White Matter Abnormalities in Multiple Sclerosis Evaluated by Quantitative Synthetic MRI, Diffusion Tensor Imaging, and Neurite Orientation Dispersion and Density Imaging.

BACKGROUND AND PURPOSE: A number of MR-derived quantitative metrics have been suggested to assess the pathophysiology of MS, but the reports about combined analyses of these metrics are scarce. Our aim was to assess the spatial distribution of parameters for white matter myelin and axon integrity in patients with relapsing-remitting MS by multiparametric MR imaging. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting MS and 24 age- and sex-matched controls were prospectively scanned by quantitative synthetic and 2-shell diffusion MR imaging. Synthetic MR imaging data were used to retrieve relaxometry parameters (R1 and R2 relaxation rates and proton density) and myelin volume fraction. Diffusion tensor metrics (fractional anisotropy and mean, axial, and radial diffusivity) and neurite orientation and dispersion index metrics (intracellular volume fraction, isotropic volume fraction, and orientation dispersion index) were retrieved from diffusion MR imaging data. These data were analyzed using Tract-Based Spatial Statistics. RESULTS: Patients with MS showed significantly lower fractional anisotropy and myelin volume fraction and higher isotropic volume fraction in widespread white matter areas. Areas with different isotropic volume fractions were included within areas with lower fractional anisotropy. Myelin volume fraction showed no significant difference in some areas with significantly decreased fractional anisotropy in MS, including in the genu of the corpus callosum and bilateral anterior corona radiata, whereas myelin volume fraction was significantly decreased in some areas where fractional anisotropy showed no significant difference, including the bilateral posterior limb of the internal capsule, external capsule, sagittal striatum, fornix, and uncinate fasciculus. CONCLUSIONS: We found differences in spatial distribution of abnormality in fractional anisotropy, isotropic volume fraction, and myelin volume fraction distribution in MS, which might be useful for characterizing white matter in patients with MS.

A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-κB degradation and cell growth suppression in neuroblastoma.

Downregulated in renal cell carcinoma 1 (DRR1) has important roles in tumor cell growth, neuron survival and spine formation, and was recently shown to bind actin. However, the roles of nuclear DRR1 remain largely unexplored. Here, we identified an interaction between filamentous actin (F-actin) and DRR1 in the nucleus, and demonstrated that copper metabolism MURR1 domain-containing 1 (COMMD1) is another binding partner of DRR1. Accordingly, DRR1, F-actin and COMMD1 were shown to form a complex in the nucleus, and the stability of COMMD1 was enhanced in this complex. Increased nuclear COMMD1 in turn promoted the degradation of NF-κB. In addition, DRR1 and COMMD1 suppressed the cyclin D1 expression, G1/S transition and cell proliferation of neuroblastoma cells. The binding between DRR1 and F-actin in the nucleus was required for these events. Consistent with these facts, low expressions of DRR1 were associated with tumorigenesis of human neuroblastoma and its mouse model. This study has thus revealed a novel nuclear complex of F-actin, DRR1 and COMMD1 that is involved in NF-κB degradation and cell cycle suppression in neuroblastoma cells.

Time course of axial and radial diffusion kurtosis of white matter infarctions: period of pseudonormalization.

BACKGROUND AND PURPOSE: Diffusion kurtosis is a statistical measure for quantifying the deviation of the water diffusion profile from a Gaussian distribution. The current study evaluated the time course of diffusion kurtosis in patients with cerebral infarctions, including perforator, white matter, cortical, and watershed infarctions. MATERIALS AND METHODS: Subjects were 31 patients, representing 52 observations of lesions. The duration between the onset and imaging ranged from 3 hours to 122 days. Lesions were categorized into 4 groups listed above. Diffusion kurtosis images were acquired with b-values of 0, 1000, and 2000 s/mm(2) applied in 30 directions; variables including DWI signal, ADC, fractional anisotropy, radial diffusivity, axial diffusivity, radial kurtosis, and axial kurtosis, were obtained. The time courses of the relative values (lesion versus contralateral) for these variables were evaluated, and the pseudonormalization period was calculated. RESULTS: Diffusion kurtosis was highest immediately after the onset of infarction. Trend curves showed that kurtosis decreased with time after onset. Pseudonormalization for radial/axial kurtosis occurred at 13.2/59.9 days for perforator infarctions, 33.1/40.6 days for white matter infarctions, 34.8/35.9 days for cortical infarctions, and 34.1/28.2 days after watershed infarctions. For perforator infarctions, pseudonormalization occurred in the following order: radial kurtosis, ADC, axial kurtosis, and DWI. CONCLUSIONS: Diffusion kurtosis variables in lesions increased early after infarction and decreased with time. Information provided by diffusion kurtosis imaging, including axial and radial kurtosis, seems helpful in conducting a detailed evaluation of the age of infarction, in combination with T2WI, DWI, and ADC.

Giant cell carcinoma causing rapidly progressive respiratory failure as the presenting feature of AIDS.

The incidence of lung cancer has been increasing among HIV-positive patients. The majority of these cases were in patients previously diagnosed as HIV-positive and treated with highly active antiretroviral therapy (HAART). Here, we report a 56-year-old male patient with lung cancer, who was diagnosed as HIV-positive after the onset of neck pain and lumbago and thus, was not treated with anti-AIDS therapy. The patient developed rapidly progressive and fatal respiratory failure. Autopsy demonstrated giant cell carcinoma of the lung responsible for carcinomatous lymphangitis. This case highlighted the possibility that pulmonary carcinogenesis in HIV-positive patients is not necessarily associated with HAART therapy.

Transient hyperintensity in the subthalamic nucleus and globus pallidus of newborns on T1-weighted images.

BACKGROUND AND PURPOSE: In the brains of newborns, changes in signal intensity in most structures can be explained by the development of myelination. However, there are some structures for which signal intensity changes cannot be accounted for by myelination alone. We examined the STN and globus pallidus signal intensities and tried to determine whether a relationship exists between the signal intensity and the postnatal age or the gestational age at the examination. MATERIALS AND METHODS: We examined T1WI and T2WI obtained from 79 neonates who showed normal development at their 2-year follow-up examinations. We performed both qualitative and quantitative (signal intensity ratio to the thalamus) evaluation of the STN and globus pallidus signals, and we examined the correlation between signal intensity changes and the age of neonates. RESULTS: With increasing postnatal age at examination, the high signal intensity on the T1WI for both STN and globus pallidus diminished. Although the disappearance of this hyperintensity was well correlated with the postnatal age at examination for both the qualitative and quantitative studies, there was no correlation with gestational age at examination. For the T2WI, there was no correlation with either the postnatal age or the gestational age at examination. CONCLUSIONS: Signal intensity on T1WI in the STN and globus pallidus is not related to the gestational age at examination; instead, signal intensities on T1WI seem to be more dependent upon the postnatal age at examination.

Single pancreatic beta cells co-express multiple islet hormone genes in mice.

AIMS/HYPOTHESIS: It is widely accepted that production of insulin, glucagon, somatostatin and pancreatic polypeptide in islet cells is specific to beta, alpha, delta and pancreatic polypeptide cells, respectively. We examined whether beta cells express other genes encoding islet hormones. METHODS: Nested RT-PCR was performed on single beta cells of transgenic mice with green fluorescent protein (GFP) driven by mouse insulin I promoter (MIP-GFP). RESULTS: Only 55% of adult beta cells expressed the insulin gene alone, while others expressed two or more islet hormone genes; 4% expressed all four hormone genes. In embryonic and neonatal cells, 60% to 80% of GFP(+) cells co-expressed pancreatic polypeptide and insulin genes in contrast to 29% in adult. To clarify cell fate, we conducted lineage tracing using rat insulin II promoter-cre mice crossed with reporter mice Gt(ROSA)26Sor-loxP-flanked STOP-cassette-GFP. All GFP(+) cells expressed insulin I and II genes, and showed similar heterogeneity of co-expression to that seen in MIP-GFP mice. Although we report expression of other hormone genes in a significant proportion of beta cells, our lineage tracing results demonstrate that after inducing InsII (also known as Ins2) expression, beta cell progenitors do not redifferentiate to non-beta cells. CONCLUSIONS/INTERPRETATION: This study shows co-expression of multiple hormone genes in beta cells of adult mice as well as in embryos and neonates. This finding could: (1) represent residual expression from beta cell precursors; (2) result from alternative developmental pathways for beta cells; or (3) denote the differentiation potential of these cells. It may be linked to functional heterogeneity. This heterogeneity in gene expression may provide a means to characterise the functional, cellular and developmental heterogeneity seen in beta cells.

Fractional anisotropy--threshold dependence in tract-based diffusion tensor analysis: evaluation of the uncinate fasciculus in Alzheimer disease.

BACKGROUND AND PURPOSE: Tract-based analysis can be used to investigate required tracts extracted from other fiber tracts. However, the fractional anisotropy (FA) threshold influences tractography analysis. The current study evaluated the influence of the FA threshold in measuring diffusion tensor parameters for tract-based analysis of the uncinate fasciculus in subjects with Alzheimer disease (AD). MATERIALS AND METHODS: Subjects included 30 patients with AD and 10 healthy controls. We acquired tractographies of the uncinate fasciculus by using different FA thresholds. We measured mean FA and the apparent diffusion coefficient (ADC) along the uncinate fasciculus for different FA thresholds and evaluated the correlation between diffusion tensor parameters (FA, ADC) and the Mini-Mental State Examination (MMSE) scores. RESULTS: The uncinate fasciculus showed lower mean FA and higher mean ADC values in cases with more severe AD. A higher FA threshold led to a lower mean ADC value and a higher mean FA value along the uncinate fasciculus, whereas the relative order of measured values according to the severity of AD was not influenced by the FA threshold. An FA threshold of 0.2 showed higher correlation between mean ADC values and MMSE scores. FA thresholds of 0.15 and 0.20 showed higher correlation between mean FA values and MMSE scores. CONCLUSIONS: Appropriate selection of the FA threshold leads to higher correlation between diffusion tensor parameters and the severity of AD. For tract-based analysis of degenerative diseases such as AD, appropriate selection of the FA threshold for tractography is important.

Differentiation of COPAS-sorted non-endocrine pancreatic cells into insulin-positive cells in the mouse.

AIMS/HYPOTHESIS: The regenerative process in the pancreas is of particular interest, since insulin-producing beta cells are lost in diabetes. Differentiation of new beta cells from pancreatic non-endocrine cells has been reported in vivo and in vitro, a finding that implies the existence of pancreatic stem/progenitor cells. However, while tissue-specific stem cells are well documented in skin, intestine and testis, pancreatic stem cells have been elusive. We hypothesised that pancreatic stem/progenitor cells within the non-endocrine fraction could be a source of new islets in vitro. METHODS: To test if there were such cells within the pancreas, we generated pancreatic cell aggregates from tissue remaining after islet isolation from mouse insulin promoter 1-green fluorescent protein (MIP-GFP) mice. To eliminate any contamination of insulin-positive cells, we deleted all GFP-positive aggregates using COPAS Select and cultured with Matrigel. Immunohistochemistry, quantitative real-time PCR and single-cell nested RT-PCR were performed to confirm formation of insulin-producing cells. RESULTS: The GFP-negative cells were expanded as monolayers and then differentiated into three-dimensional cystic structures. After 1 week of culture, GFP-positive cells were found as clusters or single cells. By quantitative real-time PCR, no insulin mRNA was detected immediately after COPAS sorting, but after differentiation insulin mRNA of the whole preparation was 1.91 +/- 0.31% that of purified MIP-GFP beta cells. All GFP-positive cells expressed insulin 1; most expressed insulin 2, pancreas duodenum homeobox-1 and cytokeratin 19 by single cell nested RT-PCR. CONCLUSIONS/INTERPRETATION: Our data support the concept that within the exocrine (acinar and ductal) pancreas of the adult mouse there are cells that can give rise to insulin-positive cells in vitro.

Granular cell tumour arising from the Kiesselbach's area of the nasal septum.

An extremely rare case of a granular cell tumour arising from the right Kiesselbach's area (Little's area) of the nasal septum is reported. A 69-year-old Japanese woman consulted our clinic and her chief complaints were of continuous serous discharge, stuffiness and occasional slight bleeding from the right nasal cavity. Fibrescopy showed a multilocular mass, which was provisionally considered a nasal polyp. Surgical excision was attempted. During surgery, the tumour shrank markedly following local application of adrenaline, suggestive of hypervascularity. The tumour was successfully excised by careful dissection after cauterisation of the mucosa surrounding the tumour. Histopathological examination revealed morphological features of granular cell tumour immunopositive for S-100 protein. This is the first report of granular cell tumour arising from the Kiesselbach's area in the English literature. The eccentric behaviour of the tumour and the management of a granular cell tumour arising from this area are discussed, together with a literature review.

Postoperative changes of sperm chromatin heterogeneity, using acridine orange staining, in varicocele patients.

The aim of this study was to evaluate postoperative changes in sperm chromatin heterogeneity in varicocele patients. In 15 infertile patients with varicocele, sperm parameters including concentration, motility, and morphology were evaluated before and after surgical correction of varicocele. Sperm motion analysis using computer-assisted semen analyzer (CASA) was also performed. To analyze the sperm nuclear proteins, the acridine orange staining method was used. On semen analysis, sperm concentration and motility significantly increased after surgery (p = 0.002, p = 0.003, respectively), although sperm morphology was unaltered postoperatively. CASA parameters, including velocity, linearity, amplitude of lateral head displacement and beat cross frequency were unaltered postoperatively. On the other hand, acridine orange staining significantly increased postoperatively (p = 0.002). Varicocele influences the sperm chromatin condition, as well as sperm concentration and motility.

Usefulness of sperm quality analyzer-V (SQA-V) for the assessment of sperm quality in infertile men.

The aim of this study was to evaluate the correlation of new of Sperm Quality Analyzer (SQA-V) with the computer-assisted sperm analysis (CASA) and manual semen analysis estimates. One hundred five fresh semen samples were analyzed using SQA-V and CASA and manual semen analysis. Significant correlations of sperm concentration (p < 0.0001), sperm motility (p < 0.0001), and normal morphology (p < 0.0001) were observed between SQA-V variables and manual semen analysis estimates. There also were significant correlations of sperm concentration (p < 0.0001), sperm motility (p < 0.0001), and sperm velocity (p = 0.0235) between SQA-V variables and CASA estimates. Meanwhile, it did not correlate with amplitude of lateral head displacement, beat cross frequency, lineality assessed by CASA. The value of the sperm concentration and the sperm motility measured by SQA-V showed high correlations with the value of those measured by CASA and manual semen analysis. In addition, velocity and sperm morphology may also be evaluated to some extent using SQA-V.

Evaluation of appropriate blood level in continuous intravenous infusion from trough concentrations after oral administration based on area under trough level in tacrolimus and cyclosporine therapy.

The target blood concentrations of tacrolimus (TAC) and cyclosporine (CYA) during continuous intravenous infusion (C(ss)) have been determined based on clinical experience. However, it is desirable that C(ss) should be set so that the AUC after intravenous infusion is equal to the AUC after oral administration (AUC(po)). Accordingly, we performed 12-hour monitoring of blood concentrations to calculate C(ss) from the blood trough levels (C(TL)) on 15 kidney recipients administered TAC and 12 recipients administered CYA (Neoral). We used an area under the trough level (AUTL) as a new pharmacokinetic parameter. The C(ss) was evaluated from C(TL), AUC(po), and AUTL was calculated to be C(ss) = C(TL) x (AUC(po)/AUTL). In addition, AUTL/AUC(po) ratio and blood peak/trough level ratio (C(max)/C(min)) were examined to compare pharmacokinetics of TAC and CYA. The formula for TAC was C(ss) = C(TL) x 1.40 and that for CYA, C(ss) = C(TL) x 2.55. The calculated target C(ss) of TAC was 1.40 times that of C(TL), which was similar to the present clinical C(TL). In contrast, the calculated target C(ss) of CYA was 2.55 times the C(TL), and therefore an extremely high C(ss) was necessary to obtain a sufficient AUC that will be available after oral administration. Consequently, intravenous administration of CYA twice a day was considered to be more appropriate to obtain sufficient CYA pharmacokinetics, rather than a continuous intravenous administration. We conclude that the formula, C(ss) = C(TL) x (AUC(po)/AUTL) was useful to calculate the target blood concentration of calcineurin inhibitors when changing from continuous intravenous infusion to oral administration of these drugs.

Assessment of sperm quality analyzer II B: comparison with manual semen analysis and CASA.

Two hundred and seven patients with male infertility were investigated. Total sperm concentration and percent progressive motility by SQA IIB showed high correlations with those of conventional manual method. Percent of normal morphology showed a significant correlation among these techniques. The sperm motility index (SMI) and total functional sperm concentration (TFSC) demonstrated high correlations with any variables of manual analysis. Only velocity and amplitude of lateral head displacement showed significant correlations with the variables obtained by SQA IIB, especially with SMI and TFSC. It was suggested that SQA IIB could be a useful instrument in the clinical practice of infertility as a screening test for semen quality.

Multiple lymphomatous polyposis of the colon originating from T-cells: a case report.

Multiple lymphomatous polyposis is an unusual form of non-Hodgkin's lymphoma characterised by myriad polyps throughout the alimentary tract. Most multiple lymphomatous polyposis cases are derived from B-cell, and there has been little information on multiple lymphomatous polyposis of T-cell origin. A 67-year-old Japanese man presented with lower abdominal pain and diarrhoea of 4-week duration. Colonoscopy revealed numerous small umbilicated polyps and several raised erosions in the colorectum. Biopsy specimens showed diffuse proliferation of lymphoma cells negative for B-cell markers but positive for T-cell markers. Polymerase chain reaction using extracted chromosomal deoxyribonucleic acid from paraffin-embedded samples identified T-cell receptor gamma and delta gene recombination. The patient was treated with combined chemotherapy, leading to complete resolution of the lesions.

Effect of Bu-zhong-yi-qi-tang on seminal plasma cytokine levels in patients with idiopathic male infertility.

Twenty-two idiopathic infertile patients were treated with Oriental herbal medicine, Bu-zhong-yi-qi-tang (Hochu-ekki-to). Seminal plasma sFas level elevated significantly after herb administration. There was an inverse correlation between seminal plasma IL-6 level and sperm concentration before treatment. After the administration of herb seminal plasma, sFas levels significantly correlated with sperm concentration. Seminal plasma IL-8 level did not change. Certain kinds of cytokine in the seminal plasma might play some role in improving semen quality with treatment.

Transurethral treatment of ejaculatory duct obstruction in infertile men.

Ten cases of ejaculatory duct obstruction with midline cyst, complaining of male infertility, were treated with transurethral incision. They had azoospermia or oligozoospermia, and physical examination did not show any abnormal findings. Serum levels of testosterone, LH, and FSH were within normal limits. The diagnosis of ejaculatory duct obstruction with midline cyst was made by transurethral ultrasonography and vasography. Thereafter, patients underwent transurethral incision of the verumontanum with a cold knife. Semen volume increased in all patients, and sperm concentration and/or motility improved in 7 patients (70%). Pregnancy was achieved by 3 couples (30%). Incision of the ejaculatory duct via an endoscopic technique could improve seminal findings and subsequent fertility.

Soluble Fas and interleukin-6 and interleukin-8 levels in seminal plasma of infertile men.

The seminal plasma levels of soluble Fas (sFas) and interleukins IL-6 and IL-8 were measured and their relationship with semen qualities was examined. The seminal plasma sFas level in fertile males was significantly higher than that in the infertile group. On the other hand, seminal plasma level of IL-6 was significantly lower in fertile males than in the infertile group. In the infertile group, patients with oligozoospermia had a lower seminal plasma sFas and a higher IL-6 level than those with normal sperm concentration. There was an inverse correlation between IL-6 and sperm concentration in infertile patients. Seminal plasma IL-8 was not correlated with sperm parameters. It would appear that certain kinds of cytokine in the seminal plasma might play an important role in improving semen quality.

Persistent Müllerian duct syndrome: a surgical approach.

Laparoscopy revealed a left inguinal testis and a right abdominal testis. Surgery revealed uterus-like structures. The bilateral testes showed primitive testis without ovarian tissue. Physical examination showed a normal and an empty scrotum with a nonpalpable gonad. Chromosome analysis revealed 46,XY. Pathological findings demonstrated the immature testis and the immature uterus.