Automatic conformal prescription of very selective saturation bands for in vivo 1H-MRSI of the prostate.

An important step in the implementation of three-dimensional in vivo proton magnetic resonance spectroscopic imaging ((1)H-MRSI) of the prostate is the placement of spatial saturation pulses around the region of interest (ROI) for the removal of unwanted contaminating signals from peripheral tissue. The present study demonstrates the use of a technique called conformal voxel magnetic resonance spectroscopy (CV-MRS). This method automates the placement, orientation, timing and flip angle of very selective saturation (VSS) pulses around an irregularly-shaped, user-defined ROI. The method employs a user adjustable number of automatically positioned VSS pulses (20 used in the present study) which null the signal from periprostatic lipids while closely conforming the shape of the excitation voxel to the shape of the prostate. A standard endorectal coil in combination with a torso-phased array coil was used for all in vivo prostate studies. Three-dimensional in vivo prostate (1)H-MRSI data were obtained using the proposed semi-automated CV-MRS technique, and compared with a standard point resolved spectroscopy (PRESS) technique at TE = 130 ms using manual placement of saturation pulses. The in vivo prostate (1)H-MRSI data collected from 12 healthy subjects using the CV-MRS method showed significantly reduced lipid contamination throughout the prostate, and reduced baseline distortions. On average there was a 50 ± 17% (range 12% - 68%) reduction in lipids throughout the prostate. A voxel-by-voxel benchmark test of over 850 voxels showed that there were 63% more peaks fitted using the LCModel when using a Cramer-Rao Lower Bound (CRLB) cut-off of 40% when using the optimized conformal voxel technique in comparison to the manual placement approach. The evaluation of this CV-MRS technique has demonstrated the potential for easy automation of the graphical prescription of saturation bands for use in (1)H-MRSI.

Use of fraction flow reserve to predict changes over time in management of superficial femoral artery.

BACKGROUND: Peripheral arterial disease is a condition characterized by progressive arterial narrowing, which affects patients' quality of life. The purposes of this study were to (1) establish the feasibility of obtaining peripheral fractional flow reserve (pFFR) in the peripheral vascular circulation, (2) demonstrate an association between baseline pFFR and peak systolic velocity (PSV) measured by duplex ultrasound, and (3) correlate postintervention pFFR with future restenosis using the change in PSV over time as a surrogate. METHODS: Twenty patients underwent baseline ankle brachial index (ABI) and PSV testing. Pre- and postintervention pFFR was performed. Patients were followed with three ABI and PSV recordings during the 1 year follow-up period. The association between baseline PSV, ABI, and pFFR with changes in PSV over time were explored. Predictors of postprocedural PSV over time were determined. RESULTS: The baseline translesional-resting ratio was significantly different from the pFFR using adenosine (0.79 ± 0.08 vs. 0.71 ± 0.09, P = 0.01). Baseline PSV was significantly associated with preintervention pFFR (-0.77, P < 0.001). Compared to patients with a postprocedure pFFR > 0.95, patients with a postprocedure pFFR < 0.95 had a significantly more rapid rise in PSV over time (P = 0.009). CONCLUSION: This is the first study to demonstrate that the peripheral vascular bed does respond to vasodilatation thereby supporting the use of pFFR for this procedure. In our study, postintervention pFFR < 0.95 predicted a more rapid increase in PSV over time, which is a reasonably accepted surrogate for restenosis.

HLA-DRB1*04 gene polymorphisms and expressions profiles of interleukin-18 and interleukin-18 binding protein following in vitro stimulation in human peripheral blood mononuclear cells of healthy individuals and patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic arthritic condition that can lead to deformities and disabilities. Interleukin-18 (IL-18) is a proinflammatory cytokine known to play a role in the acute and chronic inflammatory phases of RA. IL-18 binding protein is the natural antagonist of IL-18 protein. We aim to identify the effect of HLA-DRB1*04 gene polymorphisms on IL-18 and IL-18BP gene expressions profiles as well as the time-course profiles following in vitro stimulation with mitogens. Peripheral blood mononuclear cells from 16 RA patients and 21 healthy controls were cultured for 1, 4, 8, 12, 24, 48 and 72 h following stimulation with either LPS or PHA. mRNA expression of IL-18 and IL 18BP were determined by quantitative real-time PCR using a comparative Ct (threshold cycle) method. IL-18 levels in supernatants were measured by enzyme-linked immunosorbent assay. Basal mRNA (4.5-fold) and protein levels of IL-18 were increased and IL-18BP mRNA expression was decreased (8-fold) in RA patients when compared to controls. Similarly, increased IL-18 levels were observed in active RA patients, whereas IL-18BP expression was increased in inactive patients. There was an increase in mRNA and protein levels of IL-18 in RA patients that peaked at 4 h and 8 h respectively following LPS stimulation. A similar profile was observed for IL-18BP; however, the expression level was higher in controls than RA patients. Persistent high production of IL-18 in RA is associated with disease progression and IL-18 BP seems to inhibit this activity.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

Developing an algorithm of informative markers for evaluation of chimerism after allogeneic bone marrow transplantation.

Analysis of chimerism by polymerase chain reaction amplification of STR or VNTR has become a routine procedure for the evaluation of engraftment after allogeneic stem cell transplantation. Knowledge of the frequency of different STR or VNTR alleles in unrelated individuals in a population is useful for forensic work. In the context of HLA identical sibling bone marrow transplantation the informativeness of these markers needs to be evaluated. We evaluated five STRs (THO1, VWA, FES, ACTBP2, and F13A1) and 1 VNTR (APOB) for informativeness in stem cell transplants from HLA identical sibling donors. All four markers used individually allowed us to discriminate 20-56% of the patient donor pairs. Using a combination of all these markers along with a polymorphic marker in the beta-globin gene and the sex chromosome specific amelogenin marker, we were able to discriminate 99% of the patient donor pairs. We have established an algorithm for evaluating chimerism following HLA identical sibling donor transplants in the Indian population using molecular markers in 310 patients. Analysis of heterozygote frequencies in different populations is similar suggesting that this algorithm can be used universally for transplant centers to evaluate chimerism following allogeneic bone marrow transplantation.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis.

Adult animals continue to produce new neurons in the dentate gyrus of hippocampus. Until now, the principal method of studying neurogenesis has been to inject either tritiated thymidine or 5'-Bromo-2-deoxyuridine (BrdU) intraperitoneally followed by autoradiographic or immunohistochemical detection methods respectively. However, such exogenous markers may produce toxic effects. Our objective was to determine whether Ki-67, a nuclear protein expressed in all phases of the cell cycle except the resting phase, can be used as an alternative, endogenous marker. Using immunohistochemistry, we examined Ki-67 and BrdU expression pattern in rats. Ki-67 was expressed within the proliferative zone of the dentate gyrus and its expression pattern mimicked that of BrdU when examined soon after exogenous BrdU administration. Quantitative comparison of BrdU and Ki-67-positive cells showed 50% higher numbers of the latter when examined 24 h after the BrdU injection. This was expected, since BrdU can be incorporated into DNA only during the S-phase of the mitotic process, whereas Ki-67 is expressed for its whole duration. Experimental increases (by ischemia) or reductions (by radiation) in the number of mitotic cells produced parallel changes in BrdU and Ki-67 signals. Thus, Ki-67 is an effective mitotic marker and has most of the benefits of BrdU and none of the costs. This study provides evidence for Ki-67 to be used as a marker of proliferation in the initial phase of adult neurogenesis.

Treatment of hydrocephalus and bilateral subdural effusions in a patient with closed sutures. Case report.

For management of bilateral subdural hematomas in a hydrocephalic child with fused sutures, a simple technique is described that involves minimal cranial procedures for modification of an already installed ventriculoperitoneal shunt system.

Focal eosinophilic granuloma of the temporal lobe. Case report.

The authors describe the clinical, pathological, and therapeutic aspects of a case of focal temporal lobe eosinophilic granuloma, presenting with otitis media and meningitis, and evolving subsequently into a temporal lobe mass. This triad, otitis media, meningitis, focal cerebral lesion with systemic manifestations of inflammation, eosinophilia of blood and cerebrospinal fluid, should suggest eosinophilic granuloma in the differential diagnosis. The lesion is sensitive to relatively small doses of radiation.

Failure of computerized axial tomography to demonstrate a chronic subdural hematoma.

A chronic subdural hematoma may present in a computerized axial tomography (CAT) scan with the same density as normal brain tissue. The presence of a lesion may be suggested only by its mass effect. The lack of contrast enhancement or edema may help to differentiate a chronic subdural hematoma for a neoplasm or a cerebrovascular accident.

Renal papillary necrosis in the east coast of Peninsular Malaysia.

Six hundred and one intravenous Urograms (IVU) done at the General Hospital, Kuala Trengganu from 1981 to 1985 were reviewed retrospectively for Renal Papillary Necrosis (RPN). It was found that 1.3% of IVUs had RPN. There was a higher incidence of RPN amongst males as compared to females. RPN occurred more commonly in the younger age groups.

Medical radiation exposures for diagnostic radiology in Malaysia.

The medical radiation usage for diagnostic radiology in Malaysia (a Level II country) for 1990-1994 is reported, enabling a comparison to be made for the first time with the United Nations Scientific Committee on the Effects of Atomic Radiation Report. In 1994, the number of physicians, radiologists, x-ray units, and x-ray examinations per 1,000 population was 0.45, 0.005, 0.065, and 183, respectively. (Level I countries had averages of 2.6, 0.072, 0.35, and 860, respectively). In 1994, a total of 3.6 million x-ray examinations were performed; the annual effective dose per capita to the population was 0.05 mSv, and the collective effective dose was 1,000 person-Sv. Chest examinations contributed 63% of the total. Almost all examinations experienced increasing frequency from 1990 to 1994 except for barium studies, cholecystography, and intravenous urography (-23%, -36%, -51%). These decreases are related to the increasing use of ultrasound and greater availability of fiberoptic endoscopy. Notable increases during the same period were observed in computed tomography (161%), cardiac procedures (190%), and mammography (240%). In order to progress from Level II to Level I status Malaysia needs to expand and upgrade radiological service in tandem with the health care development of the country.

X-ray based radiological procedures in Malaysia--1990-1994.

X-ray based radiological procedure statistics and trend in Malaysia for 1990-1994 is reported; this information allows comparisons to be made with the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) Report. Additionally it is essential information for health care planners and providers. Malaysia is categorised as a health care level II country based on the UNSCEAR definition. In 1994, the number of physicians, radiologists, x-ray units and x-ray examinations per 1000 population was 0.45, 0.005, 0.065 and 183 respectively. 3.6 million x-ray examinations were performed in 1994, with chest radiography being the commonest study (63%). Information on x-ray examinations, number of hospitals and x-ray units is reported for the Ministry of Health, private practice and teaching hospitals. Examination frequency increased in computed tomography (161%), cardiac procedures (190%), and mammography (240%); while a decrease in barium studies (-23%), cholecystography (-36%), and intravenous urography (-51%) was noted. There is a potential and need to expand and upgrade radiological services.

Immunomodulation of Japanese encephalitis vaccine through CpG oligodeoxynucleotides in mice.

Synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine guanine (CpG) dinucleotides motifs act as immune adjuvant and provide means of modulation to immune responses when co-delivered with antigens. They stimulate both innate and adaptive immune responses and induce T helper 1 (Th1) immune responses. We investigated the immunomodulation of Japanese encephalitis (JE) vaccine using CpG ODN as an adjuvant. Mice were immunized with one dose of JE vaccine 0.1 ml with different concentrations (10, 25 and 100 microg) of CpG ODN. The serum antibody level and cytokines were evaluated and compared with mice immunized with two doses of JE vaccine alone. Our studies revealed that anti-JE antibody level in mice immunized with single dose of 0.1 ml JE vaccine and 100 microg CpG ODN were almost equal to mice immunized with two doses of JE vaccine alone. Furthermore, CpG ODN enhanced the production of TNF-alpha and Th1-mediated cytokines, including IFN-gamma and IL-2 compared with JE vaccine alone. In addition, absence of any significant changes in biochemical, haematological and histological studies suggest that CpG ODN are safe adjuvants for JE vaccine. Therefore, it is inferred that CpG ODN are effective and improve the efficacy of JE vaccine.

Computer assisted ventriculography.

Computed tomography was performed following iothalamate meglumine (Conray) ventriculography in two cases of colloid cyst of the third ventricle. The application of this technique in the diagnosis of intraventricular mass lesions is discussed.

Dose dependency of the post-insult protective effect of pentobarbital in the canine experimental stroke model.

In a canine stroke model, dose dependent protection by postocclusion pentobarbital was suggested from 10--40 mg/kg. In 28 dogs investigated (10 from a previous study) a distinct, significant reduction in right cerebral hemisphere infarction occurred in animals given 15--20 mg/kg pentobarbital intramuscularly 1 hour postocclusion. Increased dosages did not alter statistically the infarct size and 2 dogs at the 50 mg/kg and 80 mg/kg levels died of barbiturate-induced respiratory failure.

Single-nucleotide polymorphisms of the interleukin-18 gene promoter region in rheumatoid arthritis patients: protective effect of AA genotype.

Rheumatoid arthritis (RA) is a chronic arthritic condition that can lead to deformities and disabilities. Although numerous studies reported the association of human leukocyte antigen (HLA)-DRB1*04 and RA, other genes, e.g. cytokines genes, may contribute towards disease susceptibility. Interleukin-18 (IL-18) is a proinflammatory cytokine postulated to play a role in the acute and chronic inflammatory phases of RA. The IL-18 protein expression seems to be regulated by two single-nucleotide polymorphisms (SNPs) located at positions -607 and -137 in the promoter region of the gene. It is postulated that specific alleles may be associated with susceptibility to the development of RA. In the present study, we described the IL-18 gene promoter region genotypes and combined genotypes (-607/-137) in 106 RA patients and 273 unrelated healthy controls to evaluate the contributions of these alleles to RA predisposition in Chinese, Malays, and Indians. The genotyping were performed using sequence-specific polymerase chain reactions. Rheumatoid factors were assayed by enzyme-linked immunosorbent assay. Biodata were obtained through chart review. The controls had significantly higher frequency of AA genotype at position -607 when compared to RA patients. No significant differences were observed in the distribution of either allelic or genotypic frequencies at position -137. There was no association between the genotypes and the presence of rheumatoid factors. This study did not find evidence of a genetic susceptibility factor but demonstrated the novel finding that the AA genotype at position -607 is associated with a protective effect against development of RA in Chinese individuals. This protection may be mediated through inhibition of cyclic (Adenosine 3', 5'-cyclic monophosphate) AMP-responsive element (CRE)-binding protein by the disruption of the CRE consensus sequence.