Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia

Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis.     

Giant testicular tumor: a case report

We report a case of giant testicular tumor. A 30-year-old man visited our department complaining of a painless swelling of the right scrotal contents. In chest X-ray and abdominal computerized tomography (CT) there were no abnormal findings. Serum alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase levels were normal. Right high orchiectomy was performed. The size of the removed specimen was 13.5 x 8.5 x 7.5 cm, and weight 530 g. The pathological diagnosis was immature teratoma. The patient has received no further therapy. There has been no recurrence for 7 months postoperatively.     

Congenital hyperinsulinism: Global and Japanese perspectives

Over the past 20 years, there has been remarkable progress in the diagnosis and treatment of congenital hyperinsulinism (CHI). These advances have been supported by the understanding of the molecular mechanism and the development of diagnostic modalities to identify the focal form of ATP‐sensitive potassium channel CHI. Many patients with diazoxide‐unresponsive focal CHI have been cured by partial pancreatectomy without developing postsurgical diabetes mellitus. Important novel findings on the genetic basis of the other forms of CHI have also been obtained, and several novel medical treatments have been explored. However, the management of patients with CHI is still far from ideal. First, state‐of‐the‐art treatment is not widely available worldwide. Second, it appears that the management strategy needs to be adjusted according to the patient's ethnic group. Third, optimal management of patients with the diazoxide‐unresponsive, diffuse form of CHI is still insufficient and requires further improvement. In this review, we describe the current landscape of this disorder, discuss the racial disparity of CHI using Japanese patients as an example, and briefly note unanswered questions and unmet needs that should be addressed in the near future.     

Selective expansion of donor‐derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA‐matched sibling donor. We could achieve engraftment and regimen‐related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor‐derived Tregs and disappearance of anti‐villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor‐derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.     

Optimal dose and duration of glucose administration during fasting period preceding surgery in rabbits

Purpose. We examined preoperative glucose administration to establish what dose and cutoff point were optimal for suppression of lipolysis and prevention of hypo- or hyperglycemia. Methods. Rabbits were preoperatively fasted and simultaneously received glucose at a constant rate of 0, 0.1, 0.2, 0.3, or 0.4 g·kg⁻¹·h⁻¹ in fluid infusion for 3 h. Plasma glucose, immunoreactive insulin activity, nonesterified fatty acids, and ketone bodies were measured 0, 1.5, 3 and 4 h after the start of infusion, and hepatic glycogen content was assessed 1 h after cessation of infusion. Results. Fluid infusion without glucose decreased plasma glucose. Glucose administration at more than 0.2 g·kg⁻¹·h⁻¹ caused hyperglycemia (>200 mg·dl⁻¹) in the infusion period; the differences were significant compared with the value at zero time or in the 0 g·kg⁻¹·h⁻¹ group (P < 0.01). The highest dose also raised plasma immunoreactive insulin activity, which was significantly higher than in the 0 g·kg⁻¹·h⁻¹ group (P < 0.01) at the midpoint of the infusion period. Plasma nonesterified fatty acids increased in all groups. The changes were, however, significantly reduced in both the 0.3 and 0.4 g·kg⁻¹·h⁻¹ groups (P < 0.05 and P < 0.01, respectively) by the end of infusion. All these effects of glucose supply, including suppression of lipolysis, disappeared regardless of dose within 1 h after the cessation of infusion. Conclusion. These results suggest that the optimal dose for preoperative glucose infusion, in order to preserve carbohydrate or fat metabolism, is 0.1–0.2 or 0.3 g·kg⁻¹·h⁻¹, respectively, and indicate that administration should not be discontinued until the start of surgery. Received for publication on July 16, 1998; accepted on August 23, 1999     

A case of an intra-atrial tumor thrombus from hepatocellular carcinoma (HCC), first indicated by67Ga-citrate scintigraphy

We encountered a very rare case of an intra-atrial tumor thrombus from hepatocellular carcinoma (HCC). Conventional XCT and US gave evidence of HCC. In nuclear medicine studies performed incidentally, the first study with^99mTc-phytate liver scintigraphy showed 2 SOLs and evidence of chronic liver disease, and the second study with⁶⁷Ga-citrate scintigraphy demonstrated 2 hot lesions within the liver parenchyma, and also another unexpected hot area just above the left lobe of the liver, seemingly beyond the diaphragm. When echocardiography was performed, in addition to ECG, because the patient began to complain of dyspnea, an oblong mass lesion was detected within the right atrium. Reexamination with XCT and angiography clearly proved the existence of an intraatrial tumor thrombus. These results indicate the need for routine examination by echocardiography for HCC patients complaining of dyspnea.     

Acute transverse myelitis with urinary retention due to mycoplasma pneumoniae infection: a case report

We report a case of urinary retention complicated with acute transverse myelitis caused by Mycoplasma pneumoniae. A 16-year-old man visited a clinic because of urinary retention, fever, muscle weakness and sensory disturbance of lower extremities. He was referred to our hospital for further examination. He was diagnosed with acute transverse myelitis due to M. pneumoniae infection based on cerebrospinal fluid examination, serum titer of antibody to M. pneumoniae and magnetic resonance imaging. He was treated with corticosteroids for acute myelitis. A urethral catheter was indwellt for urinary retention. His muscle strength and sensory of lower extremities improved after 2 months of treatment, and he was discharged from our hospital. However, since urinary frequency, urge incontinence and weak urinary stream persisted, he was referred to us for further examination. A pressure-flow study examination showed a decreased maximum urinary flow rate and the findings of detrusor sphincter dyssnergia. We diagnosed him with uninhibited bladder and detrusor sphincter dyssnergia. We administered propiverine hydrochloride and imipramine hydrochloride, and his symptoms subsided significantly. Now, (8 months) after this medication, he still has incontinence at night.     

Intravenous catheter occlusion during continuous infusion of a new recombinant factor VIII concentrate

We experienced catheter occlusion in two cases during continuous infusion of a new recombinant factor VIII concentrate (Kogenate FS, Bayer) during orthopedic surgery. In one of the cases, the infusion was completed by diluting Kogenate FS 1:4 with distilled water. These catheter occlusions might be caused by local clot formation due to the relatively high concentration of factor VIII in the continuous infusion route.