Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals.

BACKGROUND: Clozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events. SOURCES OF DATA: Published literature. AREAS OF AGREEMENT: Common adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure. AREAS OF CONTROVERSY: It remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate. GROWING POINTS: There is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage.

Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses.

BACKGROUND: Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated. METHOD: This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not. RESULTS: Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25-4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44-9.56); and patients of male gender (OR 3.13 95% CI 1.35-7.23). CONCLUSIONS: For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

Clinical correlates of vitamin D deficiency in established psychosis.

BACKGROUND: Suboptimal vitamin D levels have been identified in populations with psychotic disorders. We sought to explore the relationship between vitamin D deficiency, clinical characteristics and cardiovascular disease risk factors among people with established psychosis. METHODS: Vitamin D levels were measured in 324 community dwelling individuals in England with established psychotic disorders, along with measures of mental health, cardiovascular risk and lifestyle choices. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25-OHD) levels below 10 ng/ml (equivalent to <25 nmol/L) and "sufficient" Vitamin D as above 30 ng/ml (>50 nmol/L). RESULTS: The mean 25-OHD serum level was 12.4 (SD 7.3) ng/ml, (range 4.0-51.7 ng/ml). Forty nine percent (n = 158) were vitamin D deficient, with only 14 % (n = 45) meeting criteria for sufficiency. Accounting for age, gender, ethnicity and season of sampling, serum 25-OHD levels were negatively correlated with waist circumference (r = -0.220, p < 0.002), triglycerides (r = -0.160, p = 0.024), total cholesterol (r = -0.144, p = 0.043), fasting glucose (r = -0.191, p = 0.007), HbA1c (r = -0.183, p = 0.01), and serum CRP levels (r = -0.211, p = 0.003) and were linked to the presence of metabolic syndrome. CONCLUSIONS: This is the largest cross sectional study of serum 25-OHD levels in community dwelling individuals with established psychosis, indicating a high level of vitamin D deficiency. Lower vitamin D levels are associated with increased cardiovascular disease risk factors and in particular metabolic syndrome. Further research is needed to define appropriate protocols for vitamin D testing and supplementation in practice to see if this can improve cardiovascular disease risk. TRIAL REGISTRATION: ISRCTN number is ISRCTN58667926 Date of registration: 23/04/2010.

Patient-reported factors influencing return to work after joint replacement.

BACKGROUND: An increasing number of patients in the working population are undergoing total hip and knee replacement for osteoarthritis and the timing and success of return to work (RTW) is becoming increasingly important as a measure of success for these patients. There is limited understanding of the patient variables that determine the ability to RTW. AIMS: To explore the factors influencing RTW following hip and knee replacement from the patient's perspective. METHODS: A cross-sectional population-based postal survey carried out with patients of working age after hip and knee replacement surgery in a UK teaching hospital. Free text comments were collected regarding the experiences of patients returning to work following hip and knee replacement. Qualitative thematic analysis was undertaken to identify the factors influencing RTW from the patient's perspective. RESULTS: From the patients' perspective three key factors were identified that influenced RTW. Patients reported an improved physical and psychological performance at work after surgery in comparison to pre-operative functioning, although there was a lack of informed advice regarding RTW after surgery. Workplace support and adaptation of the job role enhanced the experience of RTW. CONCLUSIONS: Return to work is influenced by a combination of patient, clinician and occupational factors. The relationship between each of these needs to be explored in greater depth through further qualitative work to gain a wider understanding of the variables influencing patients' RTW following hip and knee replacement.

Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT randomized controlled trial.

BACKGROUND: The aims of the study were to determine the prevalence of cardiometabolic risk factors and establish the proportion of people with psychosis meeting criteria for the metabolic syndrome (MetS). The study also aimed to identify the key lifestyle behaviours associated with increased risk of the MetS and to investigate whether the MetS is associated with illness severity and degree of functional impairment. METHOD: Baseline data were collected as part of a large randomized controlled trial (IMPaCT RCT). The study took place within community mental health teams in five Mental Health NHS Trusts in urban and rural locations across England. A total of 450 randomly selected out-patients, aged 18-65 years, with an established psychotic illness were recruited. We ascertained the prevalence rates of cardiometabolic risk factors, illness severity and functional impairment and calculated rates of the MetS, using International Diabetes Federation (IDF) and National Cholesterol Education Program Third Adult Treatment Panel criteria. RESULTS: High rates of cardiometabolic risk factors were found. Nearly all women and most men had waist circumference exceeding the IDF threshold for central obesity. Half the sample was obese (body mass index ≥ 30 kg/m2) and a fifth met the criteria for type 2 diabetes mellitus. Females were more likely to be obese than males (61% v. 42%, p < 0.001). Of the 308 patients with complete laboratory measures, 57% (n = 175) met the IDF criteria for the MetS. CONCLUSIONS: In the UK, the prevalence of cardiometabolic risk factors in individuals with psychotic illnesses is much higher than that observed in national general population studies as well as in most international studies of patients with psychosis.

Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT RCT study--Corrigendum.

The author regrets to announce that affiliation 8, in the above article (Gardner-Sood et al. 2015), contained an error in the author affiliation address and author surname, which were published in the approved article. The correct surname and affiliation address are given below. J. Eberhard, Clinical Psychiatric Research Center, Lund University, Skåne, Sweden

TBC1D1 reduces palmitate oxidation by inhibiting ß-HAD activity in skeletal muscle.

In skeletal muscle the Rab-GTPase-activating protein TBC1D1 has been implicated in the regulation of fatty acid oxidation by an unknown mechanism. We determined whether TBC1D1 altered fatty acid utilization via changes in protein-mediated fatty acid transport and/or selected enzymes regulating mitochondrial fatty acid oxidation. We also determined the effects of TBC1D1 on glucose transport and oxidation. Electrotransfection of mouse soleus muscles with TBC1D1 cDNA increased TBC1D1 protein after 2 wk (P<0.05), without altering its paralog AS160. TBC1D1 overexpression decreased basal palmitate oxidation (-22%) while blunting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated palmitate oxidation (-18%). There was a tendency to increase fatty acid esterification (+10 nmol·g(-1)·60 min(-1), P=0.07), which reflected the reduction in fatty acid oxidation (-12 nmol·g(-1)·60 min(-1)). Concomitantly, basal (+21%) and AICAR-stimulated glucose oxidation (+8%) were increased in TBC1D1-transfected muscles relative to their respective controls (P<0.05), independent of changes in GLUT4 and glucose transport. The reductions in TBC1D1-mediated fatty acid oxidation could not be attributed to changes in the transporter FAT/CD36, muscle mitochondrial content, CPT1 expression or the expression and phosphorylation of AS160, acetyl-CoA carboxylase, or AMPK. However, TBC1D1 overexpression reduced ß-HAD enzyme activity (-18%, P<0.05). In conclusion, TBC1D1-mediated reduction of muscle fatty acid oxidation appears to occur via inhibition of ß-HAD activity.

Prevalence of hypercalcaemia in patients on maintenance lithium therapy monitored in primary care.

The purpose of this study was to ascertain the prevalence of hypercalcaemia and hyperparathyroidism in individuals on long term lithium therapy who were monitored by their general practitioners and living within the West Galway mental health catchment area. We also wished to assess the extent of screening for calcium dysfunction in this patient cohort.Current guidelines do not specify the need for calcium monitoring in patients on lithium therapy. We conducted a retrospective analysis of clinical and laboratory data collected as part of regular monitoring for patients on long term lithium treatment. Three hundred and thirty three patients had serum lithium levels monitored over a 2 year period. Fifteen patients (5.3%) had lithium associated hypercalcaemia. The mean duration of lithium treatment for those with hypercalcaemia was 15 years and these patients had a mean serum calcium level of 2.7mmol/L. Eighty six (14%) patients did not have a calcium level monitored over the 2 year period. Three patients (1%) were found to have hyperparathyroidism. This survey supports the need for regular monitoring of serum calcium levels in patients on maintenance lithium treatment.

Admission patterns in a psychiatric intensive care unit in Ireland: a longitudinal follow-up.

OBJECTIVE: This study aims to describe the course of admission and clinical characteristics of admissions to a psychiatric intensive care unit (PICU) in the Phoenix Care Centre (PCC), Dublin, Ireland. METHODS: This retrospective chart study was conducted at the PCC, Dublin, Ireland. The cohort included all admission episodes (n = 91 complete data) over a three-year study period between January 2014 and January 2017. RESULTS: The mean age of admitted cases was 37.1 (s.d. = 11.3; range 18-63). The mean length of stay (LOS) was 59.3 days (s.d. = 61.0; median 39.5 days). All patients were admitted under Mental Health Act legislation. Antipsychotic polypharmacy was used in 61% (n = 55) of the admissions. A diagnosis of acute psychotic disorder (B = -1.027, p = 0.003, 95% CI: -1.691, -0.363) was associated with reduced LOS in PICU. CONCLUSION: Our study describes the cohort of patients admitted as being predominantly male, younger-aged, single, having a diagnosis of schizophrenia and being legally detained. The primary indication for referral is risk of assault, which highlights the need for the intensive and secure treatment model that a PICU can provide.

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat.

AIMS/HYPOTHESIS: Little is known about the subcellular distribution of lipids in insulin-resistant skeletal muscle. However, it has recently been suggested that lipid accumulation in the subsarcolemmal region directly contributes to insulin resistance. Therefore we hypothesised that regional differences in lipid distribution in insulin-resistant muscle may be mediated by: (1) a reduction in fatty acid trafficking into mitochondria; and/or (2) a regional increase in the enzymes regulating lipid synthesis. METHODS: Transmission electron microscopy was used to quantify lipid droplet and mitochondrial abundance in the subsarcolemmal and intermyofibrillar compartments in red and white muscles from lean and obese Zucker rats. To estimate rates of lipid trafficking into mitochondria, the metabolic fate of radiolabelled palmitate was determined. Key enzymes of triacylglycerol synthesis were also determined in each subcellular region. RESULTS: Subsarcolemmal-compartmentalised lipids represented a small absolute fraction of the overall lipid content in muscle, as regardless of fibre composition (red/white) or phenotype (lean/obese), lipid droplets were more prevalent in the intermyofibrillar region, whereas insulin-resistant white muscles were devoid of subsarcolemmal-compartmentalised lipid droplets. While, in obese animals, lipid droplets accumulated in both subcellular regions, in red muscle of these animals lipids only appeared to be trafficked away from intermyofibrillar mitochondria, a process that cannot be explained by regional differences in the abundance of triacylglycerol esterification enzymes. CONCLUSIONS/INTERPRETATION: Lipid accumulation in the subsarcolemmal region is not necessary for insulin resistance. In the intermyofibrillar compartment, the diversion of lipids away from mitochondria in insulin-resistant animals probably contributes to lipid accumulation in this subcellular area.

Adaptations in Visual Search Behaviour as a Function of Expertise in Rugby Union Players Completing Attacking Scenarios.

The current study investigated the adaptations which occur in visual search behaviour as a function of expertise in rugby union players when completing attacking scenarios. Ten experienced players (EP) and ten novice players (NP) completed 2 vs. 1 attacking game scenarios. Starting with the ball in hand and wearing a mobile eye tracker throughout, participants were required to score a try against a defender. The scenarios allowed for a pass to their supporting player (Spin Pass or Switch) or trying to run past the defender (Take-Player-On or Dummy Switch). No between group differences were found in fixating on the supporting attacking player (p > 0.05). However, EP increased the length (p = 0.008) and frequency (p = 0.004) looking at the area immediately ahead of the supporting player, particularly when executing a spin pass. NP fixated longer (p = 0.005) and more frequently (p = 0.032) at the defender, whilst EP fixated more frequently in the space the supporting player would run into in Switch and Dummy Switch scenarios (p = 0.025). More successful passes were completed and tries scored by EP compared to NP (p = 0.001). Differences in visual search behaviour between experienced and NP suggest that the experts extract information from areas directly related to guiding the motor action; the space immediately ahead of the support player to pass the ball in. Contrastingly, novices use a more allocentric perspective where the actions from the defender are used to guide their motor actions.

Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance.

AIMS/HYPOTHESIS: We examined in skeletal muscle (1) whether fatty acid transport protein (FATP) 1 channels long-chain fatty acid (LCFA) to specific metabolic fates in rats; and (2) whether FATP1-mediated increases in LCFA uptake exacerbate the development of diet-induced insulin resistance in mice. We also examined whether FATP1 is altered in insulin-resistant obese Zucker rats. METHODS: LCFA uptake, oxidation and triacylglycerol esterification rates were measured in control and Fatp1-transfected soleus muscles to determine FATP1-mediated lipid handling. The effects of FATP1 on insulin sensitivity and triacylglycerol accumulation were determined in high-fat diet-fed wild-type mice and in muscle-specific Fatp1 (also known as Slc27a1) overexpressing transgenic mice driven by the muscle creatine kinase (Mck [also known as Ckm]) promoter. We also examined the relationship between FATP1 and both fatty acid transport and metabolism in insulin-resistant obese Zucker rats. RESULTS: Transient Fatp1 overexpression in soleus muscle increased (p < 0.05) palmitate transport (24%) and oxidation (35%), without altering triacylglycerol esterification or the intrinsic rate of palmitate oxidation in isolated mitochondria. In Mck/Fatp1 animals, Fatp1 mRNA and 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid uptake in skeletal muscle were upregulated (75%). However, insulin sensitivity and intramuscular triacylglycerol content did not differ between wild-type and Mck/Fatp1 mice following a 16 week high-fat diet. In insulin-resistant obese Zucker rats, LCFA transport and triacylglycerol accumulation were increased (85% and 24%, respectively), but this was not attributable to Fatp1 expression, as neither total cellular nor sarcolemmal FATP1 content were altered. CONCLUSIONS/INTERPRETATION: Overexpression of Fatp1 in skeletal muscle increased the rate of LCFA transport and channelled these lipids to oxidation, not to intramuscular lipid accumulation. Therefore, skeletal muscle FATP1 overabundance does not predispose animals to diet-induced insulin resistance.

Vitamin D deficiency in schizophrenia implications for COVID-19 infection.

Vitamin D deficiency is associated with an increased risk of acute respiratory infection. There is an excess of respiratory infections and deaths in schizophrenia, a condition where vitamin D deficiency is especially prevalent. This potentially offers a modifiable risk factor to reduce the risk for and the severity of respiratory infection in people with schizophrenia, although there is as yet no evidence regarding the risk of COVID-19. In this narrative review, we describe the prevalence of vitamin D deficiency in schizophrenia, report the research examining the relationship between vitamin D levels and COVID-19 and discuss the associations between vitamin D deficiency and respiratory infection, including its immunomodulatory mechanism of action.

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats.

AIMS/HYPOTHESIS: Reductions in peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) levels have been associated with the skeletal muscle insulin resistance. However, in vivo, the therapeutic potential of PGC-1alpha has met with failure, as supra-physiological overexpression of PGC-1alpha induced insulin resistance, due to fatty acid translocase (FAT)-mediated lipid accumulation. Based on physiological and metabolic considerations, we hypothesised that a modest increase in PGC-1alpha levels would limit FAT upregulation and improve lipid metabolism and insulin sensitivity, although these effects may differ in lean and insulin-resistant muscle. METHODS: Pgc-1alpha was transfected into lean and obese Zucker rat muscles. Two weeks later we examined mitochondrial biogenesis, intramuscular lipids (triacylglycerol, diacylglycerol, ceramide), GLUT4 and FAT levels, insulin-stimulated glucose transport and signalling protein phosphorylation (thymoma viral proto-oncogene 2 [Akt2], Akt substrate of 160 kDa [AS160]), and fatty acid oxidation in subsarcolemmal and intermyofibrillar mitochondria. RESULTS: Electrotransfection yielded physiologically relevant increases in Pgc-1alpha (also known as Ppargc1a) mRNA and protein ( approximately 25%) in lean and obese muscle. This induced mitochondrial biogenesis, and increased FAT and GLUT4 levels, insulin-stimulated glucose transport, and Akt2 and AS160 phosphorylation in lean and obese animals, while bioactive intramuscular lipids were only reduced in obese muscle. Concurrently, PGC-1alpha increased palmitate oxidation in subsarcolemmal, but not in intermyofibrillar mitochondria, in both groups. In obese compared with lean animals, the PGC-1alpha-induced improvement in insulin-stimulated glucose transport was smaller, but intramuscular lipid reduction was greater. CONCLUSIONS/INTERPRETATIONS: Increases in PGC-1alpha levels, similar to those that can be induced by physiological stimuli, altered intramuscular lipids and improved fatty acid oxidation, insulin signalling and insulin-stimulated glucose transport, albeit to different extents in lean and insulin-resistant muscle. These positive effects are probably attributable to limiting the PGC-1alpha-induced increase in FAT, thereby preventing bioactive lipid accumulation as has occurred in transgenic PGC-1alpha animals.

Shock-produced olivine glass: first observation.

Transmission electron microscope (TEM) observations of an experimentally shock-deformed single crystal of natural peridot, (Mg(0.88)Fe(0.12))(2)SiO(4), recovered from peak pressures of about 56 x 10(9) pascals revealed the presence of amorphous zones located within crystalline regions with a high density of tangled dislocations. This is the first reported observation of olivine glass. The shocked sample exhibits a wide variation in the degree of shock deformation on a small scale, and the glass appears to be intimately associated with the highest density of dislocations. This study suggests that olivine glass may be formed as a result of shock at pressures above about 50 to 55 x 10(9) pascals and that further TEM observations of naturally shocked olivines may demonstrate the presence of glass.

Treatment resistant schizophrenia - review and a call to action.

Recovery rates in schizophrenia remain suboptimal with up to one-third resistant to standard treatments, a population prevalence of 0.2%. Clozapine is the only evidenced-based treatment for treatment resistant schizophrenia (TRS), yet there are significant delays in its use or it may not be trialled, potentially impacting the chance of recovery. Better outcomes with earlier use of clozapine may be possible. There is emerging evidence that early treatment resistance is not uncommon from the earliest stages of psychosis. In this review, we provide an update on TRS, its epidemiology and its management, with a specific focus on the optimal use and timing of clozapine and augmentation strategies for the one-third of patients who do not respond to clozapine.

Flexible therapeutic landscapes of labour and the place of pain relief.

Flexibility in the design and enactment of spaces of healthcare is important in how providers respond to variations in patient expectations and experience. Health geographers have contributed to a wide body of literature concerning the therapeutic qualities of landscapes and the material, social and symbolic orderings of place and their uniqueness for individuals. In this paper, we draw upon these findings and a 'culture of place' approach to consider the complexities of maternity care and issues of pain relief. Given that pain is widely held to be a subjective experience and one that, in an era of patient decision making, increasingly demands discretionary approaches to its relief, we consider how medical professionals help to construct flexibility in healthcare and how this affects therapeutic landscapes. Drawing on analysis of four focus groups involving parent educators, midwives, health visitors, anaesthetists and obstetricians in the NE of England, we explore the material and discursive construction of flexible therapeutic landscapes and pain relief. Our findings suggest that flexibility is constrained and fashioned in association with health care professional's sense of place as already constituted. We propose that providing maternity care professionals with an explicit awareness of how places are relationally constructed, may help in expanding the therapeutic qualities of particular settings, and support a (more) flexible approach.

Lipids and polyunsaturated fatty acid levels in deliberate self-harm: a 10-year follow-up study.

OBJECTIVES: To evaluate if n-3 polyunsaturated fatty acids (PUFAs) and lipid levels are associated with episodes of self-harm or depression over a 10-year period. METHODS: We included 40 individuals who self-harmed and 40 controls. Episodes of self-harm and depression were ascertained and levels of depression, impulsivity, suicidal ideation and plasma lipid levels measured at baseline and at 10-year follow-up. RESULTS: Further episode(s) of self-harm occurred in 26% of cases. Omega-3 PUFAs or lipids were not predictive of depressive or self-harm episodes. Baseline eicosapentaenoic acid levels were modestly correlated with suicidal ideation at follow-up and dihomo-γ-linolenic acid and arachidonic acid were modestly correlated with motor impulsivity at follow-up in cases. CONCLUSIONS: Despite significant negative correlations at baseline between plasma lipids, n-3 PUFAs and psychopathology, these levels were not predictive of clinical outcome over a 10-year period. Further research however is required due to the relatively low sample size and the risk of selection bias due to loss to follow-up in this study.

Hyperbaric pressure effects measured by growth of a transplantable tumor in the C3H/HeN mouse.

Both hypobaric exposure at 0.5 atmospheres absolute (ATA) and hyperbaric pressure exposure at 3.5-8 ATA slowed transplantable tumor growth. These experiments detailed the hyperbaric pressure exposure. C3H/HeN-MTV+ mice, bearing the 16/C transplantable murine mammary adenocarcinoma and exposed to 18 days' treatment by a hyperbaric chamber at 3.5-8 ATA, had tumor weights that averaged 50-75% less than the tumor weights in mice caged at ambient ("sea level") pressure. A series of experiments was run to investigate this response to hyperbaric pressure exposure. After mice underwent continuous exposure to 3.5-8 ATA normoxic (normal oxygen) hyperbaric pressure with use of either argon or nitrogen inert gas, which began 3 days after tumor inoculation, tumors were removed at about 3 weeks' growth from these pressure-exposed mice and measured for growth by weighing. Final tumor weight in pressure-exposed experimental mice was significantly less than tumor weight in paired groups of tumor-bearing controls that received no hyperbaric pressure. Tumor weight was inversely related to pressure "dose," although the small pressure range produced an effect at all pressures used. The number of compression-decompression cycles to which the animals were subjected, however, was related positively to tumor weight at necropsy. Continued tumor growth in mice subjected to frequent pressure change (in conjunction with pressure exposure that otherwise limited tumor size) was unexplained by these experiments. The greatest difference between tumor weights in controls and pressure-exposed animals was seen with 2 weeks' continuous pressure exposure. A limited profile of blood tests was performed, and these reflected only minor, expected change in the pressure-exposed experimental animals. The data at hand did not suggest a mechanism by which chronic normoxic hyperbaric pressure limited tumor size.

Atmospheric pressure effects on tumor growth: hypobaric anoxia and growth of a murine transplantable tumor.

Inasmuch as solid tumor growth and some intervention methods for tumor control have often been related to the low oxygen levels in tumor tissue, and a special role for hypoxia, perhaps even in oncogenesis, has been suggested by observations of unexpectedly low tumor incidence in mice caged a lifetime in the environment of a simulated altitude, inbred C3H/HeN mammary tumor virus-positive mice bearing transplanted tumors (16/C murine mammary adenocarcinoma) were exposed to atmospheric pressure variants ranging from 0.33 to 2.0 in different sequences 24 hours/day. Breathing gases included air, 100% oxygen, and other nitrogen--oxygen combinations. Exposure to the pressure sequences was continuous, beginning on the third day after tumor inoculation and continuing until planned necropsy at 1, 2, or 3 weeks. Actual tumor weight was used as a measure of effect. Mice caged at simulated altitude had tumors that averaged 45% of the weight of control tumors. The maximum effect occurred with continuous 2-week exposure to 0.43 atm. beginning on day 3 of tumor growth. At necropsy, these experimental tumors weighed an average of 15% of the control tumor weight. Life-span studies showed a maximum of 36% increase in longevity in the hypobaric pressure-exposed mice when compared to that of unexposed controls.