Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3- year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.     

Cloning of glycoprotein IIIa cDNA from human erythroleukemia cells and localization of the gene to chromosome 17

Platelet aggregation requires the binding of adhesive proteins such as fibrinogen to the heterodimer of membrane glycoproteins IIb (GPIIb) and IIIa (GPIIIa). Human erythroleukemia (HEL) cells synthesize both GPIIb and GPIIIa. Using poly(A+) RNA purified from HEL cells, we constructed a cDNA library in the lambda gt10 phage vector. This library was screened with a 38mer oligonucleotide derived from a platelet GPIIIa peptide, and three overlapping cDNAs were isolated. The three inserts encompassed 3.5 kilobases (kb), including the entire coding region of mature GPIIIa (2,286 basepairs, bp) and 1.3 kb of 3' untranslated sequence. All 222 residues determined directly from platelet GPIIIa tryptic peptides exactly matched the HEL cell-deduced amino acid sequence. The HEL cell sequence matched a previously reported endothelial cell cDNA sequence except for eight nucleotides. Five of these nucleotide differences were silent changes consistent with genetic polymorphisms. The other three differences resulted in changes in the deduced amino acid sequence of GPIIIa; reexamination of the endothelial cell cDNA sequence in these three areas revealed that it is actually identical to the HEL cell sequence. The virtual identity of the endothelial and HEL cell cDNA sequences provides direct evidence that GPIIIa is a subunit common to cell-adhesion receptors present in more than one cell type. We localized the gene for GPIIIa to chromosome 17, the same chromosome to which we had previously mapped the gene for GPIIb.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

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.     

An examination of the synergistic interaction of ethanol and thiamine deficiency in the development of neurological signs and long-term cognitive and memory impairments

BACKGROUND: The prolonged and heavy consumption of ethanol has been associated with thiamine deficiency and a wide range of cognitive and memory impairments. The present study was undertaken to test the hypothesis that ethanol and thiamine deficiency act synergistically, producing more severe clinical neurological disturbances and cognitive and memory impairments than either thiamine deficiency or chronic ethanol alone. METHODS: The acute neurological and long-term behavioral consequences of combined chronic (32 weeks) ethanol consumption (20% v/v in drinking water) and three separate 4-week long episodes of dietary thiamine deficiency (ET/TD) versus ethanol (ET) or thiamine deficiency (TD) treatments alone were examined in male Sprague Dawley rats aged 12 weeks at the start of treatment. RESULTS: The ET/TD group lost less weight than the TD group during each episode of thiamine deficiency. Contrary to expectations, the progression and severity of ataxia, impaired righting reflexes, and opisthotonic posturing were similar in the ET/TD and TD groups. None of the ET animals displayed any neurological or behavioral symptoms during treatment. After withdrawal from ethanol and a 7-week recovery period, none of the groups differed in spontaneous activity. On subsequent testing, the ET group displayed a significant increase in perseverative responding in a spontaneous alternation task. A small but significant proportion of ET/TD (23%), ET (17%), and TD (8%) animals were unable to reach criterion on an initial nonmatching-to-position task (NMTP) or in two subsequent reversals of the matching and NMTP tasks, which indicated persistent learning impairments. A large proportion of animals in each of the three groups demonstrated significantly reduced accuracy compared with controls at longer delays of matching-to-position tasks (MTP), but only the ET group was consistently impaired at the shorter delays. There were no significant correlations between blood ethanol concentration and any of the learning and memory measures. CONCLUSIONS: These results indicate that the interaction of chronic ethanol consumption and bouts of TD is both domain specific and not always synergistic. Learning and reference memory appear to be sensitive to a synergistic interaction of ET and TD, whereas short-term working memory disturbances are most affected by ET and neurological symptoms are most associated with TD. Furthermore, neither the presence of neurological symptoms nor blood ethanol concentrations appear to be good predictors of learning and memory deficits.     

Modulation of the immunosuppressive activities by blastocoelic fluid during rabbit pregnancy

Temporal variation in immunosuppressive activity was determined in biological samples such as embryo-foetal fluids (blastocoelic- or amino-allantoic fluid) and blood collected from pregnant and pseudopregnant rabbits. Each of the fluids to be analyzed was pre-incubated with mitogen stimulated human lymphocytes for 48 h and then inhibition of [3H]thymidine incorporation or IL-2 receptor expression was estimated. Both means of assessing immunosuppression indicated variations in the suppressive activity throughout pregnancy. This was observed in embryo-foetal fluids but not in autologous peripheral blood nor in homologous pseudopregnant blood. At days 9-13 of pregnancy, the immunosuppressive effects of blastocoelic fluids were higher than that of the autologous sera, reached a peak at days 12 and 13 and declined thereafter, to reach the lowest levels. In order to further characterize the biological activity of day-12 blastocoelic fluid and autologous serum, they were submitted to ultracentrifugation. No suppressive activity could be demonstrated in the lipoprotein fractions. But all the activity was found in the protein fraction. Precipitation with cold ethanol confirmed that the biologically active compound was a protein. Furthermore, results obtained after ultrafiltration suggest biologically active compounds of high mol. wt (greater than 300 kDa). From the above findings, we can suggest that in the rabbit, there is no pregnancy specific systemic immunosuppression. We can also infer that (1) the immuno-tolerance of the mother towards the embryo is more due to a localized effect; (2) this effect decreases with the progression of gestation and (3) a high mol. wt factor is responsible for the immunosuppression.     

3D-CT evaluation of facial asymmetry

OBJECTIVE: Recently, 3-dimensional-computed tomography (3D-CT) imaging has been used in the diagnosis and surgical treatment planning of patients with craniofacial deformities. The present authors have developed a 3D-CT imaging procedure for a 3-dimensional coordinate point evaluation system to assess and diagnose patients with facial asymmetry. STUDY DESIGN: The CT data of 16 subjects was selected retrospectively as the control group from patients who had undergone CT examinations to diagnose conditions other than maxillofacial deformities. Anatomical landmarks modified from orthodontic craniometric (cephalometric) points were defined on the 3D-CT images and the asymmetry index of each point was calculated in millimeters. A diagrammatic chart with a baseline indicating the mean asymmetry indices plus the standard deviation in the control group was designed. The resulting diagrammatic chart was used to evaluate the degree of deformity in facial asymmetry patients. RESULTS AND CONCLUSIONS: The topography of facial asymmetry was assessed. The 3D-CT imaging technique as described herein is a practical method of evaluating the morphology of facial asymmetry.     

Geographic tongue: clinical characteristics of 188 cases

The purpose of this study was to investigate the clinical characteristics and assess other factors associated with geographic tongue in Thailand. One hundred and eighty-eight Thais with geographic tongue and 188 controls were interviewed regarding their medical history, symptoms, and the nature and migratory pattern of their lesions. Variations in the clinical appearance, lesion location, and any associated tongue fissures were recorded. The age range for the 188 subjects was 9 to 79 years. The highest incidence (39.4%) occurred in the 20-29 age group. Women were affected more than men (1.5:1). The leading group of medical conditions consisted of allergy-related disorders; however, the incidence of these problems among both subjects and controls was not significantly different (55.2% vs. 44.8%). Our results demonstrated a significant co-existence of geographic tongue and fissured tongue. Most of the geographic tongue lesions manifested a typical appearance consisting of a central atrophic area bounded by a raised white circinate line (69.1%) with multiple tongue sites affected (62.8%). The most common locations were at the lateral margins and tip of the tongue. The majority of our subjects (75.5%) were asymptomatic. The results of this study correspond with the findings of previous geographic tongue studies in other populations.     

Anterior and posterior lingual depressions of the mandible.

Both posterior and anterior lingual depressions occur in the mandible. The posterior lingual mandibular depressions appear to be more common than had been previously reported. This probably due to one or both of the following causes. Shallow lesions are difficult to diagnose radiographically since an appreciable depth of lingual cortical plate must be resorbed before they can be visualized. As these may be active lesions, a slow resorptive process could place the patient into middle age or beyond before the lesion is clinically diagnosed. It is suggested that posterior lingual mandibular depressions may be benign, self-limiting lesions that are caused by a slow resorptive process resulting from pressure of unknown origin. The anterior lingual mandibular depressions are variable findings in dried mandibles that appear grossly as round or oval smooth depressions with intact buccal and lingual cortical plates and, radiographically, as ill-defined radiolucent areas with no radiopaque borders. They are usually located in the incisor-lateral-canine area and are usually bilateral. It is suggested that these depressions may be developmental anomalies related to the buttons of Gaughran or that they may simply be anatomic variants. They differ from posterior depressions in both gross and radiographic appearance, which suggests the existence of two distinct entities.     

Medical health and medication use in elderly dental patients

The objectives of this study were to obtain information on the medical conditions and medications used among elderly Thai dental patients and to investigate the relationship between the findings in relation to age and sex. The information regarding medical conditions and medication use was obtained from interviews of 510 dental patients aged 60 years and older. The incidence of medical conditions was 82.5%; women had a significantly higher incidence of medical conditions (86.5%) than men (76.5%). The incidence of medical conditions did not differ among the three age groups. Overall, cardiovascular disease was the leading problem (33.7%) with hypertension being the major component (26.1%). The prevalent problems were bone/joint disorders (32.4%), allergies (18.2%), diabetes mellitus (14.5%), and eye and ear problems (14.3%). In our sample, 65.5% reported taking medications, with an average of 1.5 drug groups per person. The average number of medications taken increased as age increased. Women took medications more frequently than men (70% vs. 58.5%). The four most prevalent drugs were cardiovascular agents (32%), endocrinologic drugs (14.5%), nutritional therapeutics (12.9%), and drugs acting on the musculoskeletal system (11.4%). The present study supports the findings of previous reports in that the presence of medical conditions is high in the elderly and the incidence of medication use increases with advancing age.