Israel Medical Association Journal

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.

Background: Primary pulmonary hypertension is a rare disorder, characterized by progressive pulmonary hypertension and right heart failure. It may be familial or sporadic. Mutations in bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor-beta receptor superfamily of receptors, underlie many cases of the disorder.

Objectives: To perform molecular analysis of a patient with familial PPH[1] and provide her and her family with suitable genetic counseling.

Methods: DNA was extracted from 10 ml whole blood, and the BMPR2 gene was screened for mutations. Individual exons were amplified by polymerase chain reaction and sequenced. Mutation confirmation and molecular characterization of additional family members was performed using restriction enzyme analysis followed by appropriate genetic counseling.

Results: We identified a novel T to C missense mutation expected to result in substitution of arginine for a conserved cysteine in the ligand-binding domain of BMPR2. Screening of family members demonstrated the presence of the mutation in the father and a younger asymptomatic sister of the index patient.

Conclusions: Molecular diagnosis in PPH allows for identification of at-risk family members and raises the option of earlier diagnosis and possibly instituting earlier treatment in affected individuals. However, molecular screening of asymptomatic family members raises difficult ethical questions that can only be resolved by conducting large multicenter prospective studies in BMPR2 carriers.

Background:  One of the major reasons for the shortage of organs for transplantation in Israel is the failure to identify potential donors. According to the World Health Organization, the expected number of potential donors in Israel is 300 per year. In recent years an average of only 200 donors (2/3) has been identified.

Objective: To identify the reasons for the gap between the potential and the actual number of organ donors.

Methods: We reviewed the medical records of all potential donors at the Soroka University Medical Center between October 1997 through September 1999.

Results: The total of 183 death records was consistent with the minimal inclusion criteria for potential organ donation, of which 41 were suspected to be potential brain death (PBD) In 31 cases an ad hoc committee had declared brain death, and the patients were evaluated for organ donation. However, in 10 cases no committee was formed. We found that 24.4% (10/41) of the potential donors had not been designated as such by their medical team.

Conclusion: We believe that a comprehensive education program for medical and nursing staff might increase awareness for organ donation and may eliminate the gap between the potential and actual number of organ donors.

Background: Intestinal malrotation is usually observed in the neonatal period with signs of acute high intestinal obstruction due to midgut volvulus. However, malrotation presenting beyond the neonatal period and well into adult life is associated with a variety of atypical and frequently non-specific gastrointestinal symptoms that may often cause prolonged delay in diagnosis and appropriate treatment.

Objectives: To emphasize the difficulty in predicting the risk of midgut volvulus based on age or symptoms, and to recommend surgery in all patients found to have intestinal malrotation even if they are considered asymptomatic.

Methods: We reviewed 41 patients with malrotation treated over a period of 24 years at the Soroka University Medical Center.

Results: In our series, 27 patients (66%) had acute midgut volvulus while 14 (34%) had malrotation found during investigation of various long-term gastrointestinal non-specific symptoms. Two patients died of total parenteral nutrition-related sepsis following extensive resection of small bowel. A total of 28 patients was available for long-term follow-up and are asymptomatic.

Conclusions: We recommend elective laparotomy and Ladd procedure in all patients found to have intestinal malrotation. This will prevent the catastrophic results of midgut volvulus and a variety of gastrointestinal symptoms wrongly attributed to other conditions in the span of a lifetime.

Fanconi anemia is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancy. FA cells are sensitive to DNA cross-linking agents. Complementation analysis of FA cells using somatic cell fusion has facilitated the identification of eight complementation groups, suggesting that FA is a genetically heterogeneous disorder. Six genes (FANCA, FANCC, FANCD2, FANCE, FANGF, FANCG) have been cloned so far. The majority of affected patients belong to FA group A. Of the 32 unrelated Israeli patients with FA that we studied, 6 carried the FANCC mutations and 15 the FANCA mutations. Among the Jewish patients, ethnic-related mutations were common. Recent cumulative evidence suggests that the FA proteins are repair proteins. FANCC, FANCA and FANCG bind and interact in a protein complex found in the cytoplasm and nucleus of normal cells. FANCD2 exists in two isoforms; the long active form, FANCD2-L, is absent from FA cells of all complementation groups. FANCD2 co-localized with BRCA1 in unclear foci, probably as part of a large genomic surveillance complex. Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-g hypersensitivity and show progressive apoptosis. The definition of the molecular basis of FA in many affected families now enables prenatal diagnosis.

Background: Concern about the side effects of allogeneic blood transfusion has led to an increased interest in methods of minimizing peri-operative transfusion. Technologies to minimize allogeneic transfusion include drugs such as aprotinin, desmopressin, tranexamic acid and erythropoietin, and techniques such as acute normovolemic hemodilution, cell salvage and autologous pre-donation.

Objective: To survey the current use in Israel of these seven technologies used to minimize allogeneic blood transfusion.

Methods: Our survey was conducted in 1996–97 in all hospitals in Israel with more than 50 beds and at least one of the following departments: cardiac or vascular surgery, orthopedics, or urology. All departments surveyed were asked: a) whether the technologies were currently being used or not, b) the degree of use, and c) the factors influencing their use and non-use. The survey was targeted at the heads of these departments.

Results: Pharmaceuticals to reduce allogeneic blood transfusion were used in a much higher proportion in cardiac surgery departments than in the other three departments. Pre-operative blood donation was used in few of the cardiac, urologic and vascular surgery departments compared to its moderate use in orthopedic departments. The use of acute normovolemic hemodilution was reported in a majority of the cardiac departments only. Moderate use of cell salvage was reported in all departments except urology where it was not used at all.

Conclusion: There is considerable practice variation in the use of technologies to minimize exposure to peri-operative allogeneic blood transfusion in Israel.