Initiation of DNA replication after fertilization is regulated by p90Rsk at pre-RC/pre-IC transition in starfish eggs

Initiation of DNA replication in eukaryotic cells is controlled through an ordered assembly of protein complexes at replication origins. The molecules involved in this process are well conserved but diversely regulated. Typically, initiation of DNA replication is regulated in response to developmental events in multicellular organisms. Here, we elucidate the regulation of the first S phase of the embryonic cell cycle after fertilization. Unless fertilization occurs, the Mos-MAPK-p90Rsk pathway causes the G1-phase arrest after completion of meiosis in starfish eggs. Fertilization shuts down this pathway, leading to the first S phase with no requirement of new protein synthesis. However, how and in which stage the initiation complex for DNA replication is arrested by p90Rsk remains unclear. We find that in G1-arrested eggs, chromatin is loaded with the Mcm complex to form the prereplicative complex (pre-RC). Inactivation of p90Rsk is necessary and sufficient for further loading of Cdc45 onto chromatin to form the preinitiation complex (pre-IC) and the subsequent initiation of DNA replication. However, cyclin A-, B-, and E-Cdk''s activity and Cdc7 accumulation are dispensable for these processes. These observations define the stage of G1 arrest in unfertilized eggs at transition point from pre-RC to pre-IC, and reveal a unique role of p90Rsk for a negative regulator of this transition. Thus, initiation of DNA replication in the meiosis-to-mitosis transition is regulated at the pre-RC stage as like in the G1 checkpoint, but in a manner different from the checkpoint.     

Cutaneous sympathetic function in patients with multiple system atrophy

Some procedures increase the sweat output (SSwR; sympathetic sweat response) and reduce the cutaneous blood flow (SVR; skin vasomotor reflex) in the hand. We evaluated SSwRs and SVRs to deep inspiration, mental arithmetic, exercise, and tactile stimulation in 40 MSA patients and 15 healthy controls. We also conducted head-up tilt tests and R-R interval variation tests (CV_R-R). SSwRs were present in all controls, but absent in 19 (47.5 %) of the MSA patients. The mean SSwR amplitudes in the MSA group were significantly lower than those in the control group. SVRs were evoked in all subjects except 3 MSA patients. There were no marked differences in SVR amplitudes between the two groups. Orthostatic hypotension and low CV_R-R values were seen in 18 (45 %) and 13 (32.5 %) of the MSA patients, respectively. SSwR amplitudes correlated significantly with postural fall in blood pressure and CV_R-R values in the MSA group. SSwRs were absent in about half of the MSA patients, and the SSwR results correlated with those of the cardiovascular autonomic tests. The SVRs were not severely disturbed in the MSA patients. We considered SSwR a useful index for the detection of autonomic dysfunction in MSA. Received: 7 January 2002, Accepted: 4 June 2002 Correspondence to: Masato Asahina, M. D.     

Metachronous pancreatic acinar cell carcinoma discovered in early stage during follow-up of breast cancer: report of a case

We present an extremely rare case of early-stage acinar cell carcinoma of the pancreas. A 49-year-old woman, who had undergone radical surgery for breast cancer 3?years earlier, was suspected to have a rib metastasis during follow-up. She also had a family history of cancer. No accumulation was seen in the left rib on ¹⁸F-fluorodeoxyglucose positron emission tomography with computed tomography, but incidental high uptake into the pancreatic head suggested malignant pancreatic tumor. The tumor was completely resected by pancreatoduodenectomy, and pancreatic acinar cell carcinoma was demonstrated histopathologically. To the best of our knowledge, this is the first reported case of a pancreatic acinar cell carcinoma smaller than 1?cm to be detected by ¹⁸F-fluorodeoxyglucose positron emission tomography and computed tomography.     

Hypofractionated stereotactic radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not eligible for other ablation therapies: Preliminary results for efficacy and toxicity

Aim: To investigate the efficacy and toxicity of hypofractionated stereotactic radiotherapy for the treatment of patients presenting with hepatocellular carcinoma (HCC) in a single institutional setting. Methods: Sixteen patients who presented with solitary HCC, including two patients with a tumor thrombus of the portal veins, were treated with stereotactic radiotherapy with or without transarterial chemoembolization. The criteria for stereotactic radiotherapy were existence of technical difficulties for other ablation therapies, inoperable disease or refusal to undergo surgery, tumor staged as Grade A or B according to the Child-Pugh classification, and solitary tumor distant from the gastrointestinal tract and kidney with a tumor volume <100 cm(3). In 14 of 16 patients, a total dose of 35- 50 Gy was delivered in 5-7 fractions over 5-9 days. Results: At the end of a mean follow-up of 612 days (median 611 days; range 244-994 days), all patients were alive. Eight of 16 patients had complete responses and seven others were judged as stable with lipiodol accumulation. In one patient, local recurrence developed after 489 days. Intrahepatic recurrences developed outside the treated volume in six patients and no extrahepatic metastases developed during follow-up. No serious treatment-related toxic manifestations developed. Conclusions: Stereotactic radiotherapy for HCC with or without transarterial chemoembolization is feasible therapy and provides good local control with a short treatment period. Stereotactic radiotherapy may be of clinical benefit in patients who are inoperable or for whom there are difficulties in other ablation therapies.     

Distribution of hip pain in osteoarthritis patients secondary to developmental dysplasia of the hip

Objectives

Our aim was to clarify the distribution of hip pain in patients with osteoarthritis of the hip secondary to developmental dysplasia of the hip (DDH).

Methods

We retrospectively studied 443 hips in 369 patients with osteoarthritis secondary to DDH; mean age was 61 years, and follow-up rate was 84 %. Hip pain was defined as preoperative pain that was relieved 3 months after total hip arthroplasty.

Results

Distribution of pain originating in the hip was 89 % (393 hips) to the groin, 38 % (170 hips) to the buttock, 33 % (144 hips) to the anterior thigh, 29 % (130 hips) to the knee, 27 % (118 hips) to the greater trochanter, 17 % (76 hips) to the low back, and 8 % (34 hips) to the lower leg. When the groin, buttock, and greater trochanter were combined as the hip region, 95 % (421 hips) of pain was located in the hip region. On the other hand, when the anterior thigh, knee, lower leg, and low back were combined as the referral region, 55 % (242 hips) showed referred pain.

Conclusions

We suggest that rheumatologists be aware of hip disease masquerading as knee pain or low back pain.     

A case report of pulmonary tumor thrombotic microangiopathy (PTTM) caused by esophageal squamous cell carcinoma

A 67-year-old male was referred to our hospital after being diagnosed with esophageal squamous cell carcinoma of the middle thoracic esophagus. The clinical stage was T1b(sm)N4M1 cStage IVb, so he was admitted to our hospital for systemic chemotherapy. He had sustained fever and a dry cough. Chest computed tomography showed the presence of irregular shadows, and unidentified respiratory insufficiency had progressed. A transbronchial lung biopsy revealed a pulmonary artery tumor embolus of esophageal squamous cell carcinoma. He developed DIC and died of respiratory failure on the 19th hospital day. The postmortem autopsy detected pulmonary tumor thrombotic microangiopathy accompanied by esophageal squamous cell carcinoma.     

Feasibility of Frameless Stereotactic High-Dose Radiation Therapy for Primary or Metastatic Liver Cancer

Between April 1995 and March 1997, 18 patients with 23 primary or metastatic liver cancers were treated with frameless stereotactic radiation therapy (F-SRT) using a multifunctional treatment unit consisting of a linear accelerator (LINAC), computed tomography (CT), an X-ray simulator (X-S), and a treatment table. Before F-SRT, all but two patients received transcatheter arterial chem-oembolization (TAE) with Lipiodol, which played a role as a metallic marker. The treatment was performed safely in all patients without any remarkable symptoms. Only one patient who had three tumors showed temporary elevation of serum transaminase, and the other patients showed no change. Although follow-up times were very short, local progression was not observed on follow-up CT in all patients.     

Oxidative DNA damage and cell proliferation in kidneys of male and female rats during 13-weeks exposure to potassium bromate (KBrO3)

It has been assumed that oxidative damage, including formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts in kidney DNA due to potassium bromate (KBrO₃), a renal carcinogen to both sexes of rats, is involved in its mechanisms of tumor induction. However, despite the presumed existence of a repair enzyme(s) for 8-OHdG, there have been no reports demonstrating the changes in adduct levels during medium- or long-term exposure. To elucidate the actual kinetics regarding this parameter during the early stages of KBrO₃ carcinogenesis, we measured 8-OHdG levels in kidney DNA together with cell proliferation in renal tubules in both sexes of rats receiving KBrO₃ at a dose of 500 ppm in the drinking water for 1, 2, 3, 4, and 13 weeks. Rapid elevation of 8-OHdG levels was noted in treated male rats which persisted until the end of the experiment. Increased cell proliferation in the proximal convoluted tubules was also observed throughout the experimental period, concomitant with ₂-globulin accumulation. Increase in 8-OHdG levels in treated females first became apparent 3 weeks after the start of exposure, with cell proliferation only elevated at the 13-week time point. The present study, employing the same route and dose of KBrO₃ known to cause tumors, strongly suggested the requirement of persistent increase of 8-OHdG for neoplastic conversion. Moreover, a clear sex difference in susceptibility to generation of oxidative stress in kidney DNA was found, in addition to ₂-globulin-dependent variation in cell proliferation in the renal tubules. Received: 10 September 1997 / Accepted: 17 November 1997     

Differences in pulmonary function before vs. 1 year after hypofractionated stereotactic radiotherapy for small peripheral lung tumors

PURPOSE: To evaluate long-term pulmonary toxicity of stereotactic radiotherapy (SRT) by pulmonary function tests (PFTs) performed before and after SRT for small peripheral lung tumors. METHODS AND MATERIALS: A total of 17 lesions in 15 patients with small peripheral lung tumors, who underwent SRT between February 2000 and April 2003, were included in this study. Twelve patients had primary lung cancer, and 3 patients had metastatic lung cancer. Primary lung cancer was T1-2N0M0 in all cases. Smoking history was assessed by the Brinkman index (number of cigarettes smoked per day multiplied by number of years of smoking). Prescribed radiation doses at the 80% isodose line were 40-60 Gy in 5-8 fractions. PFTs were performed immediately before SRT and 1 year after SRT. Test parameters included total lung capacity (TLC), vital capacity (VC), forced expiratory volume in 1 s (FEV1.0), and diffusing capacity of lung for carbon monoxide (DLCO). PFT changes were evaluated in relation to patient- and treatment-related factors, including age, the Brinkman index, internal target volume, the percentages of lung volume irradiated with >15, 20, 25, and 30 Gy (V15, V20, V25, and V30, respectively), and mean lung dose. RESULTS: There were no significant changes in TLC, VC, or FEV1.0 before vs. after SRT. The mean percent change from baseline in DLCO was significantly increased by 128.2%. Univariate and multivariate analyses revealed a correlation between DLCO and the Brinkman index. CONCLUSIONS: One year after SRT as compared with before SRT, there were no declines in TLC, VC, and FEV1.0. DLCO improved in patients who had been heavy smokers before SRT, suggesting a correlation between DLCO and smoking cessation. SRT seems to be tolerable in view of long-term lung function.