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Biomedical subjects

S Howard

Publications and source records attributed to S Howard.

At least 19 recordsLinked to original sources
PubMed2006

Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials.

BACKGROUND: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial. PATIENTS AND METHODS: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method. RESULTS: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25). CONCLUSIONS: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Combined Modality Therapy↗
PubMed2005

Bleeding esophageal GIST.

We present a case of esophageal gastrointestinal stromal tumor presenting as gastrointestinal bleeding.

Aged↗
PubMed2002

Dynamic performance of the mechanism of an automatically deployable ROPS.

The mechanism for an automatically deployable ROPS (AutoROPS) has been designed and tested. This mechanism is part of an innovative project to provide passive protection against rollover fatality to operators of new tractors used in both low-clearance and unrestricted-clearance tasks. The device is a spring-action, telescoping structure that releases on signal to pyrotechnic squibs that actuate release pins. Upper post motion begins when the release pins clear an internal piston. The structure extends until the piston impacts an elastomeric ring and latches at the top position. In lab tests the two-post structure consistently deployed in less than 0.3 s and latched securely. Static load tests of the telescoping structure and field upset tests of the fully functional AutoROPS have been successfully completed.

Accidents, Occupational↗
PubMed2001

Synthesis of chiral 1,2-diamines by asymmetric lithiation-substitution.

[reaction--see text] The imidazolidine (tetrahydroimidazole) 2, prepared in one step from N-iso-propylethylenediamine, was subjected to asymmetric lithiation and substitution using sec-butyllithium, (-)-sparteine and a range of electrophiles. Substituted imidazolidines were formed with high optical purity and could be hydrolyzed under acidic conditions to chiral, substituted ethylenediamines. Kinetic data indicate that the conformation of the carbonyl group is crucial to the extent of deprotonation, and this has implications for the lithiation of unsymmetrical carbamates and carboxylic amides.

Journal Article↗
PubMed2001

Improvement in asthma symptoms and quality of life in pediatric patients through specialty care delivered via telemedicine.

Asthma is the most common chronic disease affecting children. Studies have demonstrated improvements in asthma control when care is delivered by specialists compared with generalists. We postulated that specialist care delivered by telemedicine would result in similar improvements in control of symptoms and quality of life as compared with face-to-face encounters with specialists. Seventeen patients with persistent asthma, who were cared for by pediatricians in a rural school-based health clinic, were treated over a 6-month period in an asthma specialty program. Patients had face-to-face encounters at week zero, and then telemedicine follow-up visits at weeks 4, 12, and 24. Patients maintained a symptom diary and reliever medication use log. Spirometry and patient and caregiver quality-of-life questionnaires were completed at each visit. Mean number of symptom free days increased 83% from 2.35 days at week 0 to 4.31 days at week 24 (p < 0.05). There was a 44% reduction in mean symptom scores, from 2.32 at week 0 to 1.31 at week 24 (p < 0.001). Nine patients reported having 7 symptom-free days or 7 days of symptom scores of zero in the preceding seven days at week 24 compared with one patient at week 0 (p < 0.002). FEV(1) increased by > or = 12% in seven patients during the study period. Significant improvements in quality of life were reported by patients at week 4 (p < 0.02) and week 24 (p < 0.01), and by caregivers at week 24 (p < 0.002). Specialty asthma care delivered via telemedicine resulted in improvements in asthma symptom control and quality of life similar to improvements reported in face-to-face encounters provided by specialists.

Adolescent↗
PubMed2001

Language and conversational abilities in Williams syndrome: how good is good?

Grammatical performance of individuals with Williams syndrome (WS) has been reported as being unimpaired, despite their comparatively low IQ and poor general cognitive ability. Specific language impairment (SLI) is often seen as the converse of WS, showing poor linguistic ability relative to level of cognitive functioning. Detailed profiles of language functioning in four children with WS and four with SLI are presented which show a much less clear-cut picture than is often portrayed and suggest that children with WS may be less linguistically able than is commonly reported. A comparison of results on standardised tests with performance in real conversations shows that not only the children with SLI but also those with WS have significant linguistic difficulties. This has clear implications for their management by speech and language therapists.

Child↗
PubMed2001

An integrated multi-media package for learning clinical phonetics and linguistics.

Competence in the phonetic and linguistic analysis of normal and disordered spoken language is a basic requirement for all students and practitioners of speech and language therapy. This paper presents a learning package specifically designed for individuals who need to acquire or update practical skills and theoretical knowledge in clinical linguistic analysis. VISUAL-CLIP (VIdeo SUpported Active Learning in Clinical LInguistics and Phonetics) is a student-centred, interactive, multi-media tutorial in clinical linguistics and phonetics, based on digitised video- and audio-taped speech data from a child with a complex communication disorder. Data can be analysed from different perspectives and at different levels of difficulty using separate but inter-linked modules on phonetics, phonology, grammar, semantics and pragmatics. Case history information, formal assessment results, theoretical background and an annotated bibliography are also integrated into the CD-ROM based package.

Communication Disorders↗
PubMed2000

The synthesis, testing and use of 5-fluoro-alpha-D-galactosyl fluoride to trap an intermediate on green coffee bean alpha-galactosidase and identify the catalytic nucleophile.

5-Fluoro-alpha-D-galactopyranosyl fluoride was synthesized and its interaction with the active site of an alpha-galactosidase from green coffee bean (Coffea arabica), a retaining glycosidase, characterized kinetically and structurally. The compound behaves as an apparently tight binding (Ki = 600 nM) competitive inhibitor, achieving this high affinity through reaction as a slow substrate that accumulates a high steady-state concentration of the glycosyl-enzyme intermediate, as evidenced by ESiMS. Proteolysis of the trapped enzyme coupled with HPLC/MS analysis allowed the localization of a labeled peptide that was subsequently sequenced. Comparison of this sequence information to that of other members of the same glycosidase family revealed the active site nucleophile to be Asp145 within the sequence LKYDNCNNN. The importance of this residue to catalysis has been confirmed by mutagenesis studies.

Amino Acid Sequence↗
PubMed2000

Identification of Asp197 as the catalytic nucleophile in the family 38 alpha-mannosidase from bovine kidney lysosomes.

Bovine kidney lysosomal alpha-mannosidase is a family 38 alpha-mannosidase involved in the degradation of glycoproteins. The mechanism-based reagent, 5-fluoro-beta-L-gulosyl fluoride, was used to trap a glycosyl-enzyme intermediate, thereby labelling the catalytic nucleophile of this enzyme. After proteolytic digestion and high performance liquid chromatography/tandem mass spectrometry (MS) analysis, a labelled peptide was localised, and the sequence: HIDPFGHSRE determined by fragmentation tandem MS analysis. Taking into consideration sequence alignments of this region with those of other alpha-mannosidases of the same family, this result strongly suggests that the catalytic nucleophile in this enzyme is Asp197.

Amino Acid Sequence↗
PubMed2000

An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo.

The p53 tumour suppressor protein is down-regulated by the action of Mdm2, which targets p53 for rapid degradation by the ubiquitin-proteasome pathway. The p14ARF protein is also a potent tumour suppressor that acts by binding to Mdm2 and blocking Mdm2-dependent p53 degradation and transcriptional silencing. We have screened a series of overlapping synthetic peptides derived from the p14ARF protein sequence and found that a peptide corresponding to the first 20 amino acids of ARF (Peptide 3) could bind human Mdm2. The binding site for Peptide 3 on Mdm2 was determined by deletion mapping and lies adjacent to the binding site of the anti-Mdm2 antibody 2A10, which on microinjection into cells can activate p53-dependent transactivation of a reporter plasmid. To determine whether Peptide 3 could similarly activate p53, we expressed a fusion of green fluorescent protein and Peptide 3 in MCF7 and U-2 OS cells and were able to demonstrate induction of p53 protein and p53-dependent transcription. Peptide 3 was able to block in vitro ubiquitination of p53 mediated by Mdm2. Small peptides which are sufficient to block degradation of p53 could provide therapeutic agents able to restore p53-dependent cell death pathways in tumours that retain wild-type p53 expression.

Amino Acid Sequence↗
PubMed1999

Safety and efficacy of a continuous infusion, patient controlled anti-emetic pump to facilitate outpatient administration of high-dose chemotherapy.

We evaluated the combination of diphenhydramine, lorazepam, and dexamethasone delivered as a continuous i.v. infusion via an ambulatory infusion pump with patient-activated intermittent dosing (BAD pump) for prevention of acute and delayed nausea/vomiting in patients receiving high-dose chemotherapy (HDC) for peripheral blood progenitor cell (PBPC) mobilization (MOB) or prior to autologous PBPC rescue. The BAD pump was titrated to patient response and tolerance, and continued until the patient could tolerate oral anti-emetics. Forty-four patients utilized the BAD pump during 66 chemotherapy courses, 34 (52%) for MOB and 32 (48%) for HDC with autologous PBPC rescue. The median number of days on the BAD pump during MOB and HDC was 3 (1-6) and 9 (2-19) days, respectively. Complete overall or complete emesis control occurred on 94% of MOB and 89% of HDC treatment days during chemotherapy administration and 72% and 43%, respectively, following chemotherapy administration. Eighty-three percent of MOB and 55% of HDC treatment days were associated with no nausea. While on the BAD pump, no patient experienced severe toxicity or required hospitalization for management of nausea/vomiting. The BAD pump was safe and effective in minimizing nausea and vomiting associated with HDC, and thus, eliminated the need for hospitalization for management of chemotherapy-induced nausea and vomiting.

Adult↗
PubMed1999

Intermittent shedding of thermophilic campylobacters by sheep at pasture.

The rates at which sheep on different types of pasture shed campylobacters in their faeces were measured over 12 months. Overall, shedding of campylobacters at pasture was between a third and a half of the carriage rate (92%) of the intestines of sheep at slaughter. Shedding was highest during saltmarsh grazing, followed by upland fell and farm grazing. The rate of shedding varied at different times of the year, with the highest rates (100%) coinciding with lambing, weaning, and movement onto new pasture. The lowest rates (0%) occurred when sheep were fed on hay and silage. On the farm, low rates occurred during the whole of gestation, both when the sheep were indoors and outdoors. Campylobacter jejuni was the main species isolated and survived for up to 4 d in sheep faeces. Lambs became colonized by Campylobacter within 1-5 d of being born. Ewes, which were not shedding campylobacters prior to lambing, started to shed after lambing, and ewes which were shedding low numbers of Campylobacter before lambing, increased the numbers of bacteria being shed after lambing.

Animal Feed↗
PubMed1999

Clinical and pathologic predictors of survival in patients with thymoma.

OBJECTIVE: To evaluate the Johns Hopkins Hospital experience with 136 thymomas over the past 40 years. This number of patients allowed quantitative estimation of the independent influence of common clinicopathologic risk factors using multivariate analysis. SUMMARY BACKGROUND DATA: Thymomas vary widely in terms of recurrence and influence on overall survival. Several series have indicated the importance of initial tumor invasion, as well as the extent of surgical resection, as predictors of recurrence and survival after thymoma resection. However, findings have been equivocal when other predictors of prognosis were examined. METHODS: The authors evaluated 136 patients seen at the Johns Hopkins Hospital between 1957 and 1997 with a pathologic diagnosis of thymoma. Demographic information, clinical staging data, surgical and adjuvant treatment details, and patient follow-up data were obtained from the patient record and from detailed patient or family interviews. Microscopic sections of all 136 patients were reviewed by two pathologists blinded to the clinical data. All data were analyzed by multivariate Cox regression analysis, which allowed the quantification of the independent predictive value of 12 putative clinicopathologic prognostic indicators. RESULTS: Completeness of follow-up was 99%, 99%, and 98% of eligible patients at 5, 10, and 15 years, respectively. Forty percent of the patients had associated myasthenia gravis and 27% had a secondary primary malignancy. Overall patient survival rates were 71%, 56%, 44%, 38%, and 33% at 5, 10, 15, 20, and 25 years, respectively. Overall, the thymoma-related mortality rate was 14%; the nonthymoma-related mortality rate was 26%. Incomplete resection, preoperative absence of myasthenia gravis, and advanced Lattes/Bernatz pathologic class were found to be independent predictors of poorer overall survival. CONCLUSIONS: These findings support a policy of aggressive, complete surgical resection of all thymomas when feasible. Thymoma behaves as a rather indolent tumor, with most deaths from causes unrelated to thymoma or its direct treatment. Clinicians should have an increased awareness of the possibility of second primary malignancies in patients with thymoma.

Adolescent↗
PubMed1998

Labeling and identification of the postulated acid/base catalyst in the alpha-glucosidase from Saccharomyces cerevisiae using a novel bromoketone C-glycoside.

alpha-Glucosidase from Saccharomyces cerevisiae is a member of a sequence-related family of alpha-glycosidases (family 13) that includes digestive alpha-amylases and commercially important cyclodextrin glucanotransferases. These enzymes catalyze the hydrolysis of alpha-linked oligosaccharides by a two-step mechanism involving a glycosyl-enzyme intermediate. A novel bromoketone C-glycoside inactivator, 1'-bromo-3'-(alpha-D-mannopyranosyl)-2'-propanone, has been synthesized and used to label the putative acid/base catalyst (Glu-276) of yeast alpha-glucosidase. Electrospray ionization mass spectrometry was used to demonstrate stoichiometric labeling of the protein. The labeled residue was identified by comparative liquid chromatographic/mass spectrometric analysis of peptic digests of labeled and unlabeled enzyme samples, which confirmed the unique presence of two labeled peptides of m/z 745 and 694. Subsequent tandem mass spectrometric analysis in the daughter-ion scan mode showed the two peptides to have an overlapping sequence in which Glu-276 was the labeled residue. Together with active-site-directed protection against inactivation with deoxynojirimycin, these results prove that Glu-276 is located within the active site of yeast alpha-glucosidase and, thus, provide further evidence for this residue playing an important role in catalysis.

Affinity Labels↗