Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease

Recent experiments in cultured cyst epithelial cells from kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD) have shown that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is present in the apical surface of these cells and mediates chloride (Cl-) and fluid secretion in vitro. To determine whether the presence of CF with the expression of mutated CFTR proteins modifies cyst formation in ADPKD, we studied a large family with both inherited diseases. ADPKD in this family is linked to PKD1. The family is composed of 26 members; 11 members with ADPKD, 4 members with CF, and 2 members with both diseases. Renal volumes measured by computerized tomography (CT), calculated creatinine clearances, and other clinical parameters in the family members with ADPKD and CF were compared with those in the family members with ADPKD alone, as well as to a large population of patients with ADPKD. The patients with CF and ADPKD, but not the CF heterozygote carriers with ADPKD, had less severe polycystic kidney and liver disease, as indicated by normal renal function; smaller renal volume, even when corrected for height and body surface area; and the absence of hypertension and liver cysts. These observations suggest that the coexistence of CF may reduce the severity of ADPKD.     

Acute severe asthma

Acute exacerbations of asthma are very common reasons for a presentation to emergency departments. This paper focuses on defining the high‐risk group, consideration of the concept of phenotypes of acute asthma, the assessment of severe and life‐threatening exacerbations and an emphasis on the management of the more severe end of the exacerbation severity. A number of evidence‐based guidelines exist throughout the world and are all slightly different. This reflects the poor evidence base for some of those recommendations. Thus, a large variation of treatment drugs, doses and regimen are used and clearly not standardised. This paper aims to present a summary of the best evidence and discuss some of these controversies. The most important aspect of treating an exacerbation of acute asthma is to review regularly and assess response to treatment. Severe and life‐threatening episodes should be treated with early use of intravenous treatment in a stepwise manner following the local guidelines. Non‐invasive ventilation and high flow nasal cannulae delivery of oxygen in the emergency department are evolving modalities, but evidence for their use is currently limited.     

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63

Waanders E, Venselaar H, te Morsche RHM, de Koning DB, Kamath PS, Torres VE, Somlo S, Drenth JPH. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation‐sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, Poly Phen , and p Mut and sift . We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non‐sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.     

Alloimmunization Against Well Defined Polymorphic Major Histocompatibility or Class I MHC Transfected L Cells Antigens Can Prevent Poly IC Induced Fetal Death in Mice

METHOD : It is possible to induce increased fetal resorption in a number of inbred murine matings by injecting Poly (I) Poly (C12U) 3.5 days postconception, a maneuver associated with natural killer-mediated damage to the feto placental unit such as occurs in spontaneous fetal resorptions. RESULTS : We show here that alloimmunization can block this effect. In addition, maternal immune responses induced by alloimmunization against isolated mutant class I or class II, as well as by immunization with class I MHC alloantigens (K^d) transfected L cells are sufficient to restore normal fetal viability. It is not necessary that the maternal immune response be specifically directed against paternal alloantigens fr the fetal protecton to ensue, since the effect occurs in inbred matings when the mother is immunized against unrelated class I or class II alloantigens. As in previous studies conducted in the murine species, not all MHC alloimmunizations are protective. In addition, as control, immunization with a monomorphic class I MHC molecular (37), transfected L cells, sheep red blood cells or hen egg lysozyme is without effect. CONCLUSION : These results indicate that defined MHC antigens can mediate fetal protection from induced fetal resorption, and suggest that one driving force in promoting MHC antigen polymorphism in mammals is their capacity to confer protection from NK mediated fetal demise.     

An in vivo study of bone response to implants topographically modified by laser micromachining

Dental implants topographically modified by laser ablation of periodic arrays of micron-sized craters, were studied in a two-part laboratory investigation. The patterned and control (turned) implants were inserted in rabbit femur and tibia. After 12 weeks the fixation in the bone was evaluated mechanically or by histomorphometry (all threads along the implant and the three best consecutive threads were analysed).In the pilot study no difference was found with respect to bone-to-implant contact and peak removal torque. Significantly more bone was found for the control implants when measuring the bone area inside the threads in the tibia.In the second part of the study, the pattern was improved and significantly more bone-to-implant contact was found for the laser-machined implants. The second part of the study also demonstrated significantly greater peak removal torque values in the tibia with the test implants than the control implants.     

Design,synthesis, tandem mass spectrometric sequencing and biological activity of NGF mimetics

Nine low molecular weight nerve growth factor (NGF)-like peptides have been designed to mimic the putative receptor-binding epitope of NGF defined by two β-hairpin loops. Eight different spacers were used as variable links between the β-loop amino acid residues, which from mutagenesis experiments were found to play an important role in the biological activity of NGF. These spacers were amino acids, natural or non-natural, differing in length (5–13 Å) and polarity. The peptides were synthesized via the Fmoc solid-phase peptide synthesis and purified by reversed-phase HPLC. Their primary sequences were analyzed by a combination of automated Edman degradation and mass spectrometry. The peptides were tested using two different biological assays, the fibre outgrowth from chick embryonic sympathetic ganglia and the PC 12 cell differentiation assay. Weak antagonistic effects could be observed for some peptides. © Munksgaard 1996.     

The Role of Catheter Ablation Techniques in the Treatment of Classic (Type 1) Atrial Flutter

Several attempts at circuit interruption of type 1 atrial flutter by means of surgical or catheter techniques have been published. We recently reported the results of a series of patients who underwent catheter fulguration of the low septal right atrium, with a mean follow-up of almost 3 years. True electrophysiological success was observed in 7/14 patients (50%). Clinical success, defined as absence of symptoms, was observed in 8/14 (57%) in this patient population. No serious complications were encountered, but the potential risks of DC shock, and the experience that we gained in right atrial mapping using this approach, led us to reconsider the role of atrial DC ablation in these patients. Additional studies assessing the meaning of fragmented electrograms, and identification of one for of severall slow conduction areas of the reentrant circuit are ongoing.     

Doublet of action potentials evoked by intracellular injection of rectangular depolarization current into rat motoneurones

A doublet of action potentials is frequently observed at the beginning of motoneuronal discharge patterns and its appearance leads to a considerable increase in the motor unit force. The aims of this study were (1) to determine the relationship between the intensity of rectangular depolarization currents injected into motoneurones and their ability to generate doublets and (2) to evaluate the influence of the initial doublets on changes in motoneuronal firing frequency. Experiments were performed on anesthetized rats, and recordings were taken from motoneurones located in the L4–L5 segments of the spinal cord. The depolarization current necessary to evoke the initial doublet of action potentials was measured and expressed in multiples of the rheobase. A gradual increase in the intensity of current injected into motoneurones resulted in initial doublets in 80% of the cases studied, at doublet threshold ranges between 1.25 and 4.0 times the rheobase. This suggests that doublets are an effect of strong synaptic excitation of motoneurones that may precede a sudden change in force during a movement. Moreover, in the great majority of the studied motoneurones, this initial doublet caused changes in the subsequent firing rate by the prolongation of the first interspike interval.     

Toxic oxygen metabolites induce vasoconstriction and bronchoconstriction in isolated, plasma-perfused rat lungs

Effects of toxic oxygen metabolites (TOM) on the pulmonary vascular bed and airways were studied in isolated, plasma-perfused rat lungs. TOM were generated by xanthine oxidase (XO) (0.1 or 0.25 unit.ml-1) and hypoxanthine (HX) (1 mol.l-1). In vitro measurements by chemiluminescence indicated that the major oxygen metabolite generated by XO and HX was H2O2. Measurements of PO2 in the perfusate as an indicator of O2-consumption suggested that production of TOM by XO and HX was finished within 30 min. XO and HX induced an early dose-dependent bronchoconstriction and a late increase in transpulmonary pressure (Ptp). Pulmonary arterial pressure (Ppa) increased gradually and levelled off within 30 min with low-dose XO, but not with high-dose XO. As judged by weight increase of the lungs, interstitial edema occurred regularly. Allopurinol, an inhibitor of XO, blocked the lung responses caused by XO and HX. Catalase attenuated all lung responses induced by XO and HX, while superoxide dismutase had no effect. The hydroxyl radical scavenger dimethylsulfoxide abolished the increase in Ptp and attenuated the increase in Ppa, but did not consistently protect the lungs from edema development. This study shows that TOM induce vasoconstriction, bronchoconstriction and lung edema in plasma-perfused rat lungs, mainly due to generation of H2O2 and the hydroxyl radical.     

Atrial Septal Versus Atrial Appendage Pacing:

HERMIDA, J.-S., et al. : Atrial Septal Versus Atrial Appendage Pacing: Feasibility and Effects on Atrial Conduction, Interatrial Synchronization, and Atrioventricular Sequence. Atrial septal (Se-P) and atrial appendage pacing (Ap-P) were compared in a randomized, controlled study to assess the feasibility, the reliability, and the effects of Se-P on atrial conduction, interatrial synchronization, and the AV sequence. The main baseline characteristics of the patients were comparable in both groups. There was no difference in feasibility or reliability between the two techniques. Compared to Ap-P   (n = 28)   , Se-P   (n = 28)   decreased the P wave duration, left atrial electromechanical delay (LAEMD), and interatrial interval (−1.6% vs   +28%, P < 0.001; −3%   vs   + 30%, P < 0.001; −130%   vs   + 78%, P < 0.001   ); it induced a smaller increase of the right AEMD, a slight reversal of the timing of the atrial systoles and a shortening of the PR interval (−13% vs   + 25%, P < 0.001   ) and of the interval separating atrial systoles from ventricular activation. Finally, the shortening of the PR interval was smaller during high Se-P versus low Se-P. Se-P avoids the undesirable prolongation of the atrial, interatrial, and AV conductions observed during Ap-P. In addition, Se-P creates a slight reversal of the timing of the atrial systoles and induces a shortening of PR interval, the extent of which could depend on the height of the pacing site on the septum. (PACE 2003; 26[Pt. I]:26–35)