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1.
Ann R Coll Surg Engl ; 103(1): 29-34, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32829647

ABSTRACT

INTRODUCTION: Reoperative parathyroidectomy for persistent and recurrent primary hyperparathyroidism is dependent on radiology. This study aimed to compare outcomes in reoperative parathyroidectomy at a single centre using a combination of traditional and newer imaging studies. MATERIALS AND METHODS: Retrospective case note review of all reoperative parathyroidectomies for persistent and recurrent primary hyperparathyroidism over five years (June 2014 to June 2019; group A). Imaging modalities used and their positive predictive value, complications and cure rates were compared with a published dataset spanning the preceding nine years (group B). RESULTS: From over 2000 parathyroidectomies, 147 were reoperations (101 in group A and 46 in group B). Age and sex ratios were similar (56 vs 62 years; 77% vs 72% female). Ultrasound use remains high and shows better positive predictive value (76% vs 57 %). 99mTc-sestamibi use has declined (79% vs 91%) but the positive predictive value has improved (74% vs 53%). 4DCT use has almost doubled (61% vs 37%) with better positive predictive value (88% vs 75%). 18F-fluorocholine positron emission tomography-computed tomography and ultrasound-guided fine-needle aspiration for parathyroid hormone are novel modalities only available for group A. Both carried a positive predictive value of 100%. Venous sampling with or without angiography use has decreased (35% vs 39%) but maintains a high positive predictive value (86% vs 91%). Cure rates were similar (96% vs 100%). Group A had 5% permanent hypoparathyroidism, 1% permanent vocal cord palsy and 1% haematoma requiring reoperation. No complications for group B. CONCLUSION: Optimal imaging is key to good cure rates in reoperative parathyroidectomy. High-quality, non-interventional imaging techniques have produced a shift in the preoperative algorithm without compromising outcomes.


Subject(s)
Hyperparathyroidism, Primary/surgery , Parathyroid Glands/diagnostic imaging , Parathyroidectomy/statistics & numerical data , Reoperation/statistics & numerical data , Secondary Prevention/methods , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy, Fine-Needle/statistics & numerical data , Female , Four-Dimensional Computed Tomography/statistics & numerical data , Humans , Hyperparathyroidism, Primary/blood , Hyperparathyroidism, Primary/diagnosis , Hyperparathyroidism, Primary/pathology , Male , Middle Aged , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Glands/surgery , Parathyroid Hormone/analysis , Parathyroid Hormone/metabolism , Positron Emission Tomography Computed Tomography/methods , Positron Emission Tomography Computed Tomography/statistics & numerical data , Radionuclide Imaging , Recurrence , Retrospective Studies , Secondary Prevention/statistics & numerical data , Technetium Tc 99m Sestamibi/administration & dosage , Treatment Outcome , Ultrasonography/statistics & numerical data , Young Adult
2.
BJS Open ; 3(6): 743-749, 2019 12.
Article in English | MEDLINE | ID: mdl-31832580

ABSTRACT

Background: Primary hyperparathyroidism (PHPT), caused by an ectopic mediastinal parathyroid adenoma, is uncommon. In the past, when the adenoma was not accessible from the neck, median sternotomy was advocated for safe and successful parathyroidectomy. Video-assisted thoracoscopic surgical (VATS) parathyroidectomy represents a modern alternative approach to this problem. Methods: Information on patients undergoing VATS was obtained from a specific database, including clinical presentation, biochemistry, preoperative imaging, surgical approach and patient outcomes. A comprehensive literature review was undertaken to draw comparisons with other publications. Results: Over a 2-year period, nine patients underwent VATS parathyroidectomy for sporadic PHPT. Five patients had persistent PHPT following previous unsuccessful parathyroidectomy via cervicotomy, and four had had no previous parathyroid surgery. The median duration of surgery was 90 (range 60-160) min. Eight patients were cured biochemically, with no major complications. One patient required conversion to a median sternotomy for removal of a thymoma that had resulted in false-positive preoperative imaging. Conclusion: With appropriate preoperative imaging, multidisciplinary input and expertise, VATS parathyroidectomy is an effective, safe and well tolerated approach to ectopic mediastinal parathyroid adenoma.


Antecedentes: El hiperparatiroidismo primario (primary hyperparathyroidism, pHPT) causado por un adenoma paratiroideo ectópico mediastínico es infrecuente. Hace años, cuando un adenoma no era accesible por vía cervical se propugnaba una esternotomía media para efectuar una paratiroidectomía segura y con éxito. La paratiroidectomía por cirugía toracoscópica asistida por video (video­assisted thoracoscopic surgical, VATS) es una alternativa moderna para el abordaje de esta patología. Métodos: La información de los pacientes tratados con VATS se obtuvo de una base de datos específica, incluyendo presentación clínica, bioquímica, radiología preoperatoria, abordaje quirúrgico y resultados de los pacientes. Se efectuó una revisión extensa de la literatura para efectuar comparaciones con otras publicaciones. Resultados: Durante un periodo de 2 años, 9 pacientes fueron tratados mediante paratiroidectomía por VATS debido a un pHPT esporádico, de los cuales 5 presentaban pHPT persistente después del fracaso de una paratiroidectomía por cervicotomía, mientras que los 4 restantes no habían sido operados previamente de cirugía paratiroidea. El tiempo medio operatorio fue de 101 minutos (rango 60­160). Ocho pacientes se curaron bioquímicamente, sin ninguna complicación mayor. Un paciente precisó conversión a una esternotomía media para extirpar un timoma que había sido un falso positivo en la radiología preoperatoria. Conclusión: La paratiroidectomía por VATS es una intervención efectiva, segura y bien tolerada para la extirpación de un adenoma ectópico mediastínico, siempre y cuando se disponga de radiología preoperatoria adecuada, equipo multidisciplinar y experiencia.


Subject(s)
Adenoma/surgery , Choristoma/surgery , Hyperparathyroidism, Primary/surgery , Mediastinal Neoplasms/surgery , Parathyroid Glands , Parathyroidectomy/methods , Thoracic Surgery, Video-Assisted/methods , Adenoma/complications , Adult , Choristoma/complications , Conversion to Open Surgery/statistics & numerical data , Female , Humans , Hyperparathyroidism, Primary/etiology , Male , Mediastinal Neoplasms/complications , Mediastinum/surgery , Middle Aged , Operative Time , Parathyroidectomy/adverse effects , Prospective Studies , Sternotomy/statistics & numerical data , Thoracic Surgery, Video-Assisted/adverse effects , Treatment Outcome
4.
Clin Pharmacol Ther ; 100(6): 685-698, 2016 12.
Article in English | MEDLINE | ID: mdl-27626610

ABSTRACT

The current system of biomedical innovation is unable to keep pace with scientific advancements. We propose to address this gap by reengineering innovation processes to accelerate reliable delivery of products that address unmet medical needs. Adaptive biomedical innovation (ABI) provides an integrative, strategic approach for process innovation. Although the term "ABI" is new, it encompasses fragmented "tools" that have been developed across the global pharmaceutical industry, and could accelerate the evolution of the system through more coordinated application. ABI involves bringing stakeholders together to set shared objectives, foster trust, structure decision-making, and manage expectations through rapid-cycle feedback loops that maximize product knowledge and reduce uncertainty in a continuous, adaptive, and sustainable learning healthcare system. Adaptive decision-making, a core element of ABI, provides a framework for structuring decision-making designed to manage two types of uncertainty - the maturity of scientific and clinical knowledge, and the behaviors of other critical stakeholders.


Subject(s)
Biomedical Research/organization & administration , Decision Making , Delivery of Health Care/organization & administration , Diffusion of Innovation , Drug Industry/organization & administration , Feedback , Health Services Needs and Demand , Humans , Uncertainty
5.
Food Chem Toxicol ; 65: 269-79, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24374094

ABSTRACT

Consumer products are a primary source of chemical exposures, yet little structured information is available on the chemical ingredients of these products and the concentrations at which ingredients are present. To address this data gap, we created a database of chemicals in consumer products using product Material Safety Data Sheets (MSDSs) publicly provided by a large retailer. The resulting database represents 1797 unique chemicals mapped to 8921 consumer products and a hierarchy of 353 consumer product "use categories" within a total of 15 top-level categories. We examine the utility of this database and discuss ways in which it will support (i) exposure screening and prioritization, (ii) generic or framework formulations for several indoor/consumer product exposure modeling initiatives, (iii) candidate chemical selection for monitoring near field exposure from proximal sources, and (iv) as activity tracers or ubiquitous exposure sources using "chemical space" map analyses. Chemicals present at high concentrations and across multiple consumer products and use categories that hold high exposure potential are identified. Our database is publicly available to serve regulators, retailers, manufacturers, and the public for predictive screening of chemicals in new and existing consumer products on the basis of exposure and risk.


Subject(s)
Consumer Product Safety , Database Management Systems , Environmental Exposure
6.
IEEE Trans Vis Comput Graph ; 18(12): 2467-76, 2012 Dec.
Article in English | MEDLINE | ID: mdl-26357155

ABSTRACT

The performance of massively parallel applications is often heavily impacted by the cost of communication among compute nodes. However, determining how to best use the network is a formidable task, made challenging by the ever increasing size and complexity of modern supercomputers. This paper applies visualization techniques to aid parallel application developers in understanding the network activity by enabling a detailed exploration of the flow of packets through the hardware interconnect. In order to visualize this large and complex data, we employ two linked views of the hardware network. The first is a 2D view, that represents the network structure as one of several simplified planar projections. This view is designed to allow a user to easily identify trends and patterns in the network traffic. The second is a 3D view that augments the 2D view by preserving the physical network topology and providing a context that is familiar to the application developers. Using the massively parallel multi-physics code pF3D as a case study, we demonstrate that our tool provides valuable insight that we use to explain and optimize pF3D's performance on an IBM Blue Gene/P system.

7.
Neurology ; 76(7): 615-21, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21321335

ABSTRACT

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset behavioral diagnosis in which children often fail to meet age norms in development of motor control, particularly timed repetitive and sequential movements, motor overflow, and balance. The neural substrate of this motor delay may include mechanisms of synaptic inhibition in or adjacent to the motor cortex. The primary objective of this study was to determine whether transcranial magnetic stimulation (TMS)-evoked measures, particularly short interval cortical inhibition (SICI), in motor cortex correlate with the presence and severity of ADHD in childhood as well as with commonly observed delays in motor control. METHODS: In this case-control study, behavioral ratings, motor skills, and motor cortex physiology were evaluated in 49 children with ADHD (mean age 10.6 years, 30 boys) and 49 typically developing children (mean age 10.5 years, 30 boys), all right-handed, aged 8-12 years. Motor skills were evaluated with the Physical and Neurological Examination for Subtle Signs (PANESS) and the Motor Assessment Battery for Children version 2. SICI and other physiologic measures were obtained using TMS in the left motor cortex. RESULTS: In children with ADHD, mean SICI was reduced by 40% (p < 0.0001) and less SICI correlated with higher ADHD severity (r = -0.52; p = 0.002). Mean PANESS motor development scores were 59% worse in children with ADHD (p < 0.0001). Worse PANESS scores correlated modestly with less SICI (r = -.30; p = 0.01). CONCLUSION: Reduced TMS-evoked SICI correlates with ADHD diagnosis and symptom severity and also reflects motor skill development in children.


Subject(s)
Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/pathology , Developmental Disabilities/complications , Motor Cortex/physiopathology , Movement Disorders/etiology , Neural Inhibition/physiology , Case-Control Studies , Child , Electromyography/methods , Evoked Potentials, Motor/physiology , Female , Humans , Logistic Models , Male , Motor Activity/physiology , Psychiatric Status Rating Scales , Statistics, Nonparametric
8.
Neurology ; 71(1): 14-20, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18495953

ABSTRACT

BACKGROUND: Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. METHODS: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. RESULTS: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. CONCLUSIONS: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.


Subject(s)
Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Hereditary Sensory and Motor Neuropathy , Peripheral Nerves/physiopathology , Adult , Age of Onset , Aged , Aged, 80 and over , Chromosome Disorders/diagnosis , Chromosome Disorders/genetics , Chromosome Disorders/physiopathology , DNA Mutational Analysis , Electrodiagnosis/standards , Female , Genes, Dominant/genetics , Genetic Testing , Genotype , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Inheritance Patterns/genetics , Male , Middle Aged , Neural Conduction/genetics , Pedigree , Peripheral Nerves/pathology , Sex Factors
9.
J Chemother ; 17(3): 339-42, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16038530

ABSTRACT

Capecitabine can interact with warfarin, resulting in altered coagulation parameters and bleeding. Four cases have been reported. We describe a fifth case with life-threatening interaction between these two drugs. A 67-year-old female with metastatic breast cancer developed hemorrhagic blisters, purpura and ecchymoses. She had been well controlled on long-term warfarin (5 mg/day). Capecitabine was initiated 4.5 weeks prior to the bleeding episode. Laboratory work-up revealed an international normalized ratio of 8.56, partial prothrombin time of 61 seconds and prothrombin time of 5.2%. The coagulation parameters gradually normalized within 4 days following vitamin K administration and discontinuation of capecitabine and warfarin. Careful monitoring of coagulation parameters and proper adjustment of the warfarin dose are required in patients taking warfarin and capecitabine concomitantly.


Subject(s)
Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Deoxycytidine/analogs & derivatives , Warfarin/adverse effects , Warfarin/therapeutic use , Aged , Anticoagulants/administration & dosage , Breast Neoplasms/drug therapy , Capecitabine , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Drug Interactions , Female , Fluorouracil/analogs & derivatives , Hemorrhage/chemically induced , Humans , Warfarin/administration & dosage
10.
Neurology ; 62(6): 957-62, 2004 Mar 23.
Article in English | MEDLINE | ID: mdl-15037699

ABSTRACT

OBJECTIVE: To determine whether hepatitis C (HCV) contributes to CNS dysfunction among HIV-infected individuals. METHODS: Using a cross-sectional design, the neuropsychiatric profile of individuals with advanced HIV coinfected with hepatitis C (HIV+/HCV+) was compared to similarly advanced HIV patients without HCV coinfection (HIV+/HCV-). Participants were derived from the Manhattan HIV Brain Bank and underwent neurocognitive testing and semistructured psychiatric interviews. Evidence of HCV infection was determined by serology performed prior to study entry. Hepatic function was determined by serum chemistries (bilirubin, creatinine, and international normalized ratio) at the time of the cognitive assessments. RESULTS: Coinfected (HIV+/HCV+) individuals were significantly more likely to have had past opiate or cocaine or stimulant dependence. HIV+/HCV+ participants also had significantly greater rates of past substance-induced major depression. There were no significant differences in rates of primary mental disorders. Forty-two percent of both the HIV+/HCV+ and HIV+/HCV- participants met criteria for current major depression. There was a trend for HIV+/HCV+ patients to perform worse neurocognitively. On tests of executive functioning, HIV+/HCV+ individuals exhibited a greater rate of impairment and had significantly more perseveration. Differences in cognitive functioning were associated with serology but did not correlate with indices of liver disease severity. The HCV+ patients were also more likely to be diagnosed with HIV-associated dementia. CONCLUSIONS: There appears to be a neuropsychiatric impact of HCV that is detectable even among an advanced HIV cohort.


Subject(s)
HIV Infections/epidemiology , Hepatitis C/epidemiology , Mental Disorders/diagnosis , Mental Disorders/epidemiology , Adult , Antiretroviral Therapy, Highly Active , Chronic Disease , Cognition Disorders/diagnosis , Cognition Disorders/epidemiology , Cohort Studies , Comorbidity , Cross-Sectional Studies , Female , HIV Infections/drug therapy , Hepatitis C/diagnosis , Humans , Liver Diseases/diagnosis , Liver Diseases/epidemiology , Male , Middle Aged , Neuropsychological Tests , New York City/epidemiology , Prevalence , Substance-Related Disorders/diagnosis , Substance-Related Disorders/epidemiology
11.
Aliment Pharmacol Ther ; 17(11): 1355-64, 2003 Jun 01.
Article in English | MEDLINE | ID: mdl-12786629

ABSTRACT

BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Colitis, Ulcerative/drug therapy , Fibroblast Growth Factors/administration & dosage , Gastrointestinal Agents/administration & dosage , Adult , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Female , Fibroblast Growth Factor 10 , Humans , Infusions, Intravenous , Male , Middle Aged , Treatment Outcome
12.
Gastroenterology ; 119(6): 1461-72, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11113067

ABSTRACT

BACKGROUND & AIMS: Interleukin (IL)-10 is a cytokine with potent anti-inflammatory properties. We investigated the safety and efficacy of different doses of human recombinant (rhu)IL-10 in patients with Crohn's disease (CD). METHODS: A prospective, multicenter, double-blind, placebo-controlled study was conducted in 329 therapy-refractory patients with CD. Clinical improvement was defined by a reduction of the Crohn's Disease Activity Index (CDAI) by 100 points or more and clinical remission by a decrease of the CDAI to <150 points. At selected centers, patients underwent ileocolonoscopies and activation of the nuclear factor-kappa B (NF-kappa B) system was assessed in biopsy specimens. RESULTS: Subcutaneous treatment with rhuIL-10 over 28 days induced a fully reversible, dose-dependent decrease in hemoglobin and thrombocyte counts but no clinically significant side effects. No differences in the induction of remission were observed between rhuIL-10 groups (1 microg, 18% [9.6-29.2]; 4 microg, 20% [11.3-32.2]; 8 microg, 20% [11.1-31.8]; 20 microg, 28% [18-40.7]; and placebo, 18% [9.6-29.6]). Clinical improvement was observed in 46% (33.7-59) in the 8-microg/kg rhuIL-10 group in comparison with 27% (17-39.6) in patients taking placebo. Responders to rhuIL-10 showed inhibition of NF-kappaB p65 activation in contrast to nonresponders. CONCLUSIONS: Up to 8 microg/kg of rhuIL-10 was well tolerated. A tendency toward clinical improvement but not remission was observed in the 8-microg/kg dose group. Further studies should delineate which subgroups of patients with CD benefit from rhuIL-10 therapy.


Subject(s)
Crohn Disease/drug therapy , Interleukin-10/administration & dosage , Adult , Chronic Disease , Crohn Disease/blood , Crohn Disease/pathology , Crohn Disease/physiopathology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Resistance , Endoscopy, Digestive System , Female , Humans , I-kappa B Proteins/physiology , Interleukin-10/adverse effects , Interleukin-10/therapeutic use , Male , Patient Dropouts , Prospective Studies , Quality of Life , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Remission Induction , Retreatment , Safety , Severity of Illness Index , Steroids/therapeutic use , Treatment Outcome
13.
Exp Neurol ; 163(2): 311-23, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10833305

ABSTRACT

Calretinin (CR) is a calcium-binding protein purported to have neuroprotective properties. This study was designed to characterize the types of neurons containing CR in two different primary cultures and to determine which, if any, CR-immunoreactive (CR-ir) neurons are resistant to excitotoxic insults. Calretinin-containing neurons in cortical primary cultures derived from E14 rat embryos were not resistant to either kainic acid or a brief calcium overload induced by the calcium ionophore A23187. Equal proportions of CR-ir and GABAergic cortical neurons were lost after a 24-h exposure to 100 or 500 microM kainic acid. A 3 microM, 3-h exposure to A23187 induced equivalent amounts of cell loss in both the total cell and CR-ir cortical neuron culture populations. Cortical cultures grown for 6-7 days were more vulnerable than 12- to 13-day-old cultures to short-term, low-concentration treatments of A23187. Older cultures, however, were more severely affected when examined 24 h after a 3-h exposure to A23187. Calretinin-immunoreactive neurons derived from the diencephalon were relatively more resistant than cortical neurons to kainic acid at 6-7 days in vitro. In cortical or diencephalic cultures, CR was rarely coexpressed with GABA or calbindin D-28k. No vasoactive intestinal peptide, substance P, or parvalbumin was detected in CR-ir neurons in either culture system. We suggest that the presence of CR alone is not sufficient to spare neurons from a toxic calcium overload. Calretinin may still buffer calcium at low concentrations or be a component in a calcium-based signal transduction system.


Subject(s)
Calcium/metabolism , Neurons/metabolism , S100 Calcium Binding Protein G/metabolism , Animals , Calbindin 2 , Calcimycin/pharmacology , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Diencephalon/drug effects , Diencephalon/metabolism , Embryo, Mammalian , Excitatory Amino Acid Agonists/pharmacology , Ionophores/pharmacology , Kainic Acid/pharmacology , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Receptors, AMPA/drug effects , Receptors, AMPA/metabolism , S100 Calcium Binding Protein G/drug effects
14.
Am J Gastroenterol ; 94(10): 2905-8, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10520842

ABSTRACT

OBJECTIVE: Investigators have assessed the utility of antispasmodic agents in colonoscopy, with conflicting results. The aim of this study is to determine the effects of premedication with hyoscyamine, an anticholinergic antispasmodic, on outcomes in colonoscopy. METHODS: A total of 165 patients undergoing elective colonoscopy were randomized in a double blinded fashion to one of three arms: intravenous hyoscyamine (0.25 mg), oral hyoscyamine (0.25 mg), or placebo, administered 20-40 min before colonoscopy. Primary outcome measures included insertion time to cecum, patient's assessment of pain, and physician assessment of spasm. Secondary outcome measures included amount of analgesic medications used, total procedure time, amount and type of pathology visualized, and physician assessment of patient's pain. RESULTS: Bivariate analysis showed no difference between the three groups in insertion time (13.8 min, 14.8 min, and 13.8 min for placebo, intravenous hyoscyamine, and oral hyocyamine, respectively), analgesic medication necessary, or any other primary or secondary outcome variable. Multivariate analysis controlling for potential confounders also failed to demonstrate any differences between the groups. Women had higher procedure duration and analgesic requirement, and reported more pain than did men. CONCLUSIONS: This randomized, double blinded, placebo-controlled trial did not demonstrate efficacy of either intravenous or oral hyoscyamine as a premedication for colonoscopy.


Subject(s)
Atropine/administration & dosage , Cholinergic Antagonists/administration & dosage , Colonoscopy , Parasympatholytics/administration & dosage , Administration, Oral , Colonoscopy/adverse effects , Double-Blind Method , Female , Humans , Injections, Intravenous , Male , Middle Aged , Pain Measurement
15.
Gastroenterology ; 117(3): 527-35, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10464128

ABSTRACT

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of

Subject(s)
Azathioprine/administration & dosage , Crohn Disease/drug therapy , Immunosuppressive Agents/administration & dosage , Administration, Oral , Adult , Azathioprine/therapeutic use , Crohn Disease/blood , Dose-Response Relationship, Drug , Double-Blind Method , Erythrocytes , Female , Glucocorticoids/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Infusions, Intravenous , Leukocyte Count , Male , Methyltransferases/blood , Middle Aged , Prednisone/therapeutic use , Remission Induction , Thioguanine/blood
16.
J Neuropathol Exp Neurol ; 58(6): 637-43, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10374754

ABSTRACT

Recent studies suggest that the cognitive impairment associated with normal aging is due to neuronal dysfunction rather than to loss of neurons or synapses. To characterize this dysfunction, molecular indices of neuronal function were quantified in autopsy samples of cerebral cortex. During normal aging, the most dramatic decline was found in levels of synaptic proteins involved in structural plasticity (remodeling) of axons and dendrites. Alzheimer disease, the most common cause of dementia in the elderly, was associated with an additional 81% decrease in levels of drebrin, a protein regulating postsynaptic plasticity. Disturbed mechanisms of plasticity may contribute to cognitive dysfunction during aging and in Alzheimer disease.


Subject(s)
Aging/metabolism , Alzheimer Disease/metabolism , Nerve Tissue Proteins/metabolism , Neuronal Plasticity/physiology , Synapses/physiology , Aged , Aged, 80 and over , Humans , Immunoblotting , Immunohistochemistry
17.
Exp Dermatol ; 7(5): 273-80, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9832315

ABSTRACT

Mutations of the X-linked genes Tabby (Ta) in mice and EDA in humans result in developmental and functional abnormalities, primarily in the skin and hair follicles. Although both genes are believed to encode membrane-associated proteins, it has been suggested that, in the mouse, the mutation is linked to a deficiency of epidermal growth factor (EGF). This study investigated relationships between the skin abnormalities of Ta mice and the EGF signal pathway. The distribution of endogenous EGF in tissues of Ta/Y and +/Y animals was examined and, because of its reported morphogenetic actions and ability to overcome receptor signalling defects in vivo, the effects of exogenous EGF on the hair follicle population were determined. EGF levels were similar in a number of tissues of Ta/Y and +/Y mice, but amounts in Ta/Y submaxillary glands were reduced, probably due to a smaller gland size. Exogenous EGF inhibited hair follicle development and decreased follicle density in both genotypes. It was concluded from comparisons of the distributions of EGF and its effects in skin with those in mice bearing mutations in the EGF signal pathway that the normal phenotype results from interactions between EGF and the Ta peptide in skin.


Subject(s)
Epidermal Growth Factor/metabolism , Membrane Proteins/genetics , Mutation/physiology , Skin Physiological Phenomena , Animals , Ectodysplasins , Epidermal Growth Factor/pharmacology , Fetal Tissue Transplantation , Hair/drug effects , Hair Follicle/drug effects , Kidney/metabolism , Kidney/pathology , Male , Membrane Proteins/physiology , Mice/genetics , Mice, Nude , Phenotype , Skin/embryology , Skin/pathology , Submandibular Gland/metabolism , Submandibular Gland/pathology
18.
Neuroreport ; 9(13): 2989-93, 1998 Sep 14.
Article in English | MEDLINE | ID: mdl-9804303

ABSTRACT

Fenfluramine is an amphetamine analogue which has been widely used in the treatment of obesity. In rodents, non-human primates, and humans, fenfluramine is associated with some indices of neurotoxicity, as well as pulmonary hypertension and cardiac valve pathology. In the present study, d-fenfluramine was found to be cytotoxic to the serotonin (5-HT) transporter (5-HTT) expressing human placental choriocarcinoma cells. d-Fenfluramine caused DNA fragmentation and apoptosis. Apoptosis was not observed after the 5-HTT had been blocked by fluoxetine, indicating that intact 5-HTT function is required for d-fenfluramine to induce programmed cell death. These observations in a human cell line may reflect a possible mechanism associated with the risks of fenfluramine administration in several species, including humans.


Subject(s)
Apoptosis/drug effects , Appetite Depressants/toxicity , Fenfluramine/toxicity , Membrane Transport Proteins , Serotonin/metabolism , Biological Transport/drug effects , Carrier Proteins/metabolism , Cell Nucleus/drug effects , Cell Size/drug effects , Choriocarcinoma , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , Female , Fenfluramine/antagonists & inhibitors , Fluoxetine/pharmacology , Humans , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins , Serotonin Agents/toxicity , Serotonin Plasma Membrane Transport Proteins , Time Factors , Tumor Cells, Cultured
19.
Int J Dev Neurosci ; 16(2): 135-45, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9762586

ABSTRACT

A calretinin enriched cell culture system which comprised approximately 40% of the total neuronal population of the E14 rat embryo was established from the region of the thalamic eminence (TE), and the effects of several neurotrophins on the neurite growth of calretinin-immunoreactive (CR-IR) neurons was investigated. A 4-day treatment of BDNF significantly increased the ratio of CR-IR to microtubule-associated protein 2-immunoreactive neurons at concentrations between 50 and 250 ng/ml. IGF-I at 100 ng/ml and TGF-alpha at 250 ng/ml also increased this ratio. None of the neurotrophins examined increased the number of primary neurites. BDNF did, however, increase the number of secondary neurites. BDNF-treated primary and secondary neurites were also significantly longer than neurites from neurons in control cultures. IGF-I elicited an increase in primary neurite length, but did not affect either number or length of secondary neurites. TGF-alpha had no effect on either number or length of the primary and secondary neurites. These results indicate that the maturation and development of CR-IR neurites is specifically affected by BDNF. It is suggested that BDNF increases the CR concentration above the threshold of detection by immunohistochemistry in cells and stimulates the sprouting of secondary CR-IR neurites.


Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Nerve Tissue Proteins/physiology , Neurites/physiology , S100 Calcium Binding Protein G/physiology , Animals , Brain-Derived Neurotrophic Factor/metabolism , Calbindin 2 , Cell Count , Cells, Cultured , Immunohistochemistry , Microtubule-Associated Proteins/metabolism , Nerve Growth Factors/metabolism , Neurites/ultrastructure , Rats , Rats, Sprague-Dawley , Stimulation, Chemical , Thalamus/cytology , Thalamus/embryology , Thalamus/metabolism
20.
Anim Reprod Sci ; 51(2): 155-66, 1998 Apr 30.
Article in English | MEDLINE | ID: mdl-9672677

ABSTRACT

Several studies suggest that the concentration of immunoreactive (I) FSH measured in peripheral plasma by radioimmunoassay does not always reflect the level of bioactive (B) hormone capable of eliciting a biological response (e.g. oestradiol synthesis by Sertoli cells in vitro). The aim of this study was to measure both B-FSH and I-FSH concentrations in male and female sheep during the first year of life, and to relate this to pubertal development. The hypothesis being tested was that B-FSH is present in both male and female sheep during the prepubertal period and that discrete changes in B-FSH are associated with the onset of puberty. Eight ewe lambs and eight rams lambs were blood sampled fortnightly form 2 to 52 weeks of age. All samples were assayed for B-FSH content. Pubertal development was monitored in ewe lambs from behavioural oestrus and from plasma progesterone concentrations, and in ram lambs from penile and testicular development and from plasma testosterone concentrations. Mean I-FSH concentrations varied significantly with time after birth, in both females and males (P < 0.01). In contrast, B-FSH was found to vary with time in females only (P < 0.01). Around the expected time of puberty in ram lambs (i.e. at 30-40 weeks of age), and thereafter, I-FSH concentrations were undetectable (< 0.2 ng ml-1), whereas the B-FSH concentrations were measurable at concentrations up to twice the assay detection limit (0.8 ng ml-1) until 38 weeks of age. In ewe lambs, but not ram lambs, there was a significant linear relationship between B-FSH and I-FSH values (R = 0.595; P < 0.005). When standardised about the time of puberty, B-FSH (P < 0.05) but not I-FSH was significantly higher in ewe lambs that failed to reach puberty. No differences for either B-FSH or I-FSH between pubertal and non-pubertal ram lambs were noted. In summary, B-FSH was soften measurable in plasma throughout prepubertal development in sheep and the concentrations often differed from those of I-FSH, especially in ram lambs. However, there appeared to be no discrete change in B-FSH that could be directly related to specific pubertal events. It is concluded that although FSH may be a prerequisite for prepubertal testicular development and/or ovarian follicular growth, it is not a critical factor in determining whether puberty is attained during the first year of life in this seasonally breeding species.


Subject(s)
Follicle Stimulating Hormone/blood , Sheep/blood , Sheep/growth & development , Aging , Animals , Estrus/physiology , Female , Male , Ovarian Follicle/growth & development , Penis/growth & development , Progesterone/blood , Sexual Maturation/physiology , Testis/growth & development , Testosterone/blood
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