Biomedical subjects
Publications and source records attributed to Robert Brown.
While the study of molecular and cellular cognition has begun to elucidate the mechanisms of acquisition, consolidation, and storage of memories, the understanding of retrieval has lagged behind. In this issue of Cell, use molecular genetic approaches combined with pharmacology to demonstrate that beta-adrenergic receptor function regulates retrieval of certain forms of memory.
Ovarian cancer is the most lethal of all gynecologic neoplasms. Early-stage malignancy is frequently asymptomatic and difficult to detect and thus, by the time of diagnosis, most women have advanced disease. Most of these patients, although initially responsive, eventually develop and succumb to drug-resistant metastases. The success of typical postsurgical regimens, usually a platinum/taxane combination, is limited by primary tumors being intrinsically refractory to treatment and initially responsive tumors becoming refractory to treatment, due to the emergence of drug-resistant tumor cells. This review highlights a prominent role for epigenetics, particularly aberrant DNA methylation and histone acetylation, in both intrinsic and acquired drug-resistance genetic pathways in ovarian cancer. Administration of therapies that reverse epigenetic "silencing" of tumor suppressors and other genes involved in drug response cascades could prove useful in the management of drug-resistant ovarian cancer patients. In this review, we summarize recent advances in the use of methyltransferase and histone deacetylase inhibitors and possible synergistic combinations of these to achieve maximal tumor suppressor gene re-expression. Moreover, when used in combination with conventional chemotherapeutic agents, epigenetic-based therapies may provide a means to resensitize ovarian tumors to the proven cytotoxic activities of conventional chemotherapeutics.
OBJECTIVE: We investigated whether postexercise consumption of a supplement containing whey protein, amino acids, creatine, and carbohydrate combined with a strength training program promotes greater gains in fat-free mass (FFM), muscle strength and endurance, and anaerobic performance compared with an isocaloric, carbohydrate-only control drink combined with strength training. METHODS: The study was double blind and randomized, and the experimental supplement was compared with a carbohydrate-only control. Forty-one males (n = 20 in control group, n = 21 in the supplement group; mean age, 22.2 y) participated in a 4 d/wk, 10-wk periodized strength training program. Subjects had to complete at least 70% of the workouts. Before and after 10 wk of strength training, subjects were tested for body composition by using hydrostatic weighing and skinfold thicknesses, one repetition maximum strength and muscular endurance for the bench press and 45-degree leg press, and anaerobic performance using a 30-s Wingate test. Thirty-three subjects (80.5%) completed the training program (n = 15 in control group, n = 18 in the supplement); these 33 subjects also completed all post-training test procedures. Data were analyzed with two-way analysis of variance with repeated measures on time. P <== 0.05 was set as statistically significant. All statistical analyses, including calculation of effect size and power, were completed with SPSS 11.0. RESULTS: Across groups, FFM increased during 10 wk of strength training. Although there was no statistically significant time x group interaction for FFM, there was a trend toward a greater increase in FFM for the supplement group (+3.4 kg) compared with the control group (+1.5 kg; P = 0.077). The effect size (eta(2) = 0.100) was moderately large. Percentage of body fat declined and fat mass was unchanged; there were no differences between groups. One repetition maximum strength for the bench press and 45-degree leg press increased, but there were no differences between groups. Muscular endurance expressed as the number of repetitions completed with 85% of the one repetition maximum was unchanged; external work, which was estimated as repetitions completed x resistance used, increased for the 45-degree leg press but not for the bench press over the 10-wk training period; there were no time x group interactions for either measurement. Anaerobic power and capacity improved, but there were no differences between groups for these variables or for fatigue rate. CONCLUSIONS: Consumption of a recovery drink after strength training workouts did not promote greater gains in FFM compared with consumption of a carbohydrate-only drink; however, a trend toward a greater increase in FFM in the supplement group suggests the need for longer-term studies. Performance variables such as muscle strength and endurance and anaerobic performance were not improved when compared with the carbohydrate-only group.
OBJECTIVES: To determine whether alcohol use at time of spinal cord injury (SCI) is more common with cervical injury than with lower levels of spinal injury. METHODS: Veterans and nonveterans with SCI were assessed at a Veteran's Affairs Medical Center from 1994 through 2002 and completed a health questionnaire that included information on alcohol use at time of traumatic injury. RESULTS: Of 362 men, 45% had neurologically complete or incomplete cervical injuries. Participants with cervical injury were more likely to have used alcohol when injured (62/162, 38%) compared with participants without cervical injury (45/200, 23%). Adjusting for age at injury and accident type, participants with cervical SCI had an increased relative odds of having used alcohol at injury compared with participants without cervical SCI (2.06, 95% confidence interval = 1.24-3.43). CONCLUSION: Alcohol use at time of SCI is a risk factor for cervical injury. This finding is of public health concern and should be included in alcohol educational programs.
The rat is an important animal model for human diseases and is widely used in physiology. In this article we present a new strategy for gene discovery based on the production of ESTs from serially subtracted and normalized cDNA libraries, and we describe its application for the development of a comprehensive nonredundant collection of rat ESTs. Our new strategy appears to yield substantially more EST clusters per ESTs sequenced than do previous approaches that did not use serial subtraction. However, multiple rounds of library subtraction resulted in high frequencies of otherwise rare internally primed cDNAs, defining the limits of this powerful approach. To date, we have generated >200,000 3' ESTs from >100 cDNA libraries representing a wide range of tissues and developmental stages of the laboratory rat. Most importantly, we have contributed to approximately 50,000 rat UniGene clusters. We have identified, arrayed, and derived 5' ESTs from >30,000 unique rat cDNA clones. Complete information, including radiation hybrid mapping data, is also maintained locally at http://genome.uiowa.edu/clcg.html. All of the sequences described in this article have been submitted to the dbEST division of the NCBI.
The Canadian Collaborative Acute Pain Initiative, established in 2002, is a voluntary, multidisciplinary consortium of acute pain health professionals from across Canada whose goal is to improve acute pain management through discussion and consensus. The group met in January 2002 to define strategic areas related to the treatment of acute pain. The areas identified were: the definition of pain; the epidemiology of pain; the concept of an 'ideal' acute pain management service; education; therapeutic options; symptom management; and research and safety. In November 2002, a second meeting was held to develop objectives and recommendations for the management of acute pain based on the defined areas. The outcome of these discussions is summarized in this paper.
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Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2'-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth. An important consequence of this is that, unlike conventional cytotoxic agents, it may be best to use such drugs at concentrations lower than the maximum tolerated dose and in a manner dependent on their demethylating activity. Furthermore, synergistic activity with other types of investigational epigenetic therapies and existing chemotherapies opens the possibility of rational combinations and scheduling of these agents based on their biologic activity.
Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O(6)-meG adducts can be repaired by the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.
While not a big fan of the non-permit confined space designation, I have come to believe the approach can work if done properly. However, it is this author's opinion that the designation of a confined space as non-permit required in any work environment should be the exception rather than the rule. The up-front determination that a space is "non-permit-required" should necessarily consume more time and resources than assuming the space is "permit-required" because so fewer controls are in place. Most certainly, this decision must be based on the knowledge that no hazards are present or have the potential to develop, rather than on "convenience" or "resource limitations"; assumptions should never play a part in the decision. Attention to proper evaluation of confined spaces, documentation of actual conditions over time, and communication to those entering the spaces are all critical components of a safe confined space entry program, whether the space be permit-required or not.
MSH2 and MLH1 have a central role in correcting mismatches in DNA occurring during DNA replication and have been implicated in the engagement of apoptosis induced by a number of cytotoxic anticancer agents. The function of MLH1 is not clearly defined, although it is required for mismatch repair (MMR) and engagement of apoptosis after certain types of DNA damage. In order to identify other partners of MLH1 that may be involved in signalling MMR or apoptosis, we used human MLH1 in yeast two-hybrid screens of normal human breast and ovarian cDNA libraries. As well as known partners of MLH1 such as PMS1, MLH3 and MBD4, we identified the carboxy terminus of the human c-MYC proto-oncogene as an interacting sequence. We demonstrate, both in vitro by yeast two-hybrid and GST-fusion pull-down experiments, as well as in vivo by coimmunoprecipitation from human tumour cell extracts, that MLH1 interacts with the c-MYC protein. We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo. Using an inducible c-MYC-ER fusion gene, we show that elevated c-MYC expression leads to an increased HGPRT mutation rate of Rat1 cells and an increase in the number of frameshift mutants at the HGPRT locus. The effect on HGPRT mutation rate is small (2-3-fold), but is consistent with deregulated c-MYC expression partially inhibiting MMR activity.
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We investigated whether neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF) affected the reinnervation of slow and fast motor units. Neurotrophin-impregnated or plain fibronectin (FN) conduits were inserted into a sciatic nerve gap. Fast extensor digitorum longus (EDL) and slow soleus muscles were collected 4 months postsurgery. Muscles were weighed and fibre type proportion and mean fibre diameters were derived from muscle cross-sections. All fibre types in muscles from FN animals were severely atrophied and this correlated well with type 1 fibre loss and atrophy in soleus and type 2b loss and atrophy in EDL. Treatment with NT-4 reversed soleus but not EDL mass loss above the FN group by significantly restoring type 1 muscle fibre proportion and diameters towards those of normal unoperated animals. BDNF did not increase muscle mass but did have minor effects on fibre type and diameter. Thus, NT-4 significantly improved slow motor unit recovery, and provides a basis for therapies intended to aid the functional recovery of muscles after denervating injury.
Epigenetic regulation of gene expression has been observed in a variety of tumor types. We have used microarray technology to evaluate the predisposition of drug response by aberrant methylation in ovarian cancer. Results indicate that loss of gene activity due to hypermethylation potentially confers a predisposition in certain cancer types and is an early event in disease progression. Methylation profiles of ovarian cancer might be useful for early cancer detection and prediction of chemotherapy outcome in a clinical context.
STUDY OBJECTIVES: Because muscle paralysis makes it uncertain whether subjects with spinal cord injury (SCI) can perform spirometry in accordance with American Thoracic Society (ATS) standards, determinants of test failure were examined. DESIGN: Cross-sectional study. SETTING: Veterans Affairs (VA) medical center. PARTICIPANTS: Veterans with SCI at VA Boston Healthcare System and nonveterans recruited by mail and advertisement. MEASUREMENTS AND RESULTS: Two hundred thirty of 278 subjects (83%) were able to produce three expiratory efforts lasting > or = 6 s and without excessive back-extrapolated volume (EBEV). In 217 of 230 subjects (94%), FVC and FEV(1) were each reproducible in accordance with 1994 ATS standards. In the remaining 48 subjects, efforts with smooth and continuous volume-time tracings and acceptable flow-volume loops were identified. These subjects had a lower percentage of predicted FVC, FEV(1), and maximum expiratory and inspiratory pressures compared to the others, and a greater proportion had neurologically complete cervical injury (42% compared to 16%). In 19 subjects (40%), some expiratory efforts were not sustained maximally for > or = 6 s but had at least a 0.5-s plateau at residual volume (short efforts). In eight subjects (17%), some efforts were not short but had EBEV. In the remaining 21 subjects (44%), some efforts were short, some had EBEV, and some had both. If these efforts were not rejected, 262 of 278 subjects (94%) would have produced three acceptable efforts, and in 257 subjects (92%), the efforts were reproducible. CONCLUSIONS: Subjects with SCI with the most impaired respiratory muscles and abnormal pulmonary function are able to perform spirometry reproducibly despite not meeting usual ATS acceptability standards. Exclusion of these subjects would lead to bias in studies of respiratory function in SCI. The modification of spirometry testing standards to include efforts with EBEV and with a 0.5-s plateau if < 6 s would reduce the potential for bias.
STUDY OBJECTIVES: We sought to improve speech in tracheostomized individuals receiving positive-pressure ventilation. Such individuals often speak with short phrases, long pauses, and have problems with loudness and voice quality. SUBJECTS: We studied 15 adults with spinal cord injuries or neuromuscular diseases receiving long-term ventilation. INTERVENTIONS: The ventilator was adjusted using lengthened inspiratory time (TI), positive end-expiratory pressure (PEEP), and combinations thereof. RESULTS: When TI was lengthened (by 8 to 35% of the ventilator cycle), speaking time increased by 19% and pause time decreased by 12%. When PEEP was added (5 to 10 cm H(2)O), speaking time was 25% longer and obligatory pauses were 21% shorter. When lengthened TI and PEEP were combined (with or without reduced tidal volume), their effects were additive, increasing speaking time by 55% and decreasing pause time by 36%. The combined intervention improved speech timing, loudness, voice quality, and articulation. Individual differences in subject response to the interventions were substantial in some cases. We also tested high PEEP (15 cm H(2)O) in three subjects and found speech to be essentially identical to that produced with a one-way valve. CONCLUSIONS: These simple interventions markedly improve ventilator-supported speech and are safe, at least when used on a short-term basis. High PEEP is a safer alternative than a one-way valve.