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Biomedical subjects

A J Ross

Publications and source records attributed to A J Ross.

At least 19 recordsLinked to original sources
PubMed2001

Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.

Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.

Animals↗
PubMed2000

Characterization of the elongating alpha-D-mannosyl phosphate transferase from three species of Leishmania using synthetic acceptor substrate analogues.

Leishmania express lipophosphoglycans and proteophosphoglycans that contain Galbeta1-4Manalpha1-P phosphosaccharide repeat structures assembled by the sequential addition of Manalpha1-P and betaGal. The synthetic acceptor substrate Galbeta1-4Manalpha1-P-decenyl and a series of analogues were used to probe Leishmania alpha-D-mannosyl phosphate transferase activity. We show that the activity detected with Galbeta1-4Manalpha1-P-decenyl is the elongating alpha-D-mannosyl phosphate transferase associated with lipophosphoglycan biosynthesis (eMPT(LPG)). Differences in the apparent K(m) values for the donor and acceptor substrates were found using L. major, L. mexicana, and L. donovani promastigote membranes, but total activity correlated with the number of lipophosphoglycan repeats. Further comparisons showed that lesion-derived L. mexicana amastigotes, that do not express lipophosphoglycan, lack eMPT(LPG) and that nondividing L. major metacyclic promastigotes contain 5-fold less eMPT(LPG) activity than dividing procyclic promastigotes. The fine specificity of promastigote eMPT(LPG) activity was determined using 24 synthetic analogues of Galbeta1-4Manalpha1-P-decenyl. The three species gave similar results: the negative charge of the phosphodiester and the C-6 hydroxyl of the alphaMan residue are essential for substrate recognition, the latter most likely acting as a hydrogen bond acceptor. The C-6' hydroxyl of the betaGal residue is required for substrate recognition as well as for catalysis. The rate of Manalpha1-P transfer declines with increasing acceptor substrate chain length. The presence of a monosaccharide substituent at the C-3 position of the terminal betaGal residue abrogates Man-P transfer, showing that chain elongation must precede side chain modification during lipophosphoglycan biosynthesis. In contrast, substitution of the penultimate phosphosaccharide repeat does not abrogate transfer but is slightly stimulatory in L. mexicana and inhibitory in L. major.

Amino Acid Sequence↗
PubMed2000

Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene.

The HLXB9 homeobox gene was recently identified as a locus for autosomal dominant Currarino syndrome, also known as hereditary sacral agenesis (HSA). This gene specifies a 403-amino acid protein containing a homeodomain preceded by a very highly conserved 82-amino acid domain of unknown function; the remainder of the protein is not well conserved. Here we report an extensive mutation survey that has identified mutations in the HLXB9 gene in 20 of 21 patients tested with familial Currarino syndrome. Mutations were also detected in two of seven sporadic Currarino syndrome patients; the remainder could be explained by undetected mosaicism for an HLXB9 mutation or by genetic heterogeneity in the sporadic patients. Of the mutations identified in the 22 index patients, 19 were intragenic and included 11 mutations that could lead to the introduction of a premature termination codon. The other eight mutations were missense mutations that were significantly clustered in the homeodomain, resulting, in each patient, in nonconservative substitution of a highly conserved amino acid. All of the intragenic mutations were associated with comparable phenotypes. The only genotype-phenotype correlation appeared to be the occurrence of developmental delay in the case of three patients with microdeletions. HLXB9 expression was analyzed during early human development in a period spanning Carnegie stages 12-21. Signal was detected in the basal plate of the spinal cord and hindbrain and in the pharynx, esophagus, stomach, and pancreas. Significant spatial and temporal expression differences were evident when compared with expression of the mouse Hlxb9 gene, which may partly explain the significant human-mouse differences in mutant phenotype.

Abnormalities, Multiple↗
PubMed2000

The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.

Proapoptotic Bcl-2 family members have been proposed to play a central role in regulating apoptosis. However, mice lacking bax display limited phenotypic abnormalities. As presented here, bak(-/-) mice were found to be developmentally normal and reproductively fit and failed to develop any age-related disorders. However, when Bak-deficient mice were mated to Bax-deficient mice to create mice lacking both genes, the majority of bax(-/-)bak(-/-) animals died perinatally with fewer than 10% surviving into adulthood. bax(-/-)bak(-/-) mice displayed multiple developmental defects, including persistence of interdigital webs, an imperforate vaginal canal, and accumulation of excess cells within both the central nervous and hematopoietic systems. Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis.

Abnormalities, Multiple↗
PubMed1999

Pediatric trauma management in a rural Wisconsin trauma center.

OBJECTIVE: To determine the results of pediatric trauma care managed with a cooperative effort by general surgeons and pediatric intensivists in comparison to national standards. DESIGN: Retrospective chart review. SETTING: Referral level II trauma center in rural Wisconsin. PATIENTS: All pediatric trauma patients age 16 and younger admitted to the hospital from 1990 to 1993. METHODS: Demographics, mechanisms of injury, revised trauma score (RTS), injury severity score (ISS), surgical procedures, need for intensive care, and outcome were examined. All patients were primarily managed by the trauma surgery service. Those patients requiring intensive care were managed jointly by the trauma surgery service and pediatric intensivists. Outcome was predicted by TRISS analysis; patients identified as "unexpected deaths" underwent critical clinical review to determine potential for survival. RESULTS: There were 531 pediatric trauma admissions. The mean age was 9.0 +/- 6.2 (SEM) years and two thirds of the patients were boys. Over half of all injuries were from falls, recreational activities, and motor vehicle crashes. There were few penetrating injuries. The mean RTS was 7.58 +/- 0.05, and the majority of patients had an ISS below 10. Sixty-two percent of patients required surgical procedures, most of which were orthopedic. Fourteen percent of patients were admitted to the pediatric intensive care unit. There were 13 deaths for a mortality rate of 2.4%. TRISS analysis identified six deaths as unexpected. Four drownings were not included in TRISS analysis, and there were no unexpected survivors. Of the six unexpected deaths, there were no significant management errors identified on careful review. CONCLUSIONS: Cooperation between general surgeons and pediatric intensivists can result in excellent pediatric trauma care in a rural level II trauma center.

Accidental Falls↗
PubMed1999

The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a clinical syndrome in which the precipitating factors are unclear. An association between Epstein-Barr Virus (EBV) and IPF had previously been suggested using serology and immunohistochemistry. This study sought confirmation of the presence of EBV DNA in the lung tissue of patients with IPF. Lung tissue obtained surgically from 27 patients with IPF and 28 control subjects was investigated for the presence of EBV by immunohistochemistry and polymerase chain reaction (PCR) analysis. Immunohistochemistry used antibodies specific for EBV lytic cycle antigens (gp340/220 and VCA). Nested PCR analysis used oligonucleotide primers specific for EBV and was sensitive to one copy of EBV DNA. Twelve of the 27 patients with IPF (44%) and three of the 28 control subjects (10%) were EBV positive by immunohistochemistry (p = 0.005). Thirteen of the patients with IPF (48%) and four of the control subjects (14%) were EBV positive by PCR (p = 0.007). Eleven of the patients with IPF (41%) and none of the control subjects were EBV positive by both immunohistochemistry and PCR (p = < 0.001). These data further suggest an association between EBV and IPF. In addition it defines a novel method for detecting EBV in lung tissue. EBV may be involved in the pathogenesis of the disease; however, further studies are required to establish a causal relationship.

Adult↗
PubMed1998

A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis.

Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal dominant trait; association with anterior meningocoele, presacral teratoma and anorectal abnormalities constitutes the Currarino triad (MIM 176450). Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies. We previously reported linkage to 7q36 markers in two dominantly inherited sacral agenesis families. We now present data refining the initial subchromosomal localization in several additional hereditary sacral agenesis (HSA) families. We excluded several candidate genes before identifying patient-specific mutations in a homeobox gene, HLXB9, which was previously reported to map to 1q41-q42.1 and to be expressed in lymphoid and pancreatic tissues.

Base Sequence↗
PubMed1998

Testicular degeneration in Bclw-deficient mice.

To identify genes required for mammalian spermatogenesis, we screened lines of mutant mice created using a retroviral gene-trap system for male infertility. Homozygous ROSA41 male mice exhibit sterility associated with progressive testicular degeneration. Germ-cell defects are first observed at 19 days post-natal (p19). Spermatogenesis is blocked during late spermiogenesis in young adults. Gradual depletion of all stages of germ cells results in a Sertoli-cell-only phenotype by approximately six months of age. Subsequently, almost all Sertoli cells are lost from the seminiferous tubules and the Leydig cell population is reduced. Molecular analysis indicates that the gene mutated is Bclw, a death-protecting member of the Bcl2 family. The mutant allele of Bclw in ROSA41 does not produce a Bclw polypeptide. Expression of Bclw in the testis appears to be restricted to elongating spermatids and Sertoli cells. Potential roles for Bclw in testicular function are discussed.

Age Factors↗
PubMed1997

Problems of reproducibility--does geologically ancient DNA survive in amber-preserved insects?

Apparently ancient DNA has been reported from amber-preserved insects many millions of years old. Rigorous attempts to reproduce these DNA sequences from amber- and copal-preserved bees and flies have failed to detect any authentic ancient insect DNA. Lack of reproducibility suggests that DNA does not survive over millions of years even in amber, the most promising of fossil environments.

Amber↗
PubMed1997

Anonymous HIV surveillance with risk-factor elicitation: at Perth (for men) and Cornton Vale (for women) prisons in Scotland.

434 male and 145 female prisoners were available to participate in cross-sectional, voluntary anonymous HIV surveillance (using saliva samples) with linked self-completion questionnaire at HMP (Her Majesty's Prison) Perth on 17 May and at HMP Cornton Vale on 18 May 1995. Three hundred and four men (70%) and 136 women (94%) completed a risk-factor questionnaire and 304 and 135 samples were received for HIV antibody testing. Two hundred and eighty-two and 132 questionnaires passed logical checks. Six saliva samples from Perth (all injectors) out of 304 and none from Cornton Vale out of 134 tested were HIV antibody positive. Four were presumptively from known HIV-infected male inmates; the other 2 were local men, under 26 years, who began injecting in 1989-91, and both reported having had a recent HIV test. Overall HIV prevalence was estimated at 2% compared to a known prevalence of 1.4% (6/434), giving a 1.5 ratio of overall: disclosed HIV prevalence at HMP Perth. HIV prevalence was estimated at 7% (6/82) for injector-participants and 14% (5/35) for local injector participants. At Cornton Vale, where both known HIV-infected inmates abstained, overall and disclosed HIV prevalence, were equal at 1.4%. At Perth Prison, 29% of prisoners had injected drugs (82/278); 85% of injector-inmates reported having injected inside (some prison and 31% (25/80) had started to inject while inside, 7 during their present sentence. Of all 21 injector-inmates who first injected after 1991, 10 had started to inject inside, including one of 69 male inmates who had never been inside before. The corresponding figures for Cornton Vale, where 46% of inmates were injectors (58/132), were that 57% of injector-inmates had injected inside (32/56) but only one woman, for whom this was not her first sentence, had started to inject inside. Twenty-eight per cent of male prisoners (78/277) and 57% of male injector-inmates (47/82) had had a personal HIV test since January 1993, as had 35% of female prisoners (43/124) and 57% of female injector-inmates (30/53). A much higher proportion of Glasgow's female prisoners (64%: 38/60) were injectors than of women prisoners from the Edinburgh, Dundee and Fife area (21%: 5/26) or from elsewhere (34%: 15/45). Rape was reported by 23% of women (30/130). Women who had been raped had a more polarized distribution of male sexual partners (none to 2 plus) in the year before sentencing than other women and were more likely to report anal sex (11/30 vs 11/100, P < 0.001). Prostitution had been engaged in by 19% of female injector-inmates (11/57) and was acknowledged by one other woman. However, only 5% of women (6/130) reported ever having been treated for an STD.

Adult↗
PubMed1996

Prison rights: mandatory drugs tests and performance indicators for prisons.

Mandatory drugs testing of prisoners applies throughout England and Wales. Data from the 1995 pilot study in eight prisons show that the proportion testing positive for opiates or benzodiazepines rose from 4.1% to 7.4% between the first and second phase of random testing and that there was a 20% increase over 1993-4 in the provisional total of assaults for 1995. Interpretation of these data is difficult, but this is no excuse for prevarication over the danger that this policy may induce inmates to switch from cannabis (which has a negligible public health risk) to injectable class A drugs (a serious public health risk) in prison. The performance indicators for misuse of drugs that are based on the random mandatory drugs testing programme lack relevant covariate information about the individuals tested and are not reliable or timely for individual prisons.

Adult↗
PubMed1996

Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells.

Murine gammaherpesvirus (MHV-68) causes an acute respiratory infection followed by a latent infection in B lymphocytes. In the first 2-3 weeks after infection mice develop a marked splenomegaly, where the spleen cell number increases by 2-3 fold. Cytofluorimetric analysis during splenomegaly revealed an increase in numbers of B lymphocytes and of both CD4+ and CD8+ T lymphocytes. The largest increase relative to uninfected spleens was in the CD8+ population. The number of latently infected cells in the spleen peaked at day 10 post-intraperitoneal infection, then declined to 1/10(6)-1/10(7) cells per spleen. Depletion of CD4+ T lymphocytes prevented the splenomegaly and greatly reduced the peak infective centre level, while having no effect on the long-term of latently infected cells. Given the similarity between MHV-68-induced splenomegaly and Epstein-Barr virus-induced infectious mononucleosis, these data highlight the usefulness of MHV-68 as a mouse model for the study of gammaherpesvirus immunology and pathobiology.

Animals↗
PubMed1995

Drug injection and HIV prevalence in inmates of Glenochil prison.

OBJECTIVE: To determine prevalence of HIV infection and drug injecting behaviour among inmates of Glenochil Prison on a specified date a year after an outbreak of hepatitis B and HIV infection. DESIGN: Cross sectional: voluntary, anonymous HIV salivary antibody surveillance and linked self completion questionnaire on risk factors. SETTING: Glenochil prison, Scotland, a year after an outbreak of hepatitis B and HIV transmission related to drug injection. SUBJECTS: 352 prisoners, of whom 295 (84%) took part; 284 questionnaires (96%) passed logical checks. MAIN OUTCOME MEASURES: HIV prevalence; proportion of all inmates who had ever injected drugs, had ever injected inside prison, had started injecting drugs while inside prison. RESULTS: More than half (150/284) the current inmates were also in Glenochil Prison during the critical period of January to June 1993, when hepatitis B and HIV were transmitted. Similar proportions of current inmates and men who were also in Glenochil during the critical period were drug users (27% (75/278) v 30% (44/149)). A quarter of injecting drug users (18/72) had first injected inside prison, irrespective of whether they were in Glenochil in January to June 1993 and regardless of the calendar period when they first injected. Significantly more inmates from Glasgow (41%; 56/138) than from Edinburgh (21%; 7/34) or elsewhere (11%; 12/106) were injecting drug users. On testing for HIV, seven saliva samples out of 293 gave positive results--four were presumed to be from inmates known to be infected with HIV, and the others from injecting drug users from Glasgow, all of whom had been in Glenochil during January to June 1993, when two of the three had injected drugs and had been tested for HIV, with negative results. The ratio of overall (2.4%) to disclosed (1.4%) HIV prevalence was 1.7. For men who had injected drugs in Glenochil during January to June 1993, HIV prevalence was estimated at 29%. CONCLUSION: Between a quarter and a third of prisoners who injected drugs in Glenochil in January to June 1993 were infected with HIV. There is widespread ongoing risk of bloodborne virus infection within prisons, which is probably long standing but demands urgent attention.

Adult↗
PubMed1995

The role of surgery in the management of stage IV neuroblastoma: a single institution study.

The role of surgery in the management of Stage IV neuroblastoma is still far from clear. Seventy-nine patients with this diagnosis presented to the Children's Hospital of Philadelphia during the 10-year period, 1977 to 1986. Four-year survival was 23%. A major resection of the primary tumor was undertaken in 54 patients. The timing of the procedure (at presentation or delayed) had no effect on survival. The patients were divided into three groups based on the extent of surgical resection: Group 1, no surgery or biopsy only (25); Group 2, complete gross resection (34); Group 3, incomplete resection with residual gross disease (20). Four-year survival was 16, 15, and 45%, respectively. The patients were then classified as favorable or unfavorable, on the basis of biological prognostic factors at presentation. When this analysis was combined with the extent of surgery it was discovered that Group 3 contained a higher proportion of favorable patients, accounting for the better survival. Within each group survival correlated with the expected prognosis. The outcome for a patient with Stage IV neuroblastoma depends on the biological characteristics of the tumor, and there is currently no evidence that these can be favorably altered by the timing or extent of surgical resection. Defining the appropriate role of surgery in the management of these patients will require a prospective randomized study which takes into account the inherent biological variability of the disease.

Adolescent↗
PubMed1995

Octreotide does not prevent bacterial translocation in an infant piglet model of intestinal ischemia-reperfusion.

The process of bacterial translocation (BT) after ischemia/reperfusion (I/R) injury is reported to be mediated by local mucosal factors, the effects of pancreatic enzymes, epithelial disruption, and by dysfunctional intestinal motility. Octreotide (OCT), a somatostatin analog, has been postulated to protect against BT by influencing one or more of these factors. Twenty-two formula-fed piglets (weight, 3.5 +/- 0.5 kg; age, 20 +/- 5 days) were divided into four groups: control (no drug given; no I/R; n = 6), I/R (no drug given; n = 5), I/R plus low-dose OCT (LD OCT, 0.08 microgram/kg; n = 6), and I/R plus high-dose OCT (HD OCT, 8 micrograms/kg; n = 5). All experimental subjects had nonocclusive mesenteric ischemia induced by reversible pericardial tamponade with mesenteric flow decreased to 25 +/- 5% of baseline for 5 hours followed by 15 +/- 5 hours of reperfusion. Mesenteric lymph nodes (MLN), liver, spleen, blood, and peritoneum were harvested for blind microbial analysis. None of the animals in the control group experienced translocation to the tissues tested. All of the animals in the I/R group experienced BT to the MLN. The subjects in the LD OCT and HD OCT groups experienced BT to the MLN 66% and 80% of the time, respectively. Despite the reported clinical evidence that OCT can protect the intestinal mucosa from injury and increase the clearance of bacteria from the gastrointestinal tract, in this study in which variables other than I/R known to promote bacterial translocation were eliminated, OCT failed to modify or prevent the occurrence of translocation to the MLN after I/R injury.

Animals↗
PubMed1995

Anonymous HIV surveillance with risk factor elicitation at Scotland's largest prison, Barlinnie.

OBJECTIVE: To determine prevalence of HIV infection and risk behaviours among male inmates of Her Majesty's Prison (HMP) Barlinnie, Glasgow, Scotland on 8-9 September 1994. DESIGN: Cross-sectional study: voluntary, anonymous HIV surveillance (using saliva samples) of all inmates and linked self-completion risk-factor questionnaire. SUBJECTS: Of 1073 prisoners available to participate, 985 (92%) completed a risk-factor questionnaire and 982 salivettes were received for testing, of which 978 were tested for HIV antibodies (four were dry samples); 928 questionnaires passed logical checks for consistency. MAIN OUTCOME MEASURES: HIV prevalence on saliva testing, related risk behaviours and ratio of overall-to-disclosed HIV prevalence. Proportion of all inmates who have ever injected drugs, ever injected inside prison, started injecting inside, ever had acute hepatitis, had a recent personal HIV test (since January 1993). RESULTS: Nine saliva samples [eight injecting drug users (IDU), one recognized other risk] out of 978 were HIV-antibody-positive (three presumptively from known HIV-infected inmates). Overall HIV prevalence was estimated at 1% compared with a known prevalence of 0.4%, giving an overall-to-disclosed HIV prevalence ratio of 2.6 in HMP Barlinnie in September 1994. A higher proportion of prisoners from Glasgow (48%) than elsewhere (19%) were IDU. Year of first injection was also different by residence with 23% of Glasgow IDU having first injected after 1988 compared with 45% of IDU from elsewhere, mainly West and South Scotland. Half the IDU inmates reported having injected while incarcerated and 6% had started to inject while incarcerated. Ten per cent of all prisoners and 20% of IDU inmates had had a personal HIV test since January 1993. Logistic regression showed that there was a significant deficit of recent HIV test uptake by Glasgow residents (odds ratio, 0.5; 95% confidence interval, 0.27-0.89), that IDU were more likely to have had treatment for a sexually transmitted disease, and that IDU who had injected inside and those whose injecting career began prior to 1989 were more likely to have had acute hepatitis. CONCLUSION: A consistent harm-reduction policy is needed across prisons in the United Kingdom to avoid transmission of blood-borne viral infections. Drug injecting inside prison is common, a proportion of IDU inmates having first injected drugs while in prison, and much higher rates of hepatitis have been reported in association with injecting while incarcerated compared with that for IDU who only injected outside prison.

Adult↗