Microtubule-based nuclear movement occurs independently of centrosome positioning in migrating neurons

During neuronal migration in the developing brain, it is thought that the centrosome precedes the nucleus and provides a cue for nuclear migration along the microtubules. In time-lapse imaging studies of radially migrating granule cells in mouse cerebellar slices, we observed that the movements of the nucleus and centrosome appeared to occur independently of each other. The nucleus often migrated ahead of the centrosome during its saltatory movement, negating the supposed role of the centrosome in pulling the nucleus. The nucleus was associated with dynamic microtubules enveloping the entire nucleus and stable microtubules extending from the leading process to the anterior part of the nucleus. Neither of these perinuclear microtubules converged at the centrosome. Disruption or excess formation of stable microtubules attenuated nuclear migration, indicating that the configuration of stable microtubules is crucial for nuclear migration. The inhibition of LIS1 function, a regulator of a microtubule motor dynein, specifically blocks nuclear migration without affecting the coupling of the centrosome and microtubules in the leading process, suggesting that movements of the nucleus and centrosome are differentially regulated by dynein motor function. Thus, the nucleus moves along the microtubules independently of the position of the centrosome in migrating neurons.     

Difficulty in diagnosing autoimmune pancreatitis by imaging findings

BACKGROUND: Autoimmune pancreatitis (AIP) presents as diffuse enlargement of the pancreas and as diffuse irregular narrowing of the main pancreatic duct. However, some AIP cases are difficult to diagnose because of atypical imaging findings. OBJECTIVE: To clarify a variety of imaging findings of AIP and the reason for its misdiagnosis. DESIGN: We examined the imaging findings of 37 AIP cases and also examined misdiagnosed cases of AIP to determine their reasons for misdiagnosis. PATIENTS: A total of 37 patients with AIP who reported to our hospital or its affiliate over a 17-year period (1989 to May 2005). RESULTS: Patients in 15 AIP cases showed segmental narrowing of the main pancreatic duct. There were 6 patients with focal enlargement of the pancreas, whereas 3 patients showed no enlargement. There were 3 cases of calcification of the pancreas. Pancreatic cysts were detected in 2 patients. Abdominal US showed multiple low-echoic masses in 1 case and a single mass in 3 cases. Sixteen patients had stenosis of the bile duct at the hilar hepatic lesion and/or the intrahepatic duct. Only 7 patients had typical AIP findings. Six patients were misdiagnosed with pancreatic cancer and 2 with bile-duct cancer. Seven cases were surgically treated. Five cases were misdiagnosed because of the nonexistence of, or the unfamiliarity with, the concept of AIP and sclerosing cholangitis with AIP. Another 3 cases were diagnosed with pancreatic cancer because of segmental stenosis of the main pancreatic duct and no or focal enlargement of the pancreas. CONCLUSIONS: The results of this study suggest that AIP presents a variety of imaging findings. The most important diagnostic factor is clinician awareness of the concept of AIP and the diverse nature of imaging findings.     

Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli

Long-term warfarin use has been reported to increase fracture risk of rib and vertebra but not hip in elderly patients, but the mechanisms remain unknown. We hypothesized that warfarin would impair bone material quality but could not weaken bone strength under conditions with higher mechanical stimuli. To test this hypothesis, rats were randomized to vehicle or warfarin group at 4 weeks of age and subsequently weight matched into a sedentary or jumping exercise group at 12 weeks of age. At 6 months of age, osteocalcin content, bone mineral density (BMD), mineral size, material properties, morphological parameters, and biomechanical properties of cortical bones were evaluated. In order to seek evidence for a common mechanism of action, effects of nucleation rate of mineral crystals on their rigidity were also investigated using computer simulation. In humeral cortical bones, warfarin did not change BMD, but markedly decreased osteocalcin content, diminished mineral size, and impaired material hardness. Consistent with these results, our computer-simulation model showed that osteocalcin-induced delay of mineral crystal nucleation decreased mineral formation rate, increased mean and distribution of mineral sizes, and strengthened mineral rigidity. In tibial cortical bones, warfarin decreased material ultimate stress; however, under jumping exercise, warfarin increased cross-sectional total and bone areas of these tibiae and completely maintained their biomechanical properties including work to failure. Collectively, our findings suggest that long-term warfarin therapy weakens rib and vertebra by impairing cortical bone material quality due to a marked decrease in osteocalcin content but could not reduce hip strength through compensatory adaptation of cortical bone structure to higher mechanical stimuli.     

Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis

Perforin gene (PRF1) mutations cause the primary form of hemophagocytic lymphohistiocytosis (HLH). We report a genetic defect of PRF1 in a 62-year-old Japanese man with recurrent episodes of HLH. Sequencing of PRF1 from both peripheral blood mononuclear cells and nail clippings showed compound heterozygous mutation, including deletion of two base pairs at codons 1090 and 1091 (1090-1091delCT) and guanine-to-adenine conversion at nucleotide position 916 (916GAEA). Although primary HLH has been detected in infants and children, genetic mutation of PRF1 or other genes should be considered a differential diagnosis of HLH even in the elderly.     

Complications in the central nervous system during chemotherapy for childhood acute lymphoblastic leukemia: JACLS ALL-02 study

We evaluated central nervous system (CNS) complications treated under the ALL-02 protocol of the Japan Association of Childhood Leukemia Study (JACLS) from April 2002 to March 2005. According to NCI Toxicity Criteria, 17 events of grade 3 and 4 CNS complications were reported in 15 out of 541 patients. Out of these CNS complications, leukoencephalopathy was seen in 5 patients; seizure in 5; cerebrovascular disease in 3; conscious disturbance in 2; and hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome in one patient each. The complications were intensively observed during induction therapy and the last of the early phase chemotherapy. The protocol treatment was stopped or modified in most patients after CNS complications. MRI imaging demonstrated no improvement in one patient with leukoencephalopathy who developed an isolated CNS relapse, while other patients were alive and remain in their first complete remission without any neurological sequelae. Further studies will be required to analyze risk factors for CNS complications during chemotherapy not accompanied by irradiation and to establish alternative treatments after the appearance of such CNS complications.     

Superior mesenteric and portal vein thrombosis in a polycythemia vera patient with JAK2 mutation

A 47-year-old woman was admitted to our hospital in December 1994 with polycythemia. The patient's red blood cell volume was 33 ml/kg and bone marrow cytology was able to rule out other myeloproliferative diseases such as chronic myelogenous leukemia, essential thrombocytosis and myelofibrosis. The patient was diagnosed as having polycythemia vera. She had undergone only phlebotomy until 1999 when the thrombocytosis appeared, subsequent to which she was treated with oral hydroxyurea. However, in March 2006, she developed upper abdominal pain and was admitted to our hospital on March 14th, 2006. Computed tomography scan revealed thromboses in the portal and superior mesenteric veins. Anticoagulation therapy delivered intravenously via the superior mesenteric vein dramatically improved her symptoms and liver function. She is currently on anticoagulation therapy in our outpatient clinic.     

Toxoplasmosis encephalitis following severe graft-vs.-host disease after allogeneic hematopoietic stem cell transplantation: 17 yr experience in Fukuoka BMT group

Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4(+) cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.