美国国家骨髓库无关供者造血干细胞移植20年回顾

自美国国家骨髓库(NMDP)开展第一例无关供者移植以来,至今已有20年.NMDP目前的库容量已逾700万,已为6大洲提供了30 000多份无关供者造血干细胞.这一辉煌成就是美国国家骨髓库600多名工作人员共同努力的结果,同时也得益于广泛的国际合作,包括171个移植中心,73个供者中心,24个脐血库,97个骨髓采集中心,91个血液净化中心,26个HLA分型实验室和26个合作供者登记处.本文回顾了美国国家骨髓库的历史,阐述了20年来移植病人、移植物来源和预处理方案几方面的主要变化趋势.     

Growth hormone therapy for protein catabolism

GH and IGF-I have shown remarkable consistency of effect in a wide range of catabolic conditions. Doses of around 10 IU/m2/day of GH and 80 micrograms/kg/day of IGF-I over short periods of time can improve net protein synthesis and preserve lean body mass. Most studies have reported metabolic endpoints, but favorable clinical effects have included decreased hospital stay and mortality in burns, improved respiratory muscle function in COAD, preserved grip strength post- operatively, and improvements in cardiac and bowel failure. Adverse effects of GH treatment are uncommon and usually related to glycaemic control. GH and IGF-I have differential effects on insulin concentrations--increasing or decreasing concentrations, respectively. The hypoglycaemic effects of IGF-I are dependent on route of administration and are avoided by subcutaneous delivery. Occasional patients have needed to discontinue GH treatment due to hyperglycaemia, although the anabolic action of GH may be partially mediated by increased insulin levels. The co-administration of GH and IGF-I has theoretical advantages by both increasing IGF binding-protein concentrations and balancing glycaemic control. An initial study with combination therapy in calorically-restricted volunteers has shown anabolic effects greater than with either agent alone. This approach requires further study in catabolic patients. There is a need for large, well-designed trials with clinical rather than purely metabolic end-points, and some of these are already underway. Should these studies confirm the early findings, financial considerations will become paramount, although it remains possible that treatment may be self-financing if lengths of hospital admissions are shortened.      

Oral sumatriptan in the acute treatment of migraine and migraine recurrence in general practice

We investigated the efficacy, safety and tolerability compared with placebo of a second dose of oral sumatriptan 100 mg in 1349 general practice patients who had already treated a moderate or severe migraine headache with 100 mg sumatriptan 4 h earlier. Headache was relieved by the first sumatriptan dose in about 70% of patients, but the second dose did not produce significantly more relief than placebo, either in nonresponders or in the group as a whole, nor did it reduce other symptoms (photophobia, nausea, vomiting, etc,) at 8 h, or influence the incidence of headache recurrence. The drug was well-tolerated, and a further single dose was effective in treating recurrence after initial relief. A single 100 mg dose of sumatriptan is an effective acute treatment for migraine. A second dose should be reserved for treating headache recurrence.      

Aging in Fragile X Premutation Carriers

It is now recognized that FMR1 premutation carriers (PC) are at risk to develop a range of neurological, psychiatric, and immune-mediated disorders during adulthood. There are conflicting findings regarding the incidence of hypertension, hypothyroidism, diabetes, and cancer in these patients that warrant further study. A retrospective controlled study was performed in a convenience sample of 248 controls (130 men, 118 women) and 397 FMR1 PC with and without fragile X-associated tremor ataxia syndrome (FXTAS) (176 men, 221 women); all participants were at least 45 years old (men: mean 62.4, SD 9.5; women: mean 62.8, SD 9.9; p?=?0.63). Memory and cognitive assessments (Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III)) and molecular testing (CGG repeats and FMR1-mRNA levels) were performed. Additional data included body mass index (BMI), cholesterol levels, blood pressure, hemoglobin A1c (HbA1c) levels, and medical history. A higher percentage of PC subjects self-reported having a diagnosis of hypertension (50.0 vs. 35.0 %, p?=?0.006) and thyroid problems (20.4 vs. 10.0 %, p?=?0.012) than control subjects. When comparing controls versus PC with FXTAS, the association was higher for diabetes (p?=?0.043); however, the effect was not significant after adjusting for demographic predictors. Blood pressure, blood glucose levels, HbA1c, and BMI values were not significantly different between the two groups. The PC with FXTAS group performed consistently lower in neuropsychological testing compared with the PC without FXTAS group, but the differences were very small for all but the WAIS full-scale IQ. Based on these findings, it appears that the risk for hypertension, thyroid problems, and diabetes may be more frequent in PC with FXTAS, which will require verification in future studies.     

Developmental profiles of infants with an <Emphasis Type="Italic">FMR1</Emphasis> premutation

Background

Emerging evidence suggests that a subset of FMR1 premutation carriers is at an increased risk for cognitive, emotional, and medical conditions. However, because the premutation is rarely diagnosed at birth, the early developmental trajectories of children with a premutation are not known.

Methods

This exploratory study examined the cognitive, communication, and social-behavioral profiles of 26 infants with a premutation who were identified through participation in a newborn screening for fragile X syndrome pilot study. In this study, families whose newborn screened positive for an FMR1 premutation were invited to participate in a longitudinal study of early development. Twenty-six infants with the premutation and 21 matched, screen-negative comparison babies were assessed using validated standardized measures at 6-month intervals starting as young as 3 months of age. The babies were assessed up to seven times over a 4-year period.

Results

The premutation group was not statistically different from the comparison group on measures of cognitive development, adaptive behavior, temperament, or overall communication. However, the babies with the premutation had a significantly different developmental trajectory on measures of nonverbal communication and hyperresponsivity to sensory experiences. They also were significantly more hyporesponsive at all ages than the comparison group. Cytosine-guanine-guanine repeat length was linearly associated with overall cognitive development.

Conclusions

These results suggest that infants with a premutation may present with subtle developmental differences as young as 12 months of age that may be early markers of later anxiety, social deficits, or other challenges thought to be experienced by a subset of carriers.

     

The efficacy of subcutaneous recombinant human erythropoietin in the correction of phlebotomy-induced anemia in autologous blood donors

The efficacy of subcutaneous recombinant human erythropoietin (rhEPO) (500 U/kg; administered twice a week during the 3 weeks before surgery) in the recovery of preoperative hemoglobin concentrations within a 3- week period was studied in 40 patients, each of whom donated 2 units (900 mL) of blood for their own use before total hip replacement surgery. Twenty autologous blood donors received rhEPO (EPO group) and 20 were not treated (control group). The initial hemoglobin concentration (14.0 +/− 1.0 g/dL [140 +/− 10 g/L]) was completely recovered before surgery (14.0 +/− 1.6 g/dL [140 +/− 16 g/L]) in the EPO group, while a decrease from 13.8 +/− 1.1 to 12.2 +/− 1.3 g per dL (138 +/− 11 to 122 +/− 13 g/L) was observed in the control group. The preoperative reticulocyte count showed more than sixfold increase in the EPO group, whereas a twofold to threefold increase was found in the control group. Serum ferritin concentration fell to 42 +/− 29 micrograms per L in the EPO group and to 54 +/− 35 micrograms per L in the control group. The postoperative serum erythropoietin concentration in the EPO group was significantly lower than that in the control group, but it did not differ from the pretreatment value and was attended by a higher hemoglobin concentration after surgery. Only transient flu-like symptoms were mentioned by patients who were treated with rhEPO. Changes in blood pressure or platelet count or other adverse events were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Accelerated immune red cell destruction in the absence of serologically detectable alloantibodies

Two patients are described in whom clinically significant red blood cell alloantibodies could be demonstrated only by in vivo 51chromium (51Cr) survival studies. The first patient had experienced a severe delayed hemolytic transfusion reaction to four units of crossmatch compatible blood. Serial phenotype studies suggested the presence of a serologically undetectable anti-c (hr') antibody. 51Cr survival of c- positive red blood cells was one per cent at 24 hours, while survival of c-negative red blood cells was 80 per cent at 24 hours. The second patient had multiple red blood cell alloantibodies. An anti-c antibody was suspected but could not be convincingly demonstrated by in vitro techniques. 51Cr survival of c-positive red blood cells, however, was 57 per cent at 24 hours and 17 per cent at 48 hours. 51Chromium red blood cell survival studies should be considered whenever an unexplained hemolytic transfusion reaction occurs, or when an expected red blood cell alloantibody cannot be demonstrated by in vitro laboratory studies.     

The effect of prestorage irradiation on posttransfusion red cell survival

Transfusion-associated graft-versus-host disease (TA-GVHD) may occur whenever immunologically competent allogeneic lymphocytes are transfused to an immunocompromised recipient. Irradiation of blood components eliminates the risk of TA-GVHD but may damage the cellular elements in the transfused component, particularly if the cells are stored for prolonged periods in the irradiated state. To study the effect of irradiation on long-term storage of red cells, AS-1 red cells from eight normal subjects were prepared on two occasions. On one occasion, the units were stored as standard AS-1 red cells for 42 days at 4 degrees C; on the other, they were exposed to 3000 cGy radiation within 4 hours of collection and then were stored as AS-1 red cells for 42 days at 4 degrees C. The donations were at least 12 weeks apart. Irradiated units demonstrated significant elevations in poststorage plasma hemoglobin (Hb) (623 +/- 206 vs. 429 +/- 194 g/dL [6230 +/- 2060 vs. 4290 +/- 1940 g/L], p less than 0.02) and plasma potassium (78 +/- 4 vs. 43 +/- 9 mEq/L [78 +/- 4 vs. 43 +/- 9 mmol/L], p less than 0.01) and significant decreases in red cell ATP (1.9 +/- 0.2 vs. 2.1 +/- 0.3 microM/g Hb, p less than 0.04) and 24-hour posttransfusion red cell recovery (68.5 vs. 78.4%, p less than 0.02), as compared to nonirradiated units. It can be concluded that irradiation with 3000 cGy damages red cells and that long-term storage in the irradiated state may enhance this damage. Red cells should not be stored for 42 days after irradiation with 3000 cGy.     

Haemodynamic Studies During the Management of Severe Tetanus

Detailed invasive haemodynamic studies were performed in 27of 32 patients with severe tetanus. Nineteen had severe uncomplicatedtetanus and eight had associated major complications, chieflyinfection and pulmonary complications. The results were comparedwith those obtained from 15 healthy male volunteers who servedas controls. There were two deaths in 32 patients (mortality6.25 per cent). Severe tetanus without major complications wascharacterized by a high output hyperkinetic circulatory statewith tachycardia (heart rate 131 (19.2) beats/minute), increasedstroke volume index (43.1 (10.7) ml/m²), increased cardiac index(5.48 (0.94)1/min/m²) and a normal left ventricular stroke workindex (60.5 (15.9) g/m/m²). Volume loading demonstrated a significanthaemodynamic response and increased vascular capacitance. Evenso the maximum percent rise from baseline values of these indicesafter volume load was significantly higher in controls (p <0.001). Autonomic cardiovascular disturbances affected bothsympathetic and parasympathetic activity. Hypertension and tachycardiaalternating with hypotension and bradycardia were related tosudden fluctuations in systemic vascular resistance. Our studiessuggested some degree of myocardial dysfunction in patientswith severe uncomplicated tetanus. The haemodynamics of severetetanus were masked and altered by complicating infection, pneumonia,and atelectasis.