Investigating metabolic regulation using targeted neuromodulation.

The central nervous system (CNS) plays a vital role in regulating energy balance and metabolism. Over the last 50 years, studies in animal models have allowed us to identify critical CNS regions involved in these processes and even crucial cell populations. Now, techniques for genetically and anatomically targeted manipulation of specific neural populations using light (optogenetic), ligands (chemogenetic), or magnetic fields (radiogenetic/magnetogenetic) allow detailed investigation of circuits involved in metabolic regulation. In this review, we provide a brief overview of recent studies using light- and magnetic field-regulated neural activity to investigate the neural circuits contributing to metabolic control.

Pontomesencephalic Tegmental Afferents to VTA Non-dopamine Neurons Are Necessary for Appetitive Pavlovian Learning.

The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning.

Psychological distress and health-related quality of life among head and neck cancer patients during the first year after treatment.

PURPOSE: Patients treated for head and neck cancer present some of the most significant posttreatment morbidity of any group of patients with cancer. Our aim is to describe quality of life and psychological distress after different treatments among head and neck cancer patients during the first year after treatment. METHODS: A total of 86 patients treated for head and neck cancer were evaluated within 1 year of the end of treatment by means of the Distress Thermometer (DT) and EORTC C30 and H&N35 questionnaires. Type of treatment was classified into 3 groups: surgery, chemo-/radiotherapy, and combined treatment. RESULTS: Forty-one percent of patients showed a high level of distress (DT >5). Distress was higher in patients with a tracheotomy or with previous cancer in another district. Quality of life was homogeneous across treatment types after adjustment for stage and time since end of treatment, except for higher levels of suffering related to sensory problems, social eating, and dry mouth among patients treated with combined therapy. CONCLUSIONS: The DT and EORTC questionnaires proved to be effective and easy tools to monitor distress and quality of life in patients with head and neck cancer. Monitoring the quality of life perceived by each patient during his/her course of treatment could be useful in planning the rehabilitation process while performing follow-up visits.

Experimental simulation of radio- and chemoradio stomatitis in rats.

Experimental models of stomatitis developing in response to an isolated (radiation) and combined (radiation and chemical) exposure of experimental animals, were created. The severity of radiation-induced stomatitis was determined by the dose of radiation exposure. Additional exposure to a chemical factor (cyclophosphamide) augmented the destructive effect of ionizing radiation on the buccal mucosa of rats.

Development of an oral assessment tool to evaluate appetite in patients with head and neck cancer receiving radiotherapy.

PURPOSE: The objective of this study was to develop an oral assessment tool for evaluating the appetite of patients with head and neck cancer receiving radiotherapy, who had dysgeusia, xerostomia, and oral mucositis, as well as to verify its validity and reliability. METHODS AND SAMPLE: A draft oral assessment tool, which included a 5-point scale and 19 items, was prepared based on an interview survey of 30 patients. The resultant questionnaire survey was provided to 209 subjects. RESULTS: On the basis of factor analysis of construct validity, 3 factors (dysgeusia and loss of favors), (salivation abnormality and loss of moisture in the oral cavity), and (pain in the oral cavity and lack of motivation) comprising 14 items were adopted for the final survey. During a review of criteria validity, a correlation was found between the scores of the three factors and overall oral assessment tool, and the scores of taste sensitivity, xerostomia, oral mucositis, and appetite with a correlation coefficient of r = 0.41-0.89 (p < 0.01). With regard to reliability, stability was determined as 0.87 (p < 0.01) according to test-retest study results. Internal consistency was confirmed by a Cronbach's alpha coefficient of 0.83 (p < 0.01) and an interclass correlation coefficient of 0.80 (p < 0.01). CONCLUSIONS: On the basis of the validity and reliability of the oral assessment tool developed, it has been found to be practical for use in the assessment of appetite of patients with head and neck cancer.

Adverse effects and appetite suppression associated with particle beam therapy in patients with head and neck cancer.

AIM: This purpose of this study was to investigate the relationship between the appetite and various factors that are associated with particle beam therapy, including the adverse effects of radiation, dry-mouth period, analgesic medication use, frequency of oral care, and participants' characteristics, in 121 patients with head and neck cancer. METHODS: A path analysis was used to evaluate the causal relationship of the factors that affected the participants' appetite. RESULTS: At a cumulative dose of 40 GyE, the factors that impacted the participants' appetite included xerostomia, oral mucositis, age, frequency of oral care, and analgesic medication use. At a cumulative dose of 50 GyE, the factors that affected the participants' appetite were xerostomia, sensitivity to taste, oral mucositis, dry-mouth period (in the morning), frequency of oral care, number of artificial teeth, and analgesic medication use. The results indicate that interventions to avoid appetite suppression during particle beam therapy will differ according to a radiation schedule of 40 GyE, compared to 50 GyE. CONCLUSIONS: These results are important to consider when deciding how best to maintain the dietary intake of patients who are receiving particle beam therapy.

Appetite and adverse effects associated with radiation therapy in patients with head and neck cancer.

PURPOSE: The relationship between radiation treatment and adverse effects resulting in changes in appetite was studied in patients with head and neck (H&N) cancer. METHODS AND SAMPLE: Path analysis was used to evaluate the following factors in 117 patients receiving radiation therapy for H&N cancer: daily fluctuations in saliva production, analgesic use, frequency of oral care, subject characteristics, and appetite. RESULTS: At 20 Gy of radiation, appetite was affected by Brinkman index value, age, and sensitivity to taste (R2=0.48, p<0.001); at 30 Gy of radiation, appetite was affected by frequency of oral care, xerostomia symptoms, age, sensitivity to taste, and oral mucositis (R2=0.52, p<0.001); and at 50 Gy of radiation, appetite was affected by low saliva production in the morning, frequency of oral care, xerostomia symptoms, sensitivity to taste, analgesic use, and oral mucositis (R2=0.62, p<0.001). CONCLUSIONS: The results of this study suggest that care taken to avoid a decrease in appetite due to adverse effects of radiation therapy should differ according to the dosage and schedule of radiation therapy. These findings represent important data for health care professionals to understand and support appropriate dietary intake and improved quality of life for H&N cancer patients receiving radiation therapy.

Light experience and the development of behavioural lateralization in chicks III. Learning to distinguish pebbles from grains.

Chicks searching for food grains against a background of unfamiliar pebbles usually peck pebbles less when using the right eye (RE), or both eyes, than when using the left eye (LE), provided that the embryo's RE has been exposed to light (Li), as is normal. When pecking is fast this right/left difference is mainly due to a heightened ability of RE chicks to inhibit premature pecks (and inappropriate responses in general). Dark incubation (Da) abolishes this ability in RE chicks, and RE and LE chicks show similar frequent pebble pecks. We show now that, under conditions that cause cautious pecking, both Li and Da chicks show a new effect: in both cases LE chicks peck pebbles more than RE chicks, probably because of the novelty of pebbles. Interest in novelty in LE chicks is known to be unaffected by light in incubation. Age-dependent effects are also important. RE and LE chicks, which had either the LE or RE exposed to light before hatching, were tested on days 3, 5, 8 or 12 post-hatching, under conditions giving normal fast pecking. Artificial exposure of the embryo's LE to light reversed the lateralization: in general, chicks using the light-exposed eye performed well at all ages. Irrespective of which eye system had heightened ability to inhibit pebble pecks, RE performance differed from usual on 2 days, whereas LE chicks showed no age-dependent changes. Changes confined to the RE system, therefore, affect behaviour independently of lateralization of the ability to inhibit inappropriate response.

Acute radiation toxicity assessment of a 3-D conformal head and neck radiation treatment technique.

Patients undergoing radiation treatment for head and neck cancer have many critical structures within or adjacent to the treatment area. Avoiding these critical structures is more efficient and easier using 3-D conformal planning. At Sir Charles Gairdner Hospital an investigation into the acute radiation toxicity was undertaken when the head and neck treatment technique was changed from the conventional 2-D plan to the conformal 3-D plan. Although the primary target volume (PTV), fraction size and overall dose remain the same for the two techniques, differing beam configurations mean that treatment fields enter and exit through different parts of the head and neck. Ten patients were initially assessed to gain a baseline appearance of their head and neck region, and then graded weekly according to the toxicity criteria during treatment and at 4, 8 and 12 weeks after treatment. The results of the assessment indicate that there is no increase in toxicity as a result of treating using the conformal head and neck technique.

Subchronic in vivo effects of a high static magnetic field (9.4 T) in rats.

The potential adverse biologic effects of sub chronic (cumulatively 10 weeks) exposure to a high magnetic field (9.4 T) were evaluated in young adult male and female Fischer rats as well as in their progeny. Biologic end points in adult rats included changes in daily clinical observations; spatial memory tests; weekly heart rates, body weights, food and water consumption, and the feed efficiency ratio; terminal hematologic, blood biochemical and urinary parameter changes; gross pathologic findings; and major organ weights. In offspring, biologic end points included the gestation period, number of live births, number of pups, ratio of male to female pups/litter; postnatal time period of eye opening; birth and weekly body weights, behavioral changes, central nervous system responses, as well as hematologic, blood biochemistry, and urinary parameter changes; and gross pathologic findings. Findings from this study showed that there were no adverse biologic effects in male and female adult rats or their progeny that could be attributed to 10-week exposure to a 9.4-T static magnetic field.

Concomitant chemoradiotherapy for patients with nonmetastatic breast carcinoma: side effects, quality of life, and organization.

BACKGROUND: This study was designed to investigate the personal experience of patients with nonmetastatic breast carcinoma who were treated with the concurrent administration of radiotherapy and chemotherapy in terms of side effects and quality of life (QL). METHODS: One hundred nine patients with nonmetastatic breast carcinoma, recruited between May 1995 and February 1997, were included in a protocol combining chemotherapy with mitoxantrone and cyclophosphamide, administered intravenously in 4 cycles of 21 days, and concomitant radiotherapy. Side effects of treatment and its impact on patients' daily lives were measured using ad hoc questionnaires; QL was measured by the European Organization for Research and Treatment of Cancer QLQ-C30 QL questionnaire, and pain was measured by a visual analogue scale (VAS). RESULTS: All patients agreed to participate. The mean number of chemotherapy and radiotherapy symptoms per cycle were: 7.2+/-2.5 and 2.4+/-1.8, respectively. Chemotherapy symptoms generally were more frequent and distressing than those of radiotherapy. The average pain score reported on the VAS by patients during treatment was 3.0+/-2.0. Multidimensional QL assessment showed that treatment mainly affects physical functioning and global QL. Multivariate analysis showed that the main determinants of QL at the end of treatment were fatigue, pain, and loss of appetite experienced during treatment. Moreover, 62.8% of patients required specific help for transportation to the hospital and/or home upkeep. CONCLUSIONS: The concurrent administration of chemotherapy and radiotherapy deteriorates patients' QL but in a proportion similar to sequential administration while presenting the advantage of a shorter duration of treatment. However, increased fatigue, pain, and loss of appetite as well as difficulties in patients' daily lives have to be taken into account in therapeutic decision-making analysis.

Supportive care in radiotherapy: a review.

The normal tissue tolerance and the related early side effects represent the main constraint on the total radiation dose which can be administered to the target volume. The most common disorders during radiotherapy or chemo-radiotherapy are summarized in this review. Since in the recent years great advances have been made towards the improvement of acute tolerance, practically every adverse symptoms can be controlled or lowered with an adequate treatment. Some suggestions are reported in order to prevent or lower the degree and the incidence of major complications, specifically mucositis-related symptoms like stomatitis, diarrhea, cystitis. Possibly, a multicenter effort is to be made in order to optimize the quality of supportive care for irradiated patients in all radiation therapy centers.

Nutritional consequences of the radiotherapy of head and neck cancer.

Nutrition-related complications of radiotherapy were evaluated in 74 head and neck cancer patients. Subjective changes of mouth dryness, taste, dysphagia, appetite, and food preferences were determined by questionnaire before and at weekly intervals during curative radiotherapy. Changes in body weight during therapy were also recorded. In addition, 24-hour dietary histories were taken from eight patients at the beginning and end of treatment. Results of the study indicate that patients were subjectively aware of nutritional problems prior to therapy and that therapy exacerbated these problems. As many as 25% of the patients experienced oral complications such as taste loss and/or dry mouth prior to initiation of radiotherapy. By the end of radiotherapy, over 80% of the patients were aware of oral and nutritional problems. Patients had an average weight loss of 5 kg prior to therapy; this loss of weight did not change during therapy. Diet histories of eight patients indicate significant caloric deficiencies early and late in radiotherapy. The oral and nutritional problems experienced by patients, even prior to therapy, support the idea that nutritional evaluation and maintenance are important not only during therapy, but prior to radiotherapy as well. Nutritional evaluation should be made a routine, integral part of therapy for every cancer patient.

Appetite perversions and taste changes triggered or abolished by radiotherapy.

Special questioning of 819 oncology patients whose treatment included radiotherapy has revealed 147 instances where local tumour radiation--apparently regardless of tumour type, site, or volume radiated-has either triggered (97 cases) or abolished (50 cases) an isolated appetite perversion. Both effects typically occur when a dose of about 500-1500 cGy has been reached and at a stage when little, if any, tumour regression is evident. No correlation can be seen with anorexia or with the usually recognised side effects of radiotherapy. Spontaneous return to normal is quite common in cases triggered by tumour treatment, but rare in cases starting before diagnosis. The latter may cease when the tumour is treated. The explanation for these highly selective and rapidly reversible aversions or cravings is totally obscure, but questioning large numbers of patients has provided certain clues, including frequent descriptions of an underlying change in taste or odour and also close links with two other equally unexplained phenomena--(1) alcohol intolerance in tumour patients and (2) the cravings and aversions of pregnancy.

The biological effects of magnetic fields on man.

The biological effects of the interaction of stationary magnetic fields (SMF) with man and other animals have been reviewed. The lowest detectable limit of interaction between higher animals and a SMF is 80 to 100 G. The recommended limit on an extended-period basis for whole-body or head exposure is 200 G. Higher limits of magnetic-field exposure for limited periods of time are contained within this report.