Febrile neutropenia and refeeding syndrome.

We describe the management of a 4-year-old child with acute lymphoblastic leukaemia (ALL) who presented with febrile neutropenia, Cryptosporidium and subsequently developed refeeding syndrome. Febrile neutropenia is common and can be life-threatening and we highlight the identification of well low-risk neutropenic children with resolved febrile illnesses suitable for early discharge. We also discuss the potential management strategies for Cryptosporidium Refeeding syndrome is not common, but should be considered as a cause of acute inpatient deterioration and is a significant risk, with potential morbidity, in children who have undergone a period of catabolism. This article reviews the current literature and provides useful guidance on these issues.

Intraperitoneal atrial natriuretic peptide attenuates anxiety-related behaviour during alcohol withdrawal in mice.

Converging evidence from both preclinical and clinical studies suggests atrial natriuretic peptide (ANP) as a potential target for treatment of alcohol withdrawal and dependence. Since ANP tightly interacts with hypothalamic-pituitary-adrenocortical (HPA) axis activity, especially the modulation of stress-related anxiety during alcohol withdrawal might mediate these effects. We have now evaluated the anxiolytic activity of intraperitoneal ANP application during alcohol withdrawal in alcohol-habituated mice (C57/Bl6J). Anxiety related behaviour was attenuated during ethanol withdrawal following application of ANP (60 µg/kg) vs. saline. Our results support that anxiolytic effects of ANP mediate ANP-related gene effects with clinical data on withdrawal symptomatology.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer's disease: a multicenter assessment.

OBJECTIVE: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. METHODS: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. RESULTS: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). CONCLUSION: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.

Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus.

Several plasma membrane chloride channels are well characterized, but much less is known about the molecular identity and function of intracellular Cl- channels. ClC-3 is thought to mediate swelling-activated plasma membrane currents, but we now show that this broadly expressed chloride channel is present in endosomal compartments and synaptic vesicles of neurons. While swelling-activated currents are unchanged in mice with disrupted ClC-3, acidification of synaptic vesicles is impaired and there is severe postnatal degeneration of the retina and the hippocampus. Electrophysiological analysis of juvenile hippocampal slices revealed no major functional abnormalities despite slightly increased amplitudes of miniature excitatory postsynaptic currents. Mice almost lacking the hippocampus survive and show several behavioral abnormalities but are still able to acquire motor skills.

Anxiolyticlike effects of atrial natriuretic peptide on cholecystokinin tetrapeptide-induced panic attacks: preliminary findings.

BACKGROUND: Panic attacks induced by administration of cholecystokinin tetrapeptide (CCK-4) have been evaluated as a valuable tool to investigate the neurobiological mechanisms involved in panic anxiety. The rationale to study the effects of natriuretic peptides on the CCK-4 response is derived from observations that atrial natriuretic peptide (ANP) is released during panic attacks in humans and has anxiolyticlike actions in various animal models. METHODS: A double-blind, placebo-controlled design was conducted in 9 patients with panic disorder and 9 similar healthy control subjects. After pretreatment with an infusion of 150 microg of ANP or placebo in random order, each subject received 50 microg of CCK-4. Psychopathological parameters as well as physiological measures were sampled before and after CCK-4 administration. RESULTS: After pretreatment with ANP, the number of CCK-4-induced panic attacks decreased from 8 to 6 in patients and from 5 to 2 in controls. Acute Panic Inventory ratings were significantly reduced in patients after ANP vs placebo pretreatment. Infusion of ANP significantly curtailed the CCK-4-induced release of corticotropin in patients. Heart rate variability analysis indicated a sympathetic stimulation by CCK-4 that was inhibited by ANP in patients and controls. CONCLUSIONS: The present study indicates that ANP exerts anxiolyticlike effects on CCK-4-stimulated anxiety attacks in patients with panic disorder. In addition, ANP produced an inhibition of the hypothalamopituitary-adrenocortical system and sympatholytic effects.

Detection of antibodies against viral capsid proteins of human herpesvirus 8 in AIDS-associated Kaposi's sarcoma.

Sequences of a new herpesvirus with homology to gammaherpesvirinae were recently identified in AIDS-associated Kaposi's sarcoma (KS). Subsequently this novel virus, called KS-associated virus (KSHV) or human herpesvirus (HHV) 8 was detected in classical KS and AIDS-associated body cavity based lymphomas by polymerase chain reaction. In this report major and minor capsid proteins of HHV-8 were molecularly cloned and produced as recombinant proteins in Escherichia coli. Sera from 69 HIV-1 infected patients with KS, 30 HIV-1 infected patients without KS and 106 control individuals were tested by enzyme-linked immunosorbent assay for anti-HHV-8 capsid IgM and IgG antibodies. Sera from four patients were tested over periods ranging from 18 months to 6 years. IgG antibodies directed against HHV-8 capsid antigens were detected in patients with AIDS-associated KS and in some AIDS patients without KS. Seroconversion with IgM and IgG antibodies directed against HHV-8 capsid proteins occurred more than 1 year prior to diagnosis of KS. In a considerable portion of KS patients no IgM or IgG antibodies against HHV-8 capsid proteins were detected. In these patients there was an inverse relationship between antibodies against HHV-8orf26 and the CD4/CD8 ratio, suggesting that the inconsistency of anti-HHV-8orf26 antibodies is due at least partly to an impaired immune response. No reactivity against HHV-8 capsid antigens was detected in the vast majority of sera from HIV-negative control individuals. Our findings indicate that a specific humoral immune response against capsid proteins is raised in HHV-8 infected individuals, and that anti-capsid antibodies can be used to diagnose HHV-8 infection. The correlation between occurrence of anti-HHV-8 antibodies and KS supports the hypothesis of a causative role of HHV-8.

Suicide attempts with mirtazapine overdose without complications.

BACKGROUND: One important aim of pharmacotherapy in depressed patients is the prevention of suicide attempts. Therefore, the medication given should be efficient and safe in overdose. RESULTS: We saw two patients after they had overdosed with mirtazapine because of suicidal intention. Both patients had taken 30 and 50 times a normal daily dose and achieved a full recovery without any complications or harm. CONCLUSIONS: Mirtazapine seems to be a safe compound in overdose. Therefore, it is an important therapeutic agent in depressed and suicidal patients.

Leptin: a modulator of alcohol craving?

BACKGROUND: Leptin has been shown to regulate food intake and energy expenditure. Because leptin acts via regulation of appetite, we studied the hypothesis that suggests leptin modulates craving for alcohol as well. METHODS: We studied leptin plasma concentrations (RIA) both in alcoholic subjects during inpatient detoxification (day 1: n = 78, day 14: n = 60) and in healthy control subjects (n = 30). To rule out interference with the activation of the HPA axis during alcohol withdrawal, we also evaluated cortisol plasma levels (RIA). RESULTS: We found plasma leptin and cortisol elevated at onset of withdrawal, decreasing significantly up to day 14. Leptin (and the body-mass corrected ratio leptin/BMI) was highly correlated with self-rated craving. No correlations of craving with cortisol and BMI were observed. CONCLUSIONS: We suggest that leptin may modulate withdrawal-induced craving in alcoholic subjects.

Phenotype and function of lamina propria T lymphocytes.

Lamina propria T cells have a low expression of the CD45RA antigen and a high expression of the CD45RO antigen. This phenotype is characteristic for memory T cells (table 2). In addition, T cells in the effector compartment of the mucosa bear surface antigens which are very rarely found in other sites of the immune system. Intestinal T cells also express functional IL-2 receptors and IL-2 receptor alpha chain mRNA, and are able to synthesize high amounts of IL-2. However, another marker of memory T cells, CD29, is not expressed in high density in the lamina propria indicating that lamina propria T cells differ from 'classical' memory T cells. This is supported by functional studies in nonhuman primates infected rectally with C. trachomatis which show that lamina propria T cells do not proliferate after stimulation with antigen but rather provide helper function for immunoglobulin synthesis (table 2). The intestinal lamina propria therefore contains highly specialized T cells which have a distinctive phenotype and are activated. Functionally these T cells can be characterized as differentiated effector lymphocytes which respond to triggering the antigen-specific T cell receptor by secreting helper factors for B cells. This concept is supported by recent studies showing that the pattern of lymphokines produced by lamina propria T cells and the responsiveness to certain lymphokines differ from those of other lymphocyte populations [25]. Lamina propria T cells thus represent a subset of memory T cells with a unique maturational state.

Effects of a potassium-sparing/thiazide diuretic combination on cardiovascular reactivity to vasopressor agents.

The vascular effects of a diuretic combination (spironolactone/altizide) were studied in 5 anuric patients undergoing dialysis by measuring changes in cardiovascular reactivity to norepinephrine (NE) and angiotensin II (AII) after infusion of incremental doses of these 2 vasopressor agents. There was a marked dose-response relation between NE and AII administration and mean (NE) or diastolic (AII) blood pressure (BP). Diuretic treatment moderated the increase in mean or diastolic BP induced by NE or AII. In addition, the pressor doses of NE and AII, which are also parameters of vascular reactivity, were significantly increased after diuretic treatment (NE, +101%; AII, +163%). Right atrial and pulmonary capillary wedge pressures increased along with BP in response to NE. Diuretic treatment also moderated the increase in right atrial and pulmonary capillary wedge pressures induced by NE. These results suggest that the antihypertensive action of spironolactone and altizide in combination is mainly due to a direct effect on resistance and capacitance vessels. The mechanisms by which diuretics modify the cardioreactivity remain poorly understood; however, they may modify electrolyte transport (sodium and calcium) across vascular smooth muscle cell membranes or stimulate prostaglandin release.

Dose-related cardiovascular effects of spironolactone.

The aim of this study was to assess the short-term hemodynamic effects of increasing doses of spironolactone (25, 50, and 75 mg/day) on oliguric patients (5 men, mean age 47 +/- 12 years) undergoing hemodialysis for chronic renal impairment. Parameters of interest included heart rate (HR), cardiac output, systemic vascular resistance (SVR), arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure (PCWP). The study also evaluated how spironolactone modified the effects on arterial and right atrial pressures and PCWP of infusion of increasing doses of norepinephrine (20, 40, and 100 ng/kg/min) and angiotensin II (2, 4, and 10 ng/kg/min). Compared with placebo, the lowest dose of spironolactone (25 mg/day) produced statistically significant (p < 0.05) modifications in systemic arterial pressures without a compensatory increase in cardiac output. The modifications were more pronounced at 50 and 75 mg/day, and the latter had a significant dose-dependent effect. Moreover, doses of 50 and 75 mg/day produced significant (p < 0.05) decreases in right atrial pressure and PCWP. Spironolactone administration caused the curve expressing the relation between an infused norepinephrine or angiotensin II dose and the blood pressure response to shift significantly (p < 0.05 to < 0.01) to the right, and the pressor doses of norepinephrine or angiotensin II showed a significant (p < 0.05 to < 0.01) dose-related increase, suggesting that treatment with spironolactone inhibited cardiovascular reactivity. This effect was observed on both the capacitance (i.e., low-pressure) and resistance (i.e., high pressure) vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Long term effects of sustained release verapamil on the renal and systemic haemodynamic parameters in hypertensive patients with mild to severe chronic renal failure.

Calcium antagonists such as verapamil are among the antihypertensive agents categorised as first line treatments for essential hypertension. They have also shown efficacy in secondary forms of hypertension, including hypertension associated with chronic renal failure, irrespective of the degree of renal impairment. Systemic and renal haemodynamic parameters, and renal function were analysed in 15 hypertensive patients with mild to severe chronic renal failure after a 2-week placebo period and after 4 weeks of administration of verapamil sustained release (SR) 240 mg/day. After 4 weeks of treatment with verapamil SR, blood pressure was normalised in all patients. Arterial pressure decreased as a result of the decrease in systemic vascular resistance, while cardiac output and heart rate remained unchanged. Verapamil therapy did not significantly affect left cardiac function curves. The normalisation of arterial pressure did not result in changes in the glomerular filtration rate; however, renal vascular resistance decreased significantly, although the filtration fraction remained unchanged. Renal blood flow increased significantly and there was a significant increase in uricosuria and a subsequent decrease in plasma uric acid levels. In conclusion, verapamil SR is an effective and well tolerated treatment for hypertension associated with chronic renal failure.

Development and properties of a monoclonal antibody specific for human ecto-5'-nucleotidase.

After immunization with purified human placental ecto-5'-nucleotidase and fusion, 18 different hybrids were obtained which produce an antibody inhibitory for enzyme activity. These antibodies show complete cross-reactivity with the enzyme in a membrane-bound form or on the surface of intact cells. After cloning and ascites production, the antibody of one clone ( IFH - 5N1 ) was studied in greater detail. The IFH - 5N1 antibody is of the IgG 1 subclass. Optimal enzyme inhibition is 90% for purified 5'-nucleotidase and 80% for the enzyme on lymphoblasts. The specificity of this antibody is further demonstrated by enzyme inhibition assays and fluorescence labeling using various 5'-nucleotidase-positive and -negative human cells such as peripheral blood lymphocytes, leukemic cells, lymphoblastoid B- and T-cell-lines and fibroblasts. The antibody should provide a useful tool for the diagnosis of certain forms of acute leukemias and for the study of normal human lymphocyte subpopulations.

C-type natriuretic peptide exerts stimulatory effects on the corticotropin-releasing hormone-induced secretion of hormones in normal man.

C-type natriuretic peptide and atrial natriuretic peptide have been reported to bind to distinct receptors and to exert opposing effects on different systems. Although it is known that atrial natriuretic peptide inhibits the corticotropin-releasing hormone-stimulated hormone release in man, the corresponding action of C-type natriuretic peptide has so far not been characterized. We investigated the effects of 30-min infusions of 150 and 300 micrograms C-type natriuretic peptide on adrenocorticotropin, cortisol, and prolactin release stimulated by 100 micrograms corticotropin-releasing hormone and on cardiovascular parameters in 8 healthy male volunteers. Compared with placebo, 300 micrograms C-type natriuretic peptide significantly (P < 0.05) enhanced the stimulation of cortisol (area under curve (arbitrary units): 520 +/- 35 vs 651 +/- 55) and prolactin (area under curve: 29 +/- 3 vs 37 +/- 5). Adrenocorticotropin levels were increased, but the differences did not reach statistical significance (maximum increment: 27 +/- 4 vs 36 +/- 2 pg/ml). C-type natriuretic peptide at a dose of 150 micrograms had no clear effect on these hormones and C-type natriuretic peptide also produced no cardiovascular or subjective effects. Our data suggest stimulatory effects of C-type natriuretic peptide on corticotropin-releasing hormone-induced hormone release and offer further evidence for a complex role of different natriuretic peptides in endocrine regulation.

Ultrastructure of psoriatic epidermis.

The ultrastructure of human affected and unaffected psoriatic epidermis was studied in skin biopsies from 5 patients and 3 normal controls. Transmission electron microscopic investigations revealed abnormalities in all cell layers of the affected epidermis. Common to psoriatic keratinocytes from affected epidermis was the reduction of tonofilaments. The essential ultrastructural changes were located in the stratum granulosum and stratum corneum. Thus, absence of the fusion between the keratohyalin granules and the tonofilaments was found in stratum granulosum. The keratinocytes of the stratum corneum showed a large accumulation of ribosomes and vesicles resembling lipid vesicles.

An electron microscopic study of clinical Paget's disease of the nipple.

An ultrastructural study of the epidermis from eight patients with clinical Paget's disease of the nipple supports the epidermotropic theory. There was no evidence that the Paget's cells originated from keratinocytes. We propose the hypothesis that Paget's cells represent transformed ductal cells, from the subjacent lactiferous ducts of the nipple, which have migrated into the epidermis, either as neoplastic cells or as normal ductal cells with secondary in situ transformation in the epidermis.

Clinical profile of ioversol. A metaanalysis of 57 randomized, double-blind clinical trials.

RATIONALE AND OBJECTIVES: The authors characterize the clinical profile of ioversol, specifically in terms of radiographic efficacy and clinical tolerance. METHODS: Metaanalysis of data from all available randomized, double-blind trials, comparing ioversol with other nonionic contrast media in indicated procedures was conducted. A total of 3854 adult patients were studied (1931 ioversol, 1923 reference) from 57 clinical trials. RESULTS: Ioversol was considered diagnostic in 99.3% of examinations, with good to excellent enhancement quality in 89.3% of cases. In comparative evaluations, there was a 24% odds reduction of the investigator's nondiagnostic judgment and a 15% odds reduction of poor to fair quality in favor of ioversol. For tolerance, 20.2% and 3.3% of patients in the ioversol group reported moderate to severe sensation of heat and pain with a 10% odds reduction and a 3% odds increase, respectively. The incidence of drug-related adverse events was low: 76 (3.3%) patients in the ioversol group and 62 (2.9%) patients in control group. No statistically significant differences were noted. CONCLUSION: Based on these findings, the high-contrast efficacy and patient tolerance make ioversol a suitable agent, equivalent to other nonionic contrast media.

Influence of clonidine on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide in patients with panic disorder.

The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide (CCK-4) was characterized. Patients with panic disorder (DSM-III-R) were given 50 micrograms CCK-4 i.v. at 1100 hours on 2 separate study days. In a randomized double-blind design they were additionally infused with 150 micrograms clonidine or placebo from 1040 to 1110 hours. After CCK-4 all patients experienced symptom attacks. No effects of clonidine on panic psychopathology or blood gas parameters were observed. After CCK-4, in the clonidine condition the pituitary release of adrenocorticotropin (ACTH) and prolactin was seemingly enhanced compared to placebo. Our results suggest that CCK-4-induced panic attacks are not suppressible by presynaptic alpha-2 receptor stimulation. Moreover, they point to a synergistic postsynaptic action of clonidine to CCK-4 upon pituitary hormone secretion. The diverging sites of action might possibly explain the discrepancies of psychopathological alterations and stress hormone secretion.

Increased plasma ammonia may inhibit cellular release of branched-chain amino acids in systemic portal encephalopathy.

Plasma amino acid patterns were determined before and after hemofiltration (HF) and hemodialysis (HD) in 6 patients with portal systemic encephalopathy (PSE) and compared with the plasma AA patterns of 16 patients with chronic renal failure (CRF) treated either by HF or HD. The branched-chain amino acids (BCAA) increased paradoxically in PSE patients during HF but not with HD. There were no differences in BCAA's with HF as compared to HD in the CRF patients. The amount of amino acids lost was the same with both treatment modalities and in both patient groups. Much of the amino acids lost were released from the intracellular space. The BCAA release was significantly higher in PSE patients during HF. No correlation was found between plasma insulin, glucagon, and cortisol levels and BCAA release. An inverse correlation was found between the amount of BCAA's released from the intracellular space and the plasma ammonia levels. It is suggested that a selective cellular transport mechanism for BCAA exists which is inhibited by high plasma ammonia levels in PSE.