Circular Medicine - Being Mindful of Resources and Waste Recycling in Healthcare Systems.

In the light of the COP27 Climate Change Conference, the concept of the circular economy has come to the fore with promotion of reuse and recycling of appliances and materials from electronics to clothes. This concept has not been widely taken up by healthcare systems. In this perspective article, we discuss the idea of the circular economy and how, by extension, the concept of "circular medicine" with optimised hospital and medical clinic waste recycling might be promoted in the context of better stewardship of resources in healthcare management.

Mindfulness in Gastroenterology Training and Practice: A Personal Perspective.

BACKGROUND: Work-related stress is becoming an increasingly recognised occupational hazard that can have detrimental effects on the health of both patient and doctor. The practice of gastroenterology not only includes the demands of clinics and in-patient work faced by other medical specialities but also the additional burden of complex, and often high-risk, endoscopic interventions. Mindfulness, a secular form of meditation, can relieve stress, even if only practiced for a few minutes a day. METHODS AND RESULTS: We present a personal perspective of the burnout experienced in stressful gastroenterology careers and the personal use of mindfulness in the daily routine to provide a source of calm when surrounded by many different pressures. We review some of the literature exploring the role of mindfulness in clinical practice with an emphasis on gastroenterology. While the practice of mindfulness is not designed to obviate immediacy and quick decisions in a rapidly changing clinical environment, it has been held widely useful to mitigate the stress involved in making those decisions. CONCLUSION: Practicing mindfulness, meditation and mindful living offers many advantages to gastroenterologists' wellbeing as well improved patient care. We advocate its teaching to both gastroenterology trainees and consultants who are not familiar with the technique.

An unusual case of post-nasal "clicking" after pituitary surgery.

We report a case of a 64-year-old female who represented two months after pituitary surgery with the novel complication of intermittent disabling post-nasal pulsatile "clicking". Imaging and endoscopic examination showed a residual sella cleft with the tumour capsule and diaphragma cupping against the anterior sella bony defect with each pulsation, causing the clicking. The clicking resolved following second redo surgical endoscopic repair to jail a fat graft within the residual cleft with a central barricade of conchal cartilage graft and onlay standard repair.

Buckwheat R2R3 MYB transcription factor FeMYBF1 regulates flavonol biosynthesis.

Buckwheat (Fagopyrum esculentum) contains high amounts of flavonoids, especially flavonols (e.g., rutin), which are thought to be highly beneficial for human health. Little is known, however, about the regulation of flavonol synthesis in buckwheat. We identified a buckwheat gene encoding an R2R3 MYB transcription factor, and named this gene FeMYBF1. Analysis of the deduced amino acid sequence and phylogenetic analysis suggested that FeMYBF1 encodes an ortholog of the Arabidopsis flavonol regulators AtMYB11, AtMYB12 and AtMYB111. Expression of FeMYBF1 in a flavonol-deficient Arabidopsis triple mutant (myb11 myb12 myb111) restored flavonol synthesis. Constitutive expression of FeMYBF1 driven by the CaMV 35S promoter in Arabidopsis resulted in over-accumulation of flavonol glycosides and upregulation of the expression of AtFLS1. Transient expression assays showed that FeMYBF1 activated the promoter of the Arabidopsis gene encoding AtFLS1, and the promoters of buckwheat genes related to anthocyanin and proanthocyanidin synthesis such as dihydroflavonol 4-reductase (DFR) and leucoanthocyanidin dioxygenase (LDOX) in addition to genes encoding FLS. The results indicate that FeMYBF1 regulates flavonol synthesis and may have a role in synthesis of other flavonoid compounds, and also that buckwheat may have alternative pathway of flavonol synthesis through DFR and LDOX.

Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial.

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. CONCLUSION: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727-1738).

Regional Systems of Care to Optimize Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement.

OBJECTIVES: This study sought to describe the development of a multicenter, transcatheter aortic valve replacement program and regional systems of care intended to optimize coordinated, efficient, and appropriate delivery of this new therapy. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an accepted treatment option for patients with severe aortic stenosis who are at high surgical risk. Regional systems of care have led to improvements in outcomes for patients undergoing intervention for myocardial infarction, cardiac arrest, and stroke. We implemented a regional system of care for patients undergoing TAVR in British Columbia, Canada. METHODS: We describe a prospective observational cohort of 583 patients who underwent TAVR in British Columbia between 2012 and 2014. Regionalization of TAVR care in British Columbia refers to a centrally coordinated, funded, and evaluated program led by a medical director and a multidisciplinary advisory group that oversees planning, access to care, and quality of outcomes at the 4 provincial sites. Risk-stratified case selection for transfemoral TAVR is performed by heart teams at each site on the basis of consensus provincial indications. Referrals for lower volume and more complicated TAVR, including nontransfemoral access and valve-in-valve procedures, are concentrated at a single site. In-hospital and 30-day outcomes are reported. RESULTS: The median age was 83 years (interquartile range [IQR]: 78 to 87 years) and median STS score was 6% (IQR: 4% to 8%). Transfemoral access was performed in 499 (85.6%) cases and nontransfemoral in 84 (14.4%). Transcatheter valve-in-valve procedures in for failed bioprosthetic valves were performed in 43 patients (7.4%). A balloon-expandable valve was inserted in 386 (66.2%) and a self-expanding valve in 189 (32.4%). All-cause 30-day mortality was 3.5%. All-cause in-hospital mortality and disabling stroke occurred in 3.1% and 1.9%, respectively. Median length of stay was 3 days (IQR: 3 to 6 days), with 92.8% of patients discharged directly home. CONCLUSIONS: This experience demonstrates the potential benefits of a regional system of care for TAVR. Excellent outcomes were demonstrated: most patients had short in-hospital stays and were discharged directly home.

Omega-3 fatty acids and/or fluvastatin in hepatitis C prior non-responders to combination antiviral therapy - a pilot randomised clinical trial.

BACKGROUND & AIMS: Hepatitis C virus (HCV) utilises cholesterol and lipoprotein metabolism for replication and infectivity. Statins and omega-3 (n-3) polyunsaturated fatty acids (PUFA) have been shown to have antiviral properties in vitro. This open label pilot study evaluated the efficacy of fluvastatin (Lescol(®) 40-80 mg) and n-3 PUFA (Omacor(®) 1 g and 2-4 g) on HCV-RNA and lipoviral particles (LVP) in difficult to treat prior non-responders. METHODS: Patients (n = 60) were randomly allocated in a factorial design to: no active drug; low-dose n-3 PUFA; high-dose n-3 PUFA; fluvastatin; low-dose n-3 PUFA + fluvastatin; or high-dose n-3 PUFA + fluvastatin. 50/60 completed study drugs for 12 weeks and followed up to week 24. Comparison was made between fluvastatin (n = 24) vs no fluvastatin (n = 26) and n-3 PUFA high-dose (n = 17) vs low-dose (n = 17) vs none (n = 16). The primary outcomes were change in total HCV-RNA, LVP and ALT at week 12 compared with baseline. Secondary outcome was change in interferon-gamma-inducible protein-10 (IP10) as a measure of interferon activation. RESULTS: 35% had compensated cirrhosis and 45% were prior null responders. There was no significant change in total HCV RNA, LVP, non-LVP or LVP ratio in patients receiving fluvastatin or n-3 PUFAs. ALT was not significantly different in those treated with fluvastatin or n-3 PUFAs. 12 weeks of low-dose n-3 PUFA decreased median IP10 concentration by -39 pg/ml (-111, 7.0 pg/ml Q1-Q3). CONCLUSIONS: Fluvastatin and n-3 PUFAs have no effect on plasma HCV-RNA or LVP. The effect of low-dose n-3 PUFA on IP10 warrants further prospective evaluation as a supplemental therapy to enhance interferon sensitivity.

Comparing localized and nonlocalized dynamic 31P magnetic resonance spectroscopy in exercising muscle at 7 T.

By improving spatial and anatomical specificity, localized spectroscopy can enhance the power and accuracy of the quantitative analysis of cellular metabolism and bioenergetics. Localized and nonlocalized dynamic (31)P magnetic resonance spectroscopy using a surface coil was compared during aerobic exercise and recovery of human calf muscle. For localization, a short echo time single-voxel magnetic resonance spectroscopy sequence with adiabatic refocusing (semi-LASER) was applied, enabling the quantification of phosphocreatine, inorganic phosphate, and pH value in a single muscle (medial gastrocnemius) in single shots (T(R) = 6 s). All measurements were performed in a 7 T whole body scanner with a nonmagnetic ergometer. From a series of equal exercise bouts we conclude that: (a) with localization, measured phosphocreatine declines in exercise to a lower value (79 ± 7% cf. 53 ± 10%, P = 0.002), (b) phosphocreatine recovery shows shorter half time (t(1/2) = 34 ± 7 s cf. t(1/2) = 42 ± 7 s, nonsignificant) and initial postexercise phosphocreatine resynthesis rate is significantly higher (32 ± 5 mM/min cf. 17 ± 4 mM/min, P = 0.001) and (c) in contrast to nonlocalized (31)P magnetic resonance spectroscopy, no splitting of the inorganic phosphate peak is observed during exercise or recovery, just an increase in line width during exercise. This confirms the absence of contaminating signals originating from weaker-exercising muscle, while an observed inorganic phosphate line broadening most probably reflects variations across fibers in a single muscle.

Metabolic profiling of the rat liver after chronic ingestion of alpha-naphthylisothiocyanate using in vivo and ex vivo magnetic resonance spectroscopy.

Certain human diseases affecting the biliary tree can be modeled in rats by ingestion of the hepatobiliary toxin alpha-naphthylisothiocyanate (ANIT). Phosphorus magnetic resonance spectroscopy (MRS) allows the noninvasive monitoring of cell dynamics through detection of phosphodiesters (PDE) and phosphomonoesters (PME). Hepatic (31)P MRS techniques were therefore used to study the toxic effects of low-dose chronic ANIT ingestion, with a view toward providing biomarkers sensitive to hepatobiliary dysfunction and cholestatic liver injury. Rats were fed an ANIT supplemented diet at three doses (ANIT_0.05%, ANIT_0.04%, and ANIT_0.025%) for 2 weeks. Data from in vivo MRS were compared with results from pair-fed controls (PFCs). Blood and tissue samples were collected at 2 weeks for clinical chemistry, histology, and (1)H magic angle spinning MRS. Increases in PDE, relative to total phosphorus (tPh), were detected in both the ANIT_0.05% and ANIT_0.04% groups (0.07 ± 0.01 and 0.08 ± 0.01, respectively) relative to PFC groups (0.03 ± 0.01 and 0.05 ± 0.01, respectively). An increase in PME/tPh was observed in the ANIT_0.05% group only (0.17 ± 0.02) relative to PFC_0.05% (0.12 ± 0.01). Ex vivo (1)H MRS findings supported this, wherein measured phosphocholines (PCs) were increased in ANIT_0.05% and ANIT_0.04% groups. Increases in relative total choline (tCho) distinguished the ANIT_0.05% group from the ANIT_0.04% group. Markers of hepatotoxicity such as raised total bilirubin and alkaline phosphatase were found at all ANIT doses. Histological findings included a dose-related increase in both severity of biliary hyperplasia and focal hepatocellular necrosis. Here, we found that ANIT-induced moderate hepatobiliary dysfunction was associated with a relative increase in phosphodiesters in vivo and PCs ex vivo. Raised PME/tPh in vivo and tCho ex vivo were also present at high doses corresponding to a higher incidence of marked biliary hyperplasia and moderate hepatocellular necrosis.

Каким образом телездравоохранение может помочь в предоставлении интегрированной помощи?

Телездравоохранение, или оказание помощи на расстоянии, вне всякого сомнения, станет одной из ключевых составляющих в будущейинформационно-коммуникационной инфраструктуре, необходимой для организации интегрированной помощи. Лица, формирующие политику, уже сейчас возлагают на него большие надежды, рассматривая его как возможный способ решения обостряющихся проблем кадров. Для того,чтобы обеспечить интегрированность помощи, необходимо включить обособленные сегодня прикладные задачи, решаемые с помощьютелездравоохранения, в более комплексные стратегии электронного здравоохранения, в которых были бы предусмотрены полная координация протоколов ведения больных и процессов оказания услуг и безопасный обмен данными о пациентах. Несмотря на то, что пока в Европе и в других регионах имеется мало примеров применения телездравоохранения в порядке повседневнойпрактики (в противоположность огромному объему исследований в этой области), формируется база все более убедительных фактических данных, свидетельствующих о том, что телездравоохранение можно успешноиспользовать для того, чтобы помочь обеспечить более высокое качество интегрированной помощи, в частности, тем, кто страдает продолжительными хроническими заболеваниями.

How can telehealth help in the provision of integrated care?

Telehealth, the provision of care at a distance, is certain to be a key component in future ICT infrastructure for integrated care. It has already raised high hopes among policy-makers with regard to its potential for delivering solutions forgrowing capacity problems. For integrated care, today's segregated telehealth applications still require linking into more comprehensive eHealth strategies, in which clinical pathways and service delivery processes are fully coordinated andpatient data safely shared. Although few instances of routine application have yet emerged in Europe or elsewhere – in contrast with an enormous breadth of research activities – anincreasingly solid evidence base is emerging indicating that telehealth can be used effectively to help support better integrated care, in particular for those with long-term chronic conditions.

A resting state network in the motor control circuit of the basal ganglia.

BACKGROUND: In the absence of overt stimuli, the brain shows correlated fluctuations in functionally related brain regions. Approximately ten largely independent resting state networks (RSNs) showing this behaviour have been documented to date. Recent studies have reported the existence of an RSN in the basal ganglia - albeit inconsistently and without the means to interpret its function. Using two large study groups with different resting state conditions and MR protocols, the reproducibility of the network across subjects, behavioural conditions and acquisition parameters is assessed. Independent Component Analysis (ICA), combined with novel analyses of temporal features, is applied to establish the basis of signal fluctuations in the network and its relation to other RSNs. Reference to prior probabilistic diffusion tractography work is used to identify the basal ganglia circuit to which these fluctuations correspond. RESULTS: An RSN is identified in the basal ganglia and thalamus, comprising the pallidum, putamen, subthalamic nucleus and substantia nigra, with a projection also to the supplementary motor area. Participating nuclei and thalamo-cortical connection probabilities allow this network to be identified as the motor control circuit of the basal ganglia. The network was reproducibly identified across subjects, behavioural conditions (fixation, eyes closed), field strength and echo-planar imaging parameters. It shows a frequency peak at 0.025 +/- 0.007 Hz and is most similar in spectral composition to the Default Mode (DM), a network of regions that is more active at rest than during task processing. Frequency features allow the network to be classified as an RSN rather than a physiological artefact. Fluctuations in this RSN are correlated with those in the task-positive fronto-parietal network and anticorrelated with those in the DM, whose hemodynamic response it anticipates. CONCLUSION: Although the basal ganglia RSN has not been reported in most ICA-based studies using a similar methodology, we demonstrate that it is reproducible across subjects, common resting state conditions and imaging parameters, and show that it corresponds with the motor control circuit. This characterisation of the basal ganglia network opens a potential means to investigate the motor-related neuropathologies in which the basal ganglia are involved.

Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using Positron Emission Tomography in rat and non-human primate.

Several quinazoline derivatives were made as mitochondrial complex 1 inhibitors. Compound 4 showed an IC(50) of 11.3 nM and was the most potent compound of this series. The (18)F analog of 4, [(18)F] 4, was injected in the rat and showed high and rapid heart uptake, fast liver clearance, and low blood uptake. Images obtained using a microPET showed clear delineation of the myocardium in normal rats and perfusion deficit in ischemic rats. In the non-human primate, [(18)F] 4 showed rapid uptake and clearance from the myocardium and high liver uptake.

Amygdala activation at 3T in response to human and avatar facial expressions of emotions.

Facial expressions of emotions are important in nonverbal communication. Although numerous neural structures have been identified to be involved in emotional face processing, the amygdala is thought to be a core moderator. While previous studies have relied on facial images of humans, the present study is concerned with the effect of computer-generated (avatar) emotional faces on amygdala activation. Moreover, elicited activation patterns in response to viewing avatar faces are compared with the neuronal responses to human facial expressions of emotions. Twelve healthy subjects (five females) performed facial emotion recognition tasks with optimized 3T event-related fMRI. Robust amygdala activation was apparent in response to both human and avatar emotional faces, but the response was significantly stronger to human faces in face-sensitive structures, i.e. fusiform gyri. We suggest that avatars could be a useful tool in neuroimaging studies of facial expression processing because they elicit amygdala activation similarly to human faces, yet have the advantage of being highly manipulable and fully controllable. However, the finding of differences between human and avatar faces in face-sensitive regions indicates the presence of mechanisms by which human brains can differentiate between them. This mechanism merits further investigation.

Effect of nutritional counselling on hepatic, muscle and adipose tissue fat content and distribution in non-alcoholic fatty liver disease.

AIM: To assess the effectiveness of the current UK clinical practice in reducing hepatic fat (IHCL). METHODS: Whole body MRI and (1)H MRS were obtained, before and after 6 mo nutritional counselling, from liver, soleus and tibialis muscles in 10 subjects with non-alcoholic fatty liver disease (NAFLD). RESULTS: A 500 Kcal-restricted diet resulted in an average weight loss of 4% (-3.4 kg,) accompanied by significant reductions in most adipose tissue (AT) depots, including subcutaneous (-9.9%), abdominal subcutaneous (-10.2%) and intra-abdominal-AT (-11.4%). Intramyocellular lipids (IMCL) were significantly reduced in the tibialis muscle (-28.2%). Decreases in both IHCL (-39.9%) and soleus IMCL (-12.2%) content were also observed, although these were not significant. Several individuals showed dramatic decreases in IHCL, while others paradoxically showed increases in IHCL content. Changes in body composition were accompanied by improvements in certain liver function tests: serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Significant correlations were found between decreases in IHCL and reductions in both intra-abdominal and abdominal subcutaneous AT. Improvements in liver function tests were associated with reductions in intra-abdominal AT, but not with changes in IHCL. CONCLUSION: This study shows that even a very modest reduction in body weight achieved through lifestyle modification can result in changes in body fat depots and improvements in LFTs.

The relationship of in vivo 31P MR spectroscopy to histology in chronic hepatitis C.

Liver biopsy remains the gold standard for characterizing diffuse liver disease and is associated with significant morbidity and, rarely, mortality. Our aim was to investigate whether a noninvasive technique, in vivo phosphorus 31 ((31)P)-magnetic resonance spectroscopy (MRS), could be used to assess the severity of hepatitis C virus (HCV)-related liver disease. Fifteen healthy controls and 48 patients with biopsy-proven HCV-related liver disease were studied prospectively. Based on their histologic fibrosis (F) and necroinflammatory (NI) scores, patients were divided into mild hepatitis (F or= 4/18), and cirrhosis (F = 6/6). Hepatic (31)P MR spectra were obtained using a 1.5-T spectroscopy system. Quantitation of the (31)P signals was performed in the time domain using the Advanced MAgnetic RESonance algorithm. There was a monotonic increase in the mean +/- 1 standard error phosphomonoester (PME) to phosphodiester (PDE) ratios for the control, mild disease, moderate disease, and cirrhosis groups: 0.15 +/- 0.01, 0.18 +/- 0.02, 0.25 +/- 0.02, 0.38 +/- 0.04, respectively (ANOVA, P <.001). An 80% sensitivity and specificity was achieved when using a PME/PDE ratio less than or equal to 0.2 to denote mild hepatitis and a corresponding ratio greater than or equal to 0.3 to denote cirrhosis. No other significant spectral changes were observed. In conclusion, (31)P MRS can separate mild from moderate disease and these 2 groups from cirrhosis. The ability to differentiate these populations of patients has therapeutic implications and (31)P MRS, in some situations, would not only complement a liver biopsy but could replace it and be of particular value in assessing disease progression.

Enhanced uptake of ifosfamide into GH3 prolactinomas with hypercapnic hyperoxic gases monitored in vivo by (31)P MRS.

Previously, (31)P magnetic resonance spectroscopy (MRS) has been used to detect ifosfamide (IF) in vivo and to show that breathing carbogen (5% CO(2)/95% O(2)) enhances the uptake and increases the efficacy of IF in rat GH3 prolactinomas [Rodrigues LM, Maxwell RJ, McSheehy PMJ, Pinkerton CR, Robinson SP, Stubbs M, and Griffiths JR (1997). In vivo detection of ifosfamide by (31)P MRS in rat tumours; increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas. Br J Cancer 75, 62-68]. We now show that other hypercapnic and/or hyperoxic (5% CO(2) in air, 2.5% CO(2) in O(2)) gas mixtures also increase the uptake of IF into tumors, measured by (31)P MRS. All gases caused an increased uptake (C(max)) of IF compared to air breathing, with carbogen inducing the largest increase (85% (P<.02) compared to 46% with 2.5% CO(2) in O(2) (P<.004) and 48% with 5% CO(2) in air (P<.004)). The T(max) (time of maximum concentration in tumor posintravenous injection of IF) was significantly (P<.04) later in the cohort that breathed 5% CO(2) in air. The increased uptake of IF with carbogen breathing was selective to tumor tissue and there were no significant increases in any of the normal tissues studied, suggesting that any host tissue toxicity would be minimal. Carbogen breathing by patients causes breathlessness. There was no significant difference in IF uptake between breathing carbogen and 2.5% CO(2) in O(2) and, therefore, the ability of 2.5% CO(2) in O(2) to also increase IF uptake may be clinically useful as it causes less patient discomfort.

Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway.

Hypoxia-inducible factor-1 (HIF-1) regulates many pathways potentially important for tumor growth, including angiogenesis and glycolysis. Most attention has focused on its role in the response to hypoxia, but HIF-1 is also constitutively expressed in many tumors. To analyze the role of this pathway in vivo, we used magnetic resonance (MR) methods and complementary techniques to monitor metabolic changes in tumors derived from HEPA-1 mouse hepatoma lines that were either wild type (WT) or deficient in hypoxia-inducible transcription factor HIF-1beta (c4). The c4 tumors grew significantly more slowly than the WT tumors (P < 0.05), but were examined at a similar size (0.4-0.6 g). At the tumor size used in these studies, no differences in vascularity were observed, and MR parameters measured that related to tumor blood flow, vascularity, and oxygenation demonstrated no significant differences between the two tumor types. Unexpectedly, the ATP content of the c4 tumor was approximately 5 times less than in the WT tumor [measured in tumor extracts (P < 0.001) and by metabolic imaging (P < 0.05)]. Noninvasive (31)P MR spectroscopy showed that the nucleoside triphosphate/P(i) ratio of the two tumor types was similar, so the low ATP content of the c4 tumors was not caused by (or a cause of) impaired cellular bioenergetics. Rather, glycine, an essential precursor for de novo purine formation, was significantly lower in the c4 tumors (P < 0.05), suggesting that ATP synthesis was impaired in the mutant tumor cells. Supporting evidence for this hypothesis came from the significantly lower concentrations of betaine, phosphocholine, and choline in the c4 tumors (P < 0.05); these are intermediates in an alternative pathway for glycine synthesis. No significant differences were seen in lactate or glucose content. MR resonances from phosphodiesters, which relate to the metabolic turnover of phospholipid membranes, were significantly lower in the WT tumors than in the c4 tumors, both in vivo (P < 0.05) and in extracts (P < 0.01). We propose that loss of up-regulation of expression of the genes for glucose transporters and glycolytic enzymes in the c4 tumors decreased formation of glycine, an essential precursor of ATP synthesis, and thus caused the low ATP content of the c4 tumors. In summary, these data suggest that disruption of the HIF-1 pathway in these tumor cells impairs the supply of anabolic precursors required for cell synthesis. They suggest potential biochemical targets that may be modified by therapy blocking HIF-1 function.