Postinfectious and sporadic functional gastrointestinal disorders have different prevalences and rates of overlap: results from a controlled cohort study 3 years after acute giardiasis.

BACKGROUND: Irritable bowel syndrome (IBS) is a common complication following gastroenteritis, and a high prevalence of postgiardiasis IBS has previously been reported. This study aims to investigate the prevalence, adjusted relative risk (RRadj), and overlap of different functional gastrointestinal disorders (FGID) according to Rome III criteria following infection with Giardia lamblia. METHODS: All patients ≥18 years of age with verified giardiasis during an outbreak in 2004, and a control group matched by age and gender, were mailed a questionnaire 3 years later. KEY RESULTS: The prevalence of functional dyspepsia (FD) was 25.9% in the exposed and 6.9% in the control group, RRadj: 3.9 (95% confidence intervals [CI]: 3.1-4.8). The prevalence of IBS was 47.9% and 14.3%, respectively, with RRadj: 3.4 (95% CI: 3.0-3.8). Prevalence of other gastrointestinal symptoms ranged from 70.0% vs 39.7% for bloating (RRadj: 1.8) to 8.3% vs 2.9% for nausea (RRadj: 3.0) in the Giardia and the control group, respectively. Among individuals fulfilling criteria for IBS 44% in the exposed group and 29% in the control group also fulfilled criteria for FD. IBS subtypes based on Rome III criteria (stool consistency) showed poor agreement with subtypes based on frequency of bowel movements (Kappa-values: 0.17 and 0.27). CONCLUSIONS & INFERENCES: There were high prevalences and RRs of IBS, FD and other gastrointestinal symptoms following acute giardiasis, and a high degree of overlap between the disorders. The agreement between different IBS subtype criteria varied, and there were also differences between the exposed and control group.

Cavitation inception from bubble nuclei.

The tensile strength of ordinary water such as tap water or seawater is typically well below 1 bar. It is governed by cavitation nuclei in the water, not by the tensile strength of the water itself, which is extremely high. Different models of the nuclei have been suggested over the years, and experimental investigations of bubbles and cavitation inception have been presented. These results suggest that cavitation nuclei in equilibrium are gaseous voids in the water, stabilized by a skin which allows diffusion balance between gas inside the void and gas in solution in the surrounding liquid. The cavitation nuclei may be free gas bubbles in the bulk of water, or interfacial gaseous voids located on the surface of particles in the water, or on bounding walls. The tensile strength of these nuclei depends not only on the water quality but also on the pressure-time history of the water. A recent model and associated experiments throw new light on the effects of transient pressures on the tensile strength of water, which may be notably reduced or increased by such pressure changes.

Severe human Babesia divergens infection in Norway.

Human babesiosis is a rare but potentially life-threatening parasitic disease transmitted by ixodid ticks, and has not previously been reported in Norway. We report a case of severe babesiosis that occurred in Norway in 2007. The patient had previously undergone a splenectomy. He was frequently exposed to tick bites in an area endemic for bovine babesiosis in the west of Norway. The patient presented with severe haemolysis and multiorgan failure. Giemsa-stained blood smears revealed 30% parasitaemia with Babesia spp. He was treated with quinine in combination with clindamycin, apheresis, and supportive treatment with ventilatory support and haemofiltration, and made a complete recovery. This is the first case reported in Norway; however Babesia divergens seroprevalence in cattle in Norway is high, as is the risk of Ixodes ricinus tick bite in the general population. Babesiosis should be considered in the differential diagnosis of unexplained febrile haemolytic disease.

Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice.

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and results from a loss of Fragile X mental retardation protein (FMRP). FMRP is important for mRNA shuttling and translational control and binds to proteins important for synaptic plasticity. Like many developmental disorders, FXS is associated with alterations in synaptic plasticity that may impair learning and memory processes in the brain. However, it remains unclear whether FMRP plays a ubiquitous role in synaptic plasticity in all brain regions. We report that a loss of FMRP leads to impairments in N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the dentate gyrus (DG), but not in the cornu ammonis area 1 (CA1) subregion of the hippocampus of adult mice. DG-specific deficits are accompanied by a significant reduction in NMDAR GluN1, GluN2A, and GluN2B subunit levels and reduced serine 831 GluA1 phosphorylation specifically in this region. Importantly, we demonstrate that treatment with NMDAR co-agonists (glycine or D-serine) independently rescue impairments in NMDAR-dependent synaptic plasticity in the DG of the Fragile X mental retardation 1 (Fmr1) knockout mouse. These findings implicate the NMDAR in the pathophysiology of FXS and suggest that indirect agonists of the NMDAR may be a successful therapeutic intervention in FXS.

ß2-adrenergic stimulation enhances Ca2+ release and contractile properties of skeletal muscles, and counteracts exercise-induced reductions in Na+-K+-ATPase Vmax in trained men.

The aim of the present study was to examine the effect of ß2-adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca(2+) release and uptake, and Na(+)-K(+)-ATPase activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 males, EXP2, n = 20 males), where ß2-adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction (MVC) of m. quadriceps was measured, followed by exercise to fatigue at 120% of maximal oxygen uptake (V̇O2, max ). A muscle biopsy was taken after MVC (non-fatigue) and at time of fatigue. In EXP2, contractile properties of m. quadriceps were measured with electrical stimulations before (non-fatigue) and after two fatiguing 45 s sprints. Non-fatigued MVCs were 6 ± 3 and 6 ± 2% higher (P < 0.05) with terbutaline than placebo in EXP1 and EXP2, respectively. Furthermore, peak twitch force was 11 ± 7% higher (P < 0.01) with terbutaline than placebo at non-fatigue. After sprints, MVC declined (P < 0.05) to the same levels with terbutaline as placebo, whereas peak twitch force was lower (P < 0.05) and half-relaxation time was prolonged (P < 0.05) with terbutaline. Rates of SR Ca(2+) release and uptake at 400 nm [Ca(2+)] were 15 ± 5 and 14 ± 5% (P < 0.05) higher, respectively, with terbutaline than placebo at non-fatigue, but declined (P < 0.05) to similar levels at time of fatigue. Na(+)-K(+)-ATPase activity was unaffected by terbutaline compared with placebo at non-fatigue, but terbutaline counteracted exercise-induced reductions in maximum rate of activity (Vmax) at time of fatigue. In conclusion, increased contractile force induced by ß2-adrenergic stimulation is associated with enhanced rate of Ca(2+) release in humans. While ß2-adrenergic stimulation elicits positive inotropic and lusitropic effects on non-fatigued m. quadriceps, these effects are blunted when muscles fatigue.

Prenatal ethanol exposure has sex-specific effects on hippocampal long-term potentiation.

Alcohol consumption during pregnancy is deleterious to the developing brain of the fetus and leads to persistent deficits in adulthood. Long-term potentiation (LTP) is a biological model for learning and memory processes and previous evidence has shown that prenatal ethanol exposure (PNEE) affects LTP in a sex specific manner during adolescence. The objective of this study was to determine if there are sex specific differences in adult animals and to elucidate the underlying molecular mechanisms that contribute to these differences. Pregnant Sprague-Dawley dams were assigned to either; liquid ethanol, pair-fed or standard chow diet. In vivo electrophysiology was performed in the hippocampal dentate gyrus (DG) of adult offspring. LTP was induced by administering 400 Hz stimuli. Western blot analysis for glutamine synthetase (GS) and glutamate decarboxylase from tissue of the DG indicated that GS expression was increased following PNEE. Surprisingly, adult females did not show any deficit in N-methyl-D-aspartate (NMDA)-dependent LTP after PNEE. In contrast, males showed a 40% reduction in LTP. It was indicated that glutamine synthetase expression was increased in PNEE females, suggesting that altered excitatory neurotransmitter replenishment may serve as a compensatory mechanism. Ovariectomizing females did not influence LTP in control or PNEE animals, suggesting that circulating estradiol levels do not play a major role in maintaining LTP levels in PNEE females. These results demonstrate the sexually dimorphic effects of PNEE on the ability for the adult brain to elicit LTP in the DG. The mechanisms for these effects are not fully understood, but an increase in glutamine synthetase in females may underlie this phenomenon.

Early quantification of HCV core antigen may help to determine the duration of therapy for chronic genotype 2 or 3 HCV infection.

The aim of the present study was to evaluate the utility of hepatitis C virus (HCV) core antigen (coreAg) assessment for the identification of candidates for short-term therapy. Plasma samples from HCV genotype 2 or 3-infected patients participating in the NORDynamIC trial (n=382) comparing 12 and 24 weeks of combination treatment with pegylated interferon-α2a and a fixed dose of 800 mg ribavirin daily were analyzed for coreAg. Among the 126 patients (33% of the intention-to-treat population) achieving HCV coreAg levels in plasma below 0.2 pg/mL when assayed on treatment day 3, sustained viral response (SVR) rates of 86% and 84% were achieved in the 12- and 24-week arms, respectively. Similarly, among patients having received at least 80% of the target dose of both pegylated interferon α-2a and of ribavirin for at least 80% of the target treatment duration (per-protocol analysis), the SVR rates were 89% and 95%, respectively. Twelve weeks of combination treatment may be sufficient for genotype 2 or 3-infected patients achieving HCV coreAg levels below 0.2 pg/mL by day 3, signaling a rapid clearance of HCV viremia.

Ribavirin plasma concentration is a predictor of sustained virological response in patients treated for chronic hepatitis C virus genotype 2/3 infection.

In hepatitis C virus (HCV) genotype 1 infection, the likelihood of obtaining sustained virological response (SVR) is associated with higher ribavirin exposure. Such an association has not been demonstrated for HCV genotype 2/3 infection, where a fixed 800 mg daily dosing of ribavirin is generally recommended. The primary aim of this study was to investigate the correlation between ribavirin concentration at day 29 and therapeutic response in patients with HCV genotype 2/3 infection. A total of 382 patients were randomized to 12 or 24 weeks of treatment with pegylated interferon-alfa 2a 180 µg weekly and 800 mg ribavirin daily. Trough plasma concentration of ribavirin was measured at day 29 and week 12 and the primary outcome was SVR (HCV-RNA undetectable 24 weeks after treatment). Of the 382 patients, 355 had a ribavirin concentration available at day 29. SVR was 84% among patients with a ribavirin concentration ≥2 mg/L at day 29 compared to 66% in those with concentrations <2 mg/L (P = 0.002). The corresponding figures in the 12-week treatment group were 74% and 57% (P = 0.12), and in the 24-week treatment group 91% and 75% (P = 0.02), respectively. In a multivariate analysis, ribavirin concentration at day 29 was an independent predictor of SVR (P = 0.002). In conclusion, a higher plasma ribavirin concentration is associated with an increased likelihood of achieving SVR in HCV genotype 2/3 infection. Individualization of ribavirin dosing may be helpful in improving outcome, especially in the presence of unfavourable baseline characteristics. This, however, requires evaluation in a prospective trial.

Hepatitis C treatment response kinetics and impact of baseline predictors.

The optimal duration of treatment for hepatitis C virus (HCV) infections is highly variable but critical for achieving cure (sustained virological response, SVR). We prospectively investigated the impact of age, fibrosis, baseline viraemia and genotype on the early viral kinetics and treatment outcome. Patients treated with peginterferon alfa-2a and ribavirin in standard dosing were included: 49 with genotype 1 treated for 48weeks and 139 with genotype 2 or 3 treated for 24weeks. The reduced SVR rates in patients older than 45years, with severe liver fibrosis or pretreatment viraemia above 400,000IU/mL were strongly associated with slower second phase declines of HCV RNA. Genotype 2/3 infections responded more rapidly than genotype 1, reaching week 4 negativity (RVR) in 59%vs 22%. We conclude that baseline response predictors such as age, fibrosis and viral load were well reflected by the early viral kinetics as assessed by repeated HCV RNA quantifications. The kinetic patterns and the high relapse rate in genotype 2/3 patients without RVR suggest that this group might benefit from treatment durations longer than 24weeks.

High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis.

The aim of this study was to evaluate the prevalence of fatigue and abdominal symptoms 2 years after Giardia lamblia infection. All 1262 cases who had Giardia-positive stool samples during an outbreak in 2004 in Norway received a questionnaire in 2006 asking about fatigue and abdominal symptoms. Fatigue was reported by 41%, whereas 38% reported abdominal symptoms, and there was a highly significant association between these symptoms. Increasing age was a highly significant risk factor for fatigue. The symptoms were not due to chronic infection in this cohort. Our data warrant further investigations into the late effects of giardiasis.

Sensitivity of a Giardia antigen test in persistent giardiasis following an extensive outbreak.

The utility of a rapid antigen test for diagnosing cases of persistent giardiasis, as defined by detection of cysts by conventional microscopy following standard formalin-ether concentration or the positive rapid antigen test, was investigated following a large, waterborne outbreak of giardiasis. The sensitivity and specificity of the rapid test as compared with microscopy were 60.7% and 96.7%, respectively, in this patient group. The low sensitivity contrasts with previous reports, and may be partly explained by low cyst numbers.

Treatment-ladder and genetic characterisation of parasites in refractory giardiasis after an outbreak in Norway.

OBJECTIVES: To evaluate the efficacy of a treatment ladder in metronidazole-refractory giardiasis, and to compare genetic characteristics of the parasites. METHODS: A clinical observational study was carried out in 38 adult patients with metronidazole-refractory giardiasis, during an outbreak in Norway with more than 1200 cases. All patients were treated with albendazole in combination with metronidazole. Those who failed were treated with paromomycin. Those who failed on paromomycin were treated with quinacrine in combination with metronidazole. Giardia isolates from 17 patients were characterised by PCR and sequencing at two separate genes. RESULTS: Metronidazole in combination with albendazole was effective in 30 (79%) out of 38 patients. Paromomycin was effective in three out of six patients. Quinacrine in combination with metronidazole was effective in 3 patients. Molecular characterisation of the Giardia isolates revealed that these parasites were identical at two different gene segments, while sequence profiles from isolates at the peak of the outbreak were more heterogenous. CONCLUSIONS: Albendazole and quinacrine both in combination with metronidazole were effective in treating metronidazole-refractory giardiasis in this cohort. Paromomycin was less effective. Particular Giardia sub-genotypes may have been associated with the treatment-refractory giardiasis in these patients, although other undefined factors are probably also of importance.