From a Patient Choice Perspective: Nearly 20 Years on, Has Patient Choice Improved or Was I Just Lucky?

With Watch & Wait becoming a more recognised approach to the treatment of early-stage lower rectal cancers I wanted to look at what has changed in nearly 20 years from a patient's perspective. In 2003 I was diagnosed with a T3a tumour and offer radical surgery but found Papillon and was lucky that it worked and I'm still here. Since then, things have improved but I still have patients contacting me saying they are being given no options - so I pose the question: From a Patient Choice Perspective: Nearly 20 Years on, Has Patient Choice Improved or Was I Just Lucky?

Relationship between testosterone, estradiol and circulating PCSK9: Cross-sectional and interventional studies in humans.

BACKGROUND: Circulating PCSK9 levels are higher in women than men, in postmenopausal than premenopausal women, and in pregnant than non-pregnant women, suggesting that sex hormones may be related to PCSK9 levels. We have examined the relationship between serum estradiol (E2) and testosterone (T) and PCSK9, and the impact of E2 replacement therapy in women and T replacement and ablation therapy in men on circulating PCSK9. METHODS: We conducted a cross-sectional study to examine the correlation between serum T (in males) and E2 (in females) and serum PCSK9. We also conducted interventional studies to examine the effect of hormonal therapy on serum PCSK9 levels. RESULTS: In men, (1) serum T does not correlate with circulating PCSK9 or with LDLC in the basal state, (2) T replacement therapy does not have any effect on circulating PCSK9, and (3) T ablation therapy has mixed results. In women, (1) E2 correlates inversely with circulating PCSK9 and directly with serum LDLC, but (2) E2 replacement therapy does not have any effect on circulating PCSK9. CONCLUSIONS: We demonstrate differences between men and women in the relationship of their major sex hormones with circulating PCSK9. In men, circulating PCSK9 is not related to or affected by T except for a possible effect during T ablation therapy. In women, E2 is inversely related to circulating PCSK9 but the lack of effect of E2 therapy on circulating PCSK9 suggests that the E2-related differences in PCSK9 levels may be the result of differences in receptor-mediated PCSK9 clearance through E2-induced changes rather than production of PCSK9. The studies were registered with ClinicalTrials.gov NCT00848276.

Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels.

OBJECTIVES: Serum low density lipoprotein-cholesterol (LDL-C) correlates positively with serum PCSK9 in the general population, consistent with PCSK9 being a determinant of LDL-C levels. Patients with chronic kidney disease (CKD) on hemodialysis (HD) have lower total cholesterol (TC) and LDL-C compared to the general population. Serum PCSK9 and its relationship with serum lipids have not been reported in CKD patients on HD (CKD-HD). METHODS: We measured serum PCSK9 by ELISA and lipid levels in 66 CKD-HD patients and compared them to 178 non-CKD subjects. Since statins increase serum PCSK9 levels, CKD-HD patients were separated into those not on statin therapy (HD-NS, n = 32) and those taking statins (HD-S, n = 34). No control subjects were on statin therapy. RESULTS: Serum PCSK9, TC, LDL-C and HDL-C levels were significantly lower in the CKD-HD group (n = 66) compared to the control group. HD-NS patients showed lower PCSK9, TC and LDL-C levels than control subjects and PCSK9 levels correlated with TC and LDL-C levels (r = 0.35, p = 0.050; r = 0.423, p = 0.0158 respectively) as well as TG levels (r = 0.413, p = 0.0188). In HD-S patients, PCSK9 levels were not significantly different from the non-CKD group. There was no correlation between PCSK9 levels and TC and LDL-C levels in the HD-S group. CONCLUSION: Our data are the first quantitative analysis of serum PCSK9 levels in CKD-HD patients. We show that serum PCSK9 in HD-NS patients is decreased and it retains a positive correlation with LDL-C, suggesting that PCSK9 may remain a significant determinant of LDL-C in CKD-HD subjects. We also show that statin therapy disrupts the correlation between LDL-C and PCSK9 in CKD-HD patients. These data suggest that the regulation of LDL-C by PCSK9 remains intact in CKD-HD patients. PCSK9 may also play a role in the metabolism of triglyceride-rich lipoproteins in CKD-HD patients.

Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury.

The most obvious impairments associated with spinal cord injury (SCI) are loss of sensation and motor control. However, many subjects with SCI also develop persistent neuropathic pain below the injury which is often severe, debilitating and refractory to treatment. The underlying mechanisms of persistent neuropathic SCI pain remain poorly understood. Reports in amputees describing phantom limb pain demonstrate a positive correlation between pain intensity and the amount of primary somatosensory cortex (S1) reorganization. Of note, this S1 reorganization has also been shown to reverse with pain reduction. It is unknown whether a similar association between S1 reorganization and pain intensity exists in subjects with SCI. The aim of this investigation was to determine whether the degree of S1 reorganization following SCI correlated with on-going neuropathic pain intensity. In 20 complete SCI subjects (10 with neuropathic pain, 10 without neuropathic pain) and 21 control subjects without SCI, the somatosensory cortex was mapped using functional magnetic resonance imaging during light brushing of the right little finger, thumb and lip. S1 reorganization was demonstrated in SCI subjects with the little finger activation point moving medially towards the S1 region that would normally innervate the legs. The amount of S1 reorganization in subjects with SCI significantly correlated with on-going pain intensity levels. This study provides evidence of a link between the degree of cortical reorganization and the intensity of persistent neuropathic pain following SCI. Strategies aimed at reversing somatosensory cortical reorganization may have therapeutic potential in central neuropathic pain.

Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial.

OBJECTIVE: To evaluate pregabalin in central neuropathic pain associated with spinal cord injury. METHODS: A 12-week, multicenter study of patients randomized to either flexible-dose pregabalin 150 to 600 mg/day (n = 70) or placebo (n = 67), administered BID. Patients were allowed to remain on existing, stable pain therapy. The primary efficacy variable was the endpoint mean pain score, derived from patients' last 7 days daily pain diary entries. Key secondary endpoints included pain responder rates, the SF-MPQ, sleep interference, mood, and the patient global measure of change. RESULTS: The mean baseline pain score was 6.54 in the pregabalin group and 6.73 in the placebo group. The mean endpoint pain score was lower in the pregabalin group (4.62) than the placebo group (6.27; p < 0.001), with efficacy observed as early as week 1 and maintained for the duration of the study. The average pregabalin dose after the 3-week stabilization phase was 460 mg/day. Pregabalin was significantly superior to placebo in endpoint assessments on the SF-MPQ. The > or =30% and > or =50% pain responder rates were higher with pregabalin than placebo (p < 0.05). Pregabalin was associated with improvements in disturbed sleep (p < 0.001) and anxiety (p < 0.05), and more patients reported global improvement at endpoint in the pregabalin group (p < 0.001). Mild or moderate, typically transient, somnolence and dizziness were the most common adverse events. CONCLUSIONS: Pregabalin 150 to 600 mg/day was effective in relieving central neuropathic pain, improving sleep, anxiety, and overall patient status in patients with spinal cord injury.

An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM).

BACKGROUND: The randomized clinical trial of implantable drug delivery systems (IDDS) plus comprehensive medical management (CMM) versus CMM alone showed better clinical success at 4 weeks for IDDS patients. This 'as treated' analysis assessed if improvements in pain control, drug toxicity and survival were maintained over time. PATIENTS AND METHODS: We compared those who received IDDS with those who did not receive IDDS (non-IDDS). All patients had Visual Analogue Scores (VAS) for pain > or =5/10 on at least 200 mg morphine or equivalent daily. RESULTS: At 4 weeks, 46 of 52 (88.5%) IDDS patients achieved clinical success compared with 65 of 91 (71.4%; P=0.02) non-IDDS patients, and more often achieved > or =20% reduction in both pain VAS and toxicity [35 of 52 (67.3%) versus 33 of 91 patients (36.3%); P=0.0003]. By 12 weeks, 47 of 57 (82.5%) IDDS patients had clinical success compared with 35 of 45 (77.8%; P=0.55) non-IDDS patients, and more often had a > or =20% reduction in both pain VAS and toxicity [33 of 57 (57.9%) versus 15 of 45 patients (33.3%); P=0.01]. At 12 weeks the IDDS VAS pain scores decreased from 7.81 to 3.89 (47% reduction) compared with 7.21 to 4.53 for non-IDDS patients (42% reduction; P=0.23). The 12 week drug toxicity scores for IDDS patients decreased from 6.68 to 2.30 (66% reduction), and for non-IDDS patients from 6.73 to 4.13 (37% reduction; P=0.01). All individual drug toxicities improved with IDDS at both 4 and 12 weeks. At 6 months, only 32% of the group randomized to CMM and who did not cross over to IDDS were alive, compared with 52%-59% for patients in those groups who received IDDS. CONCLUSIONS: IDDS improved clinical success, reduced pain scores, relieved most toxicity of pain control drugs, and was associated with increased survival for the duration of this 6 month trial.

El alivio del dolor como un derecho humano / Pain relief as a human right

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Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia.

We have investigated the effect of standard doses of two fibrates, gemfibrozil and fenofibrate, on fasting and postprandial remnant-like particles (RLP) in subjects with combined hyperlipidemia. Forty-eight subjects participated; of these, 14 underwent a Vitamin A-fat loading test before and after 6 months of treatment with gemfibrozil (n = 8) and fenofibrate (n = 6). Blood was drawn every 2h for 12h after the test meal. The postprandial response was calculated as the area under the curve (AUC). There was no difference in fasting levels and pre-treatment AUC for triglycerides (TG), RLP cholesterol (RLP-C), RLP triglycerides (RLP-TG) and retinyl palmitate (RetP) between the two treatment groups. There was also no difference in the treatment effect on all parameters between the two treatment groups. Combining the two treatment groups, treatment resulted in a significant reduction in fasting levels and AUC of all four parameters. Assigning the difference observed between pre-treatment AUC of the combined study group and AUC of a normolipidemic (NL) control group as 100%, fibrate treatment resulted in decreases in AUC for TG, RLP-C, RLP-TG and RetP of 68, 69, 69 and 94%, respectively. These results indicate that fibrates are effective agents in reducing the postprandial increase in remnant lipoprotein particles.

Adolescent nicotine administration alters serotonin receptors and cell signaling mediated through adenylyl cyclase.

Nicotine is a neuroteratogen that targets synaptic function during critical developmental stages and recent studies indicate that CNS vulnerability extends into adolescence, the age at which smoking typically commences. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined 5HT receptors and related cell signaling during nicotine administration (PN45) and in the post-treatment period (PN50, 60, 75). Adolescent nicotine decreased 5HT(2) receptor binding in brain regions containing 5HT projections (hippocampus and cerebral cortex), with selectivity for females in the cerebral cortex; regions containing 5HT cell bodies showed either an increase (midbrain in males) or no change (brainstem). In contrast, there were no significant changes in 5HT(1A) receptors; however, the ability of the receptors to signal through adenylyl cyclase (AC) showed a switch from stimulatory to inhibitory effects in females during the post-treatment period. There were also transient alterations in AC responses to beta-adrenergic receptor stimulation, as well as pronounced induction of the AC response to the non-receptor-mediated stimulant, forskolin. Our results indicate that adolescent nicotine exposure alters the concentrations and functions of postsynaptic 5HT receptors in a manner commensurate with impaired 5HT synaptic function. The direction of change, emergence of defects after the cessation of nicotine administration, and sex-preference for effects in females, all support a relationship of impaired 5HT function to the higher incidence of depression seen in adolescent smokers.

Functional alterations in CNS catecholamine systems in adolescence and adulthood after neonatal chlorpyrifos exposure.

Chlorpyrifos (CPF), one of the most widely used pesticides, is a neurobehavioral teratogen in animals. We administered CPF to neonatal rats on postnatal days (PN) 1-4 (1 mg/kg) or PN11-14 (5 mg/kg), regimens devoid of overt systemic toxicity. We then examined the impact on catecholaminergic systems in adolescence (PN30) and adulthood (PN60), assessing basal neurotransmitter content and transmitter utilization rates (turnover) in brain regions comprising the major noradrenergic and dopaminergic projections. Although CPF had only sporadic effects on basal norepinephrine and dopamine content, it profoundly suppressed norepinephrine turnover across multiple regions, indicative of net reductions in presynaptic activity. Dopamine turnover showed less consistent effects, with subnormal turnover in some regions and activation in others. We also evaluated whether CPF exposure altered the ability of catecholamine systems to respond to acute cholinergic stimulation, elicited by administration of a single challenge dose of nicotine. In the normal brain, nicotine increases the utilization of norepinephrine and dopamine. With only a few exceptions, animals receiving neonatal CPF exposure showed lasting desensitization of the nicotine response; not only was the activation by nicotine blunted in the CPF group, but in some regions the nicotine response was reversed, eliciting a reduction in transmitter turnover. These results indicate that neonatal CPF exposure produces widespread deficiencies in catecholaminergic synaptic function that persist into adulthood, and that are best revealed by dynamic measures of synaptic activity and responsiveness, as opposed to static markers like basal transmitter levels. The effects seen here are likely to contribute to alterations in behavioral performance that persist or emerge long after the termination of CPF exposure.

Beta-adrenoceptor signaling in the developing brain: sensitization or desensitization in response to terbutaline.

Beta(2)-adrenoceptor agonists are commonly used to arrest preterm labor but they also penetrate the placenta to stimulate fetal beta-adrenergic receptors (betaAR), and have been implicated in subsequent neurobehavioral deficits. We administered terbutaline to pregnant rats on gestational days (GD) 17-20 and during two postnatal (PN) periods, PN2-5 and PN11-14, that correspond to third trimester human neurological development. We then examined betaAR binding sites and adenylyl cyclase (AC) signaling in fetal brain or neonatal brain regions. Although fetal terbutaline administration evoked betaAR downregulation, the ability of isoproterenol to stimulate AC was enhanced instead of desensitized. Sensitization occurred at post-receptor signaling proteins, as augmented responses were also seen for stimulants that bypass the receptors to work on G-proteins (NaF) or that stimulate AC directly (forskolin and Mn(2+)). When terbutaline was given on PN2-5, betaAR downregulation was obtained in brainstem, forebrain and cerebellum, but desensitization of the AC response was seen only in the forebrain; the desensitization was heterologous, reflecting decrements in total AC activity rather than specific loss of the betaAR response. With treatment on PN11-14, only the cerebellum showed betaAR downregulation and induction at the level of post-receptor signaling proteins maintained the betaAR-mediated AC response. Our results indicate that, unlike the adult, betaAR signaling in the fetus and neonate is resistant to homologous desensitization by beta-agonists, and in fact, displays heterologous sensitization that sustains or enhances the overall response. The inability to desensitize betaAR responses may lead to disruption of neural cell development as a consequence of tocolytic therapy.

Acute doses of d-amphetamine and bupropion increase cigarette smoking.

RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.

Direct clinical evidence for spinal hyperalgesia in a patient with irritable bowel syndrome.

OBJECTIVE: Our objective was to evaluate GI motor and sensory function and spinal cord testing in a patient with severe irritable bowel syndrome. METHODS: A patient is described who underwent an extensive assessment of GI motor and sensory function including transit studies, colonic and rectal barostat studies, sensory and manometric studies of the small bowel, and colon and anorectal physiology testing. The patient also underwent testing with spinal cord stimulation and spinal drug delivery as part of a pain management assessment. RESULTS: The viscerosomatic referral pain pattern resulting from rectal distention was consistent with spinal hyperalgesia. The patient underwent testing for spinal cord stimulation and spinal drug delivery. CONCLUSION: This novel finding provides direct clinical evidence for the presence of spinal hyperalgesia in a patient with irritable bowel syndrome, consistent with the existing indirect clinical evidence and animal data.

Postprandial remnant-like lipoproteins in hypertriglyceridemia.

It has been proposed that remnants of chylomicrons and very-low-density lipoproteins (VLDL) are atherogenic. We have used an immunochemical method to isolate remnant-like particles (RLP) and measured them in terms of their cholesterol and triglycerides (TG). RLP consist of apoB-48-containing triglyceride-rich lipoproteins and remnant-like VLDL containing apoB-100. The study aim was to look for information from postprandial RLP data that could not be known from other markers of triglyceride-rich lipoproteins and fasting TG and RLP data alone. A total of 41 subjects were studied. Eight subjects had hypertriglyceridemia (HTG) and low high-density lipoprotein (HDL), 14 had combined hyperlipidemia (CH), 5 had the apo E2/2 genotype receiving gemfibrozil, 10 were normolipidemic (NL) controls, and 4 had hypercholesterolemia. As a whole group, there was correlation among 1) fasting TG, RLP cholesterol (RLP-C), and RLP-TG but not VLDL apo B100, VLDL apo B48 and their respective postprandial responses measured as incremental area under the curve (IAUC), 2) fasting TG and postprandial IAUC of RLP-C and RLP-TG, 3) RLP-C IAUC, RLP-TG IAUC, and TG IAUC, retinyl palmitate (RP) IAUC, and VLDL apo B48 IAUC but not VLDL apo B100 IAUC. The HTG/low HDL-C and CH groups had higher IAUC for RLP-C, RLP-TG, TG, and RP than the NL group. Fasting and postprandial RLP were triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group. The HTG/low HDL-C and CH groups had a delay in their RLP-C but not RLP-TG peaks suggesting a delay in hepatic clearance of RLP and/or a protracted period of lipolysis and/or processing of RLP. The fasting and postprandial RLP-C/RLP-TG and RLP-C/TG ratios were elevated in the apo E2/2 group in spite of gemfibrozil therapy. The increment in postprandial RLP was, however, not exaggerated. Our data indicate that 1) postprandial RLP lipemia is enhanced in HTG subjects when compared with NL subjects, 2) postprandial RLP lipemia is proportional to fasting RLP and TG levels and mirrors, to a large extent, increases in postprandial TG, RP, and VLDL apo B48 but not VLDL apo B100, 3) there are compositional differences in fasting and postprandial RLP in the three forms of HTG studied, RLP being triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group, and cholesterol-enriched in the apo E2/2 group, and 4) apo E2/2 subjects had high fasting and postprandial RLP-C concentrations in spite of being on treatment with gemfibrozil and having normal fasting and postprandial TG concentrations.

Effects of a single dose of baclofen on self-reported subjective effects and tobacco smoking.

Baclofen has been reported in uncontrolled clinical studies to reduce craving for abused drugs and reduce their rewarding effects. The objective of the present study was to measure the acute effects of a single dose of baclofen on cigarette smoking, craving for nicotine, cigarette taste, and smoking satisfaction. Tobacco smokers (n = 16) who were not trying to quit received baclofen (20 mg) or placebo after overnight abstinence during two laboratory sessions in a within-subjects design. We measured the subjective effects of baclofen on mood and self-reported ratings of craving for nicotine, and on the number of cigarettes smoked of the subjects' preferred brand during a 3-h ad libitum smoking period. Baclofen did not change the number of cigarettes smoked by the subjects nor did it change ratings of nicotine craving. However, baclofen altered the sensory properties of smoked cigarettes (e.g., increasing ratings of 'harsh' and decreasing ratings of 'like cigarette's effects'). It also produced mild sedative-like subjective effects, such as increases in feeling 'relaxed'. Thus, although baclofen did not reduce cigarette craving or smoking in the present study, it did produce some mood-altering effects and changes in sensory aspects of smoking that may facilitate smoking cessation.

Are sample sizes usually at least an order of magnitude too low for reliable estimates of leaf asymmetry?

Estimates of leaf size and asymmetry for individual trees are often obtained using sample sizes that are too small to take into account the possibility that size and asymmetry may be affected by the position of the leaf on the tree. This issue was addressed by exploring variation in leaf size and asymmetry within an individual of Alder (Alnus glutinosa). We found differences between branches for leaf size and for signed asymmetry but not for unsigned asymmetry. We also found that the size of a leaf was not correlated with its position on a branch and that the asymmetry of a leaf was not correlated with either its position on a branch or with the asymmetry of its neighbour. Repeated subsampling of a sample of 870 leaves showed that a subsample size approaching 500 leaves was required for consistently reliable estimates of the standard deviation of unsigned asymmetry. Smaller subsamples were required for consistently reliable estimates of mean unsigned asymmetry and of the mean and standard deviation of leaf size, but subsamples of less than 100 leaves provided consistently reliable estimates only of mean leaf size. For this species, reliable estimates of an individual's level of asymmetry are obtained only if several hundred leaves are sampled over several branches, but it is not necessary to sample the same sequence of leaves from each branch.

Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure.

The commonly-used organophosphate insecticide, chlorpyrifos (CPF), impairs brain cell development, axonogenesis and synaptogenesis. In the current study, we administered CPF to neonatal rats on postnatal (PN) days 1-4 (1 mg/kg) or PN11-14 (5 mg/kg), treatments that were devoid of overt toxicity. We then examined two cholinergic synaptic markers, choline acetyltransferase activity (ChAT) and [3H]hemicholinium-3 binding (HC-3) in the hippocampus, midbrain, striatum, brainstem and cerebral cortex in the juvenile (PN30) and young adult (PN60). Across all brain regions, CPF exposure evoked significant reductions in both markers, with larger effects on HC-3 binding, which is responsive to neuronal impulse activity, than on ChAT, a constitutive marker. Superimposed on the deficits, there were gender-selective effects and distinct regional disparities in the critical exposure period for vulnerability. In the hippocampus, either the early or late treatment regimen evoked decreases in ChAT but the early regimen elicited a much larger decrease in HC-3; effects persisted into adulthood. In the midbrain, CPF administration on PN1-4 elicited deficits similar to those seen in the hippocampus; however, exposure on PN11-14 elicited changes preferentially in females. Gender selectivity was also apparent in the striatum, in this case reflecting deficits in females after CPF treatment on PN1-4. In contrast, the effects of CPF on the brainstem were relatively more robust in males; effects in the cerebral cortex were less notable than in other regions. These results indicate that neonatal CPF exposure produces widespread deficiencies in cholinergic synaptic function that persist into adulthood. The effects are likely to contribute to gender-selective alterations in behavioral performance that persist or emerge long after the termination of exposure and well after the restoration of cholinesterase activity.