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.

A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI.

OBJECTIVES: Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory. DESIGN, SETTING AND PARTICIPANTS: For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized. INTERVENTION: Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo. MEASUREMENTS: The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog. RESULTS: After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status. CONCLUSION: In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease.

OBJECTIVE: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). METHODS: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. RESULTS: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aß(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. CONCLUSIONS: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

Amyloid beta peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing.

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

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.

[Neuroendocrine tumors of the stomach (gastric carcinoids) are on the rise: good prognosis with early detection]. / (Neuro-)Endokrine Tumoren des Magens sind auf dem Vormarsch: Gute Prognose bei frühem Nachweis.

Neuroendocrine tumors (NET) of the stomach are on the rise. In the United States they have increased about tenfold in the last 35 years. Prognosis has been much improved over the last three to four decades. Nowadays most of such NETs are diagnosed at an early stage. Quite often gastric NETs are found incidentally during a gastroscopy, performed for other reasons. Most of the asymptomatic, well differentiated gastric NETs are less than 2 cm in diameter. Conservative management and endoscopic surveillance is adequate for well differentiated, multifocal type 1 or type 2 gastric NETs (gastric carcinoids) of 10-20 mm , unless they are angio-invasive, have infiltrated into the muscularis propria or have metastasized. Endoscopic ultrasound is the method of choice to determine tumor size and depth of infiltration. Surgery is, however, indicated for all NETs larger than 20 mm. For optimal management tumor biology, type and stage of the neoplasm as well as the individual situation of the patient have to be taken into account. Most of the patients can be treated conservatively and be followed up with endoscopic surveillance.

A multicenter (1)H-MRS study of the medial temporal lobe in AD and MCI.

OBJECTIVE: The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnetic resonance spectroscopy ((1)H-MRS) studies have provided consistent evidence for a reduction of the neuronal marker N-acetylaspartate (NAA) in patients with AD. Within the German Competence Network on Dementia, we conducted a (1)H-MRS study in patients with mild dementia and mild cognitive impairment (MCI) at four sites to investigate the multicenter feasibility of (1)H-MRS. METHODS: In total, 130 patients with dementia (98 AD, 32 non-AD), 136 subjects with MCI (70 of AD type, 66 of non-AD type), and 45 unimpaired control subjects were included. Single-volume (1)H-MRS of the left medial temporal lobe was performed at long and short echo times. Metabolites were quantified and metabolic ratios were determined. RESULTS: We found a significant reduction of NAA concentration in patients with AD as compared to healthy volunteers and compared to patients with MCI of AD type. NAA/Cr (creatine/phosphocreatine) was also lower in patients with AD compared to control subjects. NAA, choline compounds, and Cr were lower in patients with AD compared to patients with non-AD dementia. CONCLUSIONS: We demonstrated the multicenter feasibility of proton magnetic resonance spectroscopy ((1)H-MRS) of the medial temporal lobe in mild dementia and mild cognitive impairment, which is a prerequisite for the application of (1)H-MRS in large-scale clinical trials. Since the concentration measures of the metabolites are adjusted for brain tissue volume, these findings are indicators of biochemical pathology beyond brain atrophy.

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.

Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli.

BACKGROUND: In the course of inflammatory bowel diseases (IBD) and acute murine ileitis following peroral Toxoplasma gondii infection, commensal Escherichia coli accumulate at inflamed mucosal sites and aggravate small intestinal immunopathology. AIM: To unravel the molecular mechanisms by which commensal E coli exacerbate ileitis. METHODS: Ileitis was investigated in mice that lack Toll-like receptors (TLR) 2 or 4, specific for bacterial lipoproteins (LP) or lipopolysaccharide (LPS), respectively. Gnotobiotic mice, in which any cultivable gut bacteria were eradicated by antibiotic treatment, were used to study the role of LPS in ileitis. RESULTS: Microbiological analyses revealed that E coli increase in the inflamed ileum. TLR4(-/-), but not TLR2(-/-), mice displayed reduced mortality and small intestinal immunopathology. Decreased interferon (IFN)-gamma and nitric oxide (NO) levels in the inflamed terminal ileum of TLR4(-/-) mice indicated that TLR4 signalling aggravates ileitis via local mediator release from immune cells. E coli strains isolated from the inflamed ileum activated cultured mouse macrophages and induced TLR4-dependent nuclear factor kappaB activation and NO production in human embryonic kidney 293 cells and in peritoneal macrophages, respectively. Most strikingly, in contrast with wild-type mice, gnotobiotic TLR4(-/-) mice were protected from induction of ileitis by treatment with purified E coli lipid A or colonisation with live E coli. Finally, prophylactic treatment with the LPS scavenger polymyxin B ameliorated T gondii-induced ileitis. CONCLUSION: These findings highlight the innate immune system as a key player in T gondii-induced ileal immunopathology. Treatment with LPS or TLR4 antagonists may represent a novel strategy for prophylaxis and/or therapy of small intestinal inflammation in IBD.

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin.

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

A neuroendocrinological hypothesis on gender effects of naltrexone in relapse prevention treatment.

The ability of naltrexone to increase hypothalamo-pituitary-adrenocortical (HPA)-axis activity was recently reported to be associated with its effects on the reduction of craving for alcohol. We now present data showing naltrexone to be more efficacious in female alcoholics. Since HPA-axis might be interpreted as a key mechanism of action that could explain the observed gender differences in the abstinence maintenance treatment of alcohol addiction.

[Development and evaluation of a training program in shared decision making for primary care of depressive patients]. / Entwicklung und Evaluation eines Fortbildungsprogramms zur Partizipativen Entscheidungsfindung für die hausärztliche Versorgung depressiver Patienten.

Patient surveys show that many patients want broad information about their disease and treatment. Often they are interested to participate in the process of medical decision making, which could be realised with the concept of shared decision making where patient's values and needs are considered to the same extent as the treatment recommendations of evidence-based medicine. In depression care, it has been demonstrated so far that the active involvement of patients contributes to higher motivation for treatment. For enhancing patient's acceptance and motivation to avail themselves of medical treatment, a training program for general practitioners was developed and evaluated. It was the aim of the training to involve depressive patients in medical decision making. The training consists of depression-specific components (e. g. diagnosis, patient information, therapy) and general components (communication and shared decision making). The training was carried out in five sessions within a 6-month period (May to October 2003) embracing 20 h of training. Participants were 20 general practitioners in Southwest Germany. Physician's satisfaction with the training program is high. Especially in the fields of diagnosis and shared decision making the physicians clearly benefited. Transfer of shared decision making into daily routine was assessed as possible by the large majority of the trainees. Application of the training concept to other diseases and evaluation on the basis of daily routine is recommended. The training effects on medical care are presently being assessed in a randomised controlled trial.

[Diabetes mellitus as a complication of treatment with atypical neuroleptics. Possible pathomechanisms and treatment recommendations]. / Diabetes mellitus als Komplikation der Behandlung mit atypischen Neuroleptika. Mögliche Pathomechanismen und Therapieempfehlungen.

An increased risk for occurrence of diabetic metabolic states has been reported for treatment with atypical antipsychotics. Initial studies suggest that atypical antipsychotics as a heterogeneous group of substances are not equally concerned. An increased risk for development of diabetes mellitus can be assumed for clozapine and olanzapine, while other atypical and conventional antipsychotics seem to carry only a slightly elevated risk. It remains as yet unresolved whether there is a causal connection or whether other not yet identified factors are involved. However, atypical antipsychotics intervene in various ways in glucose and fatty acid metabolism due to their broad receptor profile. We suggest that some atypical antipsychotics disturb regulatory loops of fat metabolism in fatty tissue and muscle,which may result in insulin resistance and finally diabetes. Changes in leptin release and development of leptin resistance possibly play an important role. These new results should be considered when planning therapy, although a final risk analysis is not yet possible.

Long-term effects of pharmacotherapy on relapse prevention in alcohol dependence.

BACKGROUND: There is growing evidence that pharmacological treatment with two of the best validated anticraving drugs, acamprosate and naltrexone, is efficacious in promoting abstinence in recently detoxified alcohol-dependent subjects. OBJECTIVE: The stability of effects after termination of treatment remains to be answered, especially when combining both the drugs. METHOD: After detoxification, 160 alcohol-dependent subjects participated in a randomized, double-blind, placebo-controlled trial. Patients received naltrexone or acamprosate or a combination of naltrexone and acamprosate or placebo for 12 weeks. Patients were assessed weekly by interview, self-report, questionnaires and laboratory screening. Additionally, follow-up evaluation based on telephone interview of participants, general practitioners and relatives was conducted 12 weeks after terminating the medication. RESULTS: At week 12, the proportion of subjects relapsing to heavy drinking was significantly lower in the group with combined medication compared with both placebo and acamprosate (P < 0.05). No difference was detectable between acamprosate and naltrexone, both of which were superior to placebo (P < 0.05). Relapse rates were 28% (combined medication), 35% (naltrexone), 50% (acamprosate) and 75% (placebo). After follow-up (week 24), combined medication led to relapse rates significantly lower than placebo, but not lower than acamprosate. Again, both naltrexone and acamprosate were superior to placebo. Relapse rates were 80% (placebo), 54% (acamprosate), 53% (naltrexone) and 34% (combined medication). CONCLUSIONS: The results of this study highlight the stability of effects of pharmacotherapy on relapse prevention in alcohol dependence.

Alcohol intake, tumour necrosis factor-alpha, leptin and craving: factors of a possibly vicious circle?

AIMS: Since the appetite-regulating peptide leptin was recently found to be highly correlated with both craving for alcohol and lifetime ethanol intake, the aim of our study was to test the hypothesis whether tumour necrosis factor-alpha (TNF-alpha) might be the factor that links alcohol intake with elevated leptin levels. METHODS: TNF-alpha, leptin, and alcohol craving were assessed in male alcohol addicts at the onset of alcohol withdrawal and in matched controls. RESULTS: Increased leptin plasma levels in alcohol addicts correlated significantly with an enhanced secretion of TNF-alpha, which was itself related to the duration of alcohol misuse. CONCLUSIONS: Since leptin was shown to be associated with alcohol craving, a possible vicious circle is suggested, including the components: alcohol intake, increase of TNF-alpha, enhanced leptin secretion, enhanced alcohol craving, and consecutively increased alcohol intake.

Involvement of plasma atrial natriuretic peptide in protracted alcohol withdrawal.

OBJECTIVE: Atrial natriuretic peptide (ANP) has been shown to inhibit the effects of corticotrophin releasing hormone, corticotrophin and cortisol, and to influence affective and anxiety symptoms in man. We tested the hypothesis of whether ANP is associated with endocrine and psychopathological disturbances during acute alcohol withdrawal. METHOD: ANP and cortisol plasma concentrations were studied in alcoholics during in-patient detoxification and in healthy controls. Additionally, craving, depressive mood and anxiety were assessed. RESULTS: Although mean ANP levels increased significantly in alcoholics between days 1 and 14, they remained diminished compared to controls. Separating a subgroup of alcoholics with a decrease of ANP levels during withdrawal, these individuals revealed significantly elevated scores for mean and maximum craving and a trend to an elevated self-rated anxiety on day 14. CONCLUSION: We suggest that a dysregulation of ANP plasma levels during alcohol withdrawal may contribute to symptoms of protracted withdrawal such as craving and anxiety.

[Cavernous haemangioma in the Muscularis propria of the oesophagus and in the paraoesophageal tissue]. / Kavernöses Hämangiom in der Muscularis propria des Osophagus und im paraösophagealen Gewebe.

This is a case report of a 45-year-old woman who presented herself in our hospital with increasing retrosternal tenderness to pressure, dysphagia, and symptoms of reflux oesophagitis. The clinical examination and laboratory results showed no pathological findings. Oesophagogastroduodenoscopy revealed a bluish-livid, bulging mass from 32-38 cm aborally. A malignancy could not be excluded by biopsies with histological work-up, endoscopical ultrasound, nor CT-scan. By thoraco-abdominal surgery, a 5 cm large vascularised tumour of the outer layers of the oesophagus and the paraoesophageal tissue was resected. After intrathoracic oesophago-gastrostomy the patient could be discharged 17 days after surgery without further symptoms. Histology showed a benign tumour which was classified as cavernous haemangioma. To our knowledge, this is the first case of a haemangioma which involves the paraoesophageal tissue and the muscularis propria. The few published case reports of cavernous haemangioma of the oesophagus describe only an involvement of the mucosa and submucosa.