Search PubMed⌕ Search

Biomedical subjects

T Lynch

Publications and source records attributed to T Lynch.

At least 37 records · Page 2Linked to original sources
PubMed2001

Tardive dystonia of the larynx in a quadriplegic patient: an unusual cause of stridor.

We describe a case of a quadriplegic brain-damaged man with severe upper airway obstruction. A diagnosis of tardive dystonia affecting the vocal folds was made and confirmed by flexible nasopharyngoscopy. Emergency tracheotomy was required. The tardive movement disorder resolved with discontinuation of thioridazine. This case serves to heighten awareness of potentially serious airway complications associated with the use of anti-psychotics and anti-emetics particularly in those with organic brain disease.

Antipsychotic Agents↗
PubMed2001

Docetaxel (Taxotere) in combination with platinums in patients with non-small cell lung cancer: trial data and implications for clinical management.

Docetaxel (Taxotere; Aventis, Antony, France) is among the most effective agents for the treatment of non-small cell lung cancer and its use in combination with cisplatin is a logical development. Docetaxel has been combined with cisplatin and is well-tolerated with promising activity in phase II studies. Extensive phase II investigations in the first-line setting recorded response rates of 32% to 52% survival (median, 8 to 12 months) with 33% to 48% of patients alive at 1 year. Neutropenia is dose-limiting. However, the incidence of severe neuropathy is low and clinically significant nephrotoxicity is uncommon. Following these encouraging findings, the combination of docetaxel with cisplatin has been studied in two randomized phase III trials that compare the new combination against reference regimens. These studies have completed accrual and data are expected shortly. The combination of docetaxel with carboplatin is also active and feasible. Neutropenia is the main adverse event and grade II or III neurotoxicity is uncommon. In phase II trials combining doses of 65 to 100 mg/m2 docetaxel with doses of carboplatin designed to maintain an area under the curve of 5 to 7.5 mg/mL/min, response rates have ranged from 30% to 67%.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

The Everglades Nutrient Removal Project test cells: STA optimization--status of the research at the north site.

The Everglades is an oligotrophic ecosystem that is being adversely impacted by hydrologic changes and nutrient-rich runoff generated from urban and agricultural sources. The Stormwater Treatment Area (STA) Optimization Research and Monitoring program is mandated by the 1994 Everglades Forever Act and will assist the South Florida Water Management District in developing operational strategies that maximize performance of emergent macrophyte STAs. The primary objective of this research is to examine how hydrologic conditions may influence STA performance. The study was conducted in 0.2 ha, shallow, fully lined test cells located within the perimeter of the Everglades Nutrient Removal Project. Experiments were designed to examine the effect of increased and decreased hydraulic loading rate (HLR) on wetland performance and to determine, if possible, the HLR at which STA treatment fails to reduce outflow total phosphorus concentration to the interim target of 50 microg-P/L. To date, two HLR experiments have been completed at the north site. Preliminary data indicated at all HLRs tested that particulate phosphorus and dissolved organic phosphorus ratios remained virtually unchanged from inflow to outflow. The dissolved organic and particulate compounds within these test cells are extremely recalcitrant, and are not easily assimilated within the system. High HLRs may not result in detention times long enough to mineralize these forms into easily assimilated inorganic compounds, resulting in mean TP concentrations greater than 50 microg-P/L.

Ecosystem↗
PubMed2000

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

Adult↗
PubMed2000

Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease.

Selective application of metal chelators to homogenates of human Alzheimer's disease (AD) brain has led us to propose that the architecture of aggregated beta-amyloid peptide, whether in the form of plaques or soluble oligomers, is determined at least in part by high-affinity binding of transition metals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be associated with conformational and antioxidant activity. We tested the copper chelators trientine, penicillamine, and bathophenanthroline for their ability to mobilize brain Abeta as measured against our benchmark compound bathocuproine (BC). All of these agents were effective in solubilizing brain Abeta, although BC was the most consistent across the range of AD brain tissue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zinc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human Abeta but do not develop amyloid) revealed SDS-resistant dimers as Abeta was mobilized from the sedimentable to the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with Abeta to form a complex independent of the presence of copper. Such hybrid copper chelating and "chain breaking" properties may form the basis of a rational design for a therapy for Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Oxidative processes in Alzheimer's disease: the role of abeta-metal interactions.

Alzheimer's disease is characterized by signs of a major oxidative stress in the neocortex and the concomitant deposition of Amyloid beta (Abeta). Abeta is a metalloprotein that binds copper, and is electrochemically active. Abeta converts molecular oxygen into hydrogen peroxide by reducing copper or iron, and this may lead to Fenton chemistry. Hydrogen peroxide is a freely permeable prooxidant that may be responsible for many of the oxidative adducts that form in the Alzheimer-affected brain. The electrochemical activity of various Abeta species correlates with the peptides' neurotoxicity in cell culture, and participation in the neuropathology of Alzheimer's disease. These reactions present a novel target for Alzheimer therapeutics.

Alzheimer Disease↗
PubMed2000

A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy.

The objective of this study was to determine whether a mitochondrial DNA mutation and defective oxidative phosphorylation are present in a pedigree with maternally inherited sensorineural deafness, levodopa-responsive parkinsonism, and neuropathy. We sequenced the mitochondrial-encoded ribosomal RNA, cytochrome c oxidase, and transfer RNA genes by cycle sequencing. A polymerase chain reaction-based restriction enzyme assay with mismatched primers was employed to show heteroplasmy of a novel 12SrRNA mutation in the proband and to screen control subjects. Spectrophotometric mitochondrial respiratory chain assays were performed in transformed lymphoblasts from the proband and 12 normal controls. A novel, heteroplasmic, maternally inherited 12SrRNA point mutation (T1095C) was found in the pedigree. Respiratory chain enzyme analysis in cultured lymphocytes from the proband revealed a significant reduction in cytochrome c oxidase activity. Secondary structure predicts that this mutation disrupts a highly conserved loop in the small subunit ribosomal RNA, which is important in the initiation of mitochondrial protein synthesis. The mutation was not found in 270 controls of diverse ethnic origins. We conclude that this mutation is pathogenic and causes an oxidative phosphorylation defect by interfering with mitochondrial protein synthesis.

DNA, Mitochondrial↗
PubMed1999

Leukoencephalopathy and raised brain lactate from heroin vapor inhalation ("chasing the dragon")

BACKGROUND: Inhalation of heated heroin vapor ("chasing the dragon"), which is gaining popularity among drug users seeking to avoid the risks of parenteral drug administration, can produce progressive spongiform leukoencephalopathy. METHODS: We studied the clinical phenotype and course, MRI, MRS, and brain pathology in the first American patients described with this syndrome. RESULTS: Two of the three heroin users studied inhaled heroin pyrolysate together daily over the course of 2 weeks. They developed ataxia, dysmetria, and dysarthria. Patient 1 progressed to an akinetic mute state with decorticate posture and subsequent spastic quadriparesis. Patient 2 developed a mild spastic quadriparesis and gait freezing. Patient 3 was asymptomatic following less heroin exposure. Brain MRI showed diffuse, symmetrical white matter hyperintensities in the cerebellum, posterior cerebrum, posterior limbs of the internal capsule, splenium of the corpus callosum, medial lemniscus, and lateral brainstem. MRS showed elevated lactate. Brain biopsy (Patient 1) showed white matter spongiform degeneration with relative sparing of U-fibers; electron microscopy revealed intramyelinic vacuolation with splitting of intraperiod lines. Progressive deterioration occurred in Patients 1 and 2 over 4 weeks. Both were treated with antioxidants including oral coenzyme Q, and clinical improvement occurred. Patient 1 recovered nearly completely over 24 months. Patient 2 improved, but developed a delayed-onset cerebellar hand tremor. Both still have white matter abnormalities on MRI and MRS. CONCLUSIONS: Elevated lactate in white matter and the possible response to antioxidants suggests mitochondrial dysfunction in progressive spongiform leukoencephalopathy following inhalation of heated heroin vapor.

Administration, Inhalation↗
PubMed1999

Abnormal microtubule packing in processes of SF9 cells expressing the FTDP-17 V337M tau mutation.

Mutations in the gene for the microtubule associated protein, tau have been identified for fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). In vitro data have shown that FTDP-17 mutant tau proteins have a reduced ability to bind microtubules and to promote microtubule assembly. Using the baculovirus system we have examined the effect of the V337M mutation on the organization of the microtubules at the ultrastructural level. Our results show that the organization of the microtubules is disrupted in the presence of V337M tau with greater distances between the microtubules and fewer microtubules per process.

Animals↗
PubMed1999

Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease.

BACKGROUND: Although it is now well established that psychiatric depression is associated with adverse outcomes in patients with coronary heart disease (CHD), the mechanism underlying this association is unclear. Elevated heart rate (HR) and plasma norepinephrine (NE), possibly reflecting altered autonomic nervous system activity, have been documented in medically well depressed psychiatric patients, and this pattern is associated with increased risk for cardiac events in patients with CHD. The purpose of this study was to determine whether autonomic nervous system activity is altered in depressed CHD patients. METHODS: HR, plasma NE, and blood pressure (BP) were measured in 50 depressed and 39 medically comparable nondepressed CHD patients at rest and during orthostatic challenge. RESULTS: Resting HR (p = .005), and the change from resting HR at 2, 5, and 10 min after standing (p = .02, .004, and .02, respectively), were significantly higher in the depressed than in the nondepressed patients. There were no differences between the groups in NE or in BP at rest, or in standing minus resting change scores at any time during orthostatic challenge (p < .05). CONCLUSIONS: Depression is associated with altered autonomic activity in patients with CHD, as reflected by elevated resting HR and an exaggerated HR response to orthostatic challenge. Previously reported differences in NE levels between depressed and nondepressed patients were not replicated.

Aged↗
PubMed1999

Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.

A coding substitution (I93M) in the ubiquitin carboxy-terminal L1 (UCH-L1) gene has recently been identified in a German family with Parkinson's disease. We have sequenced the entire coding region of the gene in 11 families who have a pattern of disease consistent with autosomal dominant inheritance. We found a polymorphism (S18Y) in exon 3, two polymorphisms in the 5' non-coding region, upstream of the transcription start, and an insertion/deletion polymorphism in intron 4. The S18Y allele is present on approximately 20% of chromosomes in a Caucasian population. These changes are, therefore, unlikely to be pathogenic. We conclude that the I93M variant must either be a rare cause of disease or a harmless substitution whose occurrence in the family reflects a chance co-occurrence.

Adult↗
PubMed1999

No pathogenic mutations in the persyn gene in Parkinson's disease.

The persyn (gamma-synuclein) gene is highly homologous to the alpha-synuclein gene and is highly expressed in the nervous system. It is therefore, an excellent candidate gene for Parkinson's disease. However, we have sequenced the gene in a large number of families with parkinsonism and failed to find pathogenic mutations.

Age of Onset↗
PubMed1999

Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia.

Splice-site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non-Alzheimer's (non-AD) degenerative dementia. The groups included (1) a community-based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice-site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community-based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series.

Adult↗
PubMed1999

Alpha-synuclein expression in substantia nigra and cortex in Parkinson's disease.

Mutations in the human alpha-synuclein gene have been identified in several families of European descent with early-onset Parkinson's disease (PD). We sequenced the complete alpha-synuclein cDNA from substantia nigra and cortex from nine patients with PD and eight control subjects. No mutations were found. We then analyzed alpha-synuclein mRNA levels using a ribonuclease protection assay. Two major protected bands of alpha-synuclein mRNA, possibly representing two splice variants of the gene, were observed. Alpha-synuclein mRNA was significantly diminished in the substantia nigra of patients with PD compared with control subjects but not in the cortex. Our findings suggest that decreased synuclein mRNA may be an early alteration in the SN in PD, and imply that decreased levels of the protein may play a role in the pathogenesis of sporadic cases of the disease.

Adult↗