Fanconi's anemia treated by allogeneic marrow transplantation

Eight patients with Fanconi's anemia were given cyclophosphamide alone (seven patients) or combined with procarbazine and antithymocyte globulin (one patient) followed by marrow grafts from HLA-identical siblings. All patients had engraftment. Seven developed acute and three chronic graft-versus-host disease (GVHD). Three patients died with GVHD and infectious complications (days 19, 56, and 82) and one with an intracerebral hemorrhage (day 540). Four patients are surviving 647- 3435 days after grafting, two are well, and two have chronic GVHD that is improving. These results show that Fanconi's anemia can be treated successfully by allogeneic marrow transplantation.     

Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.     

Assessing the In Vitro Suppressive Capacity of Regulatory T Cells

Regulatory T cells (Treg) play a vital role in controlling peripheral immune responses in order to prevent autoimmunity and control inflammation. Altered Treg activities have been associated with the pathogenesis of multiple disorders including autoimmunity, allergy, cancer, and infection with persistent pathogens. As such, a great deal of interest has recently been directed towards developing additional tools and methods to better understand the mechanisms of suppression employed by Treg. The in vitro suppression assay has emerged as a valuable means by which to assess the functional capacity and activity of Treg. In this review, we summarize the merits and limitations of the various in vitro assays that have been utilized to assess Treg activity and present a novel two color proliferation assay that allows simultaneous monitoring of both regulatory and effector T cell activity. As further immunomodulatory therapies are explored, the need for additional methodologies to understand the cellular and molecular mechanisms of immune regulation conferred by Treg will play an increasingly important role.     

Detection of chemical mutagens using Muta(R) Mouse: a transgenic mouse model

A transgenic mouse strain with a high copy number of rescuablelac Z sequences was evaluated for its effectiveness in detectinglacZ^– mutations in selected tissues. Procarbazine, cyclophosphamide,ethylnitrosourea, 7, 12-dimethylbenz [a] anthracene (DMBA),acrylamide and chlorambucil were tested following either singleor repeated dosing regimens. Bone marrow, liver, skin and testistissues were selected to assess as target sites for mutation.Bone marrow, liver and testis tissues were examined for mutationfollowing exposures to ethylnitrosourea and chlorambucil. Increasedmutant frequencies were found for both chemicals in all threetissues. Bone marrow tissue was examined for mutation followingprocarbazine, cyclophosphamide and acrylamide exposures, andskin was examined for mutation following dermal applicationof DMBA. Mutation induction was observed in all cases. The resultsbtained from this investigation demonstrate the applicabilityof this transgenic mouse as an effective model to detect andanalyze gene mutation in selected organs including germinaltissues. Studies of organotrophic chemical mutagens and carcinogensare possible with this model as are studies of the susceptibilityof germinal tissues to mutagen exposures. ²To whom correspondence should be addressed     

Clustering of mutations in the biotin-binding region of holocarboxylase synthetase in biotin-responsive multiple carboxylase deficiency

Holocarboxylase synthetase (HCS) catalyses the biotinylation of the four biotin-dependent carboxylases found in humans. A deficiency in HCS results in biotin-responsive multiple carboxylase deficiency (MCD). We have identified six different point mutations in the HCS gene in nine patients with MCD. Two of the mutations are frequent among the MCD patients analyzed. Four of the mutations cluster in the putative biotin- binding domain as deduced from the corresponding Escherichia coli enzyme and consistent with an explanation for biotin-responsiveness based on altered affinity for biotin. The two others may define an additional domain involved in biotin-binding or biotin-mediated stabilization of the protein.      

Planned vaginal births in women with multiple sclerosis: delivery and birth outcome

Objective –  The objective of this study was to investigate the effect of maternal multiple sclerosis (MS) on delivery and birth outcome in births without planned caesarean section.
Methods –  Data were collected from the compulsory Medical Birth Registry of Norway from 1988 to 2002. Intended vaginal births in this time period were 449 births given by MS mothers and 851,060 control births.
Results –  The MS mothers had a higher rate of induction of labour, and there was a strong trend for slower progression of second stage of labour and increased use of forceps. The MS group had lower birth weight and length of the neonates. The frequency of birth defects and the neonatal mortality were not increased in the MS group.
Conclusions –  Maternal MS affects the birth process and the neonate prenatally, even when the births with planned caesarean section are excluded. MS-related neuronal dysfunction linked to the uterus, is postulated as the most likely mechanism.     

Side effects after ambulatory lumbar iohexol myelography

Summary Side effect incidences after ambulatory (22G needle and two h bed rest) and after non-ambulatory (22 and 20G needles and 20 h bed rest) lumbar iohexol myelography have been estimated and compared. Headache incidence was significantly greater in ambulatory (50%, n=107) as compared to non-ambulatory myelography (26%, n=58). Headaches in the ambulatory group tended to be of shorter duration and the difference between severe headaches in ambulatory and non-ambulatory groups was not significant. Serious adverse reactions did not occur and none of the ambulatory patients required readmission because of side effects. The headache was predominantly postural and occurred significantly earlier in the ambulatory group. Headache incidence was significantly greater after 20G needle myelography (44%, n=97) as compared to 22G needle iohexol myelography (26%, n=58). The results supports the hypothesis that CSF leakage is a major cause of headache after lumbar iohexol myelography.