I heard the bells on Christmas Day
Their old, familiar carols play,
And wild and sweet the words repeat
Of peace on earth, good-will to men!

~Henry Wadsworth Longfellow~

Abstract The gold standard for determining the efficacy of biomedical therapies is the detection of a significant difference between the therapeutic effects of an active pharmacological agent or procedure and a matched inert placebo in a randomized controlled trial. Detecting this difference has become a challenge for medicine, especially for outcomes that are based on patient self-rated scales. Yet factors that contribute to placebo responses have received scant attention. In this issue of Science Translational Medicine, Bingel et al. report on an example of how noninvasive whole-brain imaging contributes to our understanding of brain-based placebo effects. Here we highlight ways in which neuroimaging is catalyzing a revolution in society's perspective of placebo effects by providing a compelling visualization of how brain activities that reflect a person's thoughts, feelings, and past experiences can enhance or antagonize his or her response to a medical treatment.

Abstract Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: 1) with no expectation of analgesia, 2)with expectancy of a positive analgesic effect, and 3) with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

It is generally considered that the absorption of Mg is inversely related to the ingested dose. The objective of the present study was to determine if the mode of administration (bolus v. consumption throughout the day) could influence Mg bioavailability from Mg-rich natural mineral water comparing the same nutritional Mg amount (126 mg). Using a 2 d cross-over design, twelve healthy men were asked to drink 1·5 litres Mg-rich mineral water either as 2 Χ 750 ml or 7 Χ 212 ml throughout the day. Two stable isotopes (25Mg and 26Mg) were used to label the water in order to distinguish both regimens. Fractional apparent Mg absorption was determined by faecal monitoring and Mg retention was determined by measuring urinary excretion of Mg isotopes. Higher Mg absorption (50·7 (sd 12·7) v. 32·4 (sd 8·1) %; P = 0·0007) and retention (47·5 (sd 12·9) v. 29·0 (sd 7·5) %; P = 0·0008) from Mg-rich mineral water were observed when it was consumed in seven servings compared with larger servings. Thus, regular water consumption throughout the day is an effective way to increase Mg bioavailability from Mg-rich mineral water.

Alzheimer's disease is a devastating disease whose recent increase in incidence rates has broad implications for rising health care costs. Huge amounts of research money are currently being invested in seeking the underlying cause, with corresponding progress in understanding the disease progression. In this paper, we highlight how an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer's disease. A first step in the pathophysiology of the disease is represented by advanced glycation end-products in crucial plasma proteins concerned with fat, cholesterol, and oxygen transport. This leads to cholesterol deficiency in neurons, which significantly impairs their ability to function. Over time, a cascade response leads to impaired glutamate signaling, increased oxidative damage, mitochondrial and lysosomal dysfunction, increased risk to microbial infection, and, ultimately, apoptosis. Other neurodegenerative diseases share many properties with Alzheimer's disease, and may also be due in large part to this same underlying cause

Learning points 1. The amyloid-β present in Alzheimer's plaque may not be causal, since drug induced suppression of its synthesis led to further cognitive decline in the controlled studies performed so far. 2• Researchers have identified mitochondrial dysfunction and brain insulin resistance as early indicators of Alzheimer's disease. 3• ApoE-4 is a risk factor for Alzheimer's disease, and ApoE is involved in the transport of cholesterol and fats, which are essential for signal transduction and protection from oxidative damage. 4• The cerebrospinal fluid of Alzheimer's brains is deficient in fats and cholesterol. 5• Advanced glycation end-products (AGEs) are present in significant amounts in Alzheimer's brains. 6• Fructose, an increasingly pervasive sweetening agent, is ten times as reactive as glucose in inducing AGEs. 7• Astrocytes play an important role in providing fat and cholesterol to neurons. 8• Glycation damage interferes with the LDL-mediated delivery of fats and cholesterol to astrocytes, and therefore, indirectly, to neurons. 9• ApoE induces synthesis of Aβ when lipid supply is deficient. 10• Aβ redirects neuron metabolism towards other substrates besides glucose, by interfering with glucose and oxygen supply and increasing bioavailability of lactate and ketone bodies. 11• Synthesis of the neurotransmitter, glutamate, is increased when cholesterol is deficient, and glutamate is a potent oxidizing agent. 12• Over time, neurons become severely damaged due to chronic exposure to glucose and oxidizing agents, and are programmed for apoptosis due to highly impaired function. 13• Once sufficiently many neurons are destroyed, cognitive decline is manifested. 14• Simple dietary modification, towards fewer highly-processed carbohydrates and relatively more fats and cholesterol, is likely a protective measure against Alzheimer's disease.