A longitudinal immunologic evaluation of hemophiliac patients

Over an average span of one year, we performed a prospective clinical and immunologic evaluation of 30 patients with hemophilia. No patient developed life-threatening opportunistic infection or malignancy; however, the immunologic abnormalities and lymphadenopathy initially present in nine patients (lymphadenopathy group) persisted. In addition, five patients, representing 24% of the initial group without lymphadenopathy, developed generalized lymphadenopathy (converter group). One episode of idiopathic thrombocytopenia (ITP) and one episode of staphylococcal sepsis occurred in this "converter" group; one episode of ITP also occurred in the lymphadenopathy group. Sixteen patients remained asymptomatic. At the time of the follow-up evaluation, those differences in mononuclear cell (MNC) percentages and numbers noted initially among the three hemophiliac groups were no longer present. Natural killer cell function alone or in the presence of biologic response modifiers was not different among hemophiliac and control groups. Before developing lymphadenopathy, the converter group of patients had significantly better lymphocyte mitogenic function than did the other two groups of patients with hemophilia. However, lymphocyte mitogenic responses of all groups of patients with hemophilia significantly deteriorated over the course of the study. The abnormal mitogenic responses noted in these patients was explained in part by higher levels of spontaneous suppressor cell activity in mononuclear cell preparations from patients with hemophilia. We conclude that long-term immunologic studies of this patient population requires both quantitative and qualitative evaluations. Our data show that patients with hemophilia have progressive dysfunction of cell- mediated immunity.     

In vitro characterization of the human recombinant soluble granulocyte- macrophage colony-stimulating factor receptor

We have cloned, expressed, and partially purified a naturally occurring, truncated, soluble form of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha subunit to investigate its biochemical and biologic properties. The soluble receptor species lacks the transmembrane and cytoplasmic domains that are presumably removed from the intact receptor cDNA by a mechanism of alternative splicing. The resulting soluble 55- to 60-kD glycosylated receptor species binds GM-CSF with a dissociation constant (kd) of 3.8 nmol/L. The soluble GM-CSF receptor successfully competes for GM-CSF binding not only with the transmembrane-anchored GM-CSF receptor alpha subunit but also with the native oligomeric high-affinity receptor complex. In addition, in human bone marrow colony-forming assays, the soluble GM-CSF receptor species can antagonize the activity of GM-CSF. Our data suggest that the soluble GM-CSF receptor may be capable of acting in vivo as a modulator of the biologic activity of GM-CSF.     

Hypothalamic pathology in Alzheimer's disease

The hypothalamus was examined in 3 cases of Alzheimer's disease and 3 control brains, using combined acetylcholinesterase (AChE) and thioflavin-S staining. Neurons undergoing neurofibrillary degeneration were restricted to 3 AChE-positive cell populations (lateral tuberal, lateral posterior and tuberomammillary) that have been found in the rat and monkey to project to the cerebral cortex. Our results suggest that the neurofibrillary degeneration in the hypothalamus involves primarily neurons that innervate cortical areas involved by Alzheimer's disease. This finding is consistent with the hypothesis that Alzheimer's disease is transmitted from neuron to neuron via normal neuronal connections.     

混合造血干细胞移植后输注供者淋巴细胞和白细胞介素2对急性髓性白血病疗效的影响

目的:观察急性髓性白血病经混合造血干细胞移植后,应用供者淋巴细胞输注 白细胞介素2治疗的效果,并与移植后未经特殊治疗的效果进行比较。方法:①选取2000-01/2004-07解放军兰州军区兰州总医院全军血液病中心收治的19例急性髓性白血病患者,实验经医院伦理委员会批准,患者均知情同意。随机数字表法分为两组:观察组8例,年龄17～40岁,M2a 4例,M4 1例,M5a 3例;对照组11例,年龄19～39岁,M2a 2例,M3a 2例,M4 3例,M5a 4例。②两组患者采用化疗联合重组人粒细胞集落刺激因子的方法动员自体外周血造血干细胞,采集后液氮中保存5d备用。③术前采用直线加速器对患者全身及肺部照射,预处理完毕后实施混合造血干细胞移植。首先回输自体单个核细胞中位数为4×108/kg,CD34 细胞中位数为6.2×106/kg,粒-巨噬祖细胞集落形成单位中位数为5.8×104/kg。间隔1～6h后,采集人类白细胞抗原半相合异体骨髓,按回输自体单个核细胞数的1/6～1/10输注给患者。④两组患者移植期间均住无菌层流病房,给予相应并发症的防治及支持治疗。在粒细胞降至0时注射重组人粒细胞集落刺激因子150μg/12h,促进造血恢复。观察组给予供者淋巴细胞输注 白细胞介素2治疗,每次采集的供者淋巴细胞中,CD3 淋巴细胞中位数为1.43×108/kg,CD4 细胞中位数为0.97×108/kg,CD8 细胞中位数为0.41×108/kg,中位治疗次数4(1～7)次,回输后即开始应用100wu/d重组人白细胞介素2,共10d。对照组混合造血干细胞移植后未给予特殊治疗。结果:19例急性髓性白血病患者均进入结果分析。①造血恢复:两组患者均获得造血重建,术后4～9d粒细胞均降至0,12～17d粒细胞达0.5×109L-1,16～21d白细胞达4.0×108 L-1,19～23 d血小板达20×108 L-1。16～21 d骨髓检查示恢复期骨髓象。②术后并发症:两组患者不同程度地出现口腔溃疡,随着造血恢复,7～10d溃疡消失。观察组1例患者出现出血性膀胱炎,两组各2例患者出现发热。无肝静脉闭塞病和移植物抗宿主病发生。③嵌合体形成:观察组中1例M4患者形成嵌合体,对照组中2例M4患者与1例M5患者形成嵌合体,嵌合体持续存在3～12个月。④供者淋巴细胞输注 白细胞介素2疗效:观察组中有1例M2a患者在接受2次特殊治疗后7个月复发死亡;1例M2a患者接受2次特殊治疗后1年出现骨髓增生异常综合征,脑出血死亡,1例M5a患者应用特殊治疗1次后出现不明原因高热、抽搐,死于癫痫持续状态,其余5例患者随访2年均健康存活,长期生存率为62.5%(5/8)。对照组有2例M2a患者、2例M4患者、1例M5患者于移植后1～7个月复发死亡,1例M3患者于移植后25d死于脑出血,其余2例M3患者、2例M4患者、1例M5患者随访2年均健康存活,长期生存率为45.4%(5/11)。结论:混合造血干细胞移植后应用供者淋巴细胞输注 白细胞介素2治疗,急性髓性白血病患者均获得造血重建且无移植物抗宿主病发生,其长期生存率有效提高。     

Otago Glaucoma Surgery Outcome Study: long‐term results of 841 trabeculectomies

Background: To describe the long‐term outcomes of trabeculectomies performed at Dunedin Hospital and followed in the Otago Glaucoma Surgery Outcome Study. Methods: Prospective non‐comparative case series of 841 eyes of 607 patients who had first trabeculectomies for primary open‐ or closed‐angle glaucoma at Dunedin Hospital between 1976 and 2005 and followed for a mean of 7.5 years (standard deviation 6.0). Results: The probability of a trabeculectomy controlling the intraocular pressure at 21 mmHg or less at 1, 10 and 20 years was 0.96 (95% confidence interval [CI] 0.95, 0.97), 0.86 (95% CI 0.83, 0.89) and 0.79 (95% CI 0.74, 0.83), respectively. Visual acuity was maintained or improved between preoperative assessment and final follow up in 68% of cases. The probability of not being blind following trabeculectomy at 1, 10 and 20 years was 0.98 (95% CI 0.96, 0.98), 0.83 (95% CI 0.80, 0.87) and 0.70 (95% CI 0.64, 0.76), respectively. The proportion of those with glaucomatous field loss increased during follow up from 16% (44/283) at 0–5 years to 50% (10/20) for those with 21 or more years of follow up. A repeat drainage procedure was required in 65 eyes (8%) (56 Molteno implant insertions and 9 repeat trabeculectomies). Conclusions: Intraocular pressure was well controlled by trabeculectomy; however, a steady decline in intraocular pressure control, visual acuity and visual field occurred during follow up.     

Differential expression of orexin receptors 1 and 2 in the rat brain

Orexins (hypocretins) are neuropeptides synthesized in the central nervous system exclusively by neurons of the lateral hypothalamus. Orexin-containing neurons have widespread projections and have been implicated in complex physiological functions including feeding behavior, sleep states, neuroendocrine function, and autonomic control. Two orexin receptors (OX(1)R and OX(2)R) have been identified, with distinct expression patterns throughout the brain, but a systematic examination of orexin receptor expression in the brain has not appeared. We used in situ hybridization histochemistry to examine the patterns of expression of mRNA for both orexin receptors throughout the brain. OX(1)R mRNA was observed in many brain regions including the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. OX(2)R mRNA was prominent in a complementary distribution including the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial nucleus, paraventricular nucleus, and ventral premammillary nucleus. The differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX(2)R receptor in regulating sleep state stability.     

Geriatric headache. How to make the diagnosis and manage the pain

Approximately 10% of women and 5% of men at age 70 experience severe recurrent or constant headaches. Severe headache presenting for the first time in a patient over age 50 is unusual and requires a thorough medical and neurologic examination. Primary headache etiologies in older patients include migraine, tension-type, cluster, and the rare hypnic headache. For all of these, effective pain control includes pharmacologic and nonpharmacologic interventions. Secondary etiologies include temporal arteritis, medication-induced headache, cerebrovascular or cardiac ischemia, and intracranial hemorrhage or tumors. Head pain may also be cervicogenic or related to glaucoma or sleep apnea. In secondary cases, pain management is specific to treatment of the underlying structural or systemic disease.     

Genetics of the Berardinelli-Seip syndrome (congenital generalized lipodystrophy) in Norway: epidemiology and gene mapping

Five of the six families with the Berardinelli Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum lod score + 1.3). None of the last showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A heterochromatic 9qh + segregated from one parent in two families.