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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
PubMed2005

1H MRS in stroke patients with and without cognitive impairment.

The pathophysiological basis of cognitive impairment in patients with cerebrovascular disease (CVD) is not well understood, particularly in relation to the role of non-infarction ischemic change and associated Alzheimer-type pathology. We used single voxel 1H MRS to determine the differences in brain neurometabolites in non-infarcted frontal white matter and occipito-parietal gray matter of 48 stroke patients with or without cognitive impairment and 60 elderly controls. The results showed that there were no significant neurometabolite differences between the stroke cohort and healthy elderly controls, but there was a difference in NAA/H2O between the stroke patients that had cognitive impairment (vascular dementia (VaD) and vascular cognitive impairment (VCI)) compared with those patients with no impairment. This was significant in the occipito-parietal gray matter, but not in the frontal white matter, although the results were in the same direction for the latter. This suggests that cognitive impairment in stroke patients may be related to cortical neuronal dysfunction rather than purely subcortical change. Moreover, cortical regions not obviously infarcted may have dysfunctional neurons, the pathophysiological basis for which needs further study.

Aged↗
PubMed2004

Isotope effects and Born-Oppenheimer breakdown in excited singlet states of the lithium dimer.

Observation of infrared electronic transitions involving the 1 (1)Deltag state of 7Li2 has instigated an investigation of Born-Oppenheimer breakdown in four singlet electronic states correlating with (2s+2s), (2s+2p), and (2p+2p) lithium atoms. The 1 (1)Deltag state, which correlates at long range with (2p+2p) atoms, has been observed in emission from the (5p) (1)Piu Rydberg state and in 1 (1)Deltag-B (1)Piu bands, in both instances following optical-optical double-resonance excitation. The latter transition was observed previously for the lighter isotopomer, 6Li2 [C. Linton, F. Martin, P. Crozet, A. J. Ross, and R. Bacis, J. Mol. Spectrosc. 158, 445 (1993)]. By analyzing multiple-isotopomer data for several electronic systems simultaneously, we have determined the electronic isotope shifts and the leading vibrational and/or rotational Born-Oppenheimer breakdown terms for the X (1)Sigmag+, A (1)Sigmau+, B (1)Piu, and 1 (1)Deltag states of the lithium dimer. This paper also reports Fourier transform measurements of the B-X absorption spectra of 6Li2 and 7Li2, which were required to better define the bottom portion of the B (1)Piu state potential.

Journal Article↗
PubMed2003

Speech and language sequelae of severe malaria in Kenyan children.

PRIMARY OBJECTIVE: To conduct a preliminary investigation into the occurrence of speech and language impairments following severe malaria in Kenyan children. RESEARCH DESIGN: Cohort study comparing the prevalence of impairments in children exposed or unexposed to severe malaria. METHODS AND PROCEDURES: The study recruited 25 children who had previously been admitted to hospital with severe falciparum malaria and 27 unexposed to the disease. Assessments of comprehension, syntax, lexical semantics, higher level language abilities, pragmatics and phonology were administered to each child at 8-9 years of age, at least 2 years after admission to hospital in children exposed to severe malaria. MAIN OUTCOMES AND RESULTS: Exposed children were found to have lower scores on each assessment and significantly lower scores on four aspects of language ability: comprehension (p = 0.02); syntax (p = 0.02); content words (p = 0.02) and function words (p = 0.004) components of lexical semantics. CONCLUSIONS: These data suggest that speech and language deficits may be an important and under-recognized sequela of severe falciparum malaria.

Child↗
PubMed2001

An efficient and stereoselective synthesis of beta-D-Arap-(1-->2)-beta-D-Galp-(1-->3)-beta-D-Galp-(1-->4)-alpha-D-Manp, a tetrasaccharide fragment of Leishmania major lipophosphoglycan.

A tetrasaccharide fragment of Leishmania major lipophosphoglycan (which seems to be involved in a biological mechanism for the parasite transmission) has been synthesised using the thioglycoside, trichloroacetimidate and halide-exchange glycosylation procedures and step-wise chain elongation strategy.

Animals↗
PubMed2001

BCLW mediates survival of postmitotic Sertoli cells by regulating BAX activity.

Male mice deficient in BCLW, a death-protecting member of the BCL2 family, are sterile due to an arrest in spermatogenesis that is associated with a gradual loss of germ cells and Sertoli cells from the testis. As Bclw is expressed in both Sertoli cells and diploid male germ cells, it has been unclear which of these cell types requires BCLW in a cell-autonomous manner for survival. To determine whether death of Sertoli cells in Bclw mutants is influenced by the protracted loss of germ cells, we examined testes from Bclw/c-kit double mutant mice, which lack germ cells from birth. Loss of BCLW-deficient Sertoli cells occurs in the absence of germ cells, indicating that germ cell death is not required to mediate loss of Sertoli cells in BCLW-deficient mice. This suggests that Sertoli cells require BCLW in a cell-intrinsic manner for long-term survival. The loss of Sertoli cells in Bclw mutants commences shortly after Sertoli cells have become postmitotic. In situ hybridization analysis indicates that Bclw is expressed in Sertoli cells both before and after exit from mitosis. Therefore, Bclw-independent pathways promote the survival of undifferentiated, mitotic Sertoli cells. We show that BAX and BAK, two closely related death-promoting members of the BCL2 family, are expressed in Sertoli cells. To determine whether either BAX or BAK activity is required for Sertoli cell death in Bclw mutant animals, we analyzed survival of Sertoli cells in Bclw/Bax and Bclw/Bak double homozygous mutant mice. While mutation of Bak had no effect, ablation of Bax suppressed the loss of Sertoli cells in Bclw mutants. Thus, BCLW mediates survival of postmitotic Sertoli cells in the mouse by suppressing death-promoting activity of BAX.

Animals↗
PubMed2001

BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak.

The BH3-only proteins Bim and Bad bind to the antiapoptotic Bcl-2 proteins and induce apoptosis in wild-type cells and cells from either bax(-/-) or bak(-/-) animals. In contrast, constitutively active forms of Bim and Bad failed to induce apoptosis in bax(-/-)bak(-/-) cells. Expression of Bax restored susceptibility of the cells to Bim and Bad. In addition, Bax but not Bim or Bad sensitized the bax(-/-)bak(-/-) cells to a wide variety of cell death stimuli including UV irradiation, chemotherapeutic agents, and ER stress. These results suggest that neither activation of BH3-only proteins nor suppression of pro-survival Bcl-2 proteins is sufficient to kill cells in the absence of both Bax and Bak. Furthermore, whereas mouse embryo fibroblasts (MEF) expressing only Bax or Bak displayed resistance to transformation, bax(-/-)bak(-/-) MEF were nearly as prone to oncogenic transformation as p53(-/-) MEF. Thus, the function of either Bax or Bak appears required to initiate most forms of apoptosis and to suppress oncogenic transformation.

Animals↗
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↗
PubMed2001

Spermatogenesis in Bclw-deficient mice.

Bclw is a death-protecting member of the Bcl2 family of apoptosis-regulating proteins. Mice that are mutant for Bclw display progressive and nearly complete testicular degeneration. We performed a morphometric evaluation of testicular histopathology in Bclw-deficient male mice between 9 days postnatal (p9) through 1 yr of age. Germ cell loss began by p22, with only few germ cells remaining beyond 7 mo of age. A complete block to elongated spermatid development at step 13 occurred during the first wave of spermatogenesis, whereas other types of germ cells were lost sporadically. Depletion of Sertoli cells commenced between p20 and p23 and continued until 1 yr of age, when few, if any, Sertoli cells remained. Mitochondria appeared to be swollen and the cytoplasm dense by electron microscopy, but degenerating Bclw-deficient Sertoli cells failed to display classical features of apoptosis, such as chromatin condensation and nuclear fragmentation. Macrophages entered seminiferous tubules and formed foreign-body giant cells that engulfed and phagocytosed the degenerated Sertoli cells. Leydig cell hyperplasia was evident between 3 and 5 mo of age. However, beginning at 7 mo of age, Leydig cells underwent apoptosis, with dead cells being phagocytosed by macrophages. The aforementioned cell losses culminated in a testis-containing vasculature, intertubular phagocytic cells, and peritubular cell "ghosts." An RNA in situ hybridization study indicates that Bclw is expressed in Sertoli cells in the adult mouse testis. Consequently, the diploid germ cell death may be an indirect effect of defective Sertoli cell function. Western analysis was used to confirm that Bclw is not expressed in spermatids; thus, loss of this cell type most likely results from defective Sertoli cell function. Because Bclw does not appear to be expressed in Leydig cells, loss of Leydig cells in Bclw-deficient mice may result from depletion of Sertoli cells. Bclw-deficient mice serve as a unique model to study homeostasis of cell populations in the testis.

Alleles↗
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↗