Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels

Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5-HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse.     

Quantum heat engine power can be increased by noise-induced coherence

Laser and photocell quantum heat engines (QHEs) are powered by thermal light and governed by the laws of quantum thermodynamics. To appreciate the deep connection between quantum mechanics and thermodynamics we need only recall that in 1901 Planck introduced the quantum of action to calculate the entropy of thermal light, and in 1905 Einstein’s studies of the entropy of thermal light led him to introduce the photon. Then in 1917, he discovered stimulated emission by using detailed balance arguments. Half a century later, Scovil and Schulz-DuBois applied detailed balance ideas to show that maser photons were produced with Carnot quantum efficiency (see Fig. 1A). Furthermore, Shockley and Quiesser invoked detailed balance to obtain the efficiency of a photocell illuminated by “hot” thermal light (see Fig. 2A). To understand this detailed balance limit, we note that in the QHE, the incident light excites electrons, which can then deliver useful work to a load. However, the efficiency is limited by radiative recombination in which the excited electrons are returned to the ground state. But it has been proven that radiatively induced quantum coherence can break detailed balance and yield lasing without inversion. Here we show that noise-induced coherence enables us to break detailed balance and get more power out of a laser or photocell QHE. Surprisingly, this coherence can be induced by the same noisy (thermal) emission and absorption processes that drive the QHE (see Fig. 3A). Furthermore, this noise-induced coherence can be robust against environmental decoherence.Open in a separate windowFig. 1.(A) Schematic of a laser pumped by hot photons at temperature T_h (energy source, blue) and by cold photons at temperature T_c (entropy sink, red). The laser emits photons (green) such that at threshold the laser photon energy and pump photon energy is related by Carnot efficiency (4). (B) Schematic of atoms inside the cavity. Lower level b is coupled to the excited states a and β. The laser power is governed by the average number of hot and cold thermal photons, and . (C) Same as B but lower b level is replaced by two states b₁ and b₂, which can double the power when there is coherence between the levels.Open in a separate windowFig. 2.(A) Schematic of a photocell consisting of quantum dots sandwiched between p and n doped semiconductors. Open circuit voltage and solar photon energy ℏν_h are related by the Carnot efficiency factor where T_c is the ambient and T_h is the solar temperature. (B) Schematic of a quantum dot solar cell in which state b is coupled to a via, e.g., solar radiation and coupled to the valence band reservoir state β via optical phonons. The electrons in conduction band reservoir state α pass to state β via an external circuit, which contains the load. (C) Same as B but lower level b is replaced by two states b₁ and b₂, and when coherently prepared can double the output power.Open in a separate windowFig. 3.(A) Photocell current j = Γρ_αα (laser photon flux P_l/ℏ_νl) (in arbitrary units) generated by the photovoltaic cell QHE (laser QHE) of Fig. 1C (Fig. 2C) as a function of maximum work (in electron volts) done by electron (laser photon) E_α - E_β + kT_c log(ρ_αα/ρ_ββ) with full (red line), partial (brown line), and no quantum interference (blue line). (B) Power of a photocell of Fig. 2C as a function of voltage for different decoherence rates , 100γ_1c. Upper curve indicates power acquired from the sun.Quantum mechanics began with the thermodynamic studies of Planck (1) and Einstein (2). In later work Einstein introduced the concept of stimulated emission via the detailed balance arguments (3). After the advent of the maser, Scovil and Schulz-DuBois (4) showed the quantum efficiency for the maser is described by a Carnot relation, and Shockley and Quiesser (5) used detailed balance limit to obtain a similar relation for a photocell. However, in the later part of the twentieth century it was shown that detailed balance could be superseded by using quantum coherence; this is manifested in lasing without inversion (6–8).Recent studies of a photocell QHE (9) show that it is possible to use microwave induced coherence to break detailed balance and enhance quantum efficiency (i.e., open circuit voltage). But what about enhancing the cell power? It takes energy to generate the microwaves—can we avoid this? A similar question can be asked concerning the laser QHE: Can we use quantum coherence to increase the net emitted laser power? More to the point, can we increase the power output of, for example, a photocell by using noise-induced coherence (10) such as that produced by Fano interference, to break detailed balance? The perhaps surprising (11) answer is yes.^*To answer this question, let us consider the case in which the lowest level is replaced by the pair of levels as in Fig. 1C. Now the plot thickens. In addition to producing a population inversion, the hot and cold photons can induce coherence between levels b₁ and b₂; where the amount of coherence is determined by the off diagonal matrix elements (12, 13) ρ_b1b2 = ρ₁₂ given in Eq. 3. We find that this coherence can markedly enhance the power [see also Fleischhauer et al. (14, 15) and Kozlov et al. (16)].The coherence induced by the hot and cold thermal radiation can be obtained from the density matrix equations of motion (see Appendix). To understand the physical origin of the noise-induced coherence we consider the probability ρ₁₁ of being in the state b₁, which obeys the following equation of motion with physical interpretation depicted on the next line: †, and are average number of hot and cold thermal photons (17) given by the Planck factors , .The power generated by the laser is [2]where is the average number of laser photons, g is atom-field coupling constant, and γ_l is the spontaneous decay rate at the lasing transition a → β.Thus, as discussed in Appendix and in SI Text, we solve the density matrix equations for populations ρ_aa and ρ_ββ as well as quantum coherence ρ₁₂ in steady state. For γ_1h = γ_2h = γ_h, γ_1c = γ_2c = γ_c the maximum coherence and laser power (18) are given by [3]where rate A is a function of decay rates γ_c and γ_h and the Planck average photon numbers , (see Appendix and SI Text). For the appropriate choice of parameters^‡, A = γ_h for the system with no coherence and A = 2γ_h with coherence—i.e., the power can be doubled (18), as in Fig. 1. Furthermore, Figs. 1 and ​and33 show that laser power can be significantly enhanced in the presence of coherence in general. Physically this is because the coherence can lead to faster removal of atoms from the ground state b_1,2 to the upper laser level a increasing useful work. That is, quantum coherence and interference enhances absorption of solar photons; because the terms result in redistribution of the population between b₁ and b₂ states such that the state with stronger coupling to the upper level a becomes more populated. This increases the number of absorbed photons and the current through the cell. Such interference can enhance photon absorption as in the present model or suppress it, which is the case for lasing without inversion.Next we consider the photocell QHE of Fig. 2 and study the influence of quantum interference and coherence on PV operation (i.e., power generated). Here we will consider a narrow band of frequencies as in the case of a multiplex array of photocells. That is, to optimally utilize a broad solar spectrum one can divide the incident solar flux into narrow frequency intervals, each of which is directed to a quantum dot photocell with its energy spacing matched to the incident light. Monochromatic solar radiation excites electrons from the valence to conduction states in the quantum dots. The “built-in” field in the depletion layer separates electrons and holes; however, they can radiatively recombine before being separated. In the complete analysis (see SI Text) we consider the general coupling associated with emission and absorption of solar photons and thermal phonons. This requires a little more elaborate density matrix treatment but the physics is essentially the same as the preceding laser problem. Furthermore, we here focus on the power generated, not the open circuit voltage, as is the case in ref. 9. However, the issue of breaking detailed balance in a photocell via quantum coherence remains the essence of the problem.In the photocell model (19, 20) of Fig. 2 B and C the cell current j and voltage V between levels α and β are given by (see Appendix) [4]where Γ is the decay of level α and ρ_ii(i = α,β) are the occupation probabilities of states in the conduction and lower energy valence reservoirs having energies E_α and E_β. If levels b₁ and b₂ are degenerate and γ_1h = γ_2h = γ_h the quantum coherence and power = jV are found to be [5]which is similar to Eq. 3 for the laser QHE in which the laser photon flux P_l/ℏν_l is now replaced by the photocell current. Factor B is similar to A and for the appropriate choice of parameters^§ B = γ_h/2 for the system with singlet shown in Fig. 2B, B = 2γ_h/3 for the doublet model (Fig. 2C), and no coherence and B = γ_h with full coherence—i.e., the photocell QHE power can be doubled by quantum coherence just as in the case of the laser.Fig. 3A shows the photocell current j (photon flux P_l/ℏν_l) as a function of voltage (energy) of the electrons (laser photons). We find that the induced coherence substantially increases the cell current (photon flux) and therefore the power of the QHE. As in the laser QHE, quantum coherence in the photocell QHE results in the faster removal of electrons from the recombination region, so that we can reduce the a → b_1,2 transition and enhance the photocurrent α → β. This reduces recombination losses and increases the power delivered to the load. For example, in the limit of a weak pump, , appropriate for a photodetector, the signal power is doubled by quantum coherence^¶ (see Fig. 2B and C).It is important to note that effects of environmentally induced decoherence τ₂ on photocell power can be made small by proper cell design. For the typical case in which the phonon occupation number is large, Eq. 8 shows that the stimulated phonon absorption term dominates other possible decoherence channels (τ₂ effects) even when the environmental effect is substantial . As a result, one can have a photocell with P-V characteristics shown in Fig. 3B such that the noised induced quantum coherence is robust against environmental decoherence.^||To summarize: There exists a close analogy between the laser QHE pumped by hot photons and cooled by a lower temperature entropy sink and a photocell QHE that is driven by hot photons while the ambient heat reservoir serves as the lower temperature entropy sink (21). Furthermore, we have shown that quantum interference can enhance laser and PV thermodynamic power beyond the limit of a system, which does not possess quantum coherence. Moreover, coherence generated by noise-induced quantum interference is essentially different from the quantum coherence produced by an external microwave field (9), which costs energy. In the present paper, quantum coherence is generated by the photocurrent due to quantum interference. No additional energy source is necessary to create such induced coherence. Nevertheless, as we have shown, the induced coherence can, in principle, enhance the efficiency of photovoltaic devices such as solar cells and/or photodetectors. We note that in the case of solar cells, the power generated^** is always less than the incident power times the Carnot factor—i.e., . In the case of photodetector operating at low temperature the phase coherence time T₂ can be relatively long, and applications of the present work to photodetection near at hand. Practical application to solar cell systems is possible but requires further research. However it is clear that the ultimate “in principle” limit of such devices is an important question of fundamental interest.     

A phase I trial of everolimus in combination with 5-FU/LV,mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors

Purpose

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.

Methods

Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.

Results

Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.

Conclusions

While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.