Can dietary supplements improve a clinician's well-being and health?

Many people use dietary supplements to improve their physical and mental well-being and their general health, but do not know if they really have any benefit. To our knowledge, little has been published on their use in the clinical environment, so we evaluated the evidence for their benefits in people whose work is physically and mentally challenging. Studies on nutrition and supplementation in athletes and military personnel have clearly shown that several compounds improve cognition, mental well-being, and physical performance. Based on this evidence, and with the many pressures faced by healthcare workers, as well as the need for concentration and endurance, some dietary supplements might be beneficial. Supplementation of a balanced diet with omega-3 fatty acids, vitamin B3, vitamin C and associated antioxidants, vitamin D, and protein, may improve a clinician's physical and mental health and their performance at work. Specific research is, however, needed to evaluate this more fully.

Uranium toxicity and speciation during chronic exposure to the tropical freshwater fish, Mogurnda mogurnda.

The effects of chronic uranium (U) exposure on larval Northern trout gudgeon, Mogurnda mogurnda, were assessed in two experiments using a newly-developed 28d survival and growth toxicity test. Significant effects were observed in both tests, but toxicity was markedly higher in Test 2 than Test 1. The LC50s for Tests 1 and 2 were 2090microgL(-1) and 1070microgL(-1), respectively. Larval growth IC10s for Tests 1 and 2 were 860microgL(-1) and 660microgL(-1) (dry weight), and 1160microgL(-1) and 850microgL(-1) (length), respectively. Uranium speciation modelling showed that a lower pH in Test 2 (mean of 6.0) compared to Test 1 (mean of 6.7) resulted in a greater proportion of free uranyl ion (UO(2)(2+)), the predominant bioavailable form of U. A higher dissolved organic carbon concentration (DOC) in Test 2 (4.2mgL(-1)) compared to Test 1 (2.1mgL(-1)) resulted in a higher proportion of U-DOC in Test 2, but this was insufficient to counter the effect of pH on the proportion of UO(2)(2+). The difference in U toxicity between the two tests could be explained by normalising for UO(2)(2+); the concentrations of UO(2)(2+) at the LC50s for Tests 1 and 2 were calculated to be 13.3 and 13.7microgL(-1), respectively. Finally, the results of this study, and comparisons with other studies suggest that U toxicity to M. mogurnda appears to be as much, if not more, a function of exposure water quality and feeding regime, as exposure duration.

Noxious somatic inputs to hypothalamic-midbrain projection neurones: a comparison of the columnar organisation of somatic and visceral inputs to the periaqueductal grey in the rat.

The induction of Fos protein was used to localise hypothalamic neurones activated by noxious somatic stimulation. This was combined with retrograde transport of fluorescent latex microspheres from identified 'pressor' and 'depressor' sites in the dorsolateral/lateral or ventrolateral columns of the periaqueductal grey (PAG). Fos-positive neurones were found throughout the rostral hypothalamus. Of those neurones activated by noxious somatic stimuli that projected to the PAG all but one was retrogradely labelled from sites that included the lateral column. Only one neurone was double labelled following injection of tracer at a depressor site in the ventrolateral PAG. This is in marked contrast to visceroresponsive hypothalamic neurones, a larger proportion of which project to the PAG and which, as reported previously, preferentially target depressor sites in the ventrolateral sector. These results are discussed in relation to the roles of the anterior hypothalamus and the different functional columns of the PAG in co-ordinating autonomic and sensory functions in response to nociceptive inputs originating in different peripheral domains.

C-nociceptor activation of hypothalamic neurones and the columnar organisation of their projections to the periaqueductal grey in the rat.

The induction of Fos protein was used to localise hypothalamic neurones activated by ramps of noxious skin heating delivered at a rate of 2.5 degrees C s(-1) to preferentially activate C-nociceptors. This was combined with retrograde transport of cholera toxin subunit B from identified 'pressor' and 'depressor' sites in the dorsolateral/lateral or the ventrolateral columns of the periaqueductal grey. Fos-positive neurones were found throughout the rostral hypothalamus. Despite this wide distribution, those neurones double labelled retrogradely from the periaqueductal grey were focused in the lateral area of the anterior hypothalamus. More than 20 % of Fos-positive neurones in this region projected to depressor sites in the ventrolateral periaqueductal grey, and 10 % projected to its dorsolateral/lateral sector. These results are discussed in relation to the peripheral inputs to hypothalamic-midbrain pathways and their role in the cardiovascular responses to different components of the pain signal.

Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.

To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.

Immunocytochemical localization of GnRH precursor in the hypothalamus of European starlings during sexual maturation and photorefractoriness.

Immunocytochemistry with quantitative image analysis, for both GnRH and its precursor proGnRH-GAP, was used in male European starlings (Sturnus vulgaris) to investigate four stages of a photoperiodically-induced reproductive cycle. Four different groups of birds were examined: photosensitive buy sexually immature, sexually mature, undergoing gonadal regression, and after the completion of regression and fully photorefractory. The size of cells staining for GnRH and proGnRH-GAP increased during gonadal maturation. A reduction in the number of cells staining for GnRH and the size of cells staining for both GnRH and proGnRH-GAP occurred during gonadal regression, though staining for GnRH and proGnRH-GAP in the median eminence remained high at this stage. Birds examined after completion of regression showed significantly reduced staining for both GnRH and its precursor. These observations suggest that photorefractoriness is promoted by a reduction in proGnRH-GAP production and in GnRH synthesis, rather than requiring inhibition of release of GnRH at the median eminence.

Transcutaneous bilirubinometry: its role in the assessment of neonatal jaundice.

OBJECTIVE: To review the literature on transcutaneous bilirubinometry so that its exact role in the prevention of kernicterus or bilirubin encephalopathy could be determined. DESIGN AND METHODS: Literature searches were done in Medline and Current Contents. RESULTS: It is estimated that about 50% of newborns have an episode of jaundice in the first few days of life. Six percent of newborns may develop hyperbilirubinemia (> 220 mumol/L), which can potentially cause bilirubin encephalopathy or kernicterus, a severe neonatal disease. In the past, serum bilirubin (SB) has been the preferred method of detecting hyperbilirubinemia in newborns. The ordering of SB in neonates is based on visual evaluation by either physicians or nursing staff. Skin puncture collection of blood exposes the neonate to trauma and risk of infection. A noninvasive device for predicting serum bilirubin levels in newborns diminishes the need to do skin punctures. One such device that has been very extensively studied is the Minolta AirShields Jaundice Meter. It is a portable light-weight instrument that uses reflectance measurements on the skin to determine the amount of yellow color present in the skin, namely transcutaneous bilirubin (TcB). Although the TcB measurements correlate well with serum bilirubin (SB) levels, they cannot accurately predict serum bilirubin because of error related to a variety of factors. CONCLUSIONS: TcB cannot be used directly to make decisions about transfusions or phototherapy in neonates. It is a good tool for screening neonates to determine when a laboratory measurement of serum bilirubin is needed. Such a practice requires careful selection of the decision level so that false-negative TcB values do not prevent appropriate serum bilirubin tests from being done.

Clinical impact of transcutaneous bilirubinometry as an adjunctive screen for hyperbilirubinemia.

OBJECTIVE: To determine what the clinical impact would be of implementing a jaundice meter for use in a busy neonatal service as an adjunctive screening tool for hyperbilirubinemia. DESIGN AND METHODS: Test utilization data was collected for a 6-month period to determine how neonatal bilirubin was utilized in this hospital. The jaundice meter was evaluated in a study population of healthy term infants. The performance characteristics of the meter and the test utilization data were used to predict the clinical impact a meter could have on screening for hyperbilirubinemia. RESULTS: Utilization data indicated that about 60% of all single bilirubin neonatal testing (i.e., bilirubin only ordered) was done by normal nurseries. A jaundice meter cutoff decision reading of 17 was shown to have a sensitivity of 100% and a specificity of 68% for hyperbilirubinemia (> 260 mumol/L) in a study population of healthy term infants. From this data, it was estimated that use of a jaundice meter could eliminate 43% of the single (i.e., not combined with other tests) bilirubin tests done on healthy term neonates with no prior exposure to phototherapy. This constitutes an overall 20% reduction in bilirubin testing in normal nurseries when testing done on babies exposed to phototherapy and combined bilirubin testing are taken into consideration. Additionally, it was shown that there would be an improvement of 9% in the prediction of hyperbilirubinemia without loss of 100% sensitivity. CONCLUSION: Use of a jaundice meter in normal nurseries as an adjunctive screening tool enhances patient care by reducing the overall blood procurement rate in normal nurseries by 20% and increasing screening efficiency for significant hyperbilirubinemia by 5%.

Glutamatergic projections from the rostral hypothalamus to the periaqueductal grey.

Retrograde transport of fluorescent latex microspheres was combined with immunocytochemistry for glutamate to determine the organization of the projections from glutamate-containing neurones in the rostral hypothalamus to the different subdivisions of the periaqueductal grey (PAG). Double-labelled neurones, i.e. neurones immunoreactive for glutamate and projecting to the PAG, were found throughout the rostral hypothalamus. There were no apparent differences, however, in the origins of presumed glutamatergic projections from the rostral hypothalamus to the different subdivisions of the PAG.

Structure and function of desmosomal transmembrane core and plaque molecules.

Desmosomes are intercellular junctions that function in cell-cell adhesion and attachment of intermediate filaments (IF) to the cell surface. Desmogleins and desmocollins are the major components of the transmembrane adhesion complex, whereas desmoplakins (DPs) are the most prominent components of the cytoplasmic plaque. Based on sequence similarity, desmogleins and desmocollins are related to the calcium-dependent homophilic adhesion molecules known as cadherins. Like the classical cadherins, the desmosomal cadherins contain four homologous extracellular domains bearing putative calcium-binding sites, a single transmembrane spanning domain, and a C-terminal cytoplasmic tail. Molecules in the desmoglein subclass contain a unique C-terminal extension within which is found a repeating motif that is predicted to form two beta-strands and two turns. Stable cell lines expressing desmoglein 1 have been generated from normally non-adherent L cell fibroblasts, to study the contribution of this cadherin to desmosomal adhesion. The predicted sequence of desmoplakin (DP) I suggests it will form homodimers comprising a central alpha-helical coiled-coil rod and two globular end domains. The C-terminus contains three regions with significant homology, each of which is made up of a 38-residue motif also found in two other molecules involved in organization of IF, bullous pemphigoid antigen and plectin. Ectopically expressed polypeptides including the C-terminus of DP I specifically align with keratin and vimentin IF in cultured cells, whereas those lacking this domain do not align with IF. The last 68 amino acids of DP are required for alignment along keratin but not vimentin IF, and residues 48-68 from the C-terminal end are critical for this interaction. These results suggest that the C-terminus of DP plays a role in the attachment of IF to the desmosome and that a specific site is necessary for interaction with keratin IF. A sequence at the most N-terminal end of DP appears to be required for efficient incorporation into the desmosomal plaque. Interestingly, this region has not been reported to be present in the homologous bullous pemphigoid antigen or plectin molecules and may represent a desmosomal targeting sequence.

Ultrastructural evidence for changes in synaptic input to the hypothalamic luteinizing hormone-releasing hormone neurons in photosensitive and photorefractory starlings.

Neural input to the hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons was investigated in male starlings (Sturnus vulgaris) using electron microscopy combined with immunocytochemistry. Birds (4 to 6 in each group) were sampled at four stages of a photoperiodically induced reproductive cycle: (a) sexually immature but photosensitive, under short days; (b) during sexual maturation after 7 to 25 long days; (c) during gonadal regression after 35 to 50 long days; and (d) when fully photorefractory after 11 months exposure to long days. The length of the perikaryal membrane, the number and length of axo-somatic terminals in contact with it and the number and length of synaptic modifications within the terminals were measured for a minimum of six LHRH neurons in each brain. The number of axo-somatic terminals per neuron and the number per unit length of perikaryal membrane did not differ in birds of groups (a), (b) and (c), but was significantly greater (P < 0.05) in the fully refractory birds (group d). Similarly, the number of synaptic modifications was significantly greater (P < 0.05) in group (d) than in the other groups. These results are consistent with increased neural input to the LHRH perikarya in photorefractory birds after prolonged exposure to long days, although there was no indication of a change in input at the time of gonadal regression.

Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.

BACKGROUND: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS: To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS: The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

PIP: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15-50% despite antimalarial therapy. In order to determine whether combining iron chelation with quinine therapy speeds recovery of consciousness, the authors conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be under age 6, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they cannot be aroused. Deferoxamine (100 mg/kg of body weight/day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pryimethamine. The time to recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 time that among the 41 who received the placebo (95% confidence interval [CI], 0.7-2.3; the median time to recovery was 20.2 hours in the deferoxamine group, and 43.1 hours in the placebo group (p=0.38). Among 50 patients in deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95% CI, 1.1-4-7), decreasing the median recovery time from 68.2 to 24.1 hours (p=0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95% CI, 1.2-3.6). Among all 83 patients, mortality was 17% in the deferoxamine group and 22% in the placebo group (p=0.52). It is concluded that iron chelation therapy may speed the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia.

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.

Photoperiodic control of the development of the LHRH neurosecretory system of European starlings (Sturnus vulgaris) during puberty and the onset of photorefractoriness.

The development of the reproductive system was studied in juvenile starlings during the acquisition of photosensitivity, the attainment of sexual maturation after photostimulation and the subsequent onset of photorefractoriness, using immunohistochemistry for LHRH and radioimmunoassay measurements of hypothalamic, pituitary and plasma hormone concentrations. The first stage of sexual development induced by exposure of photorefractory immature starlings to short days (8 h light:16 h darkness; 8L:16D) was characterized by a decrease in pituitary prolactin content within 1 week and an increase in hypothalamic LHRH content, in the size of the LHRH perikarya and in the intensity of immunostaining in the median eminence in 4-6 weeks. Sexual maturation occurring after exposure to long days (18L:6D) was associated with further increases in LHRH content and cell size, and increases in LH and prolactin concentrations. During testicular regression, LHRH perikarya were reduced in size and staining intensity but LHRH immunostaining in the median eminence and content in the hypothalamus remained high until gonadal regression was almost complete. Prolactin levels were maximal during testicular regression. These results suggest that gonadal regression is initiated by a reduction in LHRH synthesis and possibly, in addition, an external inhibitory influence on LHRH release. Hypothalamic LHRH content eventually declined and LHRH immunostaining in the median eminence was much reduced in fully photorefractory starlings maintained under long days.

Identification of oenanthotoxin and related compounds in hemlock water dropwort poisoning.

The case histories are presented of three separate incidents of poisoning by ingestion of Hemlock Water Dropwort tubers (Oenanthe crocata). Two of these cases involved a fatality. An analytical profile is provided for oenanthotoxin, the major toxic principal of the tubers. Chromatographic, spectroscopic and mass spectral data for related compounds are also given.