Effect of intravenous fat on cholecystokinin secretion and gallbladder motility in man.

During total parenteral nutrition (TPN) gallbladder bile stasis and hypomotility have been well documented. Little is known, however, about the effect of the separate components of TPN on gallbladder motor function. Inasmuch as fat, administered intraduodenally, is a potent stimulus of cholecystokinin (CCK) secretion and gallbladder contraction we have investigated whether intravenous (IV) fat affects gallbladder motility. Six healthy volunteers were studied on two separate occasions, during infusion of Intralipid 10%, 200 mL/h or saline infusion (control) for 3 hours, to evaluate the effect of IV infusion of fat on (1) plasma CCK concentration and gallbladder volume and (2) CCK-induced gallbladder emptying. Intravenous infusion of Intralipid resulted in significant increases in serum triglycerides from 0.9 +/- 0.1 to 5.1 +/- 1.3 mmol/L (at 90 min). During fat infusion no significant changes in plasma CCK and gallbladder volume were noted when compared with basal values or to the control experiment. During IV fat, concomitant infusion of 0.25, 0.5, and 1.0 Ivy dog unit (IDU) per kilogram per hour of CCK-33 resulted in a significant reduction in gallbladder volume from 26 +/- 6 cm3 (basal) to 15 +/- 4 cm3 (p less than .05), 6 +/- 2 cm3 (p less than .05) and 2.5 +/- 1 cm3 (p less than .05), respectively. No significant differences in CCK-induced gallbladder emptying were observed between IV fat and saline infusion (control). It is concluded that, in contrast to intraduodenal fat, IV infusion of fat does not affect (1) basal plasma CCK and gallbladder volume and (2) CCK-induced gallbladder contraction.     

Characterization of an HIV-1 group M variant that is distinct from the known subtypes

We identified an HIV-1 variant that belongs to the M group, with limited similarity of short genetic regions (100-200 nt) to subtype K, but the remainder of the genome is unrelated to any established HIV-1 subtype. The isolate was obtained from an HIV-1-positive male, living in the Netherlands, who encountered the virus before 1989, most probably via heterosexual contact in Africa. We describe the full-length genome sequence of four biological clones that were obtained from two samples collected 5 years apart. At both time points all open reading frames were intact. Within the 5-year interval, the person received antiretroviral therapy with zalcitabine and zidovudine for almost 4 years. Evolution of drug-resistant variants is likely given the increase in viral RNA load to +/-10,000 copies/ml during the last year of treatment. Surprisingly, the only regular RT mutation acquired during this period was K70R, which suggests that the genetic background of this variant is perhaps not suitable for the generation of the standard 41L, 67N, and 215Y/F mutations that typically arise during prolonged, nonsuccessful, zidovudine treatment. Awaiting the discovery of at least two additional, epidemiologically unrelated patients with a phylogenetically related HIV-1 variant, we can designate this variant a new HIV-1 subtype, or a distinct branch of subtype K.     

Ticks and associated pathogens collected from domestic animals in the Netherlands

Following an outbreak of autochthonous canine babesiosis in the Netherlands, a request made to veterinarians and the public to collect ticks from companion animals resulted in 4298 ticks submitted between July 2005 and October 2006 to our center. Ticks were identified as Ixodes ricinus adults (2907/4298, 67.6%), Ixodes sp. nymphs (529/4298, 12.3%) and Ixodes sp. larvae (385/4298, 9.0%), I. hexagonus adults (328/4298, 7.6%), Dermacentor reticulatus (72/4298, 1.7%), and several other exotic tick species such as Amblyomma flavomaculatum (formerly Aponomma flavomaculatum), Hyalomma marginatum rufipes, Rhipicephalus sanguineus, and R. turanicus (55/4298, 1.3%). Eight localities were surveyed for the presence of local D. reticulatus, a tick not indigenous to the Netherlands, based on multiple submissions of D. reticulatus ticks from these areas. D. reticulatus was collected from the vegetation in six of these localities, confirming the presence of populations of this tick in the Netherlands. Adult I. ricinus (n=251), I. hexagonus (n=237), and D. reticulatus (n=344) ticks were selected at random and subsequently screened by polymerase chain reaction (PCR) and reverse line blot (RLB) hybridization for the presence of Borrelia, Babesia, Theileria, Anaplasma, Ehrlichia, and Rickettsia species. I. ricinus ticks were infected with Rickettsia helvetica (24.7%), spirochetes belonging to the Borrelia burgdorferi sensu lato group (7.2%), the Ehrlichia-like "Schotii" variant (2.4%), Anaplasma phagocytophilum (1.6%), Babesia sp. (EU1) (1.2%), Babesia divergens (0.4%), and Babesia microti (0.4%). A. phagocytophilum (5.9%) and R. helvetica (0.8%) were also detected in adult I. hexagonus ticks. Spotted fever group Rickettsiae, previously reported as Rickettsia sp. DnS14/RpA4 (14.0%), and Borrelia burgdorferi sensu lato (0.3%) were detected in the D. reticulatus ticks, which appeared to be free from B. canis infection. We concluded that a much broader spectrum of ticks and tick-borne pathogens is present in the Netherlands than previously thought, including several potential zoonotic pathogens.     

Exposure–Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting

Pharmaceutical Research - Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung...     

Identification of a Novel Human Rhinovirus C Type by Antibody Capture VIDISCA-454

Causative agents for more than 30 percent of respiratory infections remain unidentified, suggesting that unknown respiratory pathogens might be involved. In this study, antibody capture VIDISCA-454 (virus discovery cDNA-AFLP combined with Roche 454 high-throughput sequencing) resulted in the discovery of a novel type of rhinovirus C (RV-C). The virus has an RNA genome of at least 7054 nt and carries the characteristics of rhinovirus C species. The gene encoding viral protein 1, which is used for typing, has only 81% nucleotide sequence identity with the closest known RV-C type, and, therefore, the virus represents the first member of a novel type, named RV-C54.     

Detection of ‘best’ positive end-expiratory pressure derived from electrical impedance tomography parameters during a decremental positive end-expiratory pressure trial

Introduction

This study compares different parameters derived from electrical impedance tomography (EIT) data to define ‘best’ positive end-expiratory pressure (PEEP) during a decremental PEEP trial in mechanically-ventilated patients. ‘Best’ PEEP is regarded as minimal lung collapse and overdistention in order to prevent ventilator-induced lung injury.

Methods

A decremental PEEP trial (from 15 to 0 cm H₂O PEEP in 4 steps) was performed in 12 post-cardiac surgery patients on the ICU. At each PEEP step, EIT measurements were performed and from this data the following were calculated: tidal impedance variation (TIV), regional compliance, ventilation surface area (VSA), center of ventilation (COV), regional ventilation delay (RVD index), global inhomogeneity (GI index), and intratidal gas distribution. From the latter parameter we developed the ITV index as a new homogeneity parameter. The EIT parameters were compared with dynamic compliance and the PaO₂/FiO₂ ratio.

Results

Dynamic compliance and the PaO₂/FiO₂ ratio had the highest value at 10 and 15 cm H₂O PEEP, respectively. TIV, regional compliance and VSA had a maximum value at 5 cm H₂O PEEP for the non-dependent lung region and a maximal value at 15 cm H₂O PEEP for the dependent lung region. GI index showed the lowest value at 10 cm H₂O PEEP, whereas for COV and the RVD index this was at 15 cm H₂O PEEP. The intratidal gas distribution showed an equal contribution of both lung regions at a specific PEEP level in each patient.

Conclusion

In post-cardiac surgery patients, the ITV index was comparable with dynamic compliance to indicate ‘best’ PEEP. The ITV index can visualize the PEEP level at which ventilation of the non-dependent region is diminished, indicating overdistention. Additional studies should test whether application of this specific PEEP level leads to better outcome and also confirm these results in patients with acute respiratory distress syndrome.     

Lack of effect of the specific cholecystokinin receptor antagonist loxiglumide on cholecystokinin clearance from plasma in man.

Saline or loxiglumide (2.5 mg kg-1 in 10 min, followed by 5 mg kg-1 h-1 for 200 min) was administered intravenously in random order to six healthy subjects. After 60 min cholecystokinin (CCK-33) was infused (0.5 i.d.u. kg-1 h-1 for 1 h then 1.0 i.d.u. kg-1 h-1 for 1 h). Loxiglumide did not change basal levels of CCK and did not augment plasma CCK-immunoreactivity during CCK-33 infusion. After cessation of the CCK-infusion, plasma CCK concentrations decreased rapidly to basal values within 12 min, and the elimination half-life during loxiglumide infusion (4.8 +/- 0.8 min) was not significantly different from that during saline infusion (4.2 +/- 1.0 min). These results suggest that loxiglumide does not interfere with the distribution and metabolism of CCK.     

Alpha-thalassemia phenotype induced by the new IVS-II-2 (T --> A) splice donor site mutation on the alpha2-globin gene

We present a family of North European extraction referred for a refractory non iron depleted microcytic anemia. The proband, a 36 year-old male, presented with chronic borderline anemia and microcytic hypochromic parameters. No abnormal hemoglobin (Hb) fractions were observed on high performance liquid chromatography (HPLC) or on alkaline electrophoresis. Gap-polymerase chain reaction (gap-PCR) excluded the seven common alpha-thalassemia (thal) deletion defects. However, the beta/alpha-globin chain synthesis ratio measured in vitro was unbalanced, indicating a reduced expression of the alpha-globin genes. Direct sequencing of the alpha-globin genes revealed heterozygosity for a T --> A transversion at the IVS-II-2 position of the alpha2 gene. This is the first IVS-II splice donor site mutation described on the alpha2-globin gene.