Cardiopulmonary interactions with beta-blockers and inhaled therapy in COPD.

BACKGROUND: Beta-blockers remain underused in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular disease. AIM: We compared how different inhaled therapies affect tolerability of bisoprolol and carvedilol in moderate to severe COPD. DESIGN: A randomized, open label, cross-over study. METHODS: We compared the cardiopulmonary interactions of bisoprolol 5 mg qd or carvedilol 12.5 mg bid for 6 weeks in conjunction with: (i) triple: inhaled corticosteroid/long acting beta-agonist/long acting muscarinic antagonist (ICS + LABA + LAMA), (ii) dual: ICS + LABA and (iii) ICS alone. RESULTS: Eighteen patients completed, all ex-smokers, mean age 65 years, forced expiratory volume in 1 s (FEV1) 52% predicted. Bisoprolol and carvedilol produced comparable significant reduction in resting and exercise heart rate. FEV1, forced vital capacity and lung compliance (AX) were significantly lower with carvedilol vs. bisoprolol while taking concomitant ICS/LABA (P < 0.05) but not ICS/LABA/LAMA. CONCLUSIONS: In summary, bisoprolol was better tolerated than carvedilol on pulmonary function at doses which produced equivalent cardiac beta-1 blockade. Worsening of pulmonary function with carvedilol was mitigated by concomitant inhaled LAMA (tiotropium) with LABA (formoterol), but not LABA alone. Registered at clinicaltrials.gov: NCT01656005.

Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase.

The prognosis for women with breast cancer is adversely affected by the comorbidities of obesity and diabetes mellitus (DM), which are conditions associated with elevated levels of circulating fatty acids, hyperglycaemia and hyperinsulinaemia. We investigated the effects of exposure of non-malignant and malignant human breast epithelial cells to elevated levels of fatty acids and glucose on their growth, survival and response to chemotherapeutic agents. We found that palmitate induced cell death in the non-malignant cells but not in the malignant cells, which was abrogated through the inhibition of ceramide production and by oleate but not by IGF1. Fatty acid synthase (FAS) is responsible for the de novo synthesis of fatty acids from sugars, and is over-expressed in many epithelial cancers. Abundance of FAS was higher in malignant cells than in non-malignant cells, and was up-regulated by IGF1 in both cell types. IGF-induced growth of non-malignant cells was unaffected by suppression of FAS expression, whereas that of malignant cells was blocked as was their resistance to palmitate-induced cell death. Palmitate did not affect cell proliferation, whereas oleate promoted the growth of non-malignant cells but had the opposite effect, that is, inhibition of IGF1-induced growth of malignant cells. However, when the phosphatidylinositol 3-kinase pathway was inhibited, oleate enhanced IGF1-induced growth in both cell types. Hyperglycaemia conferred resistance on malignant cells, but not on non-malignant cells, to chemotherapy-induced cell death. This resistance was overcome by inhibiting FAS or ceramide production. Understanding the mechanisms involved in the associations between obesity, DM and breast cancer may lead to more effective treatment regimens and new therapeutic targets.

Laparoscopic diaphragm pacing for tetraplegia.

(1) The NeuRx DPS is a laparoscopically implanted device that provides ventilatory support. (2) This device stimulates the diaphragm muscle, rather than the phrenic nerve, and is intended to lead to less risk of nerve damage than other therapies.(3) This technology provides an alternative to mechanical ventilation, and allows patients to increase day-to-day freedom and minimize the risk of respiratory infection. (4) The NeuRx DPS safety profile is based on clinical testing, which began with clinical trials starting in 2000. It has the potential to reduce costs, but this has not been well established.

Treating asthma with omega-3 fatty acids: where is the evidence? A systematic review.

BACKGROUND: Considerable interest exists in the potential therapeutic value of dietary supplementation with the omega-3 fatty acids. Given the interplay between pro-inflammatory omega-6 fatty acids, and the less pro-inflammatory omega-3 fatty acids, it has been thought that the latter could play a key role in treating or preventing asthma. The purpose was to systematically review the scientific-medical literature in order to identify, appraise, and synthesize the evidence for possible treatment effects of omega-3 fatty acids in asthma. METHODS: Medline, Premedline, Embase, Cochrane Central Register of Controlled Trials, CAB Health, and, Dissertation Abstracts were searched to April 2003. We included randomized controlled trials (RCT's) of subjects of any age that used any foods or extracts containing omega-3 fatty acids as treatment or prevention for asthma. Data included all asthma related outcomes, potential covariates, characteristics of the study, design, population, intervention/exposure, comparators, and co interventions. RESULTS: Ten RCT's were found pertinent to the present report. CONCLUSION: Given the largely inconsistent picture within and across respiratory outcomes, it is impossible to determine whether or not omega-3 fatty acids are an efficacious adjuvant or monotherapy for children or adults. Based on this systematic review we recommend a large randomized controlled study of the effects of high-dose encapsulated omega-3 fatty acids on ventilatory and inflammatory measures of asthma controlling diet and other asthma risk factors. This review was limited because Meta-analysis was considered inappropriate due to missing data; poorly or heterogeneously defined populations, interventions, intervention-comparator combinations, and outcomes. In addition, small sample sizes made it impossible to meaningfully assess the impact on clinical outcomes of co-variables. Last, few significant effects were found.

Imagery and psychotic symptoms: a preliminary investigation.

Recent cognitive accounts of psychotic symptoms have suggested that processes involved in the maintenance of emotional disorders may also be implicated in the maintenance of hallucinations and delusions, and particularly emphasise the appraisals of such symptoms as important. Imaginal appraisals have been identified in emotional disorders, and many studies have reported spontaneously occurring images in patients with anxiety disorders. Such images appear to be linked to affect, beliefs and memories. This study examined the occurrence of imagery, using a semi-structured interview, in 35 patients who were experiencing hallucinations and/or delusions and receiving cognitive therapy. The majority of patients (74.3%) reported images, and most of these were recurrent and associated with affect, beliefs and memories. Common themes included images about feared catastrophes associated with paranoia, traumatic memories, and images about the perceived source or content of voices. The theoretical and clinical implications of these findings are discussed and directions for further research considered.

Comparison of therapeutic interchange with standard educational tools for influencing fluoroquinolone prescribing.

The abilities of therapeutic interchange (TI) and standard educational tools (SET) to change prescribing habits were compared. We evaluated the replacement of ciprofloxacin with levofloxacin in a four-hospital health system during a 14-month study period. Two hospitals used TI and two SET. The demographics, sites of infection, and severity of illness were analyzed for 554 patients treated at SET hospitals and 1323 patients treated at TI hospitals during a total of 2040 hospitalizations over a 14-month period. In TI hospitals, 97% of patients received levofloxacin, whereas 43% received levofloxacin in SET hospitals (p < 0.001). Clinical outcomes were not significantly different for the two groups, although more patients in the SET hospitals received combination antimicrobial therapy. Differences in savings per patient were significant between TI hospitals ($60) and SET hospitals ($37) (p < 0.001). The total annualized savings for all four hospitals was $156,444. TI was more effective than SET in facilitating changes in prescribing patterns in a health care system and resulted in significant cost savings to hospitals and payers.

Formal total synthesis of (+/-)-alpha- and beta-cedrene by preparation of cedrone. Construction of the tricyclic carbon skeleton by the use of a highly efficient intramolecular Khand annulation.

The cedrene carbon skeleton was rapidly assembled from a simple monocyclic precursor by the strategic use of a high yielding intramolecular Khand cyclization reaction. Further synthetic manipulations provided a concise formal total synthesis of alpha- and beta-cedrene. Reaction: see text.

Electrical stimulation of the amygdala increases the amplitude of elicited ponto-geniculo-occipital waves.

The amygdala projects massively via its central nucleus (CNA) into brain stem regions involved in alerting and ponto-geniculo-occipital (PGO) wave generation. Electrical stimulation of CNA is known to enhance the acoustic startle response (ASR) and influence spontaneous PGO waves. The role of the amygdala in the modulation of ASR and elicited PGO waves (PGOE) was investigated in albino rats. Electrically stimulating CNA within 25 ms prior to an auditory stimulus enhanced ASR and PGOE amplitude in a similar way, with the largest response occurring when the electrical and auditory stimuli were given simultaneously. The data suggest that CNA modulates alerting mechanisms.

Elicited pontogeniculooccipital waves and phasic suppression of diaphragm activity in sleep and wakefulness.

Fractionations are 20- to 100-ms pauses in diaphragm activity that occur spontaneously during rapid-eye-movement (REM) sleep, sometimes in association with pontogeniculooccipital (PGO) waves. Auditory stimuli can elicit fractionations or PGO waves during REM sleep, non-REM (NREM) sleep, and waking; however, their interrelationship has not been investigated. To determine whether the two phenomena are produced by a common phasic-event generator in REM sleep, we examined PGO waves and fractionations that were elicited by auditory stimuli (tones) presented to freely behaving cats across states. Tones elicited PGO waves and two types of fractionations: short-latency fractionation responses (SFRs; 10- to 60-ms latencies) and long-latency fractionation responses (LFRs; 60- to 120-ms latencies). Both a PGO wave and a SFR were elicited in 60-70% of trials across states, but each could be elicited alone. The latencies and durations of elicited SFRs were similar across states, but the latencies of elicited PGO waves in REM sleep (mean 62.5 ms) were significantly longer than in waking or NREM sleep. Elicited SFRs consistently occur with shorter latencies than do PGO waves, in contrast to spontaneous fractionations, which have a variable relationship to PGO waves and usually occur 10-40 ms after the onset of the PGO wave. The LFR then, elicited most frequently during REM sleep, resembles a spontaneous fractionation in its temporal relationship to the PGO wave and may reflect the bias toward motoneuronal inhibition characterizing REM sleep but not NREM sleep or waking. We conclude that, although PGO waves and SFRs share some features, like LFRs they probably are generated by different neuronal populations. In three cats there was no correlation between PGO waves and fractionations, whereas in one cat they were associated in REM sleep (LFRs and SFRs) and waking (SFRs only). Thus the majority of evidence argues against the existence of a common phasic-event generator in REM sleep.

Activation of a distinct arousal state immediately after spontaneous awakening from sleep.

In contrast to the many neural studies into the mechanisms of sleep onset and maintenance, few studies have focused specifically on awakening from sleep. However, the abrupt electrographic changes and large brief cardio-respiratory activation at awakening suggest that a distinct, transiently aroused, awake state may exist compared to later wakefulness. To test this hypothesis we utilized the acoustic startle reflex, a standard un-conditioned reflex elicited by a sudden loud noise. This reflex is modulated under specific conditions, one being a diminution of startle when a quieter pre-stimulus is presented immediately before the loud stimulus. This pre-pulse inhibition (PPI) is used as a measure of sensorimotor gating, with smaller PPI indicating less filtering of sensory inputs and increased responsiveness to external stimuli. Eight rats with electrodes for recording sleep-wake state were studied. An accelerometer measured startle responses. The startle reflex was elicited by 115 dB, 40 ms tones. PPI was produced by 74 dB, 20 ms tones preceding the 115 dB tone by 100 ms. Responses within 100 ms were measured. Stimuli were applied either 3-10 s after spontaneous awakenings, or in established wakefulness (> 30 s). Responses to the startle stimuli alone were similar in the different awake states (P = 0.821). However, PPI was smaller at awakening from non-REM sleep compared to established wakefulness (45.4 +/- 7.5% vs. 74.3 +/- 6.1%, P = 0.0002). PPI after awakening from REM sleep (52.8 +/- 17.9%) was not significantly different than established wakefulness (P = 0.297). Reduced PPI of the startle reflex at awakening from non-REM sleep supports the hypothesis that wakefulness immediately after spontaneous sleep episodes is neurophysiologically distinct from later wakefulness and associated with reduced gating of motor responses to sensory inputs. Spontaneous activation of this distinct, transiently aroused, state upon awakening may serve a protective function, preparing an animal to respond immediately to potentially threatening stimuli.

A comparison of the cost effectiveness of alternative prophylactic therapies in childhood asthma.

An economic analysis was conducted comparing the cost effectiveness of fluticasone propionate with that of sodium cromoglycate (cromolyn sodium) in a group of children aged 4 to 12 years old with asthma, who required inhaled prophylactic therapy. Over an 8-week study period, 115 patients received sodium cromoglycate 20mg 4 times daily, via the spin operated dry powder inhaler, and 110 patients received fluticasone propionate 50 micrograms twice daily, via the Diskhaler (trademark held by the Glaxo Wellcome Group of Companies). Patient healthcare resource use was examined in terms of study medication, the use of rescue medication [salbutamol (albuterol) 200 micrograms] and the number of hospitalisations. The effectiveness of both treatments was examined over a range of success and failure criteria embracing peak expiratory flow rate (PEFR) improvement, symptom control and the level of adverse events related to the study medication. Results indicate that, for each UK pound spent, fluticasone propionate was associated with twice as many successfully treated patients as sodium cromoglycate, using a range of outcomes based on the goals of treatment defined in the British Thoracic Society's asthma guidelines. It is concluded that fluticasone propionate was more cost effective than sodium cromoglycate in improving PEFR and symptom control in this group of children with asthma who had a clinical requirement for prophylactic therapy.

Stimulus-elicited behavior in rapid eye movement sleep without atonia.

Alert wakefulness (W) and rapid eye movement sleep (REM) are remarkably similar on several measures of brain activity, but 2 differences in REM are reduced sensory responsiveness and atonia in postural muscles. Pontine tegmental lesions create REM without atonia (REM-A), releasing motor behavior. In 9 cats, we studied the acoustic startle reflex (ASR), orienting (OR), and ponto-geniculo-occipital waves (PGOE) elicited by tones during W, REM, REM-A, and non-REM (NREM). OR occurred in W and REM-A, being most complete in cats with the most elaborate spontaneous behavior. ASR occurred in W, NREM, and REM-A in lesioned cats. In normal cats, ASR rarely appeared in NREM and REM. PGOE had similar characteristics in both groups. The similarity of REM to W is particularly obvious when cats lack motoneuronal inhibition.

The amplitude of elicited PGO waves: a correlate of orienting.

Ponto-geniculo-occipital (PGO) waves spontaneously occur in the pons, lateral geniculate body (LGB), and occipital cortex during rapid eye movement sleep (REM), and PGO-like waves (PGOE) may be elicited in LGB during sleep and waking. Because REM has been hypothesized to be a state of continual "orienting" or "hyper-alertness," we tested whether the amplitudes of PGOE in "alerting" situations (the abrupt onset of a loud sound or presentation of a novel stimulus within a series of stimuli) that evoke orienting responses (OR) would be greater than those following stimuli without OR. We also compared PGOE accompanying OR to PGOE during REM and NREM when OR are absent. The amplitudes of PGOE in W were greatest when OR were observed, and the amplitudes of PGOE accompanying OR were not significantly different from PGOE amplitudes in REM. Likewise, the amplitudes of PGOE during REM were not significantly different from those of the highest amplitude spontaneous PGO waves. We propose that the presence of PGOE signals registration of stimuli and that stimuli of sufficient significance to induce behavioral OR in waking also elicit PGOE of significantly greater amplitudes in all behavioral states. These findings support the hypothesis that the presence of high-amplitude PGO waves in REM indicates that the brain is in a state of more-or-less continual orienting.

Hirschsprung's disease. Evaluation of mortality and long-term function in 260 cases.

This report describes 260 patients treated for Hirschsprung's disease. There were 213 boys (82%) and 47 girls (18%). Age at diagnosis was younger than 30 days in 106 patients (41%), 1 month to 1 year in 90 patients (35%), and older than 1 year in 64 patients (25%). Diagnosis was achieved with barium enema and rectal biopsy. Aganglionosis involved the rectum or rectosigmoid in 174 patients (67%), the left colon in 38 patients (15%), and the proximal colon in 23 patients (9%); 25 patients (9%) had total colonic aganglionosis. Enterocolitis occurred in 47 cases (18%). Following an initial colostomy or ileostomy, a definitive pull-through procedure was performed in 247 patients (95%) (modified Duhamel in 185, Soave in 25, Swenson procedure in 15, and anomyectomy/sphincterotomy in 22); the overall survival rate was 93.8% (244 of 260 patients). An increased mortality was associated with Down syndrome, total colonic aganglionosis, and enterocolitis. Long-term follow-up (mean, 6 years 10 months) was available in 103 patients who underwent a Duhamel procedure. Sixty-seven (65%) had normal bowel function, 28 (27%) occasionally used enemas or stool softeners, and eight (8%) had severe constipation or soiling. Bowel habits improved with time and were considered normal in 58% of patients at less than 5 years of follow-up and in 88% of patients at more than 15 years of follow-up. The Duhamel operation is a very effective definitive procedure for Hirschsprung's disease. Long-term follow-up is an important component of patient care.

Varying expressions of alerting mechanisms in wakefulness and across sleep states.

Alerting stimuli, such as intense tones, presented to cats in wakefulness (W) elicit the orienting response (OR) and/or the acoustic startle reflex (ASR) in conjunction with elicited ponto-geniculo-occipital waves (PGOE) from the lateral geniculate body (LGB) and elicited waves from the thalamic central lateral nucleus (CLE). Alerting stimuli presented during rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM) also elicit PGOE. We presented tones in W, REM and NREM to determine whether CLE could be obtained in sleep and to examine the patterns of responsiveness of PGOE and CLE across behavioral states. Also, we recorded ASR and OR and compared the response patterns of behavioral and central correlates of alerting. The subjects were 7 cats; all exhibited spontaneously occurring waves in LGB and CL. All cats exhibited PGOE and 5 cats exhibited CLE in W, REM and NREM. PGOE and CLE showed less evidence of habituation than did ASR and OR. The pattern of responsiveness of CLE across behavioral states was different from that found for PGOE, and spontaneous CL waves were much rarer than the LGB waves. ASR was elicited in 5 cats during W trials, and in 3 cats during REM trials. OR habituated rapidly in W and did not occur in REM and NREM. The data indicate that central mechanisms of alerting function in sleep states as well as in W and suggest that CLE and PGOE reflect activity in mechanisms underlying cortical desynchronization and visual processes which may act in concert during alerting.

Risk factors for surgery for prostatic hypertrophy.

The purpose of this case-control study was to evaluate potential risk factors for prostatic hypertrophy. The cases were 910 residents of Rhode Island who had a partial or total prostatectomy that was not related to cancer in the years 1985-1987. The controls were 2,003 members of the source population who were selected from a list of holders of Rhode Island driver's licenses or a roster of older Americans compiled by the Health Care Financing Administration. Cases and controls were interviewed by telephone. The risk of prostatic hypertrophy was elevated in Jewish men compared with Protestants and Catholics and in blacks compared with whites. Risk was reduced in ever-married compared with never-married men, in men who had left school at age 16 years or more compared with those who had left earlier, and in relatively tall or relatively heavy men. Coffee drinking and cigarette smoking were inversely but only weakly related to prostatic hypertrophy. There was a relatively strong, although irregular, inverse relation of beer drinking to prostatic hypertrophy. The associations of spirits and wine consumption with prostatic hypertrophy were weak.

Attenuating the hypertensive response to laryngoscopy and endotracheal intubation using awake fibreoptic intubation.

Blood pressure and pulse rate measurements were recorded in 35 patients undergoing endotracheal intubation during general anaesthesia (Group A), and 35 patients who had an awake fibreoptic intubation under local anaesthesia (Group B). The mean arterial pressure in Group A rose by a mean of 35 mmHg immediately after intubation, compared with a mean fall of 9 mmHg in Group B. The mean pulse rate in Group A rose by 24 beats per minute (b.p.m.) immediately after intubation, compared with a rise of 3 b.p.m. in Group B. Both these differences were statistically significant (P less than 0.0001 and P less than 0.001 respectively, Mann Whitney U test). Postoperative discomfort was assessed 24 h later by means of linear analogue scales. There was a statistically higher mean score in relation to nose discomfort in Group B (P less than 0.002). Awake fibreoptic intubation successfully reduces the pressor response to endotracheal intubation in normotensive adults. It is suitable for use in those patients who are at risk from the pressor response.