Israel Medical Association Journal

Background: Granulocyte colony-stimulating factor has had a major impact on the management of severe chronic neutropenia – a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF[1] with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia (termed Kostmann’s syndrome herein) and Shwachman-Diamond syndrome have developed myelodysplastic syndrome and acute myeloid leukemia, which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS[2] or AML[3] as part of their natural history.

Objective and Methods: To address this, the Severe Chronic Neutropenia International Registry used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics.

Results: As of January 2001, of the 383 patients with congenital forms of neutropenia in the Registry, 48 had MDS or AML (crude rate, about 12.5%). No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from Kostmann’s syndrome patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. The latter in murine models produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival.

Conclusions: Since Kostmann’s syndrome and Shwachman-Diamond syndrome are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of Kostmann’s syndrome patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an innocent bystander that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. Only careful long-term follow-up of the cohort of patients receiving G-CSF will provide the answer.

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[1] G-CSF = granulocyte colony-stimulating factor

[2] MDS = myelodysplastic syndrome

[3] AML = acute myeloid leukemia

Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients.

Objective: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls.

Methods: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212-sporadic and 56 carriers of either a BRCA1:or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent auloradiography,

Results: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only {3/536, 0.6%).

Conclusions: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.
 

Background: The most frequent cause of defect in the mandible is tumor-related surgery. Larger defects or anterior arch defects cause severe morbidity due to disturbances in function and aesthetics.

Objectives: To assess the outcome of free tissue transfer for mandible reconstruction.

Methods: Since 1998 we operated on 11 patients with mandible defects using the fibula flap as the reconstruction method. We performed immediate reconstruction in eight patients after ablative surgery, and late reconstruction due to radiation-induced complications in three.

Results: All patients achieved good functional and aesthetic outcome. During the follow-up period two patients died of their malignant disease and one patient died from a non-related cause. Although two patients underwent reoperation in the first 3 months after their primary operation due to fixation failure, there were no other major complications.

Conclusions: According to the literature and our limited experience, the fibula flap is a safe and reliable option for mandible reconstruction.
 

The threat of a disease outbreak resulting from biologic warfare has been of concern for the Israeli health system for many years. In order to be prepared for such an event the health system has formulated doctrines for various biologic agents and defined the logistic elements for the procurement of drugs. During the last 4 years, and especially after the West Nile fever epidemic in 2000, efforts to prepare the healthcare system and the relevant organizations were accelerated. The Director-General of the Ministry of Health nominated a Supreme Steering Committee to fill in the gaps and upgrade the preparedness of the health system for an unusual disease outbreak. This committee and its seven subcommittees established appropriate guidelines, communication routes among different organizations, and training programs for medical personnel. The anthrax outbreak in the United States found the healthcare system in the hub of the preparation process, and all modes of action were intensified. Further work by hospitals, primary care clinics and all other institutes should be initiated to maintain a state of proper preparedness.

Background: As air travel increases and the number of commercial and non-commercial flights rises so does the number of aircraft accidents. The improved safety standards of the aviation industry result in a growing number of survivors of aircraft crashes, but there are no management guidelines for the treatment of aircraft crash survivors.

Objectives: To present our experience in treating five survivors of a light aircraft crash that occurred in August 1995 near Jerusalem.

Results: All five survivors sustained vertebral column injuries, which was the only injury in most of the survivors. We discuss the mechanism of injury.

Conclusions: Investigation of injuries’ pattern in survivors of aircraft crash is important for establishing management protocols in trauma centers.
 

Background: Genetic factors have been shown to play a major role in the development of peak bone mass, with hereditability accounting for about 50-85% of the variance in bone mass. Numerous candidate genes were proposed to be involved in osteoporosis, but the precise genes and their relative contribution remain unknown.

Objectives: To gain insight into the genetic basis of idiopathic low bone mineral density in Israeli patients by analyzing the impact of two candidate genes: polymorphism of the vitamin D receptor gene and polymorphism A986s in the calcium-sensing receptor gene.

Methods: We analyzed 86 Jewish Israeli patients with LBMD[1]: 38 premenopausal women and 48 men, and compared the allelic pattern distribution with that of the general population (126 men and 112 women). Genotyping of the VDR[2] gene was performed in three polymorphic sites using restriction enzymes, and allelic analysis of A986s polymorphism in the CaSR[3] gene was performed using the denaturing gradient gel electrophoresis technique.  

Reaults: In LBMD women the distributions of VDR alleres in Apal polymorphism were AA=7/28, Aa=16/28 and aa=5/28; in TaqI polymorphism TT=10/31, Tt=16/31 and tt=5/31; and in BsmI polymorphism BB=7/32, Bb=14/32 and 11/32. In LBMD men the distributions were AA=17/39, Aa=21/39 and aa=1/39; in TaqI polymorphism TT=12/42, Tt=23/42 and tt=7/42; and in BsmI polymorphism BB=12/41 Bb=18/41 and bb=11/41. The distributions of all these polymorphisms in the control groups were not significantly different. Adjusting for the independent age and gender parameters confirmed that these three polymorphisms of the VDR gene did not have a significant effect on bone mineral density. Thirty percent (24/79) of LBMD patients of either sex displayed heterozygosity of the CaSR A986s polymorphism, compared with 40 of 203 controls (19.7%) (P=0.059). Adjusting for age and gender in these patients revealed a significant difference in the femoral neck BMD[4] between homozygotes and heterozygotes (P=0.002). The age at menarche of the LBMD women was found to predict 61% of the variance of femoral neck BMD.

Conclusions: In Israeli Jewish men and premenopausal women VDR gene alleles do not seem to be associated with lower lumbar spine or femoral neck BMD. A trend towards heterozygosity for a CaSR polymorphism missense mutation was noted in the LBMD patients. Age at menarche in the LBMD women was found to be an important predictor of BMD. A significant difference was found between LBMD women and healthy control women towards heterozygosity for a CaSR polymorphism, as well between homozygotes and heterozygotes for a CaSR polymorphism in BMD. The significance of these findings and their applicability to a larger population awaits further studies.

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Background: Lithium has been a part of the psychiatric pharmacopoeia for more than half a century. Its efficacy is marred by a narrow therapeutic index and significant toxicity.

Objectives: To increase physicians’ awareness of the various manifestations of lithium intoxication.

Methods: We reviewed the clinical data of cases of lithium poisoning occurring in a municipal hospital during a 10 year period.

Results: Eight patient records were located. The mortality rate was 12.5%. All patients were women and the mean age was 66.4 years. The most common symptoms were neurological. One illustrative case is described in detail with lithium serum levels showing the usual two-phase decline.

Conclusions: Lithium poisoning can present in many forms. Increased physician awareness and the early use of effective treatment, mainly hemodialysis, will prevent mortality and protracted morbidity associated with this condition.
 

Background: The emergency department is one of the hospital’s busiest facilities and is frequently described as a bottleneck. Management by constraint is a managerial methodology that helps to focus on the most critical issues by identifying such bottlenecks. Based on this theory, the benefit of adding medical staff may depend on whether or not physician availability is the bottleneck in the system.

Objective: To formulate a dynamic statistical model to forecast the need for allocating additional medical staff to improve the efficacy of work in the emergency department, taking into account patient volume.

Methods: The daily number of non-trauma admissions to the general ED[1] was assessed for the period 1 January 1992 to 1 December 1995 using the hospital computerized database. The marginal benefit to shortening patient length of stay in the ED by adding a physician during the evening shift was examined for different patient volumes. Data were analyzed with the SAS software package using a Gross Linear Model.

Results: The addition of a physician to the ED staff from noon to midnight significantly shortened patient LOS[2]: an average decrease of 6.61 minutes for 80–119 admissions (P<0.001). However, for less than 80 or more than 120 admissions, adding a physician did not have a significant effect on LOS in the ED.

Conclusions: The dynamic model formulated in this study shows that patient volume determines the effectiveness of investing manpower in the ED. Identifying bottleneck critical factors, as suggested by the theory of constraints, may be useful for planning and coordinating emergency services that operate under stressful and unpredictable conditions. Consideration of patient volume may also provide ED managers with a logical basis for staffing and resource allocation.

Background: Leptin is a 16 kDa hormone synthesized by adipocytes and involved in body weight regulation.

Objectives: To determine serum leptin concentrations in heart, liver and kidney transplant recipients.

Methods: We investigated 57 patients: 18 male heart transplant recipients (age 25-69 years) at 1-66 months after transplantation, 6 female and 8 male liver transplant recipients (age 33-70) at 11-73 months after transplantation, and 10 female and 15 male kidney transplant recipients (age 20-61) at 3-138 months after transplantation. All recipients were receiving immunosuppressive therapy, including prednisone 0-20 mg/day, azathioprine 75-125 mg/day, cyclosporin 100-250 mg/day or tacrolimus 2-10 mg/day. The results were compared to those of 10 female and 10 male healthy controls. Morning serum concentrations of leptin were measured with a commercial radioimmunoassay (Linco Research Inc., USA), and serum insulin and cortisol levels were measured by radioimmunoassay.

Results: Patients (both men and women) after heart, liver and kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/body mass index ratios than controls. Serum leptin concentrations were significantly higher in women than in men and correlated very significantly with BMI[1] in all cases. The multivariate stepwise analyses showed that among parameters including BMI, gender, age, time after transplantation, prednisone dose, hematocrit, serum concentrations of glucose, albumin, creatinine, cortisol and insulin, only BMI, gender, cortisol and insulin were significant independent determinants of serum leptin levels in these patients.

Conclusions: This is the first report showing that, in addition to body mass index and gender, basal cortisol and insulin levels affect the hyperleptinemia in transplant patients. The clinical relevance of hyperleptinemia in these patients will require further investigation.