Fludarabine-based protocol for haploidentical peripheral blood stem cell transplantation in Hurler syndrome

To assess the feasibility of performing a haploidentical peripheral blood stem cell transplantation (PBSCT) in a child with Hurler syndrome after a novel conditioning regimen consisting of fludarabine monophosphate, anti-T-lymphocyte globulin, low-dose busulfan, and single-dose total body irradiation of 750 cGy. A 16-month old boy with Hurler syndrome underwent haploidentical PBSCT from his 3/6 HLA-matched sister. Pretransplant conditioning consisted of fludarabine (30 mg/m2 per day) from day -10 to day -5, busulfan (4 mg/kg per day) on days -7 and -6, rabbit anti-T-lymphocyte globulin (10 mg/kg per day) from day -4 to day -1, and total body irradiation of 750 cGy on day -1. In vitro T-cell depletion was carried out with rat antihuman CDw52 monoclonal antibody (Campath-1G). The fludarabine-based protocol was well-tolerated, with mild toxicity and no major transplant-related complications or graft-versus-host disease. Engraftment was complete and stable. Chimerism was 100% donor origin, as determined by restriction fragment length polymorphism. Cytogenetic and polymerase chain reaction-various number of tandem repeats (PCR-VNTR) analyses of peripheral blood and bone marrow showed 100% reconstitution with female donor cells. The patient underwent the transplant 30 months ago and is in good clinical condition, with normal counts, no signs of graft-versus-host disease, and no infectious episodes; neurologic signs have stabilized. Haploidentical PBSCT, T-cell-depleted by means of Campath-1G, may serve as a therapeutic alternative for patients with Hurler syndrome when a fully matched sibling is not available.     

Impaired liver function tests in patients treated with antithymocyte globulin: Implication for liver transplantation

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day — 1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 ± 37.7 U/l pre-treatment to 1394.4 ± 488.7 U/l 3 days post-treatment (n = 16;p < 0.029), and then declined to 561.4 ± 61.3 U/l 10 days post-treatment (n = 16;p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 ± 11.3 U to 184.6 ± 74.6 U (n = 16;p < 0.036), and then declined to 121.9 ± 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 ± 5.7 U to 152.0 ± 67.0 U (n = 16;p < 0.44) and then declined to 46.0 ± 14 (n = 16;p < 0.049). The mean r-glutamyltransferase (GTP) levels increased from 93.0 ± 34 to 188.0 ±36 (n = 16;p < 0.02), and were 168.0 ± 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 ± 1.9μM I^-1 to 22.7 ± 2.8 (n = 16); NS), at day +3 and to 31.9 ± 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.     

First trimester exposure to cefuroxime: a prospective cohort study

AIMS: There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime. METHODS: One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications. RESULTS: Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0. 61, relative risk = 1.56, 95% confidence interval 0.27-9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94-11.77). CONCLUSIONS: Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.     

Distribution of HIV type 1 infection in childbearing women in California.

The incidence of acquired immunodeficiency syndrome (AIDS) is increasing among California heterosexuals and children. To assess human immunodeficiency virus (HIV)-1 infection in childbearing women, we conducted a blinded serosurvey of newborns. Dried blood specimens taken from 99% of California births during the third quarter of 1988 (n = 135,808) and linked only to maternal demographic categories were tested for HIV-1 antibody by enzyme immunoassay and confirmed by Western blot. Period prevalence of HIV-1 infection was 7.4 per 10,000 childbearing women. Prevalence was highest for Black women and was also elevated for Hispanic and San Francisco Bay Area women. Findings suggest that California Hispanic women will make up an increasing proportion of new AIDS cases.     

Oropharyngeal cancer pathogenesis: ubiquitin proteolytic, apoptotic and epidermal growth factor related pathways act in concert--first report

The current study was carried out to examine the clinical characteristics and survival-probability rates of 51 patients treated for oral (tongue) cancer and to correlate it with various tumor markers. The clinical data and survival probability rates were correlated with the immunohistological analysis of p27, Skp2, p53, Bcl-2, TUNEL (apoptotic rate) and c-erbB-2 markers. The 5-year survival-probability correlated with staging, grading and base of tongue location. An inverse relation between the expression of p27 and Skp2, p27 and grading, and a direct relation between Skp2 and grading were demonstrated. Concomitantly, significant correlations between low p27, high Skp2 and high TUNEL (apoptotic rate) expressions and between low p27 and high c-erbB-2 (Her2) expressions in the cancer lesions were demonstrated. The accumulated data may be employed in the future for a better understanding of the biology behind oral cancer and for developing better means of detection and treatment.     

Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation

BACKGROUND: Stem cell transplantation (SCT) may be associated with premature aging of the hematopoietic stem cells. Telomere length reflects the proliferative history of a cell. In most studies published so far on telomere dynamics after myeloablative allogeneic SCT, recipients had shorter telomeres than their respective donors, thus reflecting "accelerated aging" of hematopoietic cells. We evaluated telomere dynamics in patients who underwent transplantation with nonmyeloablative protocols, assuming that the decreased intensity of chemotherapy might prevent telomere attrition. METHODS: Telomere length was measured using FISH-FACS method. Telomeres of recipients were compared to their respective donors. Twenty-three consecutive patients after nonmyeloablative SCT were evaluated. A control group consisted of 10 donor-recipient pairs after conventional myeloablative transplantation. RESULTS: There was significant telomere shortening in both recipients of nonmyeloablative and myeloablative conditioning (0.487+/-0.65 kb, P=0.003; 0.361+/-0.50 kb, P=0.047 respectively). The extent of telomere shortening in the two groups was not different (P=0.64). There was no correlation between the degree of shortening and parameters such as time interval from transplant, age of donor or recipient, and the number of infused cells. CONCLUSIONS: This is the first study on telomere dynamics after nonmyeloablative conditioning SCT. The study demonstrates significant shortening of telomeres in recipients in spite of decreased intensity conditioning. Results of this study suggest that the main mechanism following transplantation is the proliferative stress imposed upon the stem cells and not direct damage by cytotoxic drugs. The different kinetics of restoration of hematopoiesis and the probable ongoing process of graft-versus-leukemia in the bone marrow do not prevent the attrition of telomeric ends of chromosomes.     

The Impact of Structured Laboratory Routines in Computerized Medical Records in a Primary Care Service Setting

Inappropriate laboratory ordering is a problem affecting medical systems worldwide. An intervention was called for as a result of increasing laboratory costs. Thus, we aimed to assess the impact of introducing computerized laboratory routines to a computerized primary care setting. The study included 380 primary care physician practices of Clalit Health Service (HMO) southern district (CHS-SD) in Israel, caring for 470,000 members. Consensus laboratory routines order sets were electronically introduced into all physicians’ computerized medical record (CMR) software, after consensus and internal marketing process. The primary findings were that a previously observed annual increase in laboratory test utilization was stopped, a 2% reduction in total number of tests and a 4% reduction in the total number of tests per age adjusted person was observed. In conclusion the wide use of CMRs and communication technology combined with an appropriate organizational process can be used to increase appropriate utilization of laboratory tests.