A biological basis for depression in pancreatic cancer

Background

Patients with pancreatic adenocarcinoma frequently present with depression the symptoms of which may precede cancer diagnosis, suggesting that the pathophysiology of depression in pancreatic adenocarcinoma may result from biological changes that are induced by the presence of the tumour itself. The present study was conducted to test a hypothesized relationship with the kynurenine pathway, which has been implicated in both depression and tumour-induced immunosuppression.

Methods

17 patients with pancreatic adenocarcinoma were recruited and completed mood questionnaires (Functional Assessment of Cancer Therapy -Pancreatic Cancer, Beck Depression Inventory and the Beck Anxiety Inventory) and blood testing for serum levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid. Tumour burden was determined from pathology reports (tumour size and nodal involvement).

Results

Findings indicated a negative correlation between mood scores and the plasma kynurenic acid : tryptophan ratio in plasma, and a positive correlation between tumour burden and plasma kynurenine level.

Conclusions

This study suggests that pancreatic cancer may influence mood via the kynurenine pathway. The relationship of the kynurenine pathway with pancreatic tumour burden should be explored further in large multicentre studies because a better understanding of this physiology might have significant clinical benefit.     

The circadian rhythm of biliary colic

We evaluated 50 consecutive patients with symptomatic gallstones for the clinical features of biliary pain with particular reference to the timing of their painful episodes. Thirty-eight of the 50 patients were able to provide the time of onset of biliary pain in the 24-h cycle. The time of onset of biliary pain displays significant circadian periodicity (p = 0.0032), with its peak at 00:25 h. Forty-five patients had more than 1 episode of pain. Of these 84% had either all or over half of their attacks of biliary pain at the same clock time. Twenty-two patients with renal colic (a close parallel to biliary pain) and 31 patients with episodic abdominal pain from miscellaneous causes showed no circadian or other periodicity in the time of onset of pain. In only 1 of these patients did the abdominal pain recur consistently at the same clock time. "Typical" biliary pain has its onset at night and tends to recur at the same clock time. It is steady and relatively mild, lasting 1-5 h, it is felt in the right upper quadrant or the epigastrium, may radiate to a variety of sites, is associated with some additional symptoms, and is not usually related to meals. The chronobiological and other features of biliary pain reported here should be useful in the diagnostic evaluation of abdominal pain.     

The circadian rhythm of renin.

The circadian rhythm of plasma renin activity during continuous recumbency was determined fifty-one times in thirty subjects who either slept at night or remained awake for 24 h. Both groups had maximum values between 2400 and 0800 h, despite absence of the expected early morning fall in blood pressure, pulse, and glomerular filtration rate in the awake subjects. Infusion of normal saline between 2300 and 0300 h initially suppressed renin, but did not prevent its subsequent rise regardless of the amount of sodium appearing in the urine. Of thirteen patients tested two to five times, twelve had recurrence of the zenith within a single 4 h period on retesting, despite differences in sodium intake, basal blood pressure, and mean plasma renin activity. Peaks of lesser magnitude were also frequently noted, most commonly at 1000 h and 1800-2000 h. Minimum PRA values were not restricted to a particular time of day and did not generally recur at the same time upon retesting. The mean ratio of maximum to minimum PRA in each study was 246% +/- 18.3% (+/- 1 SEM). The circadian rhythm of renin appears to be independent of known renal mechanisms responsible for regulating renin release. It is possible that this rhythm is controlled by the central nervous system.     

The photobiology of the human circadian clock

In modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory responses of the SCN to primarily blue light, but direct measures in humans are absent. The combination of state-of-the-art neuroimaging techniques and custom-made MRI compatible light-emitting diode devices allowed to directly measure the light response of the SCN. In contrast to the general expectation, we found that blood oxygen level–dependent (BOLD) functional MRI signals in the SCN were suppressed by light. The suppressions were observed not only in response to narrowband blue light (λ_max: 470 nm) but remarkably, also in response to green (λ_max: 515 nm) and orange (λ_max: 590 nm), but not to violet light (λ_max: 405 nm). The broadband sensitivity of the SCN implies that strategies on light exposure should be revised: enhancement of light levels during daytime is possible with wavelengths other than blue, while during nighttime, all colors are potentially disruptive.

Due to the Earth’s rotation around its axis, many organisms developed an internal clock to anticipate the predictable changes in the environment that occur every 24 h, including the daily light–dark cycle. In mammals, this clock is located in the suprachiasmatic nucleus (SCN), located in the hypothalamus directly above the optic chiasm (1, 2). The SCN receives information from the retina regarding ambient light levels via intrinsically photosensitive retinal ganglion cells (ipRGCs), thus synchronizing its internal clock to the external light–dark cycle. ipRGCs contain the photopigment melanopsin, which is maximally sensitive to blue light, with a peak response to 480-nm light (3, 4). In addition, ipRGCs also receive input from rod cells and cone cells (5–7). The three cone cell subtypes in the human retina respond maximally to 420-nm, 534-nm, and 563-nm light, while rod cells respond maximally to 498-nm light (8). In rodents, input from cone cells renders the SCN sensitive to a broad spectrum of wavelengths (9), while rod cells mediate the SCN’s sensitivity to low-intensity light (10, 11). Recently, these findings in rodents were proposed to translate to humans (12), suggesting that the human clock is not only sensitive to blue light, but may also be sensitive to other colors.In humans, circadian responses to light are generally measured indirectly (e.g., by measuring melatonin levels or 24-h behavioral rhythms). These indirect measures revealed that circadian responses to light in humans are most sensitive to blue light (13–16); however, green light has also been found to contribute to circadian phase shifting and changes in melatonin to a larger extent than would have been predicted based solely on the melanopsin response, suggesting that rods and/or cones may also provide functional input to the circadian system in humans (17). Despite this indirect evidence suggesting that several colors can affect the human circadian clock, this has never been measured directly due to technical limitations. Thus, current guidelines regarding the use of artificial light are based solely on the clock’s sensitivity to blue light. For example, blue light is usually filtered out in electronic screens during the night (18, 19), and blue-enriched light is used by night shift workers to optimize their body rhythm for achieving maximum performance (20–22).The ability to directly image the human SCN in vivo has been severely limited due to its small size and the relatively low spatial resolution provided by medical imaging devices. Previous functional MRI (fMRI) studies using 3-Tesla (3T) scanners were restricted to recording the “suprachiasmatic area,” which encompasses a large part of the hypothalamus and thus includes many other potentially light-sensitive nuclei (23–25). To overcome this limitation, we used a 7T MRI scanner, which can provide images with sufficiently high spatial resolution to image small brain nuclei (26) such as the SCN. Here, we applied colored light stimuli to healthy volunteers using a custom-designed MRI-compatible light-emitting diode (LED) device designed to stimulate specific photoreceptors while measuring SCN activity using fMRI. Using analytical approaches, we then identified the SCN’s response, the smallest brain nucleus that has so far been imaged. We found that the human SCN responds to a broad range of wavelengths (i.e., blue, green and orange light). Surprisingly, we also found that the blood oxygen level–dependent (BOLD) fMRI signal at the SCN is actually suppressed—not activated—by light.     

The circadian clock controls the expression pattern of the circadian input photoreceptor, phytochrome B

Developmental and physiological responses are regulated by light throughout the entire life cycle of higher plants. To sense changes in the light environment, plants have developed various photoreceptors, including the red/far-red light-absorbing phytochromes and blue light-absorbing cryptochromes. A wide variety of physiological responses, including most light responses, also are modulated by circadian rhythms that are generated by an endogenous oscillator, the circadian clock. To provide information on local time, circadian clocks are synchronized and entrained by environmental time cues, of which light is among the most important. Light-driven entrainment of the Arabidopsis circadian clock has been shown to be mediated by phytochrome A (phyA), phytochrome B (phyB), and cryptochromes 1 and 2, thus affirming the roles of these photoreceptors as input regulators to the plant circadian clock. Here we show that the expression of PHYB::LUC reporter genes containing the promoter and 5' untranslated region of the tobacco NtPHYB1 or Arabidopsis AtPHYB genes fused to the luciferase (LUC) gene exhibit robust circadian oscillations in transgenic plants. We demonstrate that the abundance of PHYB RNA retains this circadian regulation and use a PHYB::Luc fusion protein to show that the rate of PHYB synthesis is also rhythmic. The abundance of bulk PHYB protein, however, exhibits only weak circadian rhythmicity, if any. These data suggest that photoreceptor gene expression patterns may be significant in the daily regulation of plant physiology and indicate an unexpectedly intimate relationship between the components of the input pathway and the putative circadian clock mechanism in higher plants.     

Neurochemical basis for the photic control of circadian rhythms and seasonal reproductive cycles: role for acetylcholine.

A pharmacological approach was used to examine the role of acetylcholine in the photic control of circadian rhythms and seasonal reproductive cycles. The experimental protocol was designed to determine whether the administration of carbachol, a cholinergic agonist, could mimic the effects of brief light pulses on gonadal function and/or the circadian rhythm of wheel-running activity in golden hamsters. Intraventricular injections of carbachol, administered singularly at discrete phase points throughout the circadian cycle, induced phase-dependent shifts in the free-running rhythm of activity similar to those caused by a brief light exposure. Injections of carbachol once every 23.33 hr for 9 weeks entrained the activity rhythm and stimulated the neuroendocrine-gonadal axis in a manner similar to that observed after the presentation of 1-hr light pulses at this frequency. In contrast, the administration of carbachol once every 24 hr did not consistently provide an entraining signal for the activity rhythm and did not stimulate reproductive function. Importantly, the effects of carbachol on the seasonal reproductive response were correlated with the timing of the injections relative to the activity rhythm. These findings suggest that acetylcholine may play an important role in the mechanism by which light regulates circadian rhythms and seasonal reproductive cycles.     

The circadian clock in old Drosophila melanogaster

A growing body of evidence indicates that one of theage-associated changes in the central nervous systemthat affect most old people is the loss of functionof the circadian clock system. This loss results inimpaired timing and quality of sleep, with consequentcognitive and other behavior problems. Failure of theclock contributes to the difficulties encountered withAlzheimer's disease. It also results in adversechanges in the hormonal regulation of intermediarymetabolism, stress resistance and sexual function.Drosophila melanogaster is proposed as a modelorganism where this age-related change may be studiedmore readily. Circadian patterns are disrupted inDrosophila, with considerable differences betweenstrains. In addition a fusion gene product of a keygene involved in the clock (per), and GreenFluorescent Protein, shows a 50% fall with age.     

The pathologic basis of angioplasty

Traditionally it has been said that transluminal angioplasty increases lumen diameter by compression and remodeling of atheromatous material. Recently, a new concept explaining the mechanics of angioplasty was described which challenges the classic concept of Dotter. It was argued that arterial balloon dilatation is achieved by intimal disruption and overstretching of the arterial wall, not by remodeling of atheromatous material.     

The genetic basis of cardiomyopathy

Cardiomyopathies are the primary disorders of cardiac myocytes, and their cause is usually genetic. The three common forms are hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Mutations in sarcomeric proteins typically cause HCM and, less commonly, DCM. Mutations in cytoskeletal proteins cause DCM, and those in desmosomal proteins cause ARVC. The pathways from mutations to the clinical phenotype could be categorized into three stages of initial functional defects leading to expression and activation of molecular events that mediate development of morphologic and structural phenotypes. Advances in understanding the molecular genetics and pathogenesis of cardiomyopathies could provide the opportunity for preclinical diagnosis and interventions to prevent, attenuate, or reverse the evolving phenotypes.