Artificial Coherent States of Light by Multiphoton Interference in a Single-Photon Stream.

Coherent optical states consist of a quantum superposition of different photon number (Fock) states, but because they do not form an orthogonal basis, no photon number states can be obtained from it by linear optics. Here we demonstrate the reverse, by manipulating a random continuous single-photon stream using quantum interference in an optical Sagnac loop, we create engineered quantum states of light with tunable photon statistics, including approximate weak coherent states. We demonstrate this experimentally using a true single-photon stream produced by a semiconductor quantum dot in an optical microcavity, and show that we can obtain light with g^{(2)}(0)→1 in agreement with our theory, which can only be explained by quantum interference of at least 3 photons. The produced artificial light states are, however, much more complex than coherent states, containing quantum entanglement of photons, making them a resource for multiphoton entanglement.

Combination of interferon induction therapy and ribavirin in chronic hepatitis C.

The initial clearance of hepatitis C virus (HCV) during interferon-alfa therapy is dose-dependent. Therefore, higher initial interferon doses (induction therapy) may improve treatment results. This concept was tested in a prospective, randomized controlled trial. Previously untreated patients with chronic hepatitis C were randomized to receive 3 different interferon doses during the first 14 weeks of therapy (Group A, n = 130: 10 MU IntronA [AESCA-Schering Plough, Traiskirchen, Austria]/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; Group B, n = 124: 5 MU/day for 14 weeks; Group C, n = 119; 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. Throughout the whole study all patients received 1 to 1.2 g ribavirin/day. On treatment, no differences in viral clearance rates were observed. Sustained response rates were also not different among the groups (A: 48.5%, B and C: 41.3%, intent to treat). When data were analyzed according to genotypes, sustained response was almost twice as high in patients with genotype 1 receiving high-dose interferon induction therapy (A: 44.2%, B: 28.6%, C: 27%, P <.05). In contrast, results were not different in genotype 3a patients (A: 61.3%, B: 75.9%, C: 56.3%; P >.1). These data indicate that high-dose interferon induction therapy may improve the outcome of interferon/ribavirin combination therapy in genotype 1 patients.

The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C.

BACKGROUND & AIMS: Elevated hepatic iron concentration may affect the response to antiviral therapy in chronic hepatitis C. This study explored the contribution of genetic hemochromatosis to iron accumulation in chronic hepatitis C. METHODS: HFE mutations (C282Y and H63D) were assessed in 184 patients with chronic hepatitis C virus and 487 controls. Liver biopsy specimens were available in 149 patients. Hepatic iron content was measured in 114 patients by atom-absorption spectrophotometry. RESULTS: The C282Y and H63D allele frequencies were 7.06 and 11.6 in patients and 4.83 and 11.09 in controls, respectively. Eight patients were homozygotes (5 C282Y [2.7%] and 3 H63D [1.6%]), 2 compound heterozygotes (1%), and 49 heterozygotes (14 C282Y [7.6%] and 35 H63D [19%]). Biochemical evidence of iron overload was more common in patients with HFE mutations (28 of 47) than in those without (34 of 102; P = 0.0045). Histological iron grading and hepatic iron content overlapped among patients with or without mutations. A hepatic iron index of >1.9 was observed only in 1 of the 4 C282Y homozygotes and 1 of the 3 H63D homozygotes. CONCLUSIONS: HFE mutations contribute to but do not fully explain hepatic iron accumulation in chronic hepatitis C. Furthermore, C282Y or H63D homozygosity in chronic hepatitis C is not necessarily associated with a high hepatic iron content.

Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy.

The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.

M3/M21 serum levels in women with adnexal masses and inflammatory diseases.

The aim of the present study was to evaluate the clinical usefulness of the cytokeratin tumor marker M3/M21 as a screening marker for ovarian cancer, as a predictive marker in patients with adnexal masses and as a prognostic factor in women with ovarian cancer. To determine the specificity of the M3/M21 test, we investigated M3/M21 serum levels in several benign conditions. This retrospective study comprises 37 patients with ovarian cancer FIGO stages Ia to III. Sera of patients with benign cysts, endometriosis, pelvic inflammatory disease, inflammatory bowel disease and liver cirrhosis were evaluated in 90, 10, 38, 10 and 20 cases, respectively. With a sensitivity of 57% and a specificity of 95%, M3/M21 is not suitable as a screening marker for ovarian cancer. Although M3/M21 is able to discriminate between ovarian cancer and benign adnexal tumors (univariate logistic regression, p = 0.0003), M3/M21 does not provide information additional to CA 125. M3/M21 serum levels are elevated in several benign conditions such as liver cirrhosis and inflammatory bowel disease. In ovarian cancer patients, elevated M3/M21 serum levels prior to therapy were associated with poor overall and disease-free survival (log-rank test, p = 0.03; log-rank test, p = 0.01, respectively). M3/M21, while obviously not suitable for screening or differential diagnosis of adnexal masses, could be useful as an additional prognostic factor in ovarian cancer patients.

Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C.

AIM: To evaluate the usefulness of easily assessable morphological parameters in liver biopsies in order to predict efficacy of interferon-alpha (IFN) treatment in patients with chronic hepatitis C. METHODS AND RESULTS: Inflammatory activity and fibrosis (according to Scheuer), and the hepatic iron content (according to Rowe and DiBisceglie) were assessed in pre-treatment liver biopsies of 73 de novo patients with chronic hepatitis C. Furthermore the presence of fat, lymphoid aggregates, and bile duct lesions was evaluated. With respect to IFN therapy patients were classified as responders alanine aminotransferase (ALT) normal and negative hepatitis C virus (HCV) RNA in serum at the end of treatment, n = 33) or non-responders (n = 40). Non-responders had more advanced fibrosis (P = 0.0001) and more extensive iron storage (P = 0.0008) than responders. In contrast absence of stainable iron was frequently (46%) associated with sustained response. Absence of fat droplets in hepatocytes was associated with response (P = 0.0001). Stepwise logistic regression analysis indicated that the stage of fibrosis, the hepatic iron grade, and the presence or absence of fat were independent predictors of response. CONCLUSIONS: Liver biopsy provides useful information for selection of patients with hepatitis C for IFN therapy.

Wilson's disease in patients presenting with liver disease: a diagnostic challenge.

BACKGROUND & AIMS: In patients with Wilson's disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group. METHODS: Clinical and laboratory findings of 55 patients with Wilson's disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens. RESULTS: In the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms. CONCLUSIONS: The commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilson's disease in patients with liver disease of unknown origin.

[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture]. / Veränderung des 24-Stunden-Rhythmus von Plasma-Melatonin bei Patienten mit Leberzirrhose--Beziehung zur Schlafarchitektur.

OBJECTIVE: To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. PATIENTS: A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). MEASUREMENTS: Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. RESULTS: Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. CONCLUSIONS: A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".

A low-protein diet ameliorates disrupted diurnal locomotor activity in rats after portacaval anastomosis.

In previous studies we noted a disruption of the circadian locomotor activity rhythm in rats after portacaval anastomosis (PCA). To examine whether this abnormality is related to factors that aggravate hepatic encephalopathy in humans, we studied the effect of dietary formulation and protein content on body weight, locomotor activity, and entrainment to the light-dark cycle in rats after PCA or sham operation. Postoperative weight loss was prevented by pair-feeding with a purified liquid diet. However, the behavioral abnormalities persisted in PCA rats fed a high-protein diet, with a reduction in total activity and entrainment to the light-dark cycle. These were ameliorated by a low dietary protein content. Since this treatment reduces the load of gut-derived nitrogenous substances that might alter brain metabolism, our data strengthen the hypothesis that the abnormal circadian activity patterns in PCA rats may be part of the spectrum of hepatic encephalopathy.

Modulation of hepatic encephalopathy in rats with thioacetamide-induced acute liver failure by serotonin antagonists.

OBJECTIVE: Accumulated neurochemical data in different animal models of fulminant hepatic failure and in humans with hepatic encephalopathy suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy. Since neurochemical alterations may not have behavioural or electrophysiological consequences the contribution of the serotoninergic system to the pathogenesis of hepatic encephalopathy was explored. METHODS: The effects of drugs modulating serotoninergic neurotransmission, the nonselective serotonin receptor antagonist methysergide and the serotonin2 receptor antagonist seganserin were tested neuropharmacologically in thioacetamide-induced acute liver failure in rats. RESULTS: Methysergide had no effect in control rats, but dose dependently increased motor activity in stage II-III hepatic encephalopathy by 232% (5 mg/kg methysergide), 531% (10 mg/kg) and 507% (20 mg/kg). In contrast, seganserin had no effect in encephalopathic rats. CONCLUSION: It is suggested that the beneficial effects of methysergide are serotonin, receptor mediated. Overall the results suggest that serotoninergic mechanisms contribute to some of the behavioural manifestations of hepatic encephalopathy in this animal model.

Diagnosis of Wilson's disease in an asymptomatic sibling by DNA linkage analysis.

The molecular genetic diagnosis of Wilson's disease in the 5-year-old sister of a patient with Wilson's disease is reported. The girl was clinically free of disease and had no conventional biochemical markers of Wilson's disease (i.e., normal ceruloplasmin, normal copper in the serum, normal 24-hour urinary copper excretion). Diagnosis with restriction fragment length polymorphisms and a nonradioactive polymerase chain reaction-based analysis with microsatellite markers showed her to be homozygous for the disease-associated markers. A liver biopsy was performed, and a 20-fold increased liver copper content confirmed the diagnosis. The child was treated with chelation therapy with D-penicillamine. The report of this study clearly shows the advantage of DNA linkage analysis (especially polymerase chain reaction) over conventional laboratory methods for presymptomatic diagnosis of Wilson's disease before irreparable liver and neurological damage occurs. The only limitation of this DNA-based diagnosis is the fact that it is only applicable in siblings of an index patient whose diagnosis was made by phenotypic criteria.

Disruption of circadian locomotor activity in rats after portacaval anastomosis is not gender dependent.

A recent study suggested that female rats are less affected by a portacaval anastomosis (PCA) than their male counterparts, as measured by body weight and changes in locomotor activity. In this study, we evaluated the entrainment of locomotor activity to the light/dark (LD) cycle, a consistent abnormality in the portacaval shunted rat. The degree of entrainment was measured in male and female rats before and after PCA or sham operation. All four groups of animals showed strong entrainment to an LD cycle before surgery. After portacaval anastomosis, male and female rats exhibited a highly significant decrease in overall motor activity as compared with the preoperative period and as compared with sham-operated animals of the same gender. The percentage of total activity during daytime was significantly increased after portacaval anastomosis. The reduction in parameters of entrainment indicates a disruption of circadian function in both portacaval-shunted groups. Portal pressure measurements confirmed the patency of the shunts. Cortical brain glutamine levels were similarly increased in male and female shunted rats. The loss of body weight was slightly, but not significantly, more pronounced in male animals after shunt surgery. In conclusion, our results do not support a role for gender in the disruption of circadian function in rats after PCA.

Disruption of the diurnal rhythm of plasma melatonin in cirrhosis.

OBJECTIVES: To assess 24-hour plasma melatonin profile as a marker of output rhythm from the circadian clock and to study sleep diaries as reflections of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. SETTING: Clinical research center in a university hospital. PATIENTS: Seven patients with cirrhosis but not alcoholism and seven age-, sex-, and education-matched controls. MEASUREMENTS: Neuropsychological testing to confirm subclinical hepatic encephalopathy. Plasma melatonin levels measured every 30 minutes for 24 hours by radioimmunoassay. Sleep diaries kept for 1 week before admission. RESULTS: Patients with cirrhosis had markedly elevated melatonin levels during daytime hours; in addition, the time of onset of melatonin increase and the time at which melatonin levels peaked were consistently and significantly delayed in these patients. Sleep diaries indicated more nocturnal awakenings and more frequent daytime naps in patients with cirrhosis. CONCLUSION: Disruption of the diurnal rhythm of melatonin may reflect alterations of circadian function that could contribute to the disturbances of the sleep-wake cycle frequently seen in patients with cirrhosis.

Hepatic encephalopathy in rats with thioacetamide-induced acute liver failure is not mediated by endogenous benzodiazepines.

BACKGROUND: To distinguish whether the improvement of hepatic encephalopathy by benzodiazepine receptor antagonists is mediated by their antagonistic or their inverse agonistic properties, the neurobehavioral effects of a variety of benzodiazepine receptor ligands in rats with thioacetamide-induced acute liver failure were tested. METHODS: The neural inhibitory effect of the benzodiazepine agonist flunitrazepam and its reversibility by the "pure" antagonist Ro 14-7437 were examined in thioacetamide-treated rats and controls. The effects of Ro 14-7437, of the partial inverse agonist Ro 15-4513, and the inverse agonist DMCM in rats with hepatic encephalopathy grade II/III were tested. Encephalopathic rats were pretreated with Ro 14-7437 or vehicle and then injected with Ro 15-4513. RESULTS: Thioacetamide-treated rats were more sensitive to flunitrazepam than controls. In both groups, its effect was completely antagonized with Ro 14-7437. Encephalopathy was significantly improved by Ro 15-4513, although Ro 14-7437 and vehicle had no effect. DMCM worsened the condition of encephalopathic rats but had no effect in controls. Pretreatment with Ro 14-7437 abolished the beneficial effects of Ro 15-4513. CONCLUSIONS: In rats with thioacetamide-induced liver failure, endogenous benzodiazepines do not precipitate hepatic encephalopathy. The amelioration of hepatic encephalopathy is mediated by benzodiazepine receptor ligands with both antagonistic and inverse agonistic properties.

Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: comparison with uremic encephalopathy.

Hepatic encephalopathy is ameliorated by drugs acting on the central GABAA-benzodiazepine receptor complex. To investigate whether these effects are specific for hepatic encephalopathy or just reflect a nonspecific arousal reaction, various benzodiazepine antagonists like flumazenil or with inverse agonistic properties (Ro 15-4513, Ro 15-3505) were studied in uremic encephalopathy in rats after bilateral ureteral ligation (n = 20) and compared with hepatic encephalopathy caused by thioacetamide-induced acute liver failure (n = 33). As soon as the animals developed clear signs of metabolic encephalopathy, their motor activity was recorded in an animal activity meter for 10 min. Furthermore, a composite score was calculated by grading various behavioral signs from 0 = absent to 3 = apparently normal. Rats were then injected with coded preparations of Ro 15-4513 (0.5, 2.5 and 5 mg/kg body wt intraperitoneally), flumazenil (2.5, 10, 25 and 40 mg/kg), Ro 15-3505 (10 mg/kg) or vehicle, and the measurements were repeated. The code was broken after the completion of the study. Pretreatment motor activity was decreased both in hepatic and uremic encephalopathy (20.7 +/- 6.4 [S.E.M.] and 41.3 +/- 37.1 movements/10 min). In hepatic encephalopathy motor activity and the composite score were improved both by 5 mg/kg Ro 15-4513 (by 293%, p less than 0.05) and by 10 mg/kg Ro 15-3505 (by 509%, p greater than 0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status.(ABSTRACT TRUNCATED AT 250 WORDS)