemia after subtotal pancreatectomy. They were treated successfully with alloxan (mesoxalyl urea). Alloxan is recommended as an alternative to further radical surgery.