Israel Medical Association Journal

Objectives: To test whether an early change in neurohormonal and inflammatory markers after implantation can predict the clinical response to CRT.

Methods: The study group included 32 patients with advanced symptomatic systolic heart failure and a prolonged QRS complex and who were assigned to undergo CRT. Baseline plasma levels of B-type natriuretic peptide and high sensitivity C-reactive protein were determined in the peripheral venous blood and coronary sinus. Post-implantation levels were determined 2 weeks post-procedure in the PVB[2]. Baseline levels and their change in 2 weeks were correlated with all-cause mortality and hospitalization for congestive heart failure.

Results: At baseline, coronary sinus levels of BNP[3] but not hsCRP[4] were significanly elevated compared to the PVB. Compared to baseline levels, BNP and hsCRP decreased significantly within 2 weeks after the implantation (BNP mean difference 229.1 ± 102.5 pg/ml, 95% confidence interval 24.2–434, P < 0.0001; hsCRP mean difference 5.2 ± 2.4 mg/dl, 95% CI[5] 0.3–10.1, P = 0.001). During a mean follow-up of 17.7 ± 8.2 months 6 patients died (18.7%) and 12 (37.5%) were hospitalized due to exacerbation of CHF[6]. Baseline New York Heart Association and CS[7] BNP levels predicted CHF-related hospitalizations. HsCRP levels or their change over 2 weeks did not predict all-cause mortality or hospitalizations.

Conclusions: BNP levels in the CS and peripheral venous blood during biventricular implantation and 2 weeks afterwards predict cilinical response and may guide patient management.

Polyubiquitylation of cellular proteins has long been recognized as a prelude to a degradative fate in proteasomes. In recent years, however, ubiquitin conjugation has emerged as a regulatory strategy of considerable versatility. Most notably, monoubiquitylation is attributed an intimate role in trafficking of membrane proteins between various cellular compartments. Diverse classes of transmembrane proteins from across the eukaryotic spectrum (e.g., epidermal growth factor-receptor and other receptor tyrosine kinases) become modified with monoubiquitin molecules. Monoubiquitylation of substrates, in turn, regulates both their endocytosis at the plasma membrane and sorting in endosomes for delivery to lysosomes or vacuoles. A mechanistic rationale lies in the identification of a growing list of ubiquitin-binding domains carried by a variety of endocytic adaptor proteins. Thus, ubiquitin-conjugated membrane proteins may form extensive contacts with the endocytic machinery. Further, ubiquitin-binding adaptors and other endocytic components are, likewise, often monoubiquitylated. In this case, ubiquitin conjugation may serve to enhance intermolecular avidity in cargo-bound endocytic complexes, or alternatively, to mediate timely inactivation of ubiquitin-binding adaptors. Interestingly, the ubiquitin/endocytosis interface is appropriated by pathogenic organisms, for instance, during budding of viruses from host-infected cells. Moreover, compromised ubiquitin-mediated transport of certain signaling receptors is associated with disease states, including oncogenic transformation.

We describe a unique E3, the F-box protein, Ufo1, of yeast. Ufo1 recruits the mating switch endonuclease, Ho, to the SCF complex for ubiquitylation. In addition to the F-box and WD40 protein-protein interaction domains found in all F-box proteins, Ufo1 has a unique domain comprising multiple copies of the ubiquitin-interacting motif. Ufo1 interacts with the UbL-UbA protein, Ddi1, via its UIMs[1], and this is required for turnover of SCF ^Ufo1 complexes. This is a novel function for an UbL-UbA protein. Deletion of the genomic UFO1 UIMs is lethal and our data indicate that Ufo1ΔUIM acts as a dominant negative leading to inhibition of the SCF pathway of substrate degradation and to cell cycle arrest. Furthermore, we found that Ddi1 is required for the final stages of degradation of Ho endonuclease. In the absence of Ddi1, Ho does not form a complex with the 19S RP and is stabilized. Stabilization of Ho leads to perturbation of the cell cycle and to the formation of multi-budded cells. Our experiments uncover a novel role for the ubiquitin-proteasome system in maintenance of genome stability.

In this issue of IMAJ, two articles discuss and review the roles of chronic airway infection (1) and inflammation (2) respectively in cystic fibrosis lung disease.

Background: Heat shock proteins are highly conserved immunodominant antigens found in various species. Humoral immune responses to mycobacterial HSP65[1] and human HSP60 have been established in a number of human autoimmune diseases.

Objective: To assess the prevalence of antibodies to HSP60 kDa and HSP65 kDa in patients with Sjogren's syndrome as compared to normal subjects.

Methods: Thirty-seven patients with SS[2] were compared with normal controls. The antibodies against human HSP60 were measured by the Anti-Human (IgG/IgM) HSP60 ELISA kit. IgGs[3] and IgMs to mycobacterial HSP65 were determined using an enzyme-linked immunosorbent assay with mycobacterial recombinant HSP65 antigens.

Results: The levels of both anti-HSP60 and -HSP65 were lower among patients compared with controls. IgG autoantibodies to HSP60 were significantly different between groups: 162 ± 55.1 ng/ml in controls versus 112.3 ± 30.6 ng/ml in SS patients (P < 0.001). The levels among controls of anti-HSP65 IgM isotype were also significantly higher than among patients: 111.6 ± 33.4 U/ml versus 96.1 ± 8.9 U/ml (P = 0.01).

Conclusions: The results of the present study show that the levels of different isotypes of anti- HSP60 and HSP65 antibodies were lower in patients with SS than in normal subjects. Additional studies on larger patient populations are required to evaluate the prevalence of these autoantibodies in SS patients.

Background: Food allergies in children are often very serious and can lead to anaphylactic reactions. Observations that camel milk ameliorates allergic reactions were noted over the years. The effect of the camel milk is probably related to its special composition.

Objectives: To investigate the effect of camel milk in several children with severe food (mainly milk) allergies.

Methods: We studied eight children with food allergies who did not benefit from conventional treatment. Their parents, or their physicians, decided to try camel milk as a last resort. The parents were advised by the authors – who have considerable experience with the use of camel milk – regarding how much and when the children should drink the milk. The parents reported daily on the progress of their children.

Results: All eight children in this study reacted well to the milk and recovered fully from their allergies.

Conclusions: These encouraging results should be validated by large-scale clinical trials.

Epidemiologic data demonstrate a long-linear realationship between low density lipoprotein-cholesterol levels and risk of coronary heart disease.

Objectives: To examine whether the treatment recommendations given to ischemic heart disease patients at hospital discharge are compatible with the guidelines of the Israeli Medical Societies and the U.S. National Cholesterol Education Program for coronary artery disease prevention; and to study the effects of brief educational sessions on the adherence of physicians with the guidelines.

Methods: We included consecutive IHD[1] patients admitted to four central hospitals in Israel between 1998 and 2000. The study was conducted in two phases. In phase 1, we reviewed discharge letters to document treatment recommendations given to each patient. In phase 2 we educated the practitioners by reviewing the Israeli Medical Societies and the NCEP[2] guidelines and the quality of their recommendations in phase 1, after which we reevaluated the discharge letters.

Results: The study included 2,994 patients: 627 in phase 1 and 2,367 in phase 2. Of the patients who needed cholesterol-lowering according to their low density lipoprotein levels, 37.4% were not prescribed such drugs at discharge (under-treatment group). This proportion was reduced by education to 26.6% (P < 0.001) in phase 2. Of the treated patients, 65.6% did not reach the target LDL[3] goal in phase 1 (under-dosage group) as compared to 60.2% in phase 2 (P = 0.23). In phase 2 there was an increase in the percent of patients reaching LDL levels <130 mg/day (69.3% vs. 63.8% of patients prescribed medication, P = 0.01), but the percent of patients reaching LDL levels <100 was not different in phase 2 after adjusting for age and gender (the odds ratio for reaching target LDL was 1.16, with 95% confidence interval of 0.95–1.43).

Conclusions: Physician recommendations to IHD patients discharged from hospital were suboptimal. We documented a high proportion of under-treated and under-dosage patients. Brief educational sessions have a beneficial effect on the usage of statins; however, additional effort in guideline implementations is needed.

Objectives: To describe the role of wireless capsule endoscopy in diagnosing isolated small intestinal Crohn’s disease in two adolescents.

Methods: Wireless capsule endoscopy was performed in two adolescents with severe protein-losing enteropathy and negative standard diagnostic workup.

Results: Wireless capsule endoscopy successfully diagnosed Crohn’s disease with uncharacteristic presentations and negative radiographic and endoscopic findings in both patients.

Conclusions: The non-invasiveness and ease in performance of capsule endoscopy on an ambulatory basis make this diagnostic modality especially advantageous for children.