The relationship between the daily step counts and low back pain during pregnancy.

PURPOSE: To investigate the relationship between the change of daily step counts and low back pain (LBP) during pregnancy. Materials and METHODS: Pregnant women at less than eight weeks of gestation (WG) were recruited. Daily step counts were measured with a pedometer. To assess LBP, the Oswestry disability index (ODI) score was recorded. Thirty-six individuals were divided into the LBP and non-LBP groups. The effect of step counts on LBP between the two groups was analyzed. RESULTS: At 16-19 WG, step counts were not considerably changed in the non-LBP group but were significantly increased in the LBP group. At 24-27 and 32-35 WG, step counts were increased in the non-LBP group but were significantly decreased in the LBP group. CONCLUSIONS: Acute increase of daily step counts in early pregnancy is a risk for LBP, and gradual increases of step counts after mid-pregnancy is recommended for women.

HLA-DRB1 polymorphisms distribution in chronic dysimmune polyneuropathy.

The frequency of HLA-DRB1*15 polymorphism, which is strongly associated to multiple sclerosis, was investigated in 84 adult patients with chronic dysimmune polyneuropathy and 272 healthy controls. No significant differences were detected between cases and controls and, among patients, according to gender, peripheral nerve antigen antibody seropositivity, and electrophysiological features. A trend towards an increase of HLA-DRB1*11 in anti-MAG neuropathy was detected.

Eukaryotic translation initiation factor 4E (eIF4E) binding site and the middle one-third of eIF4GI constitute the core domain for cap-dependent translation, and the C-terminal one-third functions as a modulatory region.

The mammalian eukaryotic initiation factor 4GI (eIF4GI) may be divided into three roughly equal regions; an amino-terminal one-third (amino acids [aa] 1 to 634), which contains the poly(A) binding protein (PABP) and eIF4E binding sites; a middle third (aa 635 to 1039), which binds eIF4A and eIF3; and a carboxy-terminal third (aa 1040 to 1560), which harbors a second eIF4A binding site and a docking sequence for the Ser/Thr kinase Mnk1. Previous reports demonstrated that the middle one-third of eIF4GI is sufficient for cap-independent translation. To delineate the eIF4GI core sequence required for cap-dependent translation, various truncated versions of eIF4GI were examined in an in vitro ribosome binding assay with beta-globin mRNA. A sequence of 540 aa encompassing aa 550 to 1090, which contains the eIF4E binding site and the middle region of eIF4GI, is the minimal sequence required for cap-dependent translation. In agreement with this, a point mutation in eIF4GI which abolished eIF4A binding in the middle region completely inhibited ribosomal binding. However, the eIF4GI C-terminal third region, which does not have a counterpart in yeast, modulates the activity of the core sequence. When the eIF4A binding site in the C-terminal region of eIF4GI was mutated, ribosome binding was decreased three- to fourfold. These data indicate that the interaction of eIF4A with the middle region of eIF4GI is necessary for translation, whereas the interaction of eIF4A with the C-terminal region plays a modulatory role.

A novel functional human eukaryotic translation initiation factor 4G.

Mammalian eukaryotic translation initiation factor 4F (eIF4F) is a cap-binding protein complex consisting of three subunits: eIF4E, eIF4A, and eIF4G. In yeast and plants, two related eIF4G species are encoded by two different genes. To date, however, only one functional eIF4G polypeptide, referred to here as eIF4GI, has been identified in mammals. Here we describe the discovery and functional characterization of a closely related homolog, referred to as eIF4GII. eIF4GI and eIF4GII share 46% identity at the amino acid level and possess an overall similarity of 56%. The homology is particularly high in certain regions of the central and carboxy portions, while the amino-terminal regions are more divergent. Far-Western analysis and coimmunoprecipitation experiments were used to demonstrate that eIF4GII directly interacts with eIF4E, eIF4A, and eIF3. eIF4GII, like eIF4GI, is also cleaved upon picornavirus infection. eIF4GII restores cap-dependent translation in a reticulocyte lysate which had been pretreated with rhinovirus 2A to cleave endogenous eIF4G. Finally, eIF4GII exists as a complex with eIF4E in HeLa cells, because eIF4GII and eIF4E can be purified together by cap affinity chromatography. Taken together, our findings indicate that eIF4GII is a functional homolog of eIF4GI. These results may have important implications for the understanding of the mechanism of shutoff of host protein synthesis following picornavirus infection.

Eukaryotic translation initiation factor 4AIII (eIF4AIII) is functionally distinct from eIF4AI and eIF4AII.

Eukaryotic initiation factor 4A (eIF4A) is an RNA-dependent ATPase and ATP-dependent RNA helicase that is thought to melt the 5' proximal secondary structure of eukaryotic mRNAs to facilitate attachment of the 40S ribosomal subunit. eIF4A functions in a complex termed eIF4F with two other initiation factors (eIF4E and eIF4G). Two isoforms of eIF4A, eIF4AI and eIF4AII, which are encoded by two different genes, are functionally indistinguishable. A third member of the eIF4A family, eIF4AIII, whose human homolog exhibits 65% amino acid identity to human eIF4AI, has also been cloned from Xenopus and tobacco, but its function in translation has not been characterized. In this study, human eIF4AIII was characterized biochemically. While eIF4AIII, like eIF4AI, exhibits RNA-dependent ATPase activity and ATP-dependent RNA helicase activity, it fails to substitute for eIF4AI in an in vitro-reconstituted 40S ribosome binding assay. Instead, eIF4AIII inhibits translation in a reticulocyte lysate system. In addition, whereas eIF4AI binds independently to the middle and carboxy-terminal fragments of eIF4G, eIF4AIII binds to the middle fragment only. These functional differences between eIF4AI and eIF4AIII suggest that eIF4AIII might play an inhibitory role in translation under physiological conditions.

[The efficacy of perioperative administration of steroid and erythromycin in the surgery for lung cancer complicated with interstitial pneumonia].

OBJECTIVES: We evaluated the efficacy of perioperative administration of steroid and erythromycin in surgery for lung cancer complicated with interstitial pneumonia (IP) to prevent postoperative acute exacerbation. PATIENTS AND METHODS: We operated on 21 lung cancer patients with IP for 10 years. The patients were given 400 mg of erythromycin over 1 week before surgery and re-administered on the 1st operative day. The patients were also given 125 mg of methylprednisolone intravenously just before operation and continued until the 2nd operative day. RESULTS: Lobectomy was performed in 16, segmentectomy or partial resection in 2 each, and completion pneumonectomy in 1. Three patients developed acute exacerbation of IP, but it occurred after the re-operation due to postoperative complications in 2. We experienced no operative death within 30 days, however, 2 died during the hospital stay due to multiple organ failure and sepsis. Seven of 21 patients had postoperative complications; air leakage over 1 week in 4, arrhythmia in 3, and atelectasis, postoperative bleeding, and pneumonia in 1 each, the morbidity rate was 33%. CONCLUSIONS: We conclude that the administration of steroid and erythromycin in surgery for lung cancer with IP was suspected the usefulness to prevent a postoperative acute exacerbation of IP.

[Surgical treatment for stage IV lung cancer].

OBJECTIVE: To find out the optimal surgical indication in stage IV lung cancer patients, we evaluated them retrospectively. METHODS & RESULTS: From 1975 to 2005, 62 patients without multiple metastases were operated at our hospital. The most common histological type was adenocarcinoma (67.7%). The metastatic lesions were lung (33.9%), brain (24.2%), liver, bone, adrenal gland and so on. The overall survival rate of stage IV lung cancer was 10.4% at 5-year. Five-year survival for patients with lung or brain metastasis who had no lymph node metastasis were significantly more superior than those with lymph node metastasis (p=0.0389, 0.0021). Four of 62 patients had 5-year survival. Two were lung and the others were brain and adrenal gland metastasis without lymph node metastasis. CONCLUSION: Stage IV lung cancer with lung or brain or adrenal gland metastasis without lymph node metastasis should be resected.

Comparative study of survival of patients with hepatocellular carcinoma predicted by different staging systems using multivariate analysis.

AIMS: In a previous pilot study, we reported the usefulness of the modified the Cancer of the Liver Italian Program (CLIP) score for patients with hepatocellular carcinoma (HCC). To determine the best staging system for predicting the survival of HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 210 Japanese HCC patients who underwent hepatic resection. METHODS: We compared the survival as predicted by various staging systems, including tumour node metastasis (TNM) stage of the American Joint Commission on Cancer (AJCC) and the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), CLIP score and our modified CLIP score using protein induced by vitamin K absence or antagonist II (PIVKA-II). RESULTS: Univariate analysis showed that discrimination of disease-free survival in the early and advanced stages by the JIS score and modified CLIP score was clearer than by the Japanese or AJCC TNM or the original CLIP score. Discrimination between stages of overall survival by all staging systems was significant. Multivariate analysis showed that the JIS, CLIP and modified CLIP scores were better staging systems for predicting survival than the Japanese and AJCC TNM. The modified CLIP score showed the lowest Akaike information criteria statistical value for disease-free and overall survival, which means the best discrimination ability for patient survival compared with the JIS score and CLIP score. CONCLUSIONS: A staging system that combines tumour factors, sensitive tumour marker(s) and hepatic function is the best predictor of prognosis of HCC patients.

Satellite potentials on EMG: neurophysiologic evidence of axonal transection in MS?

To detect signs of axonal damage in MS, the authors investigated the occurrence in EMG of motor unit action potentials with satellite potentials (SP-MUAP) in the upper limb muscles in 10 consecutive patients with MS with cervical spinal cord demyelinating lesions and 10 control subjects. Subjects' SP-MUAP rate was 0 to 2.5% (median 0%) in the control group, and 0 to 17.5% (median 7.5%) in the MS group (p < 0.01). Motor unit remodeling secondary to axonal transection of spinal motor neurons traversing cervical demyelinating lesions may be hypothesized.

Early neurologic complications following allogeneic bone marrow transplant for leukemia: a prospective study.

BACKGROUND: Bone marrow transplant (BMT) is used for both neoplastic and nonneoplastic diseases. Following BMT, particularly during the first 3 months, patients have a number of neurologic complications. We evaluated the early neurologic complications following BMT and their influence on survival. METHODS: We prospectively followed 115 consecutive patients having BMT for leukemia, for a median period of 90 days after transplantation. RESULTS: Sixty-four patients (56%) had neurologic complications. Sixteen developed more than one complication. Twenty-seven patients (25%) had major neurologic complications: metabolic encephalopathy (8), seizures (8), psychiatric symptoms (3), cerebral hemorrhage (1), cerebral abscess (1), leukemic meningitis (1), peripheral neuropathies (5), and myopathies (2). Forty patients (35%) had minor complications, including headache (16) and tremor (31). Major neurologic complications occurred after engraftment in most patients. Metabolic encephalopathy correlated with graft-versus-host disease (GVHD) (p < 0.03). Seven percent of patients had generalized seizures that occurred without signs of structural cerebral lesions. Probability of survival at day 90 was lower in patients with than in those without major central nervous system complications (63% versus 87.5%, p < 0.01). CONCLUSIONS: Neurologic complications are frequent during the first 3 months following BMT and affect patient survival. Drug neurotoxicity and acute GVHD are the main factors influencing their occurrence.

Natural history of cardiac involvement in myotonic dystrophy: correlation with CTG repeats.

The authors prospectively studied the natural course of cardiac involvement and its relationship to cytosine-thymine-guanine (CTG) expansion in 50 patients with myotonic dystrophy who were submitted to periodic cardiovascular EKG and EKG-Holter monitoring during a median follow-up of 56 months. Nineteen patients (38%) developed major EKG changes. CTG length was not correlated with the frequency of EKG abnormalities, but was inversely correlated with the age at onset of EKG abnormalities (p < 0.0001). CTG length influences the timing of cardiac complications in myotonic dystrophy.

Expression of a synthetic gene for initiation factor 4E-binding protein 1 in Escherichia coli and its interaction with eIF-4E and eIF-4E x m7GTP complex.

An artificial gene coding for the human initiation factor (eIF) 4E-binding protein 1 (4E-BP1) was chemically synthesized and cloned. Although the expression of the 4E-BP1 gene alone has not yet been accomplished, the gene was expressed in Escherichia coli [BL21(DE3)] as a fusion gene with the glutathione-S-transferase (GST) gene using a prokaryotic gene fusion vector (pGEX-4T-2), which contains a gene sequence coding the cleavage site for a specific protease, alpha-thrombin. The fusion gene product was purified to homogeneity by glutathione Sepharose-4B affinity column chromatography. It was shown by m7GTP- and glutathione-affinity chromatography that the binding ability of 4E-BP1 to eIF-4E is nearly the same as that to the eIF-4E x m7GTP complex, implying different binding sites of eIF-4E and its nonallosteric obligation for 4E-BP1 and mRNA cap structure. In contrast with the binding of eIF-4E to the mRNA cap structure, where some functional amino acids play an important role in the binding, the binding to 4E-BP1 was suggested to occur via multiple nonspecific interactions.

Crystallization and preliminary X-ray diffraction study of recombinant human eukaryotic initiation factor-4E.

Recombinant human eukaryotic initiation factor-4E (eIF-4E), purified by m7GTP-Sepharose 4B affinity chromatography, was used for crystallization. After concentration of the eIF-4E protein (7 mg/ml), the solution was subjected to crystallization by the hanging-drop method. Transparent needle crystals complexed with m7GTP were obtained from 50 mM 2-(N-morpholino)ethanesulfonic acid-KOH buffer (pH 6.5) containing 25% (w/v) polyethylene glycol 6000 and 0.2 M (NH4)2SO4. The crystals belong to tetragonal space group P4(1) or P4(3), of Z = 4, with unit-cell dimensions of a = 89.26, b = 89.26, and c = 38.51 angstrum, and diffract beyond 2.1 angstrum resolution. The Vm value was calculated to be 3.07 angstrum 3/Da, which indicates a solvent content of 59.9%.

Direct expression of a synthetic gene in Escherichia coli: purification and physicochemical properties of human initiation factor 4E.

An artificial synthetic gene coding for human eIF-4E was cloned into an expression vector and direct expression was attempted in Escherichia coli [BL21(DE3) strain] under the control of T7 promoter. The active gene product which was induced in high yield (ca. 4 mg/100 ml) by isopropyl-beta-D-thiogalactopyranoside was purified to homogeneity by a two-step chromatographic procedure with a good yield (ca. 74%), and was confirmed to be recombinant human eIF-4E by amino acid composition and sequence analyses, isoelectric focusing, and absorption spectral measurements. The identity of three-dimensional structures between the recombinant and native human eIF-4Es was confirmed by CD and fluorescence measurements.

Noninvasive assessment of mitoxantrone cardiotoxicity in relapsing remitting multiple sclerosis.

Multiple sclerosis is the most common cause of neurologic disability in young adults. Recent reports have suggested that Mitoxantrone might be a candidate for clinical trials in multiple sclerosis patients. The authors studied 20 patients with relapsing remitting multiple sclerosis to evaluate cardiac toxicity during a one-year follow-up period. Patients were divided into 2 groups: group A, mitoxantrone treated patients (cumulative dose of 96 mg/m2); group B, placebo patients. The clinical course of multiple sclerosis was assessed using the Expanded Disability Status Scale and the number of relapses during the follow-up. Each patient had an electrocardiogram and a spectral and color flow Doppler echocardiographic examination at enrollment, and 6 and 12 months later, to investigate cardiac toxicity. The mean exacerbation rate was reduced significantly in group A patients. No significant differences in the electrocardiograms or the echocardiographic parameters of systolic and diastolic function were noted between the two groups or in group A during the follow-up. Mitoxantrone treatment seems able to improve the clinical course of relapsing remitting multiple sclerosis patients. It does not show any cardiac toxicity in selected patients at this dosage.

Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome.

We designed a randomized, placebo-controlled, multicentre trial involving 51 relapsing-remitting multiple sclerosis patients to determine the clinical efficacy of mitoxantrone treatment over 2 years. Patients were allocated either to the mitoxantrone group (27 patients receiving I.V. infusion of mitoxantrone every month for 1 year at the dosage of 8 mg/m2) or to the placebo group (24 patients, receiving I.V. infusion of saline every month for 1 year) using a centralized randomization system. Disability at entry and at 12-24 months was evaluated by four blinded neurologists trained in the application of the Kurtzke Expanded Disability Scale (EDSS). In addition, the number and clinical characteristics of the exacerbations over the 24 months were recorded by the local investigators. MRI, at 0, 12 and 24 months, was performed with a 0.2 T permanent unit. MRI data were analysed by two blinded neuroradiologists. All patients underwent a clinical evaluation. A statistically significant difference in the mean number of exacerbations was observed between the mitoxantrone group and placebo group both during the 1st and the 2nd year. Although there was no statistically significant benefit in terms of mean EDSS progression over 2 years, the proportion of patients with confirmed progression of the disease, as measured by a one point increase on the EDSS scale, was significantly reduced at the 2nd year evaluation in the mitoxantrone group. Forty-two (23 mitoxantrone, 19 placebo) patients underwent all MRI examinations during the 24-month period. We observed a trend towards a reduction in the number of new lesions on T2-weighted images in the mitoxantrone group. Our study suggests that mitoxantrone might be effective in reducing disease activity, both by decreasing the mean number of exacerbations and by slowing the clinical progression sustained by most patients after 1 year from the end of treatment.

Selegiline in the treatment of hypersomnolence in myotonic dystrophy: a pilot study.

Patients with myotonic dystrophy frequently complain of hypersomnolence, a symptom which seriously restricts their social life. The pathogenesis of this symptom is a matter of debate: it has been attributed to both alveolar hypoventilation and pathological changes in the brainstem. As selegiline has been shown to reduce the number of sleep attacks in nacrolepsy, we tested whether hypersomnolence in myotonic dystrophy would respond to the same treatment. Ten patients with myotonic dystrophy received selegiline/placebo (20 mg daily) in a double-blind crossover trial. We monitored daytime sleepiness by means of a multiple sleep latency test. Treatment appeared to be well tolerated but did not alter hypersomnolence in myotonic dystrophy. Further studies to assess the effect of higher doses of selegiline are warranted.

Reversal of encephalopathy during treatment with amphotericin-B.

A case of reversible encephalopathy during treatment with Amphotericin-B (AMB) is described. The comparison of the clinical course of AMB encephalopathy with total dose of AMB, cranial radiotherapy and MRI data available in previously reported cases, shows that this complication is characterized by a progressive, dose-dependent course, possibly influenced by cranial irradiation.

Excessive daytime sleepiness in myotonic dystrophy.

The aim of the present study was to assess whether or not there is any correlation between magnetic resonance imaging (MRI) abnormalities and excessive daytime sleepiness (EDS) in a consecutive series of patients with myotonic dystrophy (MD). The influences of nocturnal breathing abnormalities and sleep morphology on EDS were also evaluated. Ten MD patients were studied by means of an all-night polysomnographic recording, the multiple sleep latency test (MSLT) and MRI. Diagnosis of MD was established on the basis of the clinical and electrophysiological evidence of myotonia as well as of the characteristic genetic pattern. No patient had respiratory failure. Polysomnography and MSLT were also evaluated in ten healthy age-matched controls under the same environmental conditions. The mean MSLT value was significantly lower in patients than in controls. Five of the ten patients were found to have pathological EDS. The quantitative sleep variables and the nocturnal apnoeas in these five patients were not significantly different from those of the patients without EDS. As two patients did not undergo MRI because of claustrophobia, the MRI data were considered in eight patients. Corpus callosum (CC) atrophy was detected in four patients, whereas three patients showed hyperintense areas in the white matter. No correlation was found between EDS and MRI indexes of subcortical atrophy as well as volume of the hyperintense areas. By contrast, a correlation was found between the MSLT value and the reduction in the anterior area of the CC. Our data suggest that CC atrophy might occur in MD patients, and that the size of the CC anterior area might be associated with EDS.

Modified CLIP using PIVKA-II for evaluating prognosis after hepatectomy for hepatocellular carcinoma.

AIMS: The new staging system proposed by the Cancer of the Liver Italian Program (CLIP) for hepatocellular carcinoma (HCC) accounts for both liver dysfunction and tumour characteristics. The present study was designed to analyze UICC TNM stage, CLIP and modified CLIP in 91 patients who underwent hepatic resection for HCC. METHODS: In the modified CLIP, scoring of AFP was replaced by that of protein induced by vitamin K absence or antagonist II (PIVKA-II; predictive value, > or = 400 mAU/ml). RESULTS: After hepatic resection, 54 patients developed recurrent tumours. High PIVKA-II was a significant determinant of recurrence (p<0.05). However, a high score of the modified CLIP as well as those other staging systems did not correlate with tumour-recurrence rate. Univariate analysis showed that high TNM score, CLIP score and our modified CLIP score were significant predictors of poor prognosis. Multivariate Cox's analysis revealed that high PIVKA-II and high modified CLIP score were associated with higher risk for disease-free and overall survival as well as high TNM stage. CONCLUSIONS: Compared with the original CLIP, our modified CLIP was a better predictor of prognosis of HCC patients who underwent hepatic resection.