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A Smith

Publications and source records attributed to A Smith.

At least 19 recordsLinked to original sources
PubMed2023

Exploiting Real-Time Genomic Surveillance Data To Assess 4CMenB Meningococcal Vaccine Performance in Scotland, 2015 to 2022.

The United Kingdom implemented the first national infant immunization schedule for the meningococcal vaccine 4CMenB (Bexsero) in September 2015, targeting serogroup B invasive meningococcal disease (IMD). Bexsero contains four variable subcapsular proteins, and postimplementation IMD surveillance was necessary, as nonhomologous protein variants can evade Bexsero-elicited protection. We investigated postimplementation IMD cases reported in Scotland from 1 September 2015 to 30 June 2022. Patient demographics and vaccination status were combined with genotypic data from the causative meningococci, which were used to assess vaccine coverage with the meningococcal deduced vaccine antigen reactivity (MenDeVAR) index. Eighty-two serogroup B IMD cases occurred in children >5 years of age, 48 (58.5%) of which were in unvaccinated children and 34 (41%) of which were in children who had received ≥1 Bexsero dose. Fifteen of the 34 vaccinated children had received one dose, 17 had received two doses, and two had received three doses. For 39 cases, meningococcal sequence data were available, enabling MenDeVAR index deductions of vaccine-preventable (M-VP) and non-vaccine-preventable (M-NVP) meningococci. Notably, none of the 19 of the children immunized ≥2 times had IMD caused by M-VP meningococci, with 2 cases of NVP meningococci, and no deduction possible for 17. Among the 15 children partially vaccinated according to schedule (1 dose), 7 were infected by M-VP meningococci and 2 with M-NVP meningococci, with 6 for which deductions were not possible. Of the unvaccinated children with IMD, 40/48 were ineligible for vaccination and 20/48 had IMD caused by M-VP meningococci, with deductions not being possible for 14 meningococci. IMPORTANCE This study demonstrates the value of postimplementation genomic surveillance of vaccine-preventable pathogens in providing information on real-world vaccine performance. The data are consistent with 2 and 3 doses of Bexsero, delivered according to schedule, providing good protection against invasive disease caused by meningococci deduced from genomic data to be vaccine preventable. Single doses provide poorer protection to infants. In practical terms, these data can provide public health reassurance when vaccinated individuals develop IMD with non-vaccine-preventable variants. They further indicate that additional testing is needed on variants for which no immunological data exist to improve estimates of protection, although these data suggest that the uncharacterized variants are unlikely to be covered by Bexsero. Finally, the confirmation that incomplete or absent doses in infancy lead to reduced protection supports public health and general practitioners in promoting vaccination according to schedule.

Infant↗
PubMed1992

Detection in life of confirmed Alzheimer's disease using a simple measurement of medial temporal lobe atrophy by computed tomography.

The medial temporal lobe of the brain is important for normal cognitive function, notably for memory, and is the region with the most extensive pathological change in Alzheimer's disease (AD). We wanted to find out if atrophy of the medial temporal lobe could be detected in life in patients in whom a diagnosis of AD was subsequently established histopathologically. The minimum width of the medial temporal lobe, measured by temporal-lobe-oriented computed tomography (CT) about one year before death, in 44 patients with a histopathological diagnosis of AD (cases) was nearly half (0.56 of the median) that in 75 controls of the same age with no clinical evidence of dementia (95% confidence interval 0.51-0.61). There was little overlap between the distributions of measurements in cases and controls. A cut-off (< 0.79 MoM) selected to yield a 5% false-positive rate gave an expected detection rate of 92%. A cut-off selected to yield a false-positive rate of 1% (< 0.70 MoM) yielded a 79% detection rate. 20 of the 44 patients with histopathologically diagnosed AD had been scanned more than once before death, and the test (cut-off < 0.79 MoM) was positive in all 20 more than a year before and in 9/10 more than 2 years before death. In 10 subjects with dementia but with histopathology excluding AD, the mean minimum width of the medial temporal lobe was significantly greater than that in the cases with AD, but was not significantly different from that in controls. Medial temporal lobe CT is a non-invasive, rapid, simple and effective test for AD which could have immediate application firstly in improving the accuracy of prevalence and incidence studies and, secondly, for the identification of groups of high-risk patients in the evaluation of novel treatments for AD. In the future, it could be applied as a screening test.

Aged↗
PubMed1992

Heme-hemopexin-mediated induction of metallothionein gene expression.

Hemopexin-mediated heme transport into mouse hepatoma (Hepa) cells and human promyelocytic (HL-60) cells stimulates the expression of heme oxygenase via transcriptional activation (Alam, J., and Smith, A. (1989) J. Biol. Chem. 264, 17637-17640). Incubation of both these cell types in serum-free medium containing heme-hemopexin is shown here also to increase the steady-state level of metallothionein (MT) mRNA in a time- and dose-dependent manner. Heme-hemopexin is a far more effective inducer (12-fold) of the MT isozyme 1 (MT-1) in Hepa cells than nonprotein-bound heme (4-fold). Apohemopexin has no effect on MT-1 expression, and incubation with heme-hemopexin of mouse L fibroblasts that lack hemopexin receptors does not affect MT-1 expression. Thus, an interaction between the heme-hemopexin complex and its receptor is necessary for increased accumulation of MT-1 transcripts. In vitro nuclear "run-on" analysis indicates that the heme-hemopexin-mediated accumulation of MT-1 mRNA is regulated primarily at the level of initiation of transcription. A highly labile protein is required for constitutive MT-1 gene expression and acts to repress transcription. Transcriptional activation by heme or metals may require decreased concentrations or inactivation of the repressor as well as an additional inducer-specific trans-acting factor. Inhibition of protein synthesis augments the heme-hemopexin-mediated accumulation of MT-1 mRNA. Activation of heme oxygenase (HO) gene transcription by heme requires the synthesis of one (or more) heme-inducible proteins that are labile or become labile upon cycloheximide-sensitive processing or activation. Our comparison of MT and HO points to significant differences in the mechanisms of gene regulation by heme. The concomitant regulation of gene expression of MT-1 and HO in response to heme-hemopexin appears to be a concerted adaptive response of the cells, mediated at the level of the plasma membrane hemopexin receptor, and may relate to the proposed role of MT as an intracellular antioxidant or to a need to sequester zinc which otherwise would compete with iron and occupy sites on regulatory proteins such as the iron-responsive elements.

Animals↗
PubMed1992

Meiosis-specific protein selectively associated with sex chromosomes of rat pachytene spermatocytes.

During the first meiotic prophase of mammalian spermatogenesis, the sex chromosomes X and Y show a characteristic allocyclic behavior with respect to the autosomes. This is particularly evident during pachytene stage when sex chromosomes form the so-called sex vesicle. This structure is characterized by the condensed state of chromatin, transcriptional inactivity, and the limited extension of chromosome pairing, which is usually restricted to a short segment of sex chromosome axial elements. The molecular basis and functional significance of sex vesicle formation during mammalian spermatogenesis remain obscure. Here we report on the identification of a meiosis-specific sex vesicle protein we called XY40. Immunocytochemical localization on rat testis cryosections with a XY40-specific monoclonal antibody revealed that the labeling is confined to the axial elements of sex chromosomes. Biochemical characterization showed that protein XY40 (40 kDa; pI 5.7-5.8) can be extracted from rat pachytene spermatocytes and recovered in particles of 9.5 S with a native molecular mass of approximately 152 kDa. We speculate that protein XY40 may be involved in the allocyclic behavior of sex chromosomes during male meiotic prophase.

Animals↗
PubMed1992

Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study.

OBJECTIVE: To evaluate the safety of recombinant human DNase (rhDNase) in normal subjects and in patients with cystic fibrosis. DESIGN: Nonrandomized trial in which individuals inhaled rhDNase three times a day Monday through Friday on two consecutive weeks. SETTING: The study was performed in the Clinical Research Center at the University of Washington, Seattle. Patients were recruited from the Cystic Fibrosis Center at the University of Washington. SUBJECTS AND PATIENTS: Twelve normal subjects and 14 patients with cystic fibrosis were studied (12 patients completed the protocol). The subjects and patients had to be aged 18 to 65 years and have a negative pregnancy test, if female. The normal subjects had to have a normal chest roentgenogram, be nonsmokers, and have normal pulmonary function testing. The patients with cystic fibrosis had to have a forced vital capacity greater than 40% predicted normal and have no recent exacerbation (within 2 weeks) of their lung infection or change in their medication. INTERVENTIONS: The study design was a repetitive dose escalation of aerosolized rhDNase. The subjects inhaled rhDNase three times a day, Monday through Friday, on 2 consecutive weeks and were rechallenged with a single dose 21 days after the last dose. Spirometry was measured before and 30 minutes after every rhDNase dose. MAIN OUTCOME MEASURES: Pulmonary function testing, serum DNase concentrations, and anti-DNase antibodies. Secondary outcome measures were dyspnea score and quantitative bacterial culture. MAIN RESULTS: Inhalation of rhDNase was well tolerated by all persons. There were no serious adverse reactions, and no allergic reactions were observed, even on rechallenge. No individual developed rhDNase antibodies. Improvement in both lung function and dyspnea score was observed in the adults with cystic fibrosis. Forced vital capacity was 3.2 +/- 0.3 L (mean +/- SE) on day 1 and was 3.5 +/- 0.3 L on day 12. Forced expiratory volume in 1 second was 2.1 +/- 0.2 L (mean +/- SE) on day 1 and was 2.3 +/- 0.3 L on day 12. CONCLUSIONS: Aerosolized rhDNase appears safe in normal subjects and in adults with cystic fibrosis and may improve lung function with short-term therapy.

Administration, Inhalation↗
PubMed1992

Distribution of nigrothalamic projections in the dog.

The distribution of nigrothalamic projections was studied in the dog by using the autoradiographic tracing method. On the basis of a systematic series of tritiated amino acid injections into different portions of the substantia nigra, we found that the rostral three-fourths of the substantia nigra pars reticulata (SNr) gives rise to widespread thalamic projections. The nigrothalamic label occupied a longitudinal band extending from rostral ventral anterior nucleus (VA) through to caudal mediodorsal nucleus (MD). In the dog, VA is histochemically identified as an acetylthiocholinesterase (AChE)-negative region and is distinct from the adjacent ventral lateral nuclei which stain positively for AChE. In rostral thalamus, the dense autoradiographic label was observed in rostral VA within the AchE-negative region lying alongside the mammillothalamic tract (MT). The adjacent AChE-positive ventral lateral nuclei did not contain autoradiographic label. In addition, homogeneously distributed silver grains were observed throughout the ventromedial nucleus (VM) bilaterally. More caudally, as the ventral lateral thalamic compartment emerges, label was also observed within the internal medullary lamina region, including the paralaminar portion of VA, the central lateral nucleus (CL), and the paralaminar portion of MD. Finally, in caudal thalamus, the central portion of MD, as well as the parafascicular nucleus (Pf), contained autoradiographic label. The overall nigrothalamic distribution observed in the dog was similar to the distribution of nigrothalamic projections in monkeys with one exception. Unlike that of primates, the distribution of nigral efferents is to the whole extent of VM in the dog as in other non-primate species. Overall, we found that nigral efferents primarily project to three main thalamic targets: the VA/MD region, VM, and the internal medullary lamina region, which includes dorsal CL and paralaminar VA and MD. We propose that these three nigrothalamic territories may constitute critical links subserving different functional channels.

Acetylcholinesterase↗
PubMed1992

Comparison of ciprofloxacin with netilmicin for the treatment of acute pyelonephritis.

A prospective, randomised trial was undertaken to compare the efficacy of ciprofloxacin and netilmicin for the treatment of acute pyelonephritis. Forty-three patients were enrolled and 34 (29 women) completed the protocol. Fifteen of 17 patients treated with ciprofloxacin and 15 of 17 treated with netilmicin were cured. All patients were treated for five days. One patient relapsed after ciprofloxacin and another had a reinfection, while two relapsed after netilmicin. Five of six patients with a urinary tract abnormality were cured. Side effects were generally mild and rapidly reversible. Patients treated with ciprofloxacin spent a mean of 3.7 days in hospital compared with 5.3 days for those treated with netilmicin. The difference in duration of hospital stay was statistically significant (p less than 0.01). Both drugs proved highly effective and safe for the treatment of severe acute pyelonephritis.

Acute Disease↗
PubMed1992

Manual dilatation of the anus.

A group of 100 consecutive patients undergoing manual dilatation of the anus between 1980 and 1983 were reviewed retrospectively by examining the clinical presentation, diagnosis, treatment and outcome. Anal fissure was diagnosed in 46 patients, 22 had either first- or second-degree haemorrhoids, and stenosis of the anal canal was identified in seven. Manual dilatation of the anus was performed on 25 patients in the absence of a diagnosis. Dilatation failed to treat 26 anal fissures successfully. Where it was employed alone in ten cases of haemorrhoids and seven of anal stenosis, manual dilatation failed to cure seven and five patients respectively. Of the patients with no diagnosis, 23 were relieved of their symptoms following dilatation. Episodes of incontinence occurred in 27 patients, 21 of whom were female. There should be a reduced role for manual anal dilatation in the treatment of common anorectal disorders.

Adolescent↗
PubMed1992

Management of patients with diffuse toxic goitre in Ireland, a country with low iodine intake.

The present study was undertaken to examine the response rate of thyrotoxicosis in patients with diffuse toxic goitre to thiouracil drug treatment for 1 year in an Irish population, reported to have a low iodine intake. Evidence exists that a low iodine intake is associated with a high long-term remission rate for drug treatment of diffuse toxic goitre. Seventy-five patients participated with 45% of patients entering into long-term remission which has been maintained for a mean of 52.5 +/- 38.8 months. Fifty-five per cent of patients demonstrated relapse at a mean of 7.4 +/- 10.4 months following the withdrawal of thiouracil treatment. These findings were similar to those reported from countries with abundant iodine intake. The data in the present study confirms the usefulness of drug treatment for diffuse toxic goitre in an Irish population but the reported iodine deficiency does not appear to confer a particular advantage.

Adult↗
PubMed1992

Identification of a structural protein component of rat synaptonemal complexes.

Synaptonemal complexes (SCs) are evolutionarily conserved nuclear structures of meiotic cells which form during the zygotene stage of the first meiotic prophase and are responsible for the pairing of homologous chromosomes. Their formation appears to be a prerequisite for crossing-over events and proper chromosome segregation during the first meiotic division. Despite knowledge of their central role in genetic recombination processes very little is known about the molecular composition and the mechanisms governing the assembly of the SCs. In the present study we report on the characterization of a monoclonal antibody (SC14f10) which enabled us to identify a novel SC protein termed SC48. Protein SC48 has a Mr of 48,000 and migrates in two-dimensional gels with a pH value of 6.9. By means of immunogold EM we localized this protein to the central region of the SC. In cell fractionation experiments we recovered protein SC48 together with SC-residual structures in a karyoskeletal fraction of pachytene spermatocytes. Our results indicate that SC48 is a meiosis-specific structural protein component of the SC probably involved in the pairing of homologous chromosomes.

Animals↗
PubMed1992

Onchocerca volvulus: immunization of chimpanzees with X-irradiated third-stage (L3) larvae.

To provide a theoretical basis for the potential development of vaccines against Onchocerca volvulus (Ov) a trial has been conducted to assess the protective efficacy of immunization of chimpanzees with X-irradiated L3 larvae. Approximately 1000 larvae were injected at 0, 1, and 7 months. The immunized animals, and unimmunized controls, were then challenged with 250 live L3. In order to provide possibly protective exposure to the immunologically distinct L4 epicuticle, a radiation dose (45 krad) was chosen which preserved about 50% of the molting ability of unirradiated larvae. Despite the presence of a strong immune response to crude adult worm extracts, and to cloned Ov antigens, at the time of challenge little or no significant protection against patent infection was observed: three of four immunized animals developed patent infection as compared to four of four controls. One immunized animal failed to become patent or to manifest the late antibody response to adult worm antigens seen in both subpatent and patent infections in this model, and may have been protected from infection. The implications of these studies for future attempts to immunize against O. volvulus are discussed.

Animals↗
PubMed1992

Anterior mediastinal abscess complicating septic arthritis.

An 11-year-old boy with septic arthritis of both knees presented with an anterior mediastinal abscess extending suprasternally. This was drained through a suprasternal incision and the mediastinal cavity was intermittently irrigated with povidone iodine solution and packed with gauze. Staphylococcus aureus was the responsible organism. Antibiotic therapy comprised of cloxacillin and gentamycin. Recovery was uneventful. This is, most probably, the first report on an anterior mediastinal abscess complicating a distant septic arthritis. As for any infective mediastinitis, early diagnosis and aggressive treatment is mandatory for a patient's survival.

Abscess↗
PubMed1992

Absent left-sided atrioventricular connexion, with right atrium connected to left ventricle: prospective diagnosis in infancy, and outcome.

Prospective echocardiographic diagnosis of absence of the left atrioventricular connexion, with the right atrium connected to a morphologic left ventricle through a bileaflet morphologically mitral valve, was made in six infants. The rudimentary right ventricle was left-sided in all patients, and separated from the left atrium by sulcus tissue. The ventriculoarterial connexions were discordant. Associated defects included subpulmonary stenosis (2 patients), pulmonary atresia (1 patient), and a patent duct (4 patients). All patients developed early left atrial hypertension due to a restrictive interatrial septum, and required transcatheter septostomy (5 patients), or surgical septectomy (3 patients). One patient who had a severely restrictive ventricular septal defect died following cardiac catheterization. In three others the ventricular septal defect has become progressively restrictive on serial catheterization. Successful intermediate term palliation has been performed in two patients using a bidirectional Glenn anastomosis, together with enlargement of the ventricular septal defect and a Damus-Kay-Stansel procedure in one. It is possible to distinguish this malformation from "mitral atresia" using cross-sectional echocardiography. The long-term outlook is influenced by early relief of left atrial hypertension. Balloon atrial septostomy alone is usually inadequate, and either blade septostomy or surgical septectomy are required. Serial cardiac catheterization is mandatory for planning definitive palliation.

Cardiac Catheterization↗