89 results on '"S Loughlin"'
Search Results
2. An interdisciplinary approach to volcanic risk reduction under conditions of uncertainty: a case study of Tristan da Cunha
- Author
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A. Hicks, J. Barclay, P. Simmons, and S. Loughlin
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Environmental technology. Sanitary engineering ,TD1-1066 ,Geography. Anthropology. Recreation ,Environmental sciences ,GE1-350 ,Geology ,QE1-996.5 - Abstract
The uncertainty brought about by intermittent volcanic activity is fairly common at volcanoes worldwide. While better knowledge of any one volcano's behavioural characteristics has the potential to reduce this uncertainty, the subsequent reduction of risk from volcanic threats is only realised if that knowledge is pertinent to stakeholders and effectively communicated to inform good decision making. Success requires integration of methods, skills and expertise across disciplinary boundaries. This research project develops and trials a novel interdisciplinary approach to volcanic risk reduction on the remote volcanic island of Tristan da Cunha (South Atlantic). For the first time, volcanological techniques, probabilistic decision support and social scientific methods were integrated in a single study. New data were produced that (1) established no spatio-temporal pattern to recent volcanic activity; (2) quantified the high degree of scientific uncertainty around future eruptive scenarios; (3) analysed the physical vulnerability of the community as a consequence of their geographical isolation and exposure to volcanic hazards; (4) evaluated social and cultural influences on vulnerability and resilience; and (5) evaluated the effectiveness of a scenario planning approach, both as a method for integrating the different strands of the research and as a way of enabling on-island decision makers to take ownership of risk identification and management, and capacity building within their community. The paper provides empirical evidence of the value of an innovative interdisciplinary framework for reducing volcanic risk. It also provides evidence for the strength that comes from integrating social and physical sciences with the development of effective, tailored engagement and communication strategies in volcanic risk reduction.
- Published
- 2014
- Full Text
- View/download PDF
3. Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib
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Kimberley Gilmour, T Mohanadas, Andrew J. Cant, AD Rowan, Mary Slatter, S Loughlin, Al, Shehri, T, Shahnaz Bibi, Angela Grainger, Desa Lilic, F Gothe, Timothy Ronan Leahy, and Sophie Hambleton
- Subjects
0301 basic medicine ,Male ,Ruxolitinib ,Primary Immunodeficiency Diseases ,Immunology ,SUMO protein ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Ubiquitin ,Nitriles ,medicine ,Immunology and Allergy ,Humans ,Chronic mucocutaneous candidiasis ,Child ,Immunodeficiency ,Janus kinase inhibitor ,Janus Kinases ,Mutation ,biology ,business.industry ,Candidiasis, Chronic Mucocutaneous ,Sumoylation ,medicine.disease ,030104 developmental biology ,Pyrimidines ,STAT1 Transcription Factor ,Treatment Outcome ,Gain of Function Mutation ,Cancer research ,biology.protein ,Pyrazoles ,Immunocompetence ,business ,030215 immunology ,medicine.drug - Abstract
Mutations in the coiled-coil and DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and subsequently gain-of-function. The associated clinical phenotype is broad and can include chronic mucocutaneous candidiasis (CMC) and/or combined immunodeficiency (CID). We report a case of CMC/CID in a 10-year-old boy due to a novel mutation in the small ubiquitin molecule (SUMO) consensus site at the C-terminal region of STAT1 leading to gain-of-function by impaired sumoylation. Immunodysregulatory features of disease improved after Janus kinase inhibitor (jakinib) treatment. Functional testing after treatment confirmed reversal of the STAT1 hyper-phosphorylation and downstream transcriptional activity. IL-17 and IL-22 production was, however, not restored with jakinib therapy (ruxolitinib), and the patient remained susceptible to opportunistic infection. In conclusion, a mutation in the SUMO consensus site of STAT1 can lead to gain-of-function that is reversible with jakinib treatment. However, full immunocompetence was not restored, suggesting that this treatment strategy might serve well as a bridge to definitive therapy such as hematopoietic stem cell transplant rather than a long-term treatment option.
- Published
- 2019
4. B2.1 100,000 genomes project at gosh: experience from 111 pilot families
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S Loughlin, Emma Clement, P Beales, Lucy Jenkins, Emma Ashton, Richard H Scott, Maria Bitner-Glindzicz, and Andrew Buckton
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Proband ,medicine.medical_specialty ,Likely benign ,business.industry ,Family medicine ,Medicine ,Genomics ,In patient ,Genetic diagnosis ,business ,Genome ,Likely pathogenic ,Rare disease - Abstract
Background The 100,000 Genomes Project is a national programme to perform whole genome sequencing (WGS) in families with an undiagnosed rare disorder or cancer. Multiple specialties from GOSH have recruited patients to the pilot study. Here we report on the outcome of the first 111 pilot cases. Methodology Total lymphocyte DNA was extracted (Chemagic Star, Chemagen) and exported to Genomics England for WGS (HiSeqX, Illumina). Prioritised variants were discussed and classified by a multidisciplinary team (MDT) of Clinical Scientists, Consultant Clinical Geneticists and the recruiting clinicians. Variants deemed to be ‘pathogenic’ or ‘likely pathogenic’ were flagged for diagnostic confirmation and clinical reporting. Results Genomics England returned results for 111 cases (probands); 95 (86%) were analysed as trios (proband and both parents). Variant interpretation has been completed for 97 cases (87%). Thirty-six percent of cases (40/111) and a total of 76 variants were discussed at an MDT meeting. Fifty-three percent of variants discussed (40/76) were classified as pathogenic or likely pathogenic, 30% (23/76) were classified as variants of unknown significance and 17% (13/76) were classified as benign or likely benign. This equated to a genetic diagnosis in 27/111 cases (25%) of which 5/111 (5%) were felt to be a partial rather than full explanation of the phenotype. Of the 97 cases where primary analysis was complete, 66/97 (68%) had no primary findings. This included cases in which variants of unknown significance have been detected. Conclusion WGS is a useful tool for rare disease diagnosis especially in patients who have undergone a fruitless diagnostic odyssey. Analysis of GOSH pilot cases has enabled us to develop infrastructure locally to support the return of main programme results. One quarter of GOSH pilot patients should expect a genetic diagnosis from the primary analysis. It is unclear whether this will be an accurate reflection of the diagnostic rate achieved in the main programme due to ongoing refinement of the recruitment and analysis pipelines.
- Published
- 2017
5. EP-2094 Machine QA Time Efficiency Savings with IBA Dolphin Detector
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S. Loughlin, A. Reilly, and R. Lally
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Oncology ,Computer science ,business.industry ,Detector ,Time efficiency ,Radiology, Nuclear Medicine and imaging ,Hematology ,business ,Computer hardware - Published
- 2019
6. A holistic approach to overall equipment effectiveness (OEE)
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S. Loughlin
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Engineering ,business.industry ,media_common.quotation_subject ,Computer Science Applications ,Reliability engineering ,Overall equipment effectiveness ,Product (business) ,Performance rate ,Control and Systems Engineering ,Production (economics) ,Quality (business) ,Isolation (database systems) ,Electrical and Electronic Engineering ,business ,media_common - Abstract
The effective operation of individual pieces of production equipment, assembly lines, or whole factories is dependent on three dimensions of performance: The amount of time that it is available to run (availability) 2. The speed of the equipment (performance rate) 3. The quality of the product that it produces (quality rate). Equipment that is operating effectively scores highly on each of the above dimensions. If these metrics are viewed in isolation, they provide a valuable insight into the performance of the equipment, but the compound effect of all three of the dimensions provides surprising results. The compound effect is called the overall equipment effectiveness (OEE) and is obtained by simply multiplying the availability by the performance rate and the quality rate. This paper discusses the evolution of OEE and its future direction.
- Published
- 2003
7. Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM
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S Heath, C M Cale, T Lester, G Monaghan, G Norbury, Kimberley Gilmour, D Walshe, and S Loughlin
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Adult ,Aging ,medicine.medical_specialty ,Adolescent ,CD40 Ligand ,DNA Mutational Analysis ,Immunoglobulins ,medicine.disease_cause ,Pathology and Forensic Medicine ,Hypergammaglobulinemia ,Immunopathology ,medicine ,Humans ,Child ,Cells, Cultured ,X chromosome ,Mutation ,biology ,Patient Selection ,Infant ,Genetic Diseases, X-Linked ,Anatomical pathology ,Original Articles ,Middle Aged ,medicine.disease ,Immunoglobulin M ,Child, Preschool ,Immunology ,biology.protein ,Primary immunodeficiency ,Antibody - Abstract
Background: X linked hyper-IgM (XHIM) is a primary immunodeficiency caused by mutations in the tumour necrosis factor superfamily 5 gene, TNFSF5, also known as the CD40 ligand (CD40L) gene. Patients often present with recurrent infections, and confirmation of a diagnosis of XHIM enables appropriate therapeutic interventions, including replacement immunoglobulin, antibiotics, and bone marrow transplantation. Aim: To review and optimise the institution’s diagnostic strategy for XHIM. Method: Samples from 65 boys were referred to this centre for further investigation of suspected XHIM. The results, which included a flow cytometric whole blood assay for CD40L expression followed by mutation analysis in selected patients, were reviewed. Results: Twenty one patients failed to express CD40L and TNFSF5 mutations were found in 20 of these patients. In contrast, no TNFSF5 mutations were found in 16 patients with weak expression of CD40L. Interestingly, one quarter of patients with confirmed XHIM who had TNFSF5 mutations had low concentrations of IgG, IgA, and IgM. Most of the remaining patients with XHIM had the classic pattern of normal or raised IgM with low concentrations of IgA and IgG. Conclusions: This study demonstrates the usefulness of the whole blood staining method as a rapid screen to select patients for subsequent TNFSF5 mutation analysis, and shows the benefits of a unified protein/genetic diagnostic strategy.
- Published
- 2003
8. Womenʼs Health Services
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Joyce S. Mascari, Jacquelyn S. Loughlin, and Elaine F. Bronner
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medicine.medical_specialty ,Restructuring ,Aid to Families with Dependent Children ,Health services ,Agency (sociology) ,Health care ,medicine ,Humans ,health care economics and organizations ,Academic Medical Centers ,New Jersey ,Medicaid managed care ,Health Priorities ,Medicaid ,business.industry ,Health Policy ,Managed Care Programs ,Continuity of Patient Care ,Hospital Bed Capacity, 500 and over ,United States ,Women's Health Services ,Family medicine ,Organizational Case Studies ,Managed care ,Female ,Business ,Total Quality Management - Abstract
New Jersey health care providers face the need to change dramatically the way health care is delivered as it enters a new era of managed care. This year, more than 24% of New Jersey's total population is enrolled in commercial managed care plans (New Jersey Department of Insurance, 1996). In addition, the state's Medicaid agency took steps to improve the delivery of health services to recipients by initiating implementation activities to transition from the traditional Medicaid program to a managed care model. Eighty-two percent of New Jersey's Aid to Families with Dependent Children (AFDC) and related populations have already been enrolled in managed care. The state plans to expand enrollment in managed care to the remaining 400,000 Medicaid beneficiaries. Communities with high Medicaid populations are challenged with the need to move through the managed care evolution at an accelerated rate.
- Published
- 1997
9. Testosterone, a follicular regulator: key to anovulation
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C. Flood, Qian Ying Zhao, Ray V. Haning, Jacquelyn S. Loughlin, Richard J. Hackett, and Christopher Longcope
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endocrine system ,medicine.medical_specialty ,Estrone ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Dehydroepiandrosterone ,Biochemistry ,chemistry.chemical_compound ,Aromatase ,Endocrinology ,Dehydroepiandrosterone sulfate ,Ovarian Follicle ,Internal medicine ,Follicular phase ,medicine ,Humans ,Testosterone ,Estradiol ,business.industry ,Dehydroepiandrosterone Sulfate ,Chemistry ,Biochemistry (medical) ,Obstetrics and Gynecology ,Dihydrotestosterone ,General Medicine ,Androgen ,Testosterone 5 alpha reductase ,Follicular fluid ,Follicular Fluid ,Estrogen ,Regression Analysis ,Female ,Menotropins ,business ,medicine.drug ,Anovulation - Abstract
To study the interrelationships of steroids within the follicle, combined 6-h infusions of [3H]dehydroepiandrosterone sulfate and [14C] testosterone ([14C]T) were performed in four normal women treated with menotropins who were undergoing medically indicated surgery. The concentrations of tracer and/or nonisotopic dehydroepiandrosterone sulfate, androst-5-ene-3 beta,17 beta-diol sulfate, androst-5-ene-3 beta,17 beta-diol, dehydroepiandrosterone, androstenedione, T, dihydrotestosterone, estrone (E1), and estradiol (E2) were determined in arterial and venous blood and follicular fluid. The log-transformed product/precursor ratio of [3H]dihydrotestosterone/[3H]T in follicular fluid was negatively correlated with the log-transformed follicular concentrations of E1 (P = 0.01) and E2 (P = 0.02), suggesting a reciprocal relationship between 5 alpha-reductase and follicular E1 and E2. E2 and T were positively correlated in follicular fluid (r = 0.84; P = 0.0003), suggesting a stimulatory action of follicular T on aromatase. These findings along with extensive published data suggest that follicular T functions as a follicular regulator, enhancing follicular aromatase activity when adequate amounts of FSH are available. These conclusions have important implications with regard to mechanisms for selecting the dominant follicle and producing atresia in the remaining cohort of follicles, and they describe a final common path in the pathophysiology of anovulation.
- Published
- 1993
10. Patient satisfaction and clinical outcome after injecting gonadotropins with use of a needle-free carbon dioxide injection system for controlled ovarian hyperstimulation for in vitro fertilization
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Peter G. McGovern, Michael M. Cho, Amy Solnica, Cheongeun Oh, Jacquelyn S. Loughlin, and D.H. McCulloh
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medicine.medical_specialty ,Pregnancy Rate ,medicine.drug_class ,medicine.medical_treatment ,Injections, Subcutaneous ,Controlled ovarian hyperstimulation ,Fertilization in Vitro ,law.invention ,Patient satisfaction ,Randomized controlled trial ,Ovulation Induction ,law ,Pregnancy ,medicine ,Humans ,Infusion Pumps ,Needle free ,In vitro fertilisation ,business.industry ,Obstetrics and Gynecology ,Fear ,Carbon Dioxide ,medicine.disease ,Surgery ,Pregnancy rate ,Treatment Outcome ,Reproductive Medicine ,Needles ,Patient Satisfaction ,Female ,Gonadotropin ,business ,Gonadotropins - Abstract
In this prospective, randomized clinical trial, we tested the hypothesis that a needle-free CO 2 injection system (Biojector 2000) would be better tolerated by patients when compared with traditional sharp needles used for gonadotropin injections during stimulation for IVF. As measured by our questionnaire, the needle-free CO 2 injection system was not better tolerated by patients, even though it was equally effective clinically.
- Published
- 2009
11. Metabolic Clearance Rate of Dehydroepiandrosterone Sulfate, Its Metabolism to Testosterone, and Its Intrafollicular Metabolism to Dehydroepiandrosterone, Androstenedione, Testosterone, and Dihydrotestosteronein Vivo*
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Richard J. Hackett, Christopher Longcope, C. Flood, Ray V. Haning, Jacquelyn S. Loughlin, and Neil McCLURE
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Adult ,endocrine system ,medicine.medical_specialty ,Metabolic Clearance Rate ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Radioimmunoassay ,Dehydroepiandrosterone ,Biology ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Dehydroepiandrosterone sulfate ,Internal medicine ,medicine ,Humans ,Testosterone ,Androstenedione ,Ovarian follicle ,Dehydroepiandrosterone Sulfate ,Ovary ,Biochemistry (medical) ,Androgen ,Follicular fluid ,medicine.anatomical_structure ,chemistry ,Dihydrotestosterone ,Female ,medicine.drug - Abstract
At the time of surgery, women were infused with [3H]dehydroepiandrosterone sulfate ([3H]DS)/[14C]testosterone ([14C]T) for 6 h; blood samples were obtained from an artery the ovarian veins, and a peripheral vein; and fluid was obtained from ovarian follicles. Both blood and follicular fluid samples were analyzed for radioactivity as DS, dehydroepiandrosterone (D), androstenedione (delta 4A). T, and dihydrotestosterone (DHT), and the blood was also analyzed for the concentration of nonisotopic DS by RIA. In other subjects the concentrations of D and DS were measured in paired samples of blood and follicular fluid. From these data, values of 13.6 +/- 0.69 L/day four (mean +/- SE; n = 4) for MCRDS, 607 +/- 90 L/day (n = 3) for MCRT, and 0.0190 +/- 0.0089 (n = 3) for [p]DS-T (fraction of plasma DS metabolized to plasma T) were obtained. The ratio of the concentration of the tracer-labeled steroid in the follicular fluid to the concentration in the arterial plasma sample was elevated significantly above 1 for three 3H-labeled and three [14C-labeled metabolites: [3H]D (21-fold; P less than 0.001), [3H]T (81-fold; P less than 0.001), [3H]DHT (19-fold; P less than 0.001), [14C]T (4-fold; P less than 0.025), [14C]DHT (21-fold; P less than 0.01), and [14C]delta 4A (50-fold; P less than 0.001). The estimated concentrations of steroids in follicular fluid derived from DS based on specific activity calculations were as follows: [geometric mean (95% confidence limits; n)]: DS, 5600 (4800-6500 nmol/L; 12); D, 370 (88-1500 nmol/L; 10); delta 4 A, 120 (67-220 nmol/L; 12); T, 130 (39-450 nmol/L; 10); and DHT, 64 (35-120 nmol/L; 8). Comparison of these data to known follicular fluid steroid concentrations shows that DS from the intravascular pool can be used as an ovarian prehormone.
- Published
- 1991
12. Haemochromatosis mutations in North-East Scotland
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M. J. Pippard, A. Terron, JohnC.S. Dean, Z. Miedzybrodzka, Neva E. Haites, D. Baty, S. Loughlin, K. Kelly, and Mike Greaves
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Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,education.field_of_study ,Mutation ,business.industry ,Population ,nutritional and metabolic diseases ,Hematology ,medicine.disease ,medicine.disease_cause ,Compound heterozygosity ,Hereditary hemochromatosis ,medicine ,Genetic predisposition ,Predictive testing ,education ,business ,Allele frequency ,Hemochromatosis - Abstract
The HFE gene and its mutations C282Y and H63D cause hereditary haemochromatosis (HH). Among 54 affected individuals from North-East Scotland, 91% were homozygous for C282Y and 5.5% were compound heterozygotes for C282Y and H63D. The general population allele frequencies were high (8% and 15.7% for C282Y and H63D respectively). Although it is likely that HH is under diagnosed, these figures suggest that disease expression is variable, and many of those with the genetic predisposition HH will never develop the clinical consequences of iron overload. This has implications for diagnosis and predictive testing.
- Published
- 1999
13. Rapid protein-based assays for the diagnosis of T-B+ severe combined immunodeficiency
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K C, Gilmour, T, Cranston, S, Loughlin, J, Gwyther, T, Lester, T, Espanol, M, Hernandez, G, Savoldi, E G, Davies, M, Abinun, C, Kinnon, A, Jones, and H B, Gaspar
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B-Lymphocytes ,X Chromosome ,Immunoglobulin gamma-Chains ,T-Lymphocytes ,DNA Mutational Analysis ,Immunoblotting ,Janus Kinase 3 ,Protein-Tyrosine Kinases ,Flow Cytometry ,Killer Cells, Natural ,Humans ,Interleukin-2 ,Severe Combined Immunodeficiency ,Phosphorylation - Abstract
The severe combined immunodeficiencies (SCID) are a heterogeneous group of conditions arising from a variety of molecular defects. The X-linked form of SCID (X-SCID) is caused by defects in the common gamma chain (gammac), and is characterized by a T-B+NK- immunophenotype. This lymphocyte profile is seen in an autosomal recessive form of SCID caused by mutations in the JAK3 molecule. Thus, X-SCID and JAK3-deficient SCID are clinically and immunologically indistinguishable. Knowledge of the precise molecular defect is essential for antenatal diagnosis, carrier testing and for treatment using somatic gene therapy. To identify the molecular defect in children presenting with a T-B+NK- form of SCID, we have developed rapid assays based on flow cytometric analysis of gammac, immunoblotting for JAK3 and gammac, and detection of interleukin-2 (IL-2)-induced tyrosine phosphorylation of JAK3. Sixteen T-B+NK- SCID patients from 15 families were examined. Nine had no detectable gammac, four had abnormal gammac expression and no IL-2-induced JAK3 tyrosine phosphorylation, and one had normal gammac expression but no IL-2-induced JAK3 tyrosine phosphorylation, although JAK3 was present. All these patients had mutations identified in their gammac gene. Two patients exhibited normal gammac expression, but JAK3 was not detected by immunoblotting and these patients were confirmed as having JAK3 gene mutations. Thus, these protein-based assays have led to rapid molecular diagnoses in T-B+ SCID that have subsequently been confirmed by genetic analysis.
- Published
- 2001
14. Haemochromatosis mutations in North-East Scotland
- Author
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Z, Miedzybrodzka, S, Loughlin, D, Baty, A, Terron, K, Kelly, J, Dean, M, Greaves, M, Pippard, and N, Haites
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Heterozygote ,Gene Frequency ,Scotland ,Homozygote ,Mutation ,Humans ,Female ,Hemochromatosis - Abstract
The HFE gene and its mutations C282Y and H63D cause hereditary haemochromatosis (HH). Among 54 affected individuals from North-East Scotland, 91% were homozygous for C282Y and 5.5% were compound heterozygotes for C282Y and H63D. The general population allele frequencies were high (8% and 15.7% for C282Y and H63D respectively). Although it is likely that HH is under diagnosed, these figures suggest that disease expression is variable, and many of those with the genetic predisposition HH will never develop the clinical consequences of iron overload. This has implications for diagnosis and predictive testing.
- Published
- 1999
15. Critical ovarian hyperstimulation syndrome in a coasted in-vitro fertilization patient
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Peter G. McGovern, Nanette Santoro, D Tortoriello, Jose M. Colon, and J S Loughlin
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Agonist ,Adult ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Ovarian hyperstimulation syndrome ,Physiology ,Fertilization in Vitro ,Biology ,Chorionic Gonadotropin ,Ovarian Hyperstimulation Syndrome ,Human fertilization ,Internal medicine ,medicine ,Humans ,Chorionic Gonadotropin, beta Subunit, Human ,In vitro fertilisation ,Estradiol ,Rehabilitation ,Obstetrics and Gynecology ,medicine.disease ,Embryo Transfer ,female genital diseases and pregnancy complications ,Embryo transfer ,Endocrinology ,Reproductive Medicine ,Estrogen ,Female ,Gonadotropin ,Follicle Stimulating Hormone ,Leuprolide ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
We report an instance of critical ovarian hyperstimulation syndrome in a highly responsive in-vitro fertilization patient despite the preventive measure of a 4 day 'coast' interval during which no gonadotrophins were administered while gonadotrophin-releasing hormone agonist therapy continued until serum oestradiol concentrations fell below 3000 pg/ml.
- Published
- 1998
16. Applying Artificial Intelligence in Physical Chemistry
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F.J. Smith, M. Sullivan, S. Loughlin, and J. Collis
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Pilot system ,Sequence ,Artificial Intelligence System ,Knowledge base ,business.industry ,Simple (abstract algebra) ,Computer science ,Code (cryptography) ,Physical chemistry ,business - Abstract
Databases of scientific data, such as tables of vapour pressures of gases or of intermolecular forces, can be used for the storage and retrieval of data in Physical Chemistry. Knowledge bases can be used to store not only scientific data but also the laws relating to physical sciences. However, if such a knowledge base is coupled with an Artificial Intelligence system, together they are able to solve quantitative problems directly by linking together code, formulas and data in the correct sequence to obtain solutions. Such a system has been proposed by Diercksen for Quantitative Chemistry. A pilot system, called QPS, has been developed at the Queen's University of Belfast and the system has demonstrated it's capability to solve many simple problems in the physical sciences.
- Published
- 1997
17. Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor
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J L, Abbruzzese, T, Madden, S M, Sugarman, A L, Ellis, S, Loughlin, K R, Hess, R A, Newman, L A, Zwelling, and M N, Raber
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Adult ,Diarrhea ,Male ,Neutropenia ,Vomiting ,Antineoplastic Agents ,Skin Diseases ,Neoplasms ,Granulocyte Colony-Stimulating Factor ,Humans ,Topoisomerase II Inhibitors ,Infusions, Intravenous ,Aged ,Headache ,Nausea ,DNA, Neoplasm ,Middle Aged ,Thrombocytopenia ,DNA Topoisomerases, Type II ,Treatment Outcome ,DNA Topoisomerases, Type I ,Area Under Curve ,Leukocytes, Mononuclear ,Drug Therapy, Combination ,Female ,Topoisomerase I Inhibitors ,Topotecan - Abstract
Topotecan, a semisynthetic water-soluble analogue of camptothecin, inhibits human topoisomerase I (topo I). We performed a Phase I clinical and plasma pharmacological study of topotecan administered by 24-h continuous infusion without and with granulocyte colony-stimulating factor (G-CSF). We also measured topo I-DNA complexes in peripheral blood mononuclear cells (PBMCs) in an attempt to correlate formation of topo I-DNA complexes in patients treated with topotecan with toxicity and/or response. One hundred four courses of topotecan at doses of 2.5-15.0 mg/m2 were administered to 44 patients with solid tumors. The maximum tolerated dose without G-CSF was 10.0 mg/m2; granulocytopenia was the dose-limiting toxic effect. The maximum tolerated dose could not be increased with G-CSF because of severe thrombocytopenia. Plasma pharmacology was obtained in 11 patients treated at 12.5 mg/m2 and 15.0 mg/m2. The topotecan lactone end-infusion plasma levels correlated strongly with the area under the curve. Lactone elimination was biexponential with a mean t1/2alpha of 28 min and a t1/2beta of 3.8 h at 12.5 mg/m2. Topo I-DNA complexes were measured before and after treatment in PBMCs from seven patients. Pretopotecan topo I-DNA complexes were available on two additional patients treated at 15 mg/m2. The mean increase in topo I-DNA complexes at the end of the topotecan infusion was 1.25 times the pretreatment value. There was a statistically significant relationship (P = 0.02) between lack of disease progression and the level of topo I-DNA complexes measured in PBMCs before therapy. For Phase II studies of minimally treated adults with solid tumors, the recommended topotecan starting dose administered by 24-h continuous infusion is 10 mg/m2 without G-CSF.
- Published
- 1996
18. Diminished function of the somatotropic axis in older reproductive-aged women
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Nanette Santoro, Tovaghgol Adel, J R Brown, G B Wilshire, and J S Loughlin
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Adult ,medicine.medical_specialty ,Aging ,Somatotropic cell ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Clinical Biochemistry ,Pulsatile flow ,Fertility ,Biology ,Biochemistry ,Models, Biological ,Menstruation ,Endocrinology ,Internal medicine ,medicine ,Humans ,Insulin-Like Growth Factor I ,Menstrual cycle ,Menstrual Cycle ,media_common ,Estradiol ,Biochemistry (medical) ,Phlebotomy ,Luteinizing Hormone ,Middle Aged ,Circadian Rhythm ,Follicular Phase ,Growth Hormone ,Female ,Follicle Stimulating Hormone ,Body mass index ,Blood sampling - Abstract
Circulating GH and insulin-like growth factor-I (IGF-I) levels in adults generally fall with age. Studies in aging women have rarely controlled for menstrual cycle stage or status or body mass index. We hypothesized that GH and IGF-I levels in reproductive-aged women fall with age despite the stimulatory effects of endogenous estradiol (E2). Eight older reproductive-aged women (aged 42-46 yr) with regular menses, of normal weight, and in good health were compared to a group of eight young control subjects (aged 19-34 yr). Daytime frequent blood sampling was performed in the early follicular phase of the menstrual cycle to characterize pulsatile GH and LH concentrations. Pooled samples were also analyzed for IGF-I, E2, progesterone, and FSH levels. Older reproductive-aged women had lower 12-h integrated daytime GH concentrations (mean +/- SE, 171 +/- 35 vs. 427 +/- 130 micrograms min/L; P = 0.036) than younger controls and a strong trend for lower IGF-I levels (22.7 +/- 2.1 vs. 31.3 +/- 3.5 nmol/L; P = 0.055) than younger controls despite having higher circulating E2 on the day of sampling (368 +/- 51 vs. 167 +/- 20 pmol/L; P = 0.002). We conclude that older reproductive-aged women have lower daytime GH concentrations than younger controls despite having higher E2 levels on the day of sampling and overall normal gonadal hormone parameters.
- Published
- 1995
19. Plasma dehydroepiandrosterone sulfate serves as a prehormone for 48% of follicular fluid testosterone during treatment with menotropins
- Author
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C. Longcope, C. A. Flood, Richard J. Hackett, Qian Ying Zhao, Ray V. Haning, and Jacquelyn S. Loughlin
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Adult ,medicine.medical_specialty ,Menotropins ,Chemical Phenomena ,medicine.drug_class ,Metabolic Clearance Rate ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Dehydroepiandrosterone ,Estrone ,Biology ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Dehydroepiandrosterone sulfate ,Internal medicine ,Follicular phase ,medicine ,Humans ,Testosterone ,Androstenedione ,Dehydroepiandrosterone Sulfate ,Biochemistry (medical) ,Osmolar Concentration ,Androgen ,Follicular fluid ,Hormones ,Follicular Fluid ,Chemistry ,chemistry ,Female ,Steroids - Abstract
Evidence has suggested that dehydroepiandrosterone sulfate (DS) is a prehormone for ovarian steroidogenesis. To study this hypothesis, combined 6-h infusions of [3H]dehydroepiandrosterone sulfate and [14C]testosterone ([14C]T) were performed in four normal women treated with menotropins who were undergoing medically indicated surgery, and the data were compared to those from nine normal women. The concentrations of tracer and nonisotopic DS, androst-5-ene-3 beta,17 beta-diol sulfate (delta 5diolS), androst-5-ene-3 beta,17 beta-diol (delta 5diol), dehydroepiandrosterone (D), androstenedione (delta 4A), and T were determined in arterial and venous blood and in follicular fluid. From these data, the concentrations and fractions of steroids in the follicular fluid that were derived from DS were calculated from the specific activity of intravascular DS and the concentrations of follicular fluid tracer steroids and their specific activities. The fractions of T (0.48), delta 5diol (0.31), delta 5diolS (0.42), and D (0.25) in follicular fluid arising from circulating DS were similar and were not significantly different from that of follicular DS arising from circulating DS (0.32). However, the fraction of follicular fluid delta 4A (0.041) was significantly less (P < 0.01), and the fractions of intrafollicular estrone and estradiol arising from DS were both less than 0.04. The mean MCR of DS in the women treated with menotropins of 22.0 +/- 3.5 L/day (mean +/- SE) was significantly higher than the normal control value. These findings elucidate an important mechanism of adrenal/ovarian interaction at the level of steroidogenesis; circulating DS serves as a prehormone for the production of intrafollicular delta 5diolS, delta 5 diol, D, and T.
- Published
- 1993
20. Patient satisfaction and clinical outcome after injecting gonadotropins (either bravelle® and/or menopur®) using the biojector® 2000 for controlled ovarian stimulation for in-vitro fertilization
- Author
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Peter G. McGovern, Cheongeun Oh, Jacquelyn S. Loughlin, D.H. McCulloh, M. Cho, and A. Solnica
- Subjects
Oncology ,medicine.medical_specialty ,Patient satisfaction ,In vitro fertilisation ,Reproductive Medicine ,business.industry ,Internal medicine ,medicine.medical_treatment ,Obstetrics and Gynecology ,Medicine ,Stimulation ,business ,Outcome (game theory) - Published
- 2008
21. [Untitled]
- Author
-
Jack Moore, Judith H. Veis, K.M. Ratanavanich, and S. Loughlin
- Subjects
medicine.medical_specialty ,Darbepoetin alfa ,Nephrology ,Anemia ,business.industry ,Internal medicine ,medicine ,medicine.disease ,business ,Post transplant ,medicine.drug - Published
- 2007
22. Bilateral compartment syndrome after a long gynecologicoperation in the lithotomy position
- Author
-
Christopher J. Morin, Lisa M. Adler, Ray V. Haning, and Jacquelyn S. Loughlin
- Subjects
Adult ,medicine.medical_specialty ,Time Factors ,Surgical complication ,business.industry ,Anastomosis, Surgical ,Posture ,Obstetrics and Gynecology ,Compartment Syndromes ,Lithotomy position ,Surgery ,Postoperative Complications ,medicine ,Tubal anastomosis ,Humans ,Female ,In patient ,Compartment (pharmacokinetics) ,business ,Complication ,Fallopian Tubes - Abstract
Summary Compartment syndrome occurred after a tubal anastomosis in a prolonged lithotomy position. Thissyndrome carries the risk of permanent neuromuscular and kidney damage. The pathophysiologic features of the syndrome are reviewed. Specific guidelines for the prevention and management of this syndrome in patients undergoing gynecologic procedures are presented
- Published
- 1990
23. Effects of Chronic Luteinizing Hormone-Releasing Hormone Administration on Gonadotropin Dynamics of Adult Male Rats
- Author
-
Paul M. Rosenblum, Ron E. Clement, Thomas M. Badger, and Jacquelyn S. Loughlin
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Time Factors ,Adult male ,medicine.drug_class ,Testicular volume ,General Biochemistry, Genetics and Molecular Biology ,Gonadotropin-Releasing Hormone ,Andrology ,Basal (phylogenetics) ,Internal medicine ,medicine ,Animals ,Castration ,business.industry ,Luteinizing Hormone ,Serum concentration ,Rats ,Endocrinology ,Pituitary Gland ,Follicle Stimulating Hormone ,Gonadotropin ,Once daily ,Luteinizing hormone ,business ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
The studies reported herein were conducted to determine the sequential effects of chronic luteinizing hormone-releasing hormone (LHRH) or D-Trp6-Pro9-NEt-LHRH (LHRHa) administration on LH, FSH, and T dynamics. Adult male rats (n = 6/group) were injected subcutaneously with 1 μg of LHRH or LHRHa once daily at 8:00 am for 1 through 7 days. The rats were decapitated at various times postinjection and their blood, pituitaries, and testes collected. When measured 24 hr after each injection, significant (P ≤ 0.01) decreases were observed in concentrations of serum T and pituitary LH and FSH as well as testicular volume; whereas basal serum concentrations of LH and FSH were significantly (P ≤ 0.01) elevated from Days 3 through 7 in both LHRH and LHRHa-treated rats. LH was secreted in a large single peak 1 hr after each LHRH injection, increasing 54-fold above preinjection concentrations on Day 1 and lessening to a 34-fold increase on Days 3 through 7. The magnitude of the FSH response was not altered wit...
- Published
- 1980
24. LH responses to LHRH in perifused pituitary cell culture: sex differences in the rat
- Author
-
Jacquelyn S. Loughlin, P. G. Naddaff, and Thomas M. Badger
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Pituitary gland ,Time Factors ,Physiology ,Endocrinology, Diabetes and Metabolism ,Radioimmunoassay ,In Vitro Techniques ,Biology ,Peptide hormone ,Gonadotropin-Releasing Hormone ,Sex Factors ,Estrus ,Anterior pituitary ,Pituitary Gland, Anterior ,Pregnancy ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Cells, Cultured ,Estrous cycle ,Rats, Inbred Strains ,Luteinizing Hormone ,In vitro ,Rats ,medicine.anatomical_structure ,Endocrinology ,Cell culture ,Female ,Luteinizing hormone ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
The present experiments were designed to study male and female luteinizing hormone (LH) secretory patterns following pulsatile or continuous LH-releasing hormone (LHRH) administration using a perifused dispersed rat anterior pituitary cell culture system. In male cells, consistent LH responses were elicited by hourly LHRH pulses (30 pmol), whereas in the female cells (proestrus or diestrus I), a statistically significant (P less than or equal to 0.01) decrease in the LH secretion occurred with successive LHRH pulses. Proestrous cells secreted significantly (P less than or equal to 0.01) more LH than diestrous cells during the first 24 h but not after 48 h in culture. When exposed to a 6-h continuous infusion of LHRH (10 nM), male cells released LH in a single phase and female cells secreted LH in a biphasic pattern. These data suggest that significant sex differences exist in the rat LH secretory pattern elicited by LHRH in vitro.
- Published
- 1984
25. Puberty without Gonadotropins
- Author
-
John F. Crigler, Hans H. Bode, John D. Crawford, D. Beardsworth, William F. Crowley, Robert E. Scully, Joan Mansfield, Thomas M. Badger, Jacquelyn S. Loughlin, Margaret E. Wierman, D. C. Kushner, and William H. Hoffman
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,media_common.quotation_subject ,Puberty, Precocious ,Gonadotropin-Releasing Hormone ,Internal medicine ,medicine ,Humans ,Sexual maturity ,Precocious puberty ,Testosterone ,Sexual Maturation ,Girl ,Family history ,Child ,media_common ,Estradiol ,business.industry ,Obstetrics and Gynecology ,Leydig Cells ,General Medicine ,Luteinizing Hormone ,medicine.disease ,Endocrinology ,Gonadarche ,Female ,Follicle Stimulating Hormone ,Age of onset ,Gonadotropin ,business ,Neuroscience ,Mechanism (sociology) ,Gonadotropins ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.
- Published
- 1985
26. The Luteinizing Hormone-Releasing Hormone (LHRH) Desensitized Rat Pituitary: Luteinizing Hormone Responsiveness to LHRH in Vitro*
- Author
-
Jacquelyn S. Loughlin, Patricia G. Naddaff, and Thomas M. Badger
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,In Vitro Techniques ,Gonadotropin-Releasing Hormone ,Endocrinology ,Anterior pituitary ,Desensitization (telecommunications) ,Pituitary Gland, Anterior ,Internal medicine ,Infusion Procedure ,medicine ,Animals ,Chemistry ,Rats, Inbred Strains ,Luteinizing Hormone ,In vitro ,Rats ,Rat Pituitary ,Kinetics ,medicine.anatomical_structure ,Cell culture ,Luteinizing hormone ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Desensitization of the anterior pituitary has been observed after continuous infusion of LHRH or repetitive administration of LHRH at concentrations or frequencies exceeding physiological limits. We have studied the LH responsiveness of the LHRH-desensitized male rat anterior pituitary in a continuously perifused dispersed cell culture system. Infusion of 10 nM LHRH initially stimulated a 4- to 5-fold increase in LH secretion which became maximal at 6-9 min and which declined gradually to a preinfusion baseline over 6 h. Since the cells did not maintain peak levels of LH secretion in the presence of continuous exposure to LHRH, they were considered to be desensitized. These desensitized cells were studied to determine their LH responsiveness to LHRH. Cells desensitized by a 6-h LHRH infusion responded to four hourly LHRH boluses of 200 pm by releasing four statistically equal LH pulses. The response of desensitized cells to 200 pm LHRH was similar to that of 10 pm LHRH of nondesensitized cells. Furthermore, desensitized anterior pituitary cells responded to LHRH in a linear dose-dependent manner. The dose response of desensitized cells ranged from 75-500 pm, whereas for nondesensitized cells a dose response was observed from 1-75 pm. In addition, anterior pituitary cells desensitized with continuous LHRH infusion can respond to a second LHRH infusion of a greater concentration and become desensitized for a second time. These data suggest that the capacity of the pituitary gland to store and secrete LH while desensitized is similar to that of the nondesensitized anterior pituitary. The major difference between cells desensitized with LHRH and nondesensitized cells is that desensitized cells require a larger dose of LHRH to elicit a given LH response.
- Published
- 1983
27. What does a home health agency really want from suppliers
- Author
-
S, Loughlin
- Subjects
Patient Education as Topic ,Industry ,Self-Help Devices ,Home Care Services - Published
- 1982
28. Winning business at a home health agency
- Author
-
S, Loughlin
- Subjects
Equipment and Supplies ,Industry ,Home Care Services - Published
- 1981
29. Perifused pituitary cultures: a model for LHRH regulation of LH secretion
- Author
-
Thomas M. Badger, Jacquelyn S. Loughlin, and William F. Crowley
- Subjects
Male ,medicine.medical_specialty ,Lh secretion ,Physiology ,Endocrinology, Diabetes and Metabolism ,Biology ,Luteinizing Hormone ,Models, Biological ,Cell system ,Rats ,Gonadotropin-Releasing Hormone ,Perfusion ,Kinetics ,medicine.anatomical_structure ,Endocrinology ,Anterior pituitary ,Pituitary Gland, Anterior ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Cells, Cultured ,Hormone - Abstract
In this paper, a dispersed anterior pituitary cell system that is continuously perifused and suitable for the study of luteinizing hormone-releasing hormone (LHRH)-anterior pituitary physiology is described. Adult male Sprague-Dawley rats were decapitated and the anterior pituitaries removed, dispersed using collagenase, mixed with Biogel P2, and packed into 0.9-cm columns using sterile technique. All experiments were conducted using Krebs-Ringer-bicarbonate-glucose buffer, and a stable base line was achieved. A constant dose of LHRH (50 ng) administered several times at 1-h intervals stimulated the same quantal release of LH. LH secretion is linear in response to LHRH over the range of 1-50 nM and to rat hypothalamic extracts over a range of 1/32 to 1/2 hypothalamic equivalents, regardless of whether the extracts are administered in ascending or descending order. These results indicate that perifusion of dispersed pituitary cells provides a useful model for the study of LHRH physiology, combining the advantages of the long-term viability of pituitary cells in culture with the dynamic nature afforded by perifusion.
- Published
- 1981
30. Preferred supplier to the preferred provider?
- Author
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S, Loughlin
- Subjects
Insurance, Health ,Commerce ,Equipment and Supplies, Hospital ,United States - Published
- 1983
31. Distinguishing between your home health agency customers
- Author
-
S, Loughlin
- Subjects
Equipment and Supplies ,Ownership ,Classification ,Home Care Services - Published
- 1982
32. A conservative approach to the management of uterine leiomyoma: Pituitary desensitization by a luteinizing hormone-releasing hormone analogue
- Author
-
William F. Crowley, Deborah A. Hall, Wylie Vale, Marco Filicori, Jean Rivier, and Jacquelyn S. Loughlin
- Subjects
Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Gonadotropin-Releasing Hormone ,Internal medicine ,medicine ,Humans ,Ultrasonics ,Menorrhagia ,Triptorelin Pamoate ,Uterine leiomyoma ,Hysterectomy ,Leiomyoma ,business.industry ,Estrogen secretion ,Obstetrics and Gynecology ,Metrorrhagia ,medicine.disease ,Uterine myomectomy ,Endocrinology ,Hematocrit ,Menometrorrhagia ,Uterine Neoplasms ,Female ,medicine.symptom ,Luteinizing hormone ,business - Abstract
Uterine leiomyoma is the most common solid tumor of the female genital tract and may cause heavy menometrorrhagia and infertility. Uterine myomectomy is not always feasible and total hysterectomy may be necessaryin young women who have not yet completed their families. Herein we report the regression of a presumed uterine leiomyoma induced by long-term treatment with a long-acting luteinizing hormone-releasing hormone (LHRH) agonist, which was administered to suppress ovarian estrogen secretion. sent from the patient. Metrorrhagia subsided within 48 hours from the initiation of treatment, at the time of the rapidly rising estradiol levels that characterize the agonist phase of LHRH, administration (Fig. 2). Another episode of uterine bleeding occurred 13 days after the beginning of therapy, coincident with suppression of serum estradiol to prepubertal levels. During the first 2 months of therapy the patient reported only minor episodes of vagina1 bleeding, usually lasting no longer than 1 day. No further bleeding occurred after the eighth week of therapy, and the hemoglobin level rose steadily from a pretherapy value of 7.4 gm/dl to 12.8 gmldl within 60 days. Plasma estradiol levels became undetectable (~20 pg/mI) during the third week (Fig. 2) and the patient noted the onset of hot flashes shortly thereafter. At 8 weeks of treatment the leiomyoma had decreased to 5 by 5 by 4 cm according to ultrasound examination and a further reduction to 4 by 4 by 4 cm had occurred by the twelfth week (Fig. 1, B). At 15 weeks the size of the mass was noted to be unchanged at 4by4by4cm.
- Published
- 1983
33. Long-Term Treatment of Central Precocious Puberty with a Long-Acting Analogue of Luteinizing Hormone-Releasing Hormone. Effects on Somatic Growth and Skeletal Maturation
- Author
-
Hans H. Bode, M. J. Mansfield, D. C. Kushner, John F. Crigler, John D. Crawford, Wylie Vale, Jean Rivier, William F. Crowley, Jacquelyn S. Loughlin, and D. Beardsworth
- Subjects
Agonist ,endocrine system ,medicine.medical_specialty ,Long term treatment ,medicine.drug_class ,Somatic cell ,Central precocious puberty ,Puberty, Precocious ,Growth ,Peptide hormone ,Gonadotropic cell ,Gonadotropin-Releasing Hormone ,Age Determination by Skeleton ,Internal medicine ,Humans ,Precocious puberty ,Medicine ,Sexual Maturation ,Child ,Bone Development ,Triptorelin Pamoate ,business.industry ,Obstetrics and Gynecology ,Bone age ,General Medicine ,Luteinizing Hormone ,medicine.disease ,Long-Term Care ,Body Height ,Long acting ,Endocrinology ,Skeletal maturation ,Child, Preschool ,Bone maturation ,Female ,Follicle Stimulating Hormone ,Gonadotropin ,business ,Luteinizing hormone ,Hormone - Abstract
The gonadotropin-releasing hormone-like agonist D-Trp6-Pro9-NEt-LHRH (LHRHa) has been shown to induce a reversible short-term suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. Since accelerated statural growth and bone maturation are clinical features of precocity not well controlled by conventional therapies, we examined the effects of prolonged LHRHa therapy for 18 consecutive months on growth and skeletal maturation in nine girls with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin pulsations and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (+/- S.E.M.) of 9.35 +/- 0.64 cm per year during the 19 months before treatment to 4.58 +/- 0.60 cm per year during treatment (P less than 0.001). Bone age advanced a mean of 9.4 +/- 2.3 months during treatment. These changes resulted in a mean increase of 3.3 cm in predicted height (P less than 0.01). Complete suppression of the pituitary-gonadal axis can be maintained by LHRHa therapy, resulting in slowing of excessively rapid growth and skeletal maturation and in increased predicted adult height in girls with precocious puberty.
- Published
- 1984
34. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.
- Author
-
Calame DG, Wong JH, Panda P, Nguyen DT, Leong NCP, Sangermano R, Patankar SG, Abdel-Hamid M, AlAbdi L, Safwat S, Flannery KP, Dardas Z, Fatih JM, Murali C, Kannan V, Lotze TE, Herman I, Ammouri F, Rezich B, Efthymiou S, Alavi S, Murphy D, Firoozfar Z, Nasab ME, Bahreini A, Ghasemi M, Haridy NA, Goldouzi HR, Eghbal F, Karimiani EG, Srinivasan VM, Gowda VK, Du H, Jhangiani SN, Coban-Akdemir Z, Marafi D, Rodan L, Isikay S, Rosenfeld JA, Ramanathan S, Staton M, Kerby C Oberg, Clark RD, Wenman C, Loughlin S, Saad R, Ashraf T, Male A, Tadros S, Boostani R, Abdel-Salam GMH, Zaki M, Abdalla E, Manzini MC, Pehlivan D, Posey JE, Gibbs RA, Houlden H, Alkuraya FS, Bujakowska K, Maroofian R, Lupski JR, and Nguyen LN
- Abstract
FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis., Competing Interests: Potential Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. Other authors have no potential conflicts to disclose.
- Published
- 2024
- Full Text
- View/download PDF
35. Mapping the Transcriptome Underpinning Acute Corticosteroid Action within the Cortical Collecting Duct.
- Author
-
Loughlin S, Costello HM, Roe AJ, Buckley C, Wilson SM, Bailey MA, and Mansley MK
- Subjects
- Adrenal Cortex Hormones, Transcriptome, Kidney Tubules, Collecting
- Published
- 2023
- Full Text
- View/download PDF
36. Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.
- Author
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Polubothu S, Zecchin D, Al-Olabi L, Lionarons DA, Harland M, Horswell S, Thomas AC, Hunt L, Wlodarchak N, Aguilera P, Brand S, Bryant D, Carrera C, Chen H, Elgar G, Harwood CA, Howell M, Larue L, Loughlin S, MacDonald J, Malvehy J, Barberan SM, da Silva VM, Molina M, Morrogh D, Moulding D, Nsengimana J, Pittman A, Puig-Butillé JA, Parmar K, Sebire NJ, Scherer S, Stadnik P, Stanier P, Tell G, Waelchli R, Zarrei M, Puig S, Bataille V, Xing Y, Healy E, Moore GE, Di WL, Newton-Bishop J, Downward J, and Kinsler VA
- Subjects
- Humans, Immunohistochemistry, Phenotype, Melanoma genetics, Nevus, Skin Neoplasms genetics
- Abstract
Purpose: Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach., Methods: Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays., Results: We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70., Conclusion: This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
37. Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib.
- Author
-
Al Shehri T, Gilmour K, Gothe F, Loughlin S, Bibi S, Rowan AD, Grainger A, Mohanadas T, Cant AJ, Slatter MA, Hambleton S, Lilic D, and Leahy TR
- Subjects
- Candidiasis, Chronic Mucocutaneous diagnosis, Candidiasis, Chronic Mucocutaneous drug therapy, Child, Gain of Function Mutation, Humans, Janus Kinases antagonists & inhibitors, Male, Nitriles, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases drug therapy, Pyrazoles pharmacology, Pyrimidines, Sumoylation genetics, Treatment Outcome, Candidiasis, Chronic Mucocutaneous genetics, Primary Immunodeficiency Diseases genetics, Pyrazoles therapeutic use, STAT1 Transcription Factor genetics
- Abstract
Mutations in the coiled-coil and DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and subsequently gain-of-function. The associated clinical phenotype is broad and can include chronic mucocutaneous candidiasis (CMC) and/or combined immunodeficiency (CID). We report a case of CMC/CID in a 10-year-old boy due to a novel mutation in the small ubiquitin molecule (SUMO) consensus site at the C-terminal region of STAT1 leading to gain-of-function by impaired sumoylation. Immunodysregulatory features of disease improved after Janus kinase inhibitor (jakinib) treatment. Functional testing after treatment confirmed reversal of the STAT1 hyper-phosphorylation and downstream transcriptional activity. IL-17 and IL-22 production was, however, not restored with jakinib therapy (ruxolitinib), and the patient remained susceptible to opportunistic infection. In conclusion, a mutation in the SUMO consensus site of STAT1 can lead to gain-of-function that is reversible with jakinib treatment. However, full immunocompetence was not restored, suggesting that this treatment strategy might serve well as a bridge to definitive therapy such as hematopoietic stem cell transplant rather than a long-term treatment option.
- Published
- 2019
- Full Text
- View/download PDF
38. Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons.
- Author
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Bolze A, Boisson B, Bosch B, Antipenko A, Bouaziz M, Sackstein P, Chaker-Margot M, Barlogis V, Briggs T, Colino E, Elmore AC, Fischer A, Genel F, Hewlett A, Jedidi M, Kelecic J, Krüger R, Ku CL, Kumararatne D, Lefevre-Utile A, Loughlin S, Mahlaoui N, Markus S, Garcia JM, Nizon M, Oleastro M, Pac M, Picard C, Pollard AJ, Rodriguez-Gallego C, Thomas C, Von Bernuth H, Worth A, Meyts I, Risolino M, Selleri L, Puel A, Klinge S, Abel L, and Casanova JL
- Subjects
- 5' Untranslated Regions, Female, Founder Effect, Heterozygote, Humans, Immunologic Deficiency Syndromes metabolism, Male, Primary Immunodeficiency Diseases, Receptors, Laminin biosynthesis, Ribosomal Proteins biosynthesis, Spleen metabolism, Exons, Immunologic Deficiency Syndromes genetics, Mutation, Penetrance, Protein Biosynthesis genetics, RNA Splicing genetics, Receptors, Laminin genetics, Ribosomal Proteins genetics, Spleen abnormalities
- Abstract
Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA , encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance., Competing Interests: Conflict of interest statement: A.B. works at Helix.
- Published
- 2018
- Full Text
- View/download PDF
39. A Roundtable Discussion: AAMI Turns 50: Sharing Memories and Looking into the Future of Healthcare Technology.
- Author
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Loughlin S, Boisier P, Cogdill CP, Finke K, Jensen R, Logan M, Prust J, Schade S, and Yelton S
- Published
- 2017
- Full Text
- View/download PDF
40. New President and CEO: With Curiosity and Determination, Jensen Takes Reins of AAMI.
- Author
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Bauer A and Loughlin S
- Subjects
- Humans, Biomedical Engineering organization & administration, Biomedical Technology organization & administration
- Published
- 2016
- Full Text
- View/download PDF
41. A Roundtable Discussion: Exploring Major Trends in Dialysis Practice and Technology.
- Author
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Loughlin S, Concepcion D, Gonzalez G, Maltais JA, Neuland C, Pulliam J, Treu D, and Williams RJ
- Subjects
- Dialysis trends, Equipment Design, Equipment Failure Analysis, Humans, Kidney Function Tests trends, Therapy, Computer-Assisted trends, Biofeedback, Psychology instrumentation, Dialysis instrumentation, Kidney Function Tests instrumentation, Kidneys, Artificial trends, Renal Insufficiency therapy, Therapy, Computer-Assisted instrumentation
- Published
- 2016
- Full Text
- View/download PDF
42. A Roundtable Discussion: Combating the Complex Challenge of Healthcare-Associated Infections.
- Author
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Loughlin S, Alfa M, Arduino M, Gaffey A, Kumar A, Scott P, Swenson D, Tomac D, and Waldowski L
- Subjects
- Anti-Infective Agents pharmacology, Drug Resistance, Microbial, Humans, Quality Assurance, Health Care, Cross Infection prevention & control, Infection Control methods
- Published
- 2016
- Full Text
- View/download PDF
43. A Roundtable Discussion: The Qualities of Great Managers.
- Author
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Loughlin S, Dysko J, Mickletz JF, and Whalen S
- Subjects
- Motivation, Personality, United States, Biomedical Engineering organization & administration, Biomedical Technology organization & administration, Health Facility Administration methods, Health Facility Administrators organization & administration, Interprofessional Relations, Leadership
- Published
- 2016
- Full Text
- View/download PDF
44. Dose-Volume Histogram Analysis of Stereotactic Body Radiotherapy Treatment of Pancreatic Cancer: A Focus on Duodenal Dose Constraints.
- Author
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Goldsmith C, Price P, Cross T, Loughlin S, Cowley I, and Plowman N
- Subjects
- Dose Fractionation, Radiation, Dose-Response Relationship, Radiation, Humans, Radiosurgery statistics & numerical data, Radiotherapy Dosage, Duodenum radiation effects, Pancreatic Neoplasms radiotherapy, Radiation Tolerance, Radiosurgery methods
- Abstract
Pancreatic carcinoma is an aggressive disease and radiotherapy treatment delivery to the primary tumor is constrained by the anatomical close location of the duodenum, stomach, and small bowel. Duodenal dose tolerance for radiosurgery in 2-5 fractions has been largely unknown. The literature was surveyed for quantitative models of risk in 1-5 fractions and we analyzed our own patient population of 44 patients with unresectable pancreatic tumors who received 3 or 5 fractions of stereotactic body radiotherapy (SBRT) between March 2009 and March 2013. A logistic model was constructed in the dose-volume histogram (DVH) Evaluator software for the duodenal D50%, D30cc, D5cc, D1cc, and maximum point dose D0.035cc. Dose tolerance limits from the literature were overlaid onto the clinical duodenal data in the form of a DVH Risk Map, with risk levels of the published limits estimated from the model of clinical data. In 3 fractions, Kopek 2010 found a statistically significant difference in D1cc of patients with no common terminology criteria for adverse events (CTCAE) v3 grade 2 or higher duodenal complications (mean D1cc = 25.3Gy) as compared with patients with grade 2 or higher toxicity (mean D1cc = 37.4Gy). From the logistic model of our duodenal data in 3 fractions, D1cc = 25.3Gy had 4.7% risk of grade 3-4 hemorrhage or stricture and D1cc = 37.4Gy had 20% risk. The 10% risk level was D1cc = 31.4Gy and we were able to keep duodenum dose for all our patients later this level., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
45. A Roundtable Discussion: Forging a Path toward Seamless Health IT.
- Author
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Loughlin S, Castro G, Classen D, Lewelling J, Lowry L, Marchlik M, McCoy M, and Segal M
- Subjects
- Humans, Patient-Centered Care, Biomedical Technology, Medical Informatics
- Published
- 2016
- Full Text
- View/download PDF
46. In Contracts with Device Vendors, Mayo Clinic Emphasizes Security.
- Author
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Loughlin S
- Subjects
- Computer Security, United States, Confidentiality legislation & jurisprudence, Contracts legislation & jurisprudence, Equipment Safety standards, Equipment and Supplies standards, Health Care Sector legislation & jurisprudence, Purchasing, Hospital legislation & jurisprudence
- Published
- 2016
- Full Text
- View/download PDF
47. A Roundtable Discussion: Enhancing Supportability of Healthcare Technology.
- Author
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Loughlin S, Capuano M, Huerta J, Maddock K, and Mestek M
- Subjects
- United States, Biomedical Engineering organization & administration, Biomedical Technology organization & administration, Equipment Safety, Maintenance and Engineering, Hospital organization & administration, Patient Safety
- Published
- 2016
- Full Text
- View/download PDF
48. A Roundtable Discussion: safeguarding information and resources against emerging cybersecurity threats.
- Author
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Loughlin S, Fu K, Gee T, Gieras I, Hoyme K, Rajagopalan SR, Ransford B, Vasserman E, and Wirth A
- Subjects
- Equipment and Supplies, Humans, Medical Records Systems, Computerized, Software Design, Computer Security, Delivery of Health Care organization & administration, Hospitals
- Published
- 2014
- Full Text
- View/download PDF
49. Frontlines: a powerful subject.
- Author
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Loughlin S
- Published
- 2014
- Full Text
- View/download PDF
50. Frontlines: the thrill of a new problem.
- Author
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Loughlin S
- Subjects
- Computer-Aided Design trends, Equipment and Supplies, Forecasting, Imaging, Three-Dimensional trends, Manufactured Materials
- Published
- 2014
- Full Text
- View/download PDF
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