Brain metastases: An update on the multi-disciplinary approach of clinical management.

IMPORTANCE: Brain metastasis (BM) is the most common malignant intracranial neoplasm in adults with over 100,000 new cases annually in the United States and outnumbering primary brain tumors 10:1. OBSERVATIONS: The incidence of BM in adult cancer patients ranges from 10-40%, and is increasing with improved surveillance, effective systemic therapy, and an aging population. The overall prognosis of cancer patients is largely dependent on the presence or absence of brain metastasis, and therefore, a timely and accurate diagnosis is crucial for improving long-term outcomes, especially in the current era of significantly improved systemic therapy for many common cancers. BM should be suspected in any cancer patient who develops new neurological deficits or behavioral abnormalities. Gadolinium enhanced MRI is the preferred imaging technique and BM must be distinguished from other pathologies. Large, symptomatic lesion(s) in patients with good functional status are best treated with surgery and stereotactic radiosurgery (SRS). Due to neurocognitive side effects and improved overall survival of cancer patients, whole brain radiotherapy (WBRT) is reserved as salvage therapy for patients with multiple lesions or as palliation. Newer approaches including multi-lesion stereotactic surgery, targeted therapy, and immunotherapy are also being investigated to improve outcomes while preserving quality of life. CONCLUSION: With the significant advancements in the systemic treatment for cancer patients, addressing BM effectively is critical for overall survival. In addition to patient's performance status, therapeutic approach should be based on the type of primary tumor and associated molecular profile as well as the size, number, and location of metastatic lesion(s).

Molecular characterization of astroviruses by reverse transcriptase PCR and sequence analysis: comparison of clinical and environmental isolates from South Africa.

A comparative analysis was performed with 25 isolates of astroviruses (AstVs) detected in sewage sources and 22 concurrently identified clinical AstV isolates from the Tshwane (Pretoria) Metropolitan Area in South Africa. The samples and specimens were screened for AstVs by using an enzyme immunoassay and/or a reverse transcriptase PCR (RT-PCR) for the highly conserved untranslated region (3' end) of the genome. The RT-PCR results were confirmed by oligonucleotide probe dot blot hybridization. Viable viruses were propagated in cell cultures for amplification when a minimal specimen was available or indeterminate sequences were obtained. AstV strains were characterized by RT-PCR and partial sequence analysis of the capsid region. The presence of multiple human AstV (HAstV) types in a single sewage sample complicated identification of individual strains, and additional type-specific RT-PCR and sequence analyses of the capsid region were required for characterization. Amplification and characterization of one genotype from a sample, therefore, did not preclude the possibility that a sample harbored additional different genotypes. Genotype and sequence information obtained from AstVs in wastewater samples were compared to information obtained from AstV strains from human stools. HAstV type 1 (HAstV-1), as well as HAstV-3, -5, -6, and -8, were identified among the clinical isolates, and HAstV-1, -2, -3, -4, -5, -7, and -8 were identified among the environmental samples. Phylogenetic analysis demonstrated that HAstV-1, -3, -5, and -8, which were present in human stool and sewage samples, clustered together, indicating that these viruses are closely related. The concurrent presence of identical HAstV strains in wastewater samples and in hospitalized patients suggests that AstVs present in the environment pose a potential risk to communities in which fecally contaminated water is used for recreational and domestic purposes.

Characterisation of a South African human astrovirus as type 8 by antigenic and genetic analyses.

Human astroviruses (HAstV) can, on the basis of immunoassays using type-specific rabbit antisera, be classified into eight serotypes that correlate with genotypes. Very few isolates of HAstV type 8 have been described and there is a paucity of data available with regard to the antigenic and genetic relationships between HAstV type 8 (HAstV-8) and HAstV types 1 (HAstV-1) to 7 (HAstV-7). A wild-type HAstV from a South African paediatric patient with diarrhoea was analysed antigenically, by immune electron microscopy and enzyme immunoassay, and genetically in selected regions of the ORF1a, ORF1b and ORF2 and characterised as a HAstV-8. This HAstV-8 strain exhibited greatest homology with HAstV-4 in the 5' end of the capsid gene and ORF1a and 1b, and greatest homology with HAstV-5 in the 3' end of the capsid region. This study confirms, by both antigenic and genetic analyses, that HAstV-8 represents a distinct antigenic and genotype and is the first report of a HAstV-8 from a hospitalised paediatric patient with diarrhoea in southern Africa.

Molecular epidemiology of human astrovirus diarrhea among children from a periurban community of Mexico City.

Human astroviruses (HAstVs) were detected in 23 stool samples from 365 diarrhea episodes among 214 children (<18 months old) prospectively monitored for diarrhea in Mexico City. Stool samples were tested by EIA and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. EIA was less sensitive (74%) and equally specific, compared with RT-PCR analysis using type-common primers for HAstV detection. Of 31 HAstV isolates, EIA typed 18 (69%) of 26 EIA-positive samples, and RT-PCR analysis typed 26 (84%) of 31 RT-PCR-positive samples. Phylogenetic analysis of the 3' end of the capsid region (363 nucleotides) confirmed the type assignment by EIA and RT-PCR analysis and determined the type for 5 previously untyped samples. Six HAstV antigenic types cocirculated in the community: HAstV-2 (42%), HAstV-4 (23%), HAstV-3 (13%), HAstV-1 (10%), HAstV-5 (6%), and HAstV-7 (6%). RT-PCR and sequence analysis provided more detailed epidemiology of HAstV in the community than did antigenic detection methods.

Molecular characterization of a novel recombinant strain of human astrovirus associated with gastroenteritis in children.

We report a naturally occurring human astrovirus (HAstV) strain detected in two different geographic locations. We identified two isolates of this strain in a diarrhea outbreak at a child care center in Houston, Texas; and two isolates in diarrhea stool samples from two children in Mexico City. All four isolates were detected in stool samples by enzyme immunoassay (EIA). One of the Mexican isolates was typed by EIA and all four isolates were HAstV-5 by typing RT-PCR. The four isolates were >97% nucleotide-identical in two different genomic regions: ORF1a (246 nt), and the 3' end of the genome (471 nt). One isolate from each geographic location was further sequenced in the transition region from ORF1b to ORF2 (1255 nt) and this region of the two isolates showed > or = 99% nt identity. Phylogenetic analyses of sequences of eight HAstV antigenic types and the novel strain in the transition region demonstrated the new strain being closely related to HAstV-3 in ORF1b, but closest to HAstV-5 in ORF2. These results and high sequence identity among all HAstV antigenic types in the transition region and RNA structural predictions supported a potential recombination site at the ORF1b/ORF2 junction. This is the first evidence that recombination occurs among human astroviruses.

Role of astroviruses in childhood diarrhea.

Human astrovirus (HAstV) is a significant cause of acute diarrhea among children, resulting in outbreaks of diarrhea and occasionally in hospitalization. Improved detection methods for eight antigenic types of HAstV and studies assessing the frequency and severity of HAstV diarrhea have further defined the impact of HAstV infections in children. These studies have shown that HAstV infections are clinically milder (diarrhea, vomiting, fever) than rotavirus infections. However, frequent coinfection of HAstV with rotavirus and caliciviruses in childhood diarrhea complicates the epidemiology. Seroprevalence studies have provided evidence that the majority of children are infected by HAstV by 6 years of age. The route of transmission is probably fecal-oral from food or water sources. Recent and planned studies will help to define the epidemiology and in the future lead to prevention strategies, which could include vaccination.

Molecular epidemiology of childhood astrovirus infection in child care centers.

This study assessed the role of human astrovirus (HAstV) in outbreaks and sporadic cases of diarrhea among children attending child care centers (CCCs) and determined the infecting astrovirus antigenic types by reverse transcriptase-polymerase chain reaction (RT-PCR) and sequence analysis. Eight astrovirus outbreaks occurred in 6 CCCs. Of 179 children with diarrhea, 36 (20%) had astrovirus-associated diarrhea. Diarrhea stools obtained during diarrhea outbreaks were more likely to contain astrovirus (40/476) than were samples not associated with a diarrhea outbreak (14/452) (P<.001). Type-specific RT-PCR and DNA sequencing identified 5 outbreaks associated with HAstV-1 and 3 outbreaks with HAstV-2. Sequential outbreaks in 2 CCCs occurred with a different type in the same year. Phylogenetic analysis identified 6 clades of HAstV-1 and 2 clades of HAstV-2 during this 1-year surveillance. Astrovirus was a significant cause of diarrhea outbreaks, and 2 antigenic types were present in the community during 1 diarrhea season.

Prevalence of antibodies to astrovirus types 1 and 3 in children and adolescents in Norfolk, Virginia.

OBJECTIVE: To determine the prevalence of antibody to human astrovirus types 1 (HAstV-1) and 3 (HAstV-3) in children. METHODS: Sera from children hospitalized in Norfolk, VA, for noninfectious conditions were collected for a 1-month period every 6 months from 1993 to 1996 and tested by enzyme immunoassay for antibody to HAstV-1 and HAstV-3 with the use of baculovirus-expressed recombinant capsid proteins as antigens. RESULTS: The seroprevalence of 393 infants and children to HAstV-1 decreased from 67% in infants <3 months of age to 7% by 6 to 8 months of age, consistent with loss of transplacental antibodies. Children acquired HAstV-1 antibody with a peak prevalence of 94% at 6 to 9 years of age (P < 0.001). Antibodies to HAstV-3 exhibited a lower prevalence, with 26% positive at <3 months, 0% at 6 to 11 months and 42% by 6 to 9 years of age. HAstV-1 seroprevalence in children O to 2 months of age decreased from 89% in November, 1993, to 40% in November, 1996 (P = 0.009). CONCLUSIONS: Astrovirus type-specific antibody prevalence can be measured by baculovirus-expressed capsid antigens in an enzyme immunoassay. Children developed antibody to HAstV-1 (94%) and to HAstV-3 (42%) by 6 to 9 years of age indicating frequent exposure to these enteric viruses in infancy and early childhood.

Application of electronmicroscopy, enzyme immunoassay, and RT-PCR to monitor an outbreak of astrovirus type 1 in a paediatric bone marrow transplant unit.

During 1997, an extensive outbreak of astrovirus occurred in a unit where paediatric patients were being treated for leukaemias and inherited immune deficiency disorders. Prolonged shedding of virus for many months following infection was demonstrated in three patients who had undergone bone marrow transplantation. Comparison of reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay (EIA), and electronmicroscopy (EM) to monitor the outbreak showed that many subclinical infections, mainly in children aged > 3 years could only be detected by RT-PCR. Use of RT-PCR revealed that several patients were infected earlier and shed virus for longer than by using EM or EIA. The virus responsible for the outbreak was identified as HAstV-1 and was shown to have a sequence that differed from a strain obtained in 1988.

A prospective study of astrovirus diarrhea of infancy in Mexico City.

AIM: To describe the epidemiologic and clinical characteristics of astrovirus-associated diarrhea in a cohort of young children from a periurban community in Mexico City. METHODS: From November, 1988, through December, 1991, a total of 214 children were enrolled in a longitudinal study of diarrhea and monitored from birth to 18 months of age. A stool specimen was collected during each episode of diarrhea. Specimens from a total of 510 diarrhea episodes were tested for astrovirus by enzyme immunoassay and examined for other enteric pathogens. The antigenic types of astrovirus were determined by a typing enzyme immunoassay. RESULTS: Astrovirus was detected in 26 (5%) of 510 diarrhea episodes, with an incidence rate of 0.1 episode/child year; the highest rate was in children 13 to 18 months of age. Astrovirus-associated diarrhea was characterized by a median of 4 stools (range, 2 to 10) during the first 24 h, a median duration of 3 days (range, 1 to 21), vomiting (20%), and fever (7%). No cases of dehydration or repeat symptomatic infections were observed. Coinfection with another pathogen was detected in 11 of the 26 episodes (42%). Serotype 2 (35%) was most common, followed by serotypes 4 (15%), 3 (11%), and 1 and 5 (4% each); 31% were nontypable. Astrovirus-associated diarrhea was less severe, as measured by the number of stools (4.3 +/- 1.9), than diarrhea caused by rotavirus (7.1 +/- 2.8) or when coinfections occurred (5.5 +/- 1.6; P = 0.008). CONCLUSIONS: Astrovirus was associated with 5% of the episodes of diarrhea in this cohort of young Mexican children and presented as a mild secretory diarrhea. Five predominant antigenic types were detected with type 2 being the most common.

Prospective study of toxigenic Clostridium difficile in children given amoxicillin/clavulanate for otitis media.

OBJECTIVE: Evaluate antibiotic-associated diarrhea and toxigenic Clostridium difficile in stool specimens obtained from children before and after 10 days of amoxicillin/clavulanate for otitis media. DESIGN: Children, 12 to 47 months of age, treated with amoxicillin/clavulanate for otitis media in an outpatient setting were enrolled. Stool specimens were obtained at enrollment, when diarrhea occurred and at the end of therapy. All stool specimens were tested for C. difficile toxins A and B by enzyme immunoassay. RESULTS: Seventy-six children who had stool specimens collected at enrollment and after therapy were included in the analysis. None had C. difficile toxin in stool specimens at enrollment. Six (27%) of 22 children with diarrhea, and 4 (7%) of 54 children without diarrhea had C. difficile toxin present at completion of therapy (P = 0.03). CONCLUSION: Toxigenic C. difficile was identified in 13% of children at the conclusion of amoxicillin/clavulanate therapy with a significantly higher frequency in children with diarrhea.

Virologic features of an astrovirus diarrhea outbreak in a day care center revealed by reverse transcriptase-polymerase chain reaction.

Astroviruses cause outbreaks of diarrhea in children attending day care centers (DCCs). Reverse transcriptase-polymerase chain reaction (RT-PCR) was compared with EIA detection of astrovirus in stool specimens to characterize further the molecular epidemiology of an outbreak of astrovirus-associated gastroenteritis. Three hundred sixty-eight stool specimens collected prospectively from 36 children enrolled in a DCC during an 11-week outbreak of diarrhea were evaluated by EIA and RT-PCR. Astrovirus was detected in 32% of specimens by RT-PCR versus 10% by EIA (P < .001) and in 89% of children by RT-PCR versus 50% by EIA. The median duration of astrovirus excretion episodes detected by EIA was 1.5 days versus 4 days by RT-PCR (P = .06). Astrovirus was excreted for prolonged periods by immunocompetent children during this outbreak. RT-PCR was more sensitive than EIA for detection of astrovirus in stool specimens and redefined the epidemiology of astrovirus infection in this setting.

Outbreaks of astrovirus gastroenteritis in day care centers.

OBJECTIVE: This study evaluated astrovirus as a cause of diarrhea outbreaks among infants and toddlers in day care centers. DESIGN: Stool specimens were collected weekly during four periods (from January 1986 through December 1991) from children 6 to 30 months of age who were enrolled in prospective studies of diarrhea in day care centers. All diarrheal stool specimens were tested for bacterial enteropathogens, rotavirus, enteric adenovirus, and Giardia lamblia. A total of 1365 stool specimens from 70 outbreaks in which no etiologic agent was identified and from another 11 outbreaks with a known cause were tested for astrovirus, by means of a monoclonal antibody-based enzyme immunoassay. Confirmatory testing was performed by reverse transcriptase-polymerase chain reaction with primers designed to produce an 89 base-pair product. RESULTS: Astrovirus was detected in 6 (7%) of the 81 outbreaks. Of 217 children tested, 73 (34%) were infected with astrovirus; infections in 35 (48%) were symptomatic and in 38 (52%) asymptomatic. The six outbreaks lasted 11 to 44 days (median 22 days). Astrovirus excretion was detected for a duration of 2 to 30 days, with excretion occurring from 1 to 8 days (median 2 days) before diarrhea began to 1 to 20 days (median 2 days) after diarrhea ceased. Younger children (< or = 12 months) were at greater risk than older children (p = 0.011) of becoming infected with astrovirus during an outbreak and were more likely (p = 0.015) to have symptoms when infected. Of 24 specimens with astrovirus by enzyme immunoassay, 20 (83%) were confirmed to have the virus by reverse transcriptase-polymerase chain reaction. CONCLUSION: Astrovirus was an important cause of outbreaks of diarrhea among children attending day care centers, more frequently infected younger children, and often produced asymptomatic infections.

The use of band-selectable digital filtering in magnetic resonance image enhancement.

Manipulation of the data describing two-dimensional magnetic resonance (MR) images can be used to zoom an image, decrease image noise and artifacts by modeling, or emphasize object edges in the field of view. In this paper, a two-dimensional band-selectable digital filtering (2D-BSDF) technique is detailed. This can be used to decrease the computational burden and increase algorithm stability associated with such data manipulation. Many display devices have the ability of expanding an image by pixel or linear interpolation. Application of the efficient zooming fast Fourier transformation algorithms provides a superior quality sinc-function interpolated image. In 2D-BSDF, the ideal rectangular windows used in sinc-function interpolation are replaced by windows with a more gradual roll-off. This gradual roll-off results in a slight degradation of the image edges but substantially reduces the computation time. Modeling of MRI data has been attempted to remove noise and artifacts from the image. These algorithms are computationally expensive and frequently unstable because of the high model orders required. The 2D-BSDF can be used to prepare a reduced data set, without loss of information. A lower order model may be applied to the subset and computation times approaching that required for normal fast Fourier transform algorithms result. The absence of noise and signal from objects outside the region of interest can considerably enhance the stability of the modeling algorithms. The use of BSDF is equally applicable when used in association with the modeling of 2D NMR spectroscopy data or with edge enhancement or any other data manipulation of magnetic resonance imaging images. In this paper an explanation of 1D-BSDF is provided and an algorithm for 2D-BSDF is developed. A comparison of filter designs and computational times is given when applying the technique to zooming and modeling of MR images. Images from medical MRI data are provided.

Profound neurological illness, relieved by protein restriction, in a baby with a transient disturbance in the metabolism of ingested isoleucine.

An 8-month-old infant presented because of poor development followed by the acute onset of cortical blindness and a severe seizure disorder at the time of changing from breast to formula feeding. Metabolic investigations revealed an increased urinary excretion of 2-methyl-3-hydroxybutyric, methylmalonic and 2-ethylhydracrylic acids. The concentration of these compounds in urine was augmented by oral protein (5 g/kg per day) and isoleucine loading. A low protein diet (1.5 g/kg per day) produced a dramatic response with complete cessation of seizures and a marked improvement in vision and general development. After many months of low protein diet, the biochemical abnormalities were no longer detectable, even after protein loading. Extensive investigations have failed to reveal an intrinsic enzyme defect which would account for these clinical and biochemical findings. A toxic effect of a bacterial metabolite of isoleucine is proposed.