Disseminated deep tissue infection with draining sinus tracts in a healthy seven-year-old.
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Abscess↗
Biomedical subjects
S Kumar
Publications and source records attributed to S Kumar.
Molecular confirmation of Ewing sarcoma.
OBJECTIVE: To analyze retrospectively results of reverse transcription polymerase chain reaction (RT-PCR) testing and demographic information in patients with known or suspected Ewing sarcoma/primitive neuroectodermal tumor family of tumors referred to the National Cancer Institute and to describe factors influencing the determination of molecular marker status. PATIENTS AND METHODS: Tumor samples from 76 patients from February 1997 to December 1999 were analyzed. In all cases, the diagnosis of this family of tumors was confirmed by histopathologic review. RESULTS: In 58 patients, the presence of a translocation associated with this family of tumors was confirmed using RT-PCR. Specifically, there were 45 Ewing sarcoma (EWS)-FLI type 1 translocations, four EWS-FLI type 2 translocations, five EWS-ERG translocations, and four less common EWS-FLI variants. Of patients with a confirmed translocation, four were confirmed only after nested RT-PCR techniques were used. In five patients who initially underwent needle biopsy, the diagnosis was confirmed only after open biopsy or repeat needle biopsy was undertaken. Samples from 18 patients were translocation-negative. Of these, seven samples were deemed inadequate for RT-PCR testing as a result of inappropriate tissue handling or the presence of necrotic material. Five patients were found to have a different diagnosis after complete histopathologic and molecular characterization. Six samples remained, in which adequate tissue was obtained with no evidence of a characteristic translocation. CONCLUSIONS: In apparently translocation-negative samples, close attention should be given to the possibility of an alternative diagnosis, the potential need for nested RT-PCR, and the possibility of an inadequate sample. Strong consideration should be given to the use of open biopsy as opposed to needle biopsy to avoid the need for repeat biopsies and the potential for inaccurate assessment of molecular marker status.
12E7 Antigen↗
Progressive fluctuant hearing loss, enlarged vestibular aqueduct, and cochlear hypoplasia in branchio-oto-renal syndrome.
OBJECTIVE: To study the results of petrosal bone imaging and audiometric long-term follow-up of two patients with branchio-oto-renal (BOR) syndrome and relate them to the clinical features, including caloric responses. STUDY DESIGN: Longitudinal case study. SETTING: Tertiary referral center. PATIENTS: A father and son with the BOR syndrome. MAIN OUTCOME MEASURES: Both patients underwent imaging studies to detect and evaluate inner ear anomalies. Longitudinal audiometric analysis of the hearing threshold data over the previous 23 years was performed. Caloric tests were performed at various ages. RESULTS: The son had a short, wide internal acoustic canal, a hypoplastic cochlea, a plump vestibule, and a wide vestibular aqueduct on both sides; the semicircular canals and endolymphatic sac were of normal size. He showed progressive fluctuant sensorineural hearing loss. Caloric tests disclosed hyporeflexia on the left side. The father had a plump internal acoustic canal and hypoplastic cochlea on both sides. The left vestibule was hypoplastic, and the left vestibular aqueduct was marginally enlarged. He showed severe hearing impairment, without substantial progression or fluctuation, and caloric areflexia on the left side. CONCLUSION: These findings suggest a correlation between progressive fluctuant sensorineural hearing loss with caloric hypofunction and the presence of an enlarged vestibular aqueduct in the BOR syndrome. Additional longitudinal case studies are needed to further evaluate such a correlation.
Adult↗
Inhibition of the in-vitro growth of Mycobacterium tuberculosis by a phytosiderophore.
Non-compliance by patients and poor clinical management due to the use of incorrect regimens are the main reasons for the development of drug resistance by mycobacterial strains. New strategies for the control of multi-drug-resistant mycobacterial strains have become a necessity for proper management of tuberculosis, which, according to the WHO report (1997), is estimated to remain among the top 10 mortality-causing diseases of the twenty-first century. One of the strategies is the use of iron-sequestering agents like siderophores as active therapeutic agents in the treatment of tuberculosis. This report describes for the first time the inhibition of the growth of Mycobacterium tuberculosis H37Ra in vitro by a phytosiderophore isolated from the root washings of Tephrosia purpurea. This finding may help in the establishment of a new drug regimen which will be more effective in the treatment of tuberculosis.
Dose-Response Relationship, Drug↗
Codon optimization of gene fragments encoding Plasmodium falciparum merzoite proteins enhances DNA vaccine protein expression and immunogenicity in mice.
In contrast to conventional vaccines, DNA and other subunit vaccines exclusively utilize host cell molecules for transcription and translation of proteins. The adenine plus thymine content of Plasmodium falciparum gene sequences (approximately 80%) is much greater than that of Homo sapiens (approximately 59%); consequently, codon usage is markedly different. We hypothesized that modifying codon usage of P. falciparum genes encoded by DNA vaccines from that used by the parasite to those resembling mammalian codon usage would lead to increased P. falciparum protein expression in vitro in mouse cells and increased antibody responses in DNA-vaccinated mice. We synthesized gene fragments encoding the receptor-binding domain of the 175-kDa P. falciparum erythrocyte-binding protein (EBA-175 region II) and the 42-kDa C-terminal processed fragment of the P. falciparum merozoite surface protein 1 (MSP-1(42)) using the most frequently occurring codon in mammals to code for each amino acid, and inserted the synthetic genes in DNA vaccine plasmids. In in vitro transient-expression assays, plasmids containing codon-optimized synthetic gene fragments (pS plasmids) showed greater than fourfold increased protein expression in mouse cells compared to those containing native gene fragments (pN plasmids). In mice immunized with 0.5, 5.0, or 50 microg of the DNA plasmids, the dose of DNA required to induce equivalent antibody titers was 10- to 100-fold lower for pS than for pN plasmids. These data demonstrate that optimizing codon usage in DNA vaccines can improve protein expression and consequently the immunogenicity of gene fragments in DNA vaccines for organisms whose codon usage differs substantially from that of mammals.
Animals↗
HLA-A*01-restricted cytotoxic T-lymphocyte epitope from the Plasmodium falciparum circumsporozoite protein.
Here, we report the identification of a novel CD8+ cytotoxic T-lymphocyte epitope on the Plasmodium falciparum circumsporozoite protein (3D7; amino acids 310 to 319 [EPSDKHIKEY]) that is restricted by HLA-A*01 and is recognized by human volunteers immunized with irradiated P. falciparum sporozoites. HLA-A*01 is the second most common HLA allele among Caucasians.
Alleles↗
Immunogenicity of well-characterized synthetic Plasmodium falciparum multiple antigen peptide conjugates.
Given the emerging difficulties with malaria drug resistance and vector control, as well as the persistent lack of an effective vaccine, new malaria vaccine development strategies are needed. We used a novel methodology to synthesize and fully characterize multiple antigen peptide (MAP) conjugates containing protective epitopes from Plasmodium falciparum and evaluated their immunogenicity in four different strains of mice. A di-epitope MAP (T3-T1) containing two T-cell epitopes of liver stage antigen-1 (LSA-1), a di-epitope MAP containing T-cell epitopes from LSA-1 and from merozoite surface protein-1, and a tri-epitope MAP (T3-CS-T1) containing T3-T1 and a potent B-cell epitope from the circumsporozoite protein central repeat region were tested in this study. Mice of all four strains produced peptide-specific antibodies; however, the magnitude of the humoral response indicated strong genetic restriction between the different strains of mice. Anti-MAP antibodies recognized stage-specific proteins on the malaria parasites in an immunofluorescence assay. In addition, serum from hybrid BALB/cJ x A/J CAF1 mice that had been immunized with the tri-epitope MAP T3-CS-T1 successfully inhibited the malaria sporozoite invasion of hepatoma cells in vitro. Spleen cells from immunized mice also showed a genetically restricted cellular immune response when stimulated with the immunogen in vitro. This study indicates that well-characterized MAPs combining solid-phase synthesis and conjugation chemistries are potent immunogens and that this approach can be utilized for the development of subunit vaccines.
Animals↗
Multistage multiantigen heterologous prime boost vaccine for Plasmodium knowlesi malaria provides partial protection in rhesus macaques.
A nonhuman primate model for malaria vaccine development allowing reliable, stringent sporozoite challenge and evaluation of both cellular and antibody responses is needed. We therefore constructed a multicomponent, multistage DNA vaccine for the simian malaria species Plasmodium knowlesi including two preerythrocytic-stage antigens, the circumsporozoite protein (PkCSP) and sporozoite surface protein 2 (PkSSP2), and two blood stage antigens, apical merozoite antigen 1 (PkAMA1) and merozoite surface protein 1 (PkMSP1p42), as well as recombinant canarypox viruses encoding the four antigens (ALVAC-4). The DNA vaccine plasmids expressed the corresponding antigens in vitro and induced antiparasite antibodies in mice. Groups of four rhesus monkeys received three doses of a mixture of the four DNA vaccine plasmids and a plasmid encoding rhesus granulocyte-monocyte colony-stimulating factor, followed by boosting with a single dose of ALVAC-4. Three groups received the priming DNA doses by different routes, either by intramuscular needle injection, by intramuscular injection with a needleless injection device, the Biojector, or by a combination of intramuscular and intradermal routes by Biojector. Animals immunized by any route developed antibody responses against sporozoites and infected erythrocytes and against a recombinant PkCSP protein, as well as gamma interferon-secreting T-cell responses against peptides from PkCSP. Following challenge with 100 P. knowlesi sporozoites, 1 of 12 experimental monkeys was completely protected and the mean parasitemia in the remaining monkeys was significantly lower than that in 4 control monkeys. This model will be important in preclinical vaccine development.
Animals↗
The wide-domain carbon catabolite repressor CreA indirectly controls expression of the Aspergillus nidulans xlnB gene, encoding the acidic endo-beta-(1,4)-xylanase X(24).
The Aspergillus nidulans xlnB gene, which encodes the acidic endo-beta-(1,4)-xylanase X(24), is expressed when xylose is present as the sole carbon source and repressed in the presence of glucose. That the mutation creA(d)30 results in considerably elevated levels of xlnB mRNA indicates a role for the wide-domain repressor CreA in the repression of xlnB promoter (xlnBp) activity. Functional analyses of xlnBp::goxC reporter constructs show that none of the four CreA consensus target sites identified in xlnBp are functional in vivo. The CreA repressor is thus likely to exert carbon catabolite repression via an indirect mechanism rather than to influence xlnB expression by acting directly on xlnB.
Aspergillus nidulans↗
Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis.
The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus and cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocalizes with the endoplasmic reticulum (ER)-associated protein grp78. Expression of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellular fractionation studies further indicate that over 20% of cellular c-Abl is detectable in the ER. The results also demonstrate that induction of ER stress with calcium ionophore A23187, brefeldin A, or tunicamycin is associated with translocation of ER-associated c-Abl to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in the response to ER stress by a c-Abl-dependent mechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficient cells. These findings indicate that c-Abl is involved in signaling from the ER to mitochondria and thereby the apoptotic response to ER stress.
Animals↗
Obtunded sensorium in a trauma patient.
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Accidents, Traffic↗
Does nonneutral evolution shape observed patterns of DNA variation in animal mitochondrial genomes?
Early studies of animal mitochondrial DNA (mtDNA) assumed that nucleotide sequence variation was neutral. Recent analyses of sequences from a variety of taxa have brought the validity of this assumption into question. Here we review analytical methods used to test for neutrality and evidence for nonneutral evolution of animal mtDNA. Evaluations of mitochondrial haplotypes in different nuclear backgrounds identified differences in performance, typically favoring coevolved mitochondrial and nuclear genomes. Experimental manipulations also indicated that certain haplotypes have an advantage over others; however, biotic and historical effects and cyto-nuclear interactions make it difficult to assess the relative importance of nonneutral factors. Statistical analyses of sequences have been used to argue for nonneutrality of mtDNA; however, rejection of neutral patterns in the published literature is common but not predominant. Patterns of replacement and synonymous substitutions within and between species identified a trend toward an excess of replacement mutations within species. This pattern has been viewed as support for the existence of mildly deleterious mutations within species; however, other alternative explanations that can produce similar patterns cannot be eliminated.
Animals↗
Vaginal and omental metastasis from superficial bladder cancer.
A 58-year-old lady, diagnosed as having superficial bladder cancer 6 years earlier presented to us with a vaginal nodule. Investigations and biopsy revealed a metastatic transitional cell carcinoma in the pelvic lymph nodes, omentum and vagina.
Carcinoma, Transitional Cell↗
Bilateral transection of the vas deferens: an unusual trauma from a cross stab injury of the scrotum.
An unusual case of division of both vas deferens in a patient with a cross stab injury to the root of scrotum is described. The management of this case in the emergency setting is discussed. The case illustrates the need to explore every case of penetrating trauma to the scrotum, even in the absence of active bleeding, to avoid missing such injuries. These injuries, although not life-threatening, can have a profound impact on the patient's future fertility and this may only manifest several years after the injury.
Adult↗
Ward crowding and incidents of violence on an acute psychiatric inpatient unit.
OBJECTIVE: Violence in psychiatric wards is common, and it is on the rise. This study examined the relationship between ward occupancy level and staff-to-patient ratio and incidents of aggressive behavior, both physical and verbal, on an acute inpatient unit in rural New Zealand. METHODS: Logistic regression was used to analyze data collected from the ward's log of adverse incidents and the ward census over a 12-month period. A physical incident was defined as an unwelcome physical contact or willful damage to property. Incidents of self-harm were excluded. Verbal aggression was any threat of physical or sexual harm. RESULTS: Among 381 admissions during the study period, 58 incidents were recorded--25 incidents of verbal aggression and 33 incidents of physical violence. Logistic regression demonstrated that the occupancy level was positively associated with the occurrence of any type of violent incident. The average occupancy level when an incident occurred was 77 percent, compared with 69 percent when no incidents occurred. The average occupancy level was significantly higher when verbal incidents occurred (80 percent) than when physical incidents occurred (70 percent). No association was found between violence and staff-to-patient ratio. Incidents were significantly more likely to occur during the afternoon shifts (3 p.m. to 11 p.m.). CONCLUSIONS: Crowding was found to be significantly associated with aggressive incidents, and in particular with verbal aggression.
Acute Disease↗
Stiff-man syndrome in childhood.
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Child↗
Crowding and violence on psychiatric wards: explanatory models.
OBJECTIVE: Violence is widely prevalent on acute-care psychiatric wards, and crowding has been identified as a major risk factor. This paper explores why patients may respond to crowding with violence. METHOD: We carried out a literature review on Medline, using the key words "violence" and "crowding." We conducted an additional hand search of the references collected from the reviewed papers. RESULTS: Factors specific to the relation between crowding on acute-care inpatient psychiatric wards and violence can be divided under the following headings: 1) patient density, privacy, and control; 2) ward architecture; 3) the social organization of psychiatric wards; 4) interpersonal space; 5) phylogenic theories; and 6) anthropological theories of human behaviour. CONCLUSIONS: We offer explanatory models for this relation and suggest strategies to counter the effects of crowding. Recommendations are made for future studies.
Crowding↗
Identification and implantation stage-specific expression of an interferon-alpha-regulated gene in human and rat endometrium.
Implantation of the developing blastocyst is regulated by multiple effectors, such as steroid hormones, growth factors, and cytokines. To understand how these diverse signaling pathways interact to modulate uterine gene expression, we employed a gene expression screen technique to identify the molecules that are induced in the periimplantation rat uterus. Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). This gene exhibits significant homology to interferon (IFN)-alpha/beta-inducible human genes p27 and 6-16, indicating that these genes may belong to the same family. Consistent with this finding, expression of IRG1 messenger RNA (mRNA) in rat uterus increased about 20-fold in response to IFNalpha. Uterine expression of IRG1 was also stimulated by estrogen and was partially inhibited by an antiestrogen, ICI 182,780. In pregnant rats, IRG1 expression was high on day 1, but declined on days 2 and 3. The level of IRG1 mRNA again rose transiently on day 4 immediately preceding implantation. In situ hybridization analysis localized the IRG1 mRNA expression in the endometrial epithelium and the surrounding stroma. Interestingly, the expression of p27, which shows high homology to IRG1, was strongly enhanced in human endometrium during the midsecretory phase of the menstrual cycle, overlapping the putative window of implantation. Both IRG1 and p27 mRNAs are therefore induced in the endometrium in an implantation stage-specific manner. We also observed a synergistic interaction between IFNalpha and estrogen receptor signaling pathways that led to maximal induction of p27 mRNA in Ishikawa cells. Although the functional roles of IRG1 and p27 remain unclear, we describe for the first time, identification of a gene family regulated by IFNalpha in both rodent and human uteri. More importantly, our studies reveal that a complex interplay between the steroid hormone and IFN pathways regulates the expression of these genes in the endometrium at the time of implantation.
Adult↗