Biomedical subjects
K Gill
Publications and source records attributed to K Gill.
Acute effects of paroxetine on genioglossus activity in obstructive sleep apnea.
STUDY OBJECTIVE: To determine the acute effects of paroxetine on genioglossus activity during NREM sleep. DESIGN: A single dose of Paroxetine (40 mg) or placebo was administered four hours before bedtime on nights separated by one week in a double blind randomized crossover manner. The moving time average of genioglossus muscle activity (EMGgg) expressed as a percentage of maximum was measured using a mouthpiece electrode customized for each subject. The peak inspiratory and tonic values of EMGgg and the corresponding esophageal pressure deflections (DP) during the last three occluded breaths of obstructive apneas during NREM sleep were analyzed. SETTING: NA. PARTICIPANTS: 8 adult men with severe obstructive sleep apnea (OSA). INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Paroxetine increased the peak inspiratory EMGgg (29.8+/-2.4 (SE) versus 24.4+/-2.7 % max, p<0.05) and peak EMGgg/DP ratio (0.78+/-0.12 versus 0.65+/-0.11 % max/cm H2O, p<0.01) but not the tonic EMGgg (11.6+/-0.9 versus 9.8+/-0.7 % max) nor the DP (39.4+/-2.2 versus 38.2+/-2.8 cm H2O). Linear regression analysis of the peak inspiratory EMGgg versus DP relationship showed that paroxetine increased the slope (0.62+/-0.11 versus 0.49+/-0.09 % max/cm H2O, p<0.01). However, the apnea + hypopnea index (paroxetine: 75.2+/-5.5 versus placebo: 73.7+/-6.9 events/hour) did not differ. CONCLUSIONS: Paroxetine augmented peak inspiratory genioglossus activity during NREM sleep but this effect was not sufficient to decrease the frequency of obstructive apnea in this group with severe OSA.
An examination of ALDH2 genotypes, alcohol metabolism and the flushing response in Native Americans.
OBJECTIVE: The study was designed to examine the relationship between aldehyde dehydrogenase (ALDH2) genotype and the flushing response in a population of Native Americans. METHOD: Objective measures of the flushing response were obtained by monitoring skin temperature, heart rate, blood pressure, as well as blood alcohol concentrations, in flushing and nonflushing Native Americans (n = 105) as well as in Oriental (n = 15) and white (n = 15) control subjects following a dose of alcohol (0.2 or 0.4 gm/kg). ALDH genotypes were determined via polymerase chain reaction followed by hybridization to 32P or biotin-labeled allele-specific oligonucleotide probes. RESULTS: There were no ALDH2 mutations detectable in Native Americans reporting the flushing response, nor any objective evidence of an Oriental-like response to alcohol. The rate of alcohol metabolism was shown to be the same among whites, Native flushers and Native nonflushers. CONCLUSIONS: The results demonstrate that the flushing reaction experienced by Native Americans appears to be milder and less unpleasant than the "Oriental" flushing reaction, with little effect on drinking frequency and amount. In addition, the flushing is not mediated by the ALDH2 mutation or elevated blood acetaldehyde. A critical analysis of the discrepancies in the literature regarding alcohol metabolism in Native Americans is provided.
Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands.
To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.
Acute tolerance to the ataxic effects of ethanol in short-sleep (SS) and long-sleep (LS) mice.
The objective of this series of studies was to examine the relationship between alcohol sensitivity and the development of very rapid acute tolerance to alcohol in mice. In order to measure acute tolerance to alcohol, a behavioral test was developed using a rotorod. In the first study, mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute hypnotic effects of ethanol were used, as well as mice from the base population (heterogeneous stock, HS). Mice were trained to run on the rotorod at a speed of 14 rpm to a criterion of 200 s, in four daily training sessions. On the test day, baseline measurements of rotorod performance were taken and mice were injected i.p. with alcohol in doses from 0 to 2.5 g/kg. Animals were tested at 1-min intervals for the first 5 min following injection, then at 5-min intervals for a total of 30 min. The results demonstrated that SS and HS mice developed tolerance within 10 min following the alcohol injections. LS mice did develop some acute tolerance, but at a much slower rate than the SS or HS mice. In the second study, the effects of intoxicated practice on the rates of acute tolerance development were examined in the SS, HS and LS mice at a dose of 2.0 g/kg alcohol. A total of ten groups of each strain were given a different number of practice trials (ranging from one to ten) on the rotorod prior to a final test session at 30 min post-injection. The results provide evidence that SS and HS mice are capable of developing acute tolerance independent of practice. That is, the group of animals injected at 0 time and tested ten times up to 30 min were no better at the 30-min time point than the group injected at 0 time and tested only once at 30 min. On the other hand, the LS mice showed a modest practice effect, developing additional tolerance to the ataxic effects of alcohol with increasing intoxicated practice. Overall, these studies demonstrated that mice can develop acute tolerance within minutes following alcohol exposure, and that this ability is correlated with the initial sensitivity to alcohol.
Alcohol preference in AXB/BXA recombinant inbred mice: gender differences and gender-specific quantitative trait loci.
The purpose of the present study was to characterize the C57BL/6J, A/J, and AXB/BXA Recombinant Inbred (RI) strains of mice for voluntary alcohol consumption. Quantitative Trait Locus (QTL) analysis was used to provide provisional location of QTLs for alcohol consumption. The inbred strains were screened for levels of alcohol intake (calculated as alcohol preference and absolute alcohol consumption) by receiving 4 days of forced exposure to a 10% (wt/vol) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. A wide and continuous distribution of values for alcohol consumption and preference was obtained in the AXB/BXA RI strains, confirming polygenic influences on alcohol-related behaviors. Significant gender differences were found for both alcohol preference [F28,651 = 2.12, p < 0.001] and absolute alcohol consumption [F28,647 = 2.57, p < 0.001]. In males, putative QTLs were mapped to chromosomes (Chrs) 2, 5, 7, 10, 11, and 16. Multiple regression analysis indicated that approximately 75% of the genetic variance in alcohol preference in males could be accounted for by three of the QTL regions. Several of the putative QTLs appeared to be male-specific (Tyr on Chr 7; D10Mit126 on Chr 10; D11Mit61 on Chr 11). In females, seven putative QTLs were mapped to Chrs 2, 4, 5, 7, 11, 16, and 19. Approximately 90% of the genetic variance in alcohol preference in females could be accounted for by four QTL regions, as determined by multiple regression. The QTL on Chr 11 near D11Mit35 appeared to be female-specific. This site was close to a female-specific QTL (Alcp2) previously mapped in C57BL/6J x DBA/2J backcrosses by Melo and coworkers (Nat Genet 13, 147, 1996). The QTLs mapped for alcohol preference in the present study must be considered suggestive at the present time, since only D2Mit74 met very strict statistical criteria for significance. However, the concordance across several studies for the loci on Chrs 2, 4, 7, 9, and 11 suggest that some common QTLs influencing alcohol preference have been identified. Confirmation of QTLs mapped in the present study is currently being conducted in a new series of recombinant congenic (RC) strains developed from reciprocal backcrosses between the A/J and C57BL/6J progenitors. The concomitant use of both RI and RC strains developed from the same progenitors should provide a powerful means of detecting, confirming, and mapping QTLs for alcohol-related traits.
High-dose chemotherapy followed by autologous blood cell transplantation: a safe and effective outpatient approach.
High-dose chemotherapy (HDCT) followed by autologous blood cell (ABC) transplantation has been used widely for patients with metastatic breast cancer (MBC). It has been shown by our group and others to be an effective means of achieving very high response rates including complete remission. Therefore, further reduction in toxicity and increased patient satisfaction is necessary. Fifty-three patients with MBC were enrolled in a feasibility study at our cancer centre with a three-step approach to outpatient observation after HDCT and ABC transplantation discharging our patients from hospital 6 days after reinfusion of ABC, 1 day after reinfusion of ABC and 1 day prior to reinfusion of ABC. The supportive care consisted of the use of 5-HT3 antagonists for nausea and vomiting, DMSO depletion, through body hygiene, prophylactic antibiotic, antifungal and virustatic drugs. In the event of febrile neutropenia, a standard evaluation and treatment was used. Only 22 patients were admitted for febrile neutropenia and two for haemorrhage. The median hospital stay was 2 days (range 1-7). The time to engraftment, need for transfusion and other toxicities were not different in patients who stayed entirely as outpatients. No toxic deaths occurred. In conclusion, HDCT followed by ABC transplantation can be safely administered to patients in the clinic with outpatient post-transplant observation.
Lifetime exercise and disk degeneration: an MRI study of monozygotic twins.
Participation in some competitive sports has been shown to increase disk degeneration; however, the long-term effects of recreational physical activities are unclear. We investigated the effects of endurance exercise and power sports on disk degeneration in monozygotic male twins with contrasting lifetime exercise histories. The effects of endurance exercise were studied in 22 discordant twin pairs (mean lifetime frequencies of 3.9 vs 1.1 times/wk), and the effects of power sports were investigated in 12 discordant pairs (2,300 vs 200 h of weightlifting). The age range of the twins was from 35 to 69 yr. No differences in MRI findings between co-twins discordant for endurance exercise were found at any of the spinal regions. Subjects with more power sport involvement had greater disk degeneration in the T6-T12 region (P < 0.03), but similar findings were not present in the lumbar spine. Controlling for recalled back injuries, occupational loading, smoking, and driving did not significantly affect the results. No signs of beneficial or harmful effects of lifetime endurance exercise on disk degeneration were seen. Increased power sport participation was associated with slightly greater disk degeneration in the lower thoracic spine, but not in the lumbar spine.
A description of alcohol/drug use and family history of alcoholism among urban American Indians.
The patterns of alcohol consumption, family history of alcoholism, and lifetime and current diagnoses of substance dependence were determined in a sample of American Indians (n = 105) living in Denver. Subjects were recruited through flyers, posters, and advertisements placed in local newspapers, the Denver Indian Center, and Denver Indian Health and Family Services. Subjects were interviewed regarding their education, employment, past and present drug and alcohol use (including frequency/quantity, beverage type, and pattern of intake) and family history of alcoholism. The drug and alcohol sections of the Diagnostic Interview Schedule were administered in order to determine lifetime and current prevalence of substance dependence. Although there are limits to the generalizability of these data due to the use of a non-random sampling method, the results indicate that approximately half of the sample (50.5%) were abstinent or irregular drinkers with moderate intake (3.3 drinks/occasion). Binge drinkers (3.8%) consumed large amounts of alcohol per occasion, with a mean of 21.6 drinks. Also, 45.5% of the sample were regular drinkers (at least once/wk) with a mean of 11 standard drinks/occasion. The rate of current alcohol dependence (33.3%) and other drug dependence (18.1%) was relatively high with cocaine and cannabis the primary drugs of abuse. The most striking aspect of the sample was the very high rate of family history of alcoholism (60.6% with at least one alcoholic parent) and only 11.1% with no primary or secondary alcoholic family members.
[Multiple drug use by the elderly in need of care and nursing and possibility of reducing this practice].
OBJECTIVE: To determine and evaluate the simultaneous use of multiple drugs in elderly people (aged > or = 65 years). DESIGN: Cohort study. SETTING: Region Rijnstreek, the Netherlands. METHOD: In 200 consecutive persons who were evaluated for admission to a hospice or a nursing home, and who used > or = 5 drugs simultaneously, the drug use was determined and evaluated according to published guidelines and on the premise that the use of drugs ought to be reduced. RESULTS: A total number of 1131 persons (mean age: 80.4 years (SD: 6.4)) were evaluated in two study periods (January 1993-February 1994 and March-October 1994). The 200 selected patients (17.7%) used a mean of 6.9 drugs (SD: 1.9). Evaluation of these pharmacotherapeutic regimens, abolishing drugs deemed redundant, interaction screening and checks on dosage showed a number of opportunities for improvement although only a slight reduction in the number of drugs could be achieved (to 5.3 (SD: 1.9)). CONCLUSION: In practice, systematic re-evaluation of actual pharmacotherapeutic regimens on a regular basis is necessary. The increasing possibilities for self-medication should be taken into consideration.
Alcohol as a food: a commentary on Richter.
The present study examined the maintenance of voluntary alcohol intake in male Long-Evans rats. A microstructural analysis of consummatory behaviors (food, alcohol, water) was carried out using a computerized drinkometer system. In this sample of animals, there was no association (r = 0.07) between total food intake and total alcohol intake. There was no compensation for the extra calories ingested in the form of alcohol via a reduction in total food intake, or a reduction in food bout sizes associated with pre- or postprandial alcohol consumption. Further microstructural analyses determined that there were no significant difference between water and alcohol in terms of their distribution in relation to food (non-, pre-, or postprandial bouts). Of the total of 586 bouts of fluid intake analyzed, 45.6% were consumed postprandially, with a similar number (43.2%) consumed nonprandially. A comparison of the size of food bouts associated with different fluid bout types (pre- or postprandial) indicated that food bouts were the same size regardless of whether they were accompanied by water or alcohol. A final analysis determined that 55% of the total daily alcohol intake was consumed postprandially, and that the sizes of non-, pre-, or postprandial fluid bouts were significantly different for water vs. alcohol. Post hoc pairwise comparisons found that alcohol postprandial bouts were significantly larger than all types of water bouts. Alcohol and water bouts ranged in size from < 0.5 ml to > 5.5 ml. There was a significant difference in the distribution of bout sizes with more alcohol bouts at the high end of the distribution. Only 24% of the water bouts were > 2.5 ml compared to 48.4% of the alcohol bouts. The results of this study demonstrate that rats organize their consummatory behavior in many discrete, short bouts. There were considerable individual differences in alcohol preference, alcohol-bout frequency, duration, and size, as well as the prandial distribution of bouts. All of these variables together produce the "pattern" of alcohol intake in individual animals, and is likely to influence the level of intoxication achieved. Although rats do not dissociate their alcohol intake from normal feeding patterns, alcohol bouts occurring postprandially are significantly larger than other bouts of fluid consumption, suggesting that animals perceive the pharmacological effects of and are affected by the alcohol they consume. In animals with a preference for alcohol solutions, it is unlikely that alcohol is consumed as a food.
Voluntary alcohol consumption in BXD recombinant inbred mice: relationship to alcohol metabolism.
Studies were initiated to characterize behaviorally and biochemically C57BL/6J and DBA/2J inbred mice, as well as BXD Recombinant Inbred (RI) strains derived from them. The C57BL/6J, DBA/2J, and 7 BXD RI strains were tested for voluntary alcohol consumption (VAC) by receiving 4 days of forced exposure to a 10% (w/v) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. Measures of VAC included the absolute intake of alcohol (g/kg), as well as alcohol preference. A wide range of VAC was displayed by the various BXD RI strains with a continuous (rather than bimodal) distribution, indicating that there is likely to be additive effects of several genes involved in regulating alcohol-related behaviors. Kinetic characteristics of aldehyde dehydrogenase and catalase in liver and brain of the C57BL/6J, DBA/2J, and BXD strains of mice were determined to test the hypothesis that the genetic regulation of the levels of alcohol-metabolizing enzymes mediate differences in VAC. Aldehyde dehydrogenase activity was determined spectrophotometrically by observing the change in absorption at 340 nm. Catalase activity was determined by measuring oxygen production with a Yellow Springs Biological Oxygen monitor and oxygen electrode. There was a strong negative relationship between VAC and brain catalase activity in the BXD RI and parental strains. These data suggest that RI strains are likely to be useful genetic models in the examination of quantitative trait loci controlling VAC and other responses to alcohol.
Effect of administered ethanol on protein kinase C in human platelets.
There are numerous reports of the effect of ethanol on protein kinase C (PKC) in animals or with in vitro systems. However, the effect of ethanol on PKC in humans has not been extensively investigated despite the large number of studies involving PKC and human platelets. In this study, we administered ethanol to human volunteers and determined the level of PKC before and after a 0.4 g/kg dose of ethanol. We studied Native Americans and Caucasians of both sexes. There was an increases in PKC activity 60 min after ethanol administration. There were no ethnic, age, nor gender differences detected, nor was there any correlation between family history of alcoholism and the basal or stimulated platelet PKC levels. Neither was there any correlation of basal or stimulated PKC activity with the genotypes for ADH2, ADH3, ALDH2, CYP2E1, and CYP1A2.
Toxic shock syndrome.
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Deep venous thrombosis prophylaxis with low molecular weight heparin and elastic compression in patients having total hip replacement. A randomised controlled trial.
Seventy-eight patients having elective total hip replacement were randomised into 3 groups A) control; B) low molecular weight heparin: (enoxaparin 40 mg once daily) and C) enoxaparin (40 mg once daily) plus graduated elastic compression (TEDR stockings) for 8-12 days. All patients had a preoperative perfusion lung scan and chest X-Ray and a postoperative perfusion/ventilation scan together with bilateral ascending venography on days 8-12. A blood sample was taken preoperatively, on the 1st, 3rd and 5th postoperative day and at the end of the study. The control group received placebo injections. The venograms and V/Q scans were reported blindly by an independent panel of three and one radiologists respectively. An independent panel of assessors stopped entry in the control group when a total of 45 patients were admitted according to Ethics Committee directives. The study continued with groups B and C. The incidence of DVT (including isolated asymptomatic calf thrombi) was as follows: Group A (n = 14) 93%; Group B (n = 32) 38%; Group C (n = 32) 25% (chi 2; p < 0.001 for group A versus B or C). The incidence of proximal DVT was: Group A 57%; group B 28%; group C 13% (chi 2; p = 0.057 for group A versus B and p < 0.005 for group A versus C). The incidence of silent pulmonary embolism (PE) (new defect on V/Q scan) was 28% (8 out of 29) in patients with and 5% (2 out of 43) in patients without DVT (chi 2; p < 0.02). The combination of high TAT and low anti-Xa activity on the 1st postoperative day identified a high risk group of patients who had a 56% incidence of proximal DVT on the 8th to 12th postoperative day. Further studies are needed to confirm the suggested increased efficacy in prophylaxis by the combination of LMWH and GEC as compared with LMWH alone.
1995 Volvo Award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging findings in identical twins.
STUDY DESIGN: Retrospective cohort. OBJECTIVES: To investigate the effects of lifetime exposure to commonly suspected risk factors on disc degeneration using magnetic resonance imaging, and to estimate the effects of these suspected risk factors relative to age and familial aggregation, reflecting genetic and shared environmental influences. SUMMARY OF BACKGROUND DATA: Structural and biochemical changes associated with disc degeneration are suspected as the underlying conditions of many back-related symptoms. Little is known about the determinants of disc degeneration. METHODS: Based on lifetime discordance in suspected environmental risk factors for disc degeneration, 115 male identical twin pairs were selected. An in-depth interview was conducted of occupational and leisure time physical loading, driving, and smoking. Disc degeneration was evaluated using observational and digital magnetic resonance imaging assessment methods. RESULTS: Heavier lifetime occupational and leisure physical loading was associated with greater disc degeneration in the upper lumbar levels (P = 0.055 - 0.001), whereas sedentary work was associated with lesser degeneration (P = 0.006). These univariate associations did not reach statistical significance in the lower lumbar region. In multivariate analyses of the upper lumbar levels, the mean job code explained 7% of the variability in observational disc degeneration scores; the addition of age explained 16%, and familial aggregation improved the model such that 77% of the variability was explained. In the lower lumbar levels, leisure time physical loading entered the multivariate model, explaining 2% of the variability. Adding age explained 9%, and familial aggregation raised the variability in disc degeneration scores explained to 43%. CONCLUSIONS: The present study findings suggest that disc degeneration may be explained primarily by genetic influences and by unidentified factors, which may include complex, unpredictable interactions. The particular environmental factors studied, which have been among those most widely suspected of accelerating disc degeneration, had very modest effects.
Fluoxetine for premenstrual dysphoria.
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[Characteristics of patients with the diagnosis 'mental strain' in family practice].
OBJECTIVE: To investigate the characteristics of general practitioners' patients given the diagnosis of 'surmenage' (French for 'nervous breakdown'). DESIGN: Descriptive. SETTING: General practices in Almere, the Netherlands. METHOD: Four groups of general practice attenders were selected based on the general practitioners' diagnosis: a group of surmenage patients (n = 106), a group of somatic patients without apparent psychological problems (n = 159), a group of patients with a psychosocial diagnosis (n = 136) and a group of patients with a psychiatric diagnosis (n = 57). Symptoms, social functioning, background data, life events and problems were collected by questionnaires. RESULTS: Most surmenage patients were employed young adults. They experienced more work or study related problems than the other patients. They also experienced more other problems than the somatic patients but not more than the patients with a psychosocial or psychiatric diagnosis. More than half of the surmenage patients were on sick leave. The most important symptoms in surmenage patients were nervousness, brooding, fatigue and insomnia. On the basis of their symptoms the surmenage patients could be distinguished well from the somatic and psychosocial patients, but not from the patients with a psychiatric diagnosis. The surmenage patients had a shorter duration of symptoms than the patients with a psychosocial or a psychiatric diagnosis. The group of surmenage patients was very heterogeneous. CONCLUSION: The diagnosis of surmenage is associated with nonspecific psychological symptoms, a relatively recent onset, being employed, experiencing problems related to work or study, and being on sick leave. Patients diagnosed as suffering from surmenage by their general practitioner, form a heterogeneous group.