Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene

Wolcott-Rallison syndrome (WRS) is an autosomal recessive disorder characterized by neonatal or early infancy type 1 diabetes, epiphyseal dysplasia, and growth retardation. Mutations in the EIF2AK3 gene, encoding the eukaryotic initiation factor 2alpha-kinase 3 (EIF2AK3), have been found in WRS patients. Here we describe a girl who came to our attention at 2 months of age with severe hypertonic dehydration and diabetic ketoacidosis. A diagnosis of type 1 diabetes was made and insulin treatment initiated. Growth retardation and microcephaly were also present. Anti-islet cell autoantibodies were negative, and mitochondrial diabetes was excluded. Imaging revealed a hypoplastic pancreas and typical signs of spondylo-epiphyseal dysplasia. The diagnosis of WRS was therefore made at age 5 years. Sequencing analysis of her EIF2AK3 gene revealed the presence of a homozygous T to C exchange in exon 13 leading to the missense serine 877 proline mutation. The mutated kinase, although it partly retains the ability of autophosphorylation, is unable to phosphorylate its natural substrate, eukaryotic initiation factor 2alpha (eIF2alpha). This is the first case in which the pathophysiological role of EIF2AK3 deficiency in WRS is confirmed at the molecular level. Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans, and we suggest EIF2AK3 as a possible target for therapeutic intervention in diabetes.     

Counteraction of type 1 diabetic alterations by engineering skeletal muscle to produce insulin: insights from transgenic mice

Insulin replacement therapy in type 1 diabetes is imperfect because proper glycemic control is not always achieved. Most patients develop microvascular, macrovascular, and neurological complications, which increase with the degree of hyperglycemia. Engineered muscle cells continuously secreting basal levels of insulin might be used to improve the efficacy of insulin treatment. Here we examined the control of glucose homeostasis in healthy and diabetic transgenic mice constitutively expressing mature human insulin in skeletal muscle. Fed transgenic mice were normoglycemic and normoinsulinemic and, after an intraperitoneal glucose tolerance test, showed increased glucose disposal. When treated with streptozotocin (STZ), transgenic mice showed increased insulinemia and reduced hyperglycemia when fed and normoglycemia and normoinsulinemia when fasted. Injection of low doses of soluble insulin restored normoglycemia in fed STZ-treated transgenic mice, while STZ-treated controls remained highly hyperglycemic, indicating that diabetic transgenic mice were more sensitive to the hypoglycemic effects of insulin. Furthermore, STZ-treated transgenic mice presented normalization of both skeletal muscle and liver glucose metabolism. These results indicate that skeletal muscle may be a key target tissue for insulin production and suggest that muscle cells secreting basal levels of insulin, in conjunction with insulin therapy, may permit tight regulation of glycemia.     

Tumour excision plus continuous tamoxifen compared with modified radical mastectomy in patients over 70 years of age with operable breast cancer

Between 1985 and 1991, we randomly assigned 77 women over the age of 70 years with stage I-3a breast cancer to undergo a modified radical mastectomy or tumour excision followed by tamoxifen. Median follow-up was 45 months. Patients treated by tumour excision and tamoxifen had a significantly better survival (P = 0.04). The disease-free survival of the tumour excision and tamoxifen group was close to significantly better (P = 0.10). Only two patients in the tamoxifen group required an axillary dissection on follow-up for progressive nodal enlargement. Two patients underwent a local mastectomy for locally recurrent disease. We conclude that tumour excision followed by continous tamoxifen is an acceptable, safe alternative to a modified radical mastectomy in patients over 70 years of age.     

Juvenile chronic myelogenous leukemia: In vitro characterization before and after allogeneic bone marrow transplantation

In previously published studies on patients with juvenile chronic myelogenous leukemia (JCML), excessive proliferation of malignant monocyte-macrophage elements and impaired growth of normal hematopoietic progenitors were demonstrated. A selective hypersentivity of granulocytemachrophage progenitors (CFU-GM) to granulocyte-macrophage colony stimulating factor (GM-CSF) seems to represent the main pathogenetic mechanism. Allogeneic bone marrow transplantation (BMT) has been demonstrated to be the only curative strategy for patients with JCML. In this study, we evaluated the growth of peripheral blood hematopoietic progenitors in semisolid cultures in two children with JCML before and after allogeneic BMT. Serum levels of GM-CSF, interleukin-1 (JCIL-1) and tumor necrosis factor-α (TNF-α) were also assessed. IL-1-β, GM-CSF and TNF-α serum levels of the patients before and after BMT did not differ significantly from those obtained in 45 healthy controls. After marrow transplant, the engraftment of donor hematopoietic stem cell was associated with the disappearance of both pretransplant GM-CSF hypersensitivity and CFU-GM spontaneous growth. The inhibitory effect on the growth of normal hematopoietic progenitors also resolved. This confirms that the substitution of the pathological hematopoietic progenitors represents the basis for the curvative effect of allogeneic BMT in the treatment of JCML, abolishing both the excessive responsiveness of JCML progenitor cells even to very low concentrations of GM-CSF and the growth-inhibitory effect on normal hematopoiesis. © 1995 Wiley-Liss, Inc.     

The impact of spinal angiography on the neurological outcome after surgery on the descending thoracic and thoracoabdominal aorta

BACKGROUND: Neurologic complications remain one of the major concerns in surgery on the descending thoracic and thoracoabdominal aorta. The impact of preoperative spinal angiography on postoperative neurologic outcome was assessed. METHODS: Between September 1993 and December 1999, 109 patients (mean age, 58.2 years; range, 24 to 77) underwent preoperative spinal angiography: 50 (45.9%) for aneurysm and 59 (54.1%) for chronic dissection. Sixty-one patients (56.0%) underwent replacement of the descending thoracic aorta whereas the thoracoabdominal aorta was replaced in 48 (44.0%) patients. All intercostal or lumbar arteries that had previously been visualized as the origin of the great radicular artery (GRA) were preserved. RESULTS: The origin of the GRA was located by spinal angiography in 65 of the 109 patients (59.6%). It was found between level T-5 and L-3 and on the left side in 75.4% (49 of 65) patients. In patients with aneurysms, it was identified less frequently (48%) compared with patients with chronic dissection (69.5%, p = 0.02). The overall operative mortality rate was 5.5% (6 of 109 patients). There were 7 patients (6.4%) with postoperative paraplegia. In 3 of them the origin of the GRA had been reimplanted. CONCLUSIONS: Even in patients with an identified and subsequently reimplanted GRA, postoperative paraplegia could not always be prevented. Spinal angiography has no impact on the neurologic outcome of thoracic and thoracoabdominal aortic replacement.     

南药植物线虫种类调查

１９９１￣２９９３年调查了广东、海南两省８个县、市１２种植点９种南药植物的寄生线虫，共鉴定出２８属、４２种，隶属于１２科、１８亚科。     

Nonoperative management of blunt renal trauma: a prospective study

Despite the abundance of literature on nonoperative management (NOM) of blunt trauma to the liver and spleen there is limited information on NOM of blunt renal injuries. In an effort to evaluate the role of NOM 37 consecutive unselected patients with renal injuries (grade 1, four; grade 2, 12; grade 3, 11; grade 4, six; and grade 5, four) were followed prospectively over 30 months (Match 1999 to September 2001). Patients without peritonitis or hemodynamic instability were managed nonoperatively regardless of the appearance of the kidney on CT scan. Six (16%) patients were operated on immediately but only two (5.4%) for the kidney (grades 3 and 5 respectively). Of the remaining 31 patients 26 (84%) were managed successfully without an operation (grade 1 or 2, 12; grades 3-5, 14). Five patients were taken to the operating room after a period of observation (3, 3.5, 9, 36, and 44 hours respectively) but only three for the kidney (grades 4 and 5). The overall failure rate was 16 per cent (5 of 31); the rate of failure specifically related to the renal injury was 9.6 per cent (three of 31). Compared with the patients with successful NOM the five patients with failed NOM were more severely injured (Injury Severity Score > or = 15 in 80% vs 27%, P = 0.04), required in the first 6 hours more fluids (4.17 +/- 1.72 vs 1.87 +/- 1.4 liters, P = 0.003) and blood transfusions (2.40 +/- 2 vs 0.42 +/- 1.17 units, P = 0.005), and more frequently had a positive trauma ultrasound (80% vs 11.5%, P = 0.005). We conclude that NOM is the prevailing method of treatment after blunt renal trauma. It is successful in the majority of patients without peritonitis or hemodynamic instability and should be considered regardless of the severity of renal injury. Predictors of failure may exist on the basis of injury severity, fluid and blood requirements, and abdominal ultrasonographic findings and need validation by a larger sample size.