Israel Medical Association Journal

Background: Genetic hemochromatosis leads to iron overload in many tissues and may lead to liver cirrhosis and hepatocellular carcinoma. Early diagnosis and therapy are crucial. Since 80–100% of hemochromatosis patients of European origin are homozygous for a cysteine to tyrosine exchange in the HFE gene at codon 282, genetic screening might be useful. Representative population studies are needed to evaluate the phenotype of people heterozygous and homozygous for the C282Y mutation.

Objective: To determine the correlation between parameters of iron metabolism and the hemochromatosis genotype in a large population-based study.

Methods: A representative population-based survey, the Diabetomobil study, analyzed 5,083 German probands. Serum transferrin saturation and ferritin levels were determined, and the C282Y mutation of the HFE gene was analyzed by restriction fragment length polymorphism- polymerase chain reaction analysis.

Results: Nine of 373 probands with a transferrin saturation > 55% (2.4%) and none of 264 randomly selected probands with a transferrin saturation £ 55% (0%) were homozygous for the C282Y mutation. Three of the nine homozygous probands had ferritin values less than 250 µg/L. The frequency of the heterozygous genotype was 8.8%, and the percentage of heterozygous probands increased with increasing levels of transferrin saturation.

Conclusion:We propose a population screening strategy with an initial transferrin saturation test, followed by genotyping for the C282Y mutation if the transferrin saturation is above 55%, regardless of the ferritin level. Heterozygous individuals with higher transferrin saturation values may be protected against iron loss but may also be more susceptible for certain liver diseases, depending on the simultaneous prevalence of other diseases.
 

In recent years, umbilical cord blood has emerged as an alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients who lack an human leukocyte antigen-matched marrow donor. Since 1998, about 2,500 patients have received UCB[1] transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20 kg, however more than 500 UCB transplantations have already been performed in adults. The “naive” nature of UCB lymphocytes may explain the lower incidence and severity of graft versus host disease encountered in UCBT[2] compared to the allogeneic transplant setting. Furthermore, UCB is rich in primitive CD16^-CD56⁺⁺ natural killer cells, which possess significant proliferative and cytotoxic capacities and can be expanded using interleukin-12 or 15, so as to mount a substantial graft versus leukemia effect. The major disadvantage of UCB is the low yield of stem cells, resulting in higher graft failure rates and slower time to engraftment compared to bone marrow transplantation. A rational approach thus involves ex vivo expansion of UCB-derived hematopoietic precursors.

Background: Ovarian vein embolization was recently suggested as the preferred treatment for chronic pelvic pain syndrome.

Objective: To evaluate the technical feasibility, complications and early clinical and radiographic results of ovarian vein embolization in women with pelvic pain syndrome.

Methods: Percutaneous transcatheter ovarian vein embolization with coils was performed in six patients aged 27–53 years who presented with pelvic pain syndrome. All had lower abdominal pain, and pelvic varicosities were found on Doppler ultrasound and retrograde ovarian vein venography. Embolization was done unilaterally in three patients (on the left side) and bilaterally in three. Mean follow-up by telephone questionnaire was 7.3 months.

Results: The procedure was technically successful in all patients. Two patients reported partial relief of symptoms (33.3%) and three had complete relief (50%), for a total of 5 patients (83.3%) with some measure of improvement. There were no complications following the procedure.

Conclusions: Percutaneous transcatheter ovarian vein embolization seems to be safe and feasible for the treatment of pelvic pain syndrome. The procedure is performed on an outpatient basis and is well tolerated by patients.

Background: Nasal colonization with methicillin-resistant Staphylococcus aureus in the community is being increasingly reported, but there is a general lack of data on MRSA[1] colonization in children in chronic care institutions and on colonization rates in Israeli children.

Objectives: To define the rate of MRSA nasal colonization in a generally healthy pediatric population in Jerusalem, to compare it with that of children in chronic care institutions, to define risk factors for colonization, and to compare community and hospital-acquired MRSA strains.

Methods: Anterior nares culture for the presence of methicillin-sensitive and methicillin-resistant S. aureus was taken from 831 healthy children attending primary pediatric clinics or emergency department and 118 children hospitalized in three chronic care institutions in Jerusalem.

Results: Of the 831 healthy children, 195 (23.5%) were colonized with S. aureus, as compared to 43 of 118 (36.4%) chronically institutionalized children (P < 0.005). Five of the 195 S. aureus isolates from healthy children (2.6%) were MRSA, as compared to 9 of 43 (21%) from chronically institutionalized children (P < 0.001). Older age and a family member who is a healthcare worker were associated with S. aureus colonization in the population of healthy children, and older age was associated with MRSA colonization in the chronically institutionalized children. The antibiotic susceptibility pattern was similar for both groups, and pulsed field gel electrophoresis of the isolates showed a wide and random distribution in both groups.

Conclusions: MRSA colonization in the studied pediatric community in Jerusalem was very low, whereas that of patients hospitalized in chronic care institutions was significantly higher. In the small number of isolates detected, no significant differences were found in antibiotic susceptibility or PFGE[2] pattern between hospital-acquired and community-acquired strains.

Background: Reperfusion practices have changed markedly over the last few years with the introduction of primary percutaneous coronary intervention. This technique has gained growing popularity in Israel, but little published data are available regarding the delays to primary PCI[1] in real life in this country.

Objectives: To examine temporal trends in time to reperfusion achieved in a large tertiary center over 6 years.

Results: Between 1997 and 2002, 1,031 patients were admitted to our hospital with ST elevation myocardial infarction. Of these, 62% underwent thrombolysis and 38% primary PCI. The proportion of patients referred for primary PCI increased steadily, from 14% in 1997 to 68% in 2002. Door to treatment time among patients referred for thrombolysis or primary PCI was 54 ± 42 and 117 ± 77 minutes, respectively (P < 0.00001). The door to needle time in patients given thrombolysis remained virtually unchanged during the study period at around 54 minutes. In contrast, the door to balloon time has progressively and substantially decreased, from 175 ± 164 minutes in 1997 to 96 ± 52 minutes in 2002.

Conclusions: There is a steady increase in the proportion of patients referred for primary PCI than for thrombolysis. The door to needle delay in patients given thrombolysis substantially exceeds the recommended time. The door to balloon time has declined considerably but still slightly exceeds the recommended time. Given the inherent delay between initiation of lysis and arterial recanalization, it appears from our experience that PCI does not substantially delay arterial reperfusion as compared to thrombolysis. Efforts should continue to minimize delays to reperfusion therapy.

Background: The Dead Sea in Israel has a very high mineral content. Near-drowning in the Dead Sea is expected to result in severe electrolyte abnormalities and respiratory failure. Previous limited studies reported a high mortality rate.

Objective: To evaluate the clinical and biochemical manifestations and disease outcome of near-drowning in the Dead Sea.

Methods: Data were abstracted from the archives of Soroka University Medical Center. The cohort comprised 69 patients who nearly drowned in the Dead Sea.

Results: The median age of the patients was 68 years (range 21–84). There were two major manifestations of near-drowning in the Dead Sea: electrolyte imbalance and acute lung injury. Serum calcium, magnesium and phosphorus (but not sodium, potassium and chloride) were abnormal in most patients. Median serum electrolyte levels (and range) on admission were 10.9 mEq/dl (9–24) for calcium, 4.3 mEq/dl (1–30) for magnesium, and 4.1 mEq/dl (2–9) for phosphorus. These levels quickly normalized with forced diuresis within 24 hours. Acute lung injury – namely, hypoxic bilateral pneumonitis – occurred in 29 patients. Mechanical ventilation was required in 11 patients. Sixty-five patients recovered fully, while the remaining 4 had minor sequelae.

Conclusions: Near-drowning in the Dead Sea is a syndrome of severe electrolyte abnormalities and lung injury. Early treatment, with forced diuresis and supportive care, results in prompt recovery.

Background: The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo.

Objectives: To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or negative transdominants (Tat, Rev).

Methods: Human monocytoid cell line (U937) was transfected with IFNa[1], b or g genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1[2]. Viral load was followed.

Results: IFNa or b were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo.

Conclusions: Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.

Background: Transcobalamin II is a serum transport protein for vitamin B₁₂. Small variations in TC-II[1] affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B₁₂ deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes.

Objectives: To study 23 members of a four-generation family with hereditary vitamin B₁₂ deficiency and neurologic disorders.

Methods: Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members.

Results: Partial TC-II deficiency was found in 19 subjects. Apo TC- II (free TC-II unbound to vitamin B₁₂) and total unsaturated B₁₂ binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B₁₂) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B₁₂ levels but were not anemic. Low serum B₁₂ levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B₁₂ injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency.

Conclusions: We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances – despite normal serum vitamin B₁₂ levels. Low serum UBBC[2] and apo TC-II should confirm the diagnosis. Early vitamin B₁₂ therapy may prevent irreversible neurologic damage.

The human placenta is the interface between the mother and fetus in the uterus. Until recently it was generally believed that the uterus provides a protective environment for the fetus. It is now accepted that any chemical substance, including any therapeutic agent, administered to a mother is able to permeate across the placental barrier. Unfortunately, the placental transfer of substances and their distribution in the placenta is not well established. Understanding the structure of placental transporters and their function may serve as the ideal tool for drug development and the cure of mother and fetus during pregnancy.