Autonomic dysfunction in hereditary spastic paraplegia type 4.

BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.

Different X-linked KDM5C mutations in affected male siblings: is maternal reversion error involved?

Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low-prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10(-28) ), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases.

MR Imaging Detection of CNS Lesions in Tuberous Sclerosis Complex: The Usefulness of T1WI with Chemical Shift Selective Images.

BACKGROUND AND PURPOSE: CNS lesions of tuberous sclerosis complex are diagnosed mainly by T2WI, FLAIR, and sometimes T1WI with magnetization transfer contrast. The usefulness of T1WI with chemical shift selective images was recently reported in focal cortical dysplasia type IIb, which has histopathologic and imaging features similar to those of tuberous sclerosis complex. We investigated the usefulness of the T1WI with chemical shift selective images in detecting CNS lesions of tuberous sclerosis complex. MATERIALS AND METHODS: We retrospectively reviewed 25 consecutive patients with tuberous sclerosis complex (mean age, 11.9 [SD, 8.9] years; 14 males) who underwent MR imaging including T1WI, T1WI with magnetization transfer contrast, T1WI with chemical shift selective, T2WI, and FLAIR images. Two neuroradiologists assessed the number of CNS lesions in each sequence and compared them in 2 steps: among T1WI, T1WI with magnetization transfer contrast and T1WI with chemical shift selective images, and among T2WI, FLAIR, and T1WI with chemical shift selective images. We calculated the contrast ratio of the cortical tubers and of adjacent normal-appearing gray matter and the contrast ratio of radial migration lines and adjacent normal-appearing white matter in each sequence and compared them. RESULTS: T1WI with chemical shift selective images was significantly superior to T1WI with magnetization transfer contrast for the detection of radial migration lines and contrast ratio of radial migration lines. There was no significant difference between T1WI with chemical shift selective images and T1WI with magnetization transfer contrast for the detection of cortical tubers and the contrast ratio of the cortical tubers. Both T2WI and FLAIR were statistically superior to T1WI with chemical shift selective images for the detection of cortical tubers. T1WI with chemical shift selective images was significantly superior to T2WI and FLAIR for the detection of radial migration lines. CONCLUSIONS: The usefulness of T1WI with chemical shift selective images in detecting radial migration lines was demonstrated. Our findings suggest that the combination of T1WI with chemical shift selective images, T2WI, and FLAIR would be useful to evaluate the CNS lesions of patients with tuberous sclerosis complex in daily clinical practice.

Characteristics of Escherichia coli isolated from broiler chickens with colibacillosis in commercial farms from a common hatchery.

To investigate the epidemiologic aspects of colibacillosis in broiler chickens, 83 Escherichia coli isolates obtained from the pericarditis and perihepatitis lesions in broiler chickens from 4 commercial farms, 5 isolates recovered from 5 samples of yolk sac contents that were pooled from 25 emaciated chicks, and 4 fecal isolates obtained from a hatchery that supplied chicks to the 4 commercial farms mentioned above were genetically and bacteriologically characterized. Using pulsed-field gel electrophoresis (PFGE), a total of 92 isolates were classified into 33 pulsotypes. Identical pulsotypes were observed in isolates obtained from hatchery samples and the affected broiler chickens on multiple farms at various sampling times. Seventeen representative isolates with no common origin belonging to 6 pulsotypes and an additional 27 isolates with the other pulsotypes were used for further experiments. Isolates with identical pulsotypes exhibited common traits for virulence-associated genes, lipopolysaccharide core types, and phylogenetic groups. Nine of the isolates were serologically typed as O125 with various types of H antigens and 3 were typed as O25:H4. In the 27 isolates resistant to ceftiofur (CTF), which is a third generation cephalosporin, the blaCTX-M-2, blaCMY-2, blaCTX-M-14, blaCTX-M-65 genes were found in 15, 8, 3, and 1 isolate(s), respectively, and another isolate resistant to CTF had both the blaCTX-M-2 and the blaCMY-2 genes. In the 16 isolates with the blaCTX-M-2 gene, the chromosomal location of the gene was identified in 12 isolates. The plasmid-mediated quinolone resistance genes, oqxAB and aac(6')-Ib-cr, were found in 2 and 3 isolates, respectively. Conjugation experiments revealed that the blaCTX-M-2 (4 isolates), blaCTX-M-14 (3 isolates), blaSHV-12 (1 isolate), and oqxAB (2 isolates) genes were transferred. Our data suggest that E. coli strains with identical pulsotypes had been caused the incidences of colibacillosis and that the antimicrobial resistance genes on conjugative plasmids and those integrated into the chromosome may be spread among avian pathogenic E. coli strains in multiple farms.

Contribution of donor and host mesenchyme to the transplanted tooth germs.

Autologous tooth germ transplantation of immature teeth is an alternative method of tooth replacement that could be used instead of dental implants in younger patients. However, it is paramount that the dental pulp remain vital and that root formation continue in the transplanted location. The goal of this study is to characterize the healing of allogenic tooth grafts in an animal model using GFP-labeled donor or host postnatal mice. In addition, the putative stem cells were labeled before transplantation with a pulse-chase paradigm. Transplanted molars formed cusps and roots and erupted into occlusion by 2 wk postoperatively. Host label-retaining cells (LRCs) were maintained in the center of pulp tissue associating with blood vessels. Dual labeling showed that a proportion of LRCs were incorporated into the odontoblast layer. Host cells, including putative dendritic cells and the endothelium, also immigrated into the pulp tissue but did not contribute to the odontoblast layer. Therefore, LRCs or putative mesenchymal stem cells are retained in the transplanted pulps. Hertwig's epithelial root sheath remains vital, and epithelial LRCs are present in the donor cervical loops. Thus, the dynamic donor-host interaction occurred in the developing transplant, suggesting that these changes affect the characteristics of the dental pulp.

Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture.

Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system (CNS). However, little is known about expression of EPO and EPO receptor (EPOR) in human CNS tissues. In the present study, we investigated the effects of proinflammatory cytokines on EPO and EPOR expression in highly purified cultures of human neurons, astrocytes, microglia, and oligodendrocytes using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). EPO mRNA was demonstrated only in human astrocytes, while EPOR expression was found in human neurons, astrocytes, and microglia. Neither EPO nor EPOR expression was found in oligodendrocytes. In human astrocytes, EPO mRNA and secreted EPO protein levels were downregulated after exposure to proinflammatory cytokines (IL-1beta, IL-6, or TNF-alpha). In human neurons, TNF-alpha treatment markedly increased EPOR expression. These results suggest that proinflammatory cytokines regulate expression of EPO and EPOR in human neurons, astrocytes, and microglia and further facilitate interactions among different cell types in the human CNS.

Contralateral parafalcine approach for parasagittal and callosal arteriovenous malformations.

Most neurosurgeons prefer an ipsilateral approach for medial surface arteriovenous malformations. Based on recent surgical experiences, we believe that a contralateral approach has some advantages in dealing with such lesions. Two cases are reported, and the rationale for the contralateral approach is discussed.

Basilar aneurysm surgery: the subtemporal approach with section of the zygomatic arch.

The authors propose a modification of the classic subtemporal approach for basilar aneurysm. This modification allows excellent access to the floor of the temporal fossa, the tentorial edge, and the interpeduncular fossa with less brain retraction than is required with the original technique. The procedure is described, our experience with it is presented, and suggestions are made for its use.

Pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin.

Nedaplatin (cis-diammine glycolate platinum) is one of the effective platinum agents for gynecologic carcinoma. In order to assess the pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin, we calculated 10 course AUCs (area under the curve) of the free and total platinum from blood samples of 4 patients. Peak serum platinum concentrations were dependent on infusion times. In the case of a patient with renal dysfunction or ascites, the concentration of serum platinum tended to stay at a high level for a long time. Serum-free platinum ratios were maintained longer than cisplatin. Low dose nedaplatin administration and divided administration were effective, but total AUC was not so great. The relation between AUC ratio (free platinum AUC/total platinum AUC) and dose/m(2) was not clarified.

Clinical evaluation of mature teratomas containing malignant elements.

We investigated the possibility of preoperative diagnosis and clinical features of mature ovarian teratoma containing malignant elements (MOTME). Between 1982 and 1998 in our hospital, MOTME accounted for 2.0% (5 cases) of the total of 251 patients with mature ovarian teratoma (ages, 37-72; mean age, 60.6). Serum CA19-9, CA125, SCC and CEA levels were high. All cases were strongly suspected malignancies, preoperatively diagnosed using serum tumor markers with diagnostic imaging. Two cases of stage I squamous cell carcinoma and one case of borderline malignancy survived, while the other two advanced cases died within 8 months.

Cyclooxygenase-2 expression in malignant mesenchymal tumors and related uterine lesions.

The aim of this study was to determine whether the expression of cyclooxygenase-2 (COX-2) in uterine sarcoma cells and carcinosarcoma cells is associated with cell type. Nineteen sections of tissues from uterine sarcomas, carcinosarcomas, and an adenosarcoma, and endometrial stromal sarcomas, were immunohistochemically analyzed for the cellular expression of COX-2. Positive immunostaining for COX-2 was observed in 88.9% (8/9) uterine carcinosarcomas, uterine adenosarcomas but was not observed in uterine sarcomas and the endometrial stromal sarcoma (0/10). But positive immunostaining for COX-2 was observed in some sarcomatoid cells in carcinosarcoma tissue. These findings suggest that some of the sarcoma cells in uterine carcinosarcomas resemble epithelial malignant cells in regard to the increase in COX-2 expression, and support the hypothesis that some uterine carcinosarcomas are combination tumors. This may serve as a basis for new chemoprevention and treatment strategies for uterine carcinosarcomas through the inhibition of COX-2 activity.

Probucol decreases total body fat loss in VX2-carcinoma-induced cachectic rabbits.

We previously reported the continuous decrease of total body fat in VX2-carcinoma-bearing rabbits after tumor implantation, as well as changes in the serum lipid profile. Probucol, an antioxidant drug, has a cholesterol lowering effect against hyperlipidemic subjects. VX2-carcinoma-bearing rabbits fed with a diet containing 1% probucol did not show any difference in serum lipid compositions as compared with rabbits fed with a control diet. Similarly serum lipolytic activity showed no differences, whether probucol was administered or not, while the decrease in total body fat was significantly less when probucol was administered.

Cyclooxygenase-2 expression in normal ovaries and epithelial ovarian neoplasms.

Cyclooxygenase-2 (COX-2) expression was investigated immunohistochemically in 57 epithelial ovarian neoplasms and in histologically normal ovaries. Positive immunostaining for COX-2 was observed in 78.6% (22/28) of the ovarian cancers and in 66.7% (14/21) of the borderline-malignant tumors. The rate of expression was significantly higher among the ovarian cancers than the benign cystadenomas (4/8; 50%) (p<0.05). There was a significant correlation between vascular endothelial growth factor (VEGF) expression and microvessel count (MVC), but no correlation between COX-2 expression and MVC. There was a significant correlation between VEGF expression and COX-2 expression in all of the ovarian neoplasms as a whole (p<0.05). These findings suggest that an increase in COX-2 expression may be associated with malignant transformation and tumorigenesis of epithelial ovarian neoplasms.

Expression of cyclooxygenase-2 in ovarian mature cystic teratomas with malignant transformation.

Cyclooxygenase-2 (COX-2) has been reported to be associated with tumor progression and angiogenesis and we previously reported that an increase in COX-2 expression might be associated with malignant transformation and tumorigenesis of epithelial ovarian neoplasms. In this study, COX-2 expression of ovarian mature cystic teratomas with malignant transformation, a rare entity accounting for just 1.8% of all mature cystic teratomas, was investigated using immunohistochemical techniques. There were 89 cases of mature cystic teratomas treated with surgery as their initial therapy at Osaka City University Medical School Hospital between 1995 and 2001. Ten cases of these were selected for study; five cases of mature cystic teratoma with malignant transformation, and five cases of mature benign teratoma. Expressions of CD34, vascular endothelial growth factor (VEGF), and COX-2 were investigated. Expressions of VEGF and COX-2 were strong in tissues of mature cystic teratomas with squamous cell carcinoma; however, expressions of them were hardly apparent in mature benign teratomas and in mature cystic teratomas with adenocarcinomas. These results tend to suggest that COX-2 is associated with tumor growth and progression in mature cystic teratomas with squamous cell carcinoma, as opposed to mature benign teratomas and mature cystic teratomas with adenocarcinomas.

Expression of skeletal muscle cells apoptosis regulatory proteins in plasma-perfused VX2 carcinoma-bearing rabbits.

BACKGROUND: In tumor-bearing animals we found that the skeletal muscle apoptosis might be involved in muscle wasting. In this study, we investigated changes in the skeletal muscle cell apoptosis regulatory proteins after cyclic plasma-perfusion (CPP). MATERIALS AND METHODS: We studied changes in body weight, lean body mass (LBM), apoptotic index (AI) and expression of Bax and Bcl-2 in skeletal muscle in VX2 carcinoma-bearing rabbits. RESULTS: 20 days after tumor implantation, LBM had decreased by 5.06+/-1.10%, while the AI had increased to 40.5+/-3.20%. By 40 days, LBM had decreased by 11.0+/-0.81% and the AI was only 0.93+/-0.96%. Bax expression was detected in proportion to the AI, but no Bcl-2 expression was detected in either the experimental or control groups. CPP improved LBM, but did not prevent Bax expression. CONCLUSION: Skeletal muscle cell apoptosis related to Bax was concluded to be the cause of muscle wasting in VX2 carcinoma-bearing rabbits. CPP appears to reduce muscle wasting and increase LBM, but it did not suppress Bax expression or skeletal muscle cell apoptosis.

Vermis lesions in acute cerebellar ataxia: a sequential imaging study.

We report a case of acute cerebellar ataxia (ACA) with discrete paleocerebellar clinical symptoms who underwent serial cranial magnetic resonance images not only with conventional spin echo sequences but also fluid attenuated inversion recovery (FLAIR) sequences. The images with the latter sequences demonstrated more conspicuously the high signal intensity lesions in the superior cerebellar vermis and cerebellar peduncle than those with the former sequences. In the convalescent phase, the lesions became markedly atrophic. Thus, the causative lesions for ACA were demonstrated on MRI, and FLAIR provided clear images of the lesion in the vermis.

Progressive brainstem and white matter lesions in Kearns-Sayre syndrome: a case report.

We performed serial cranial MRI examinations on an 11-year-old boy with Kearns-Sayre syndrome. Proton density (PD)-, T2-weighted and T2-weighted fluid attenuated inversion recovery (FLAIR) sequences revealed progressive high signal intensity areas in the brainstem, globus pallidus, thalamus, and white matter of the cerebrum and cerebellum bilaterally. The probable gliotic lesions in the brainstem may be part of the neurogenic origin of the external ophthalmoplegia in addition to the primary defect of the extraocularmuscle in KSS.

Long-term therapy with cytochrome c, flavin mononucleotide and thiamine diphosphate for a patient with Kearns-Sayre syndrome.

Cardiocrome, containing cytochrome c, flavin mononucleotide and thiamine diphosphate, was administered intravenously for 22 months to a patient with Kearns-Sayre syndrome. This combined therapy alleviated the patient's easy fatigability, motor disability, corneal edema and chilblains, but was not effective for his ophthalmoplegia, blepharoptosis or hearing loss. Truncal ataxia, dysphagia and an atrioventricular block appeared even with this therapy. Although the abnormal distribution of cerebral blood flow demonstrated by single photon emission computed tomography was improved, serial cranial magnetic resonance imaging and electrophysiological examination revealed progressive changes. In conclusion, this therapy was favorably effective for impaired skeletal muscle function and corneal edema, but not for ocular movements, central nervous system symptoms or cardiac conduction abnormalities, because irreversible degeneration had probably occurred in these organs.

Pentobarbital therapy for status epilepticus in children: timing of tapering.

Three children with refractory status epilepticus, unresponsive to intravenous administration of diazepam, phenytoin, and lidocaine, received pentobarbital therapy and were monitored by electroencephalography (EEG). They required mechanical ventilation and vasopressor therapy. Intravenous pentobarbital therapy was successful and without distinct sequelae in all 3 patients, and could be incrementally discontinued without breakthrough seizures after 12-65 hours of a burst-suppression or complete suppression pattern on EEG. Obtaining a suppression pattern was important for controlling status epilepticus in children as well as adults. We suggest that 12 hours after a burst-suppression pattern is obtained, tapering of pentobarbital should be attempted to avoid serious complications of extended pentobarbital anesthesia (e.g., respiratory depression, hypotension, pneumonia).