Constantinos Parisinos | University College London (original) (raw)
Papers by Constantinos Parisinos
Diagnostic and prognostic research, May 23, 2019
European Journal of Human Genetics, 2019
Gastroenterology, Aug 1, 2018
Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to... more Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to contribute to development of inflammatory bowel diseases (IBD). The single nucleotide polymorphism rs2228145 in IL6R associates with increased levels of soluble IL6R (s-IL6R), as well as reduced IL6R signaling and risk of inflammatory disorders; its effects are similar to those of a therapeutic monoclonal antibody that blocks IL6R signaling. We used the effect of rs2228145 on s-IL6R level as an indirect marker to investigate whether reduced IL6R signaling associates with risk of ulcerative colitis (UC) or Crohn's disease (CD). In a genome-wide meta-analysis of 20,550 patients with CD, 17,647 patients with UC, and more than 40,000 individuals without IBD (controls), we found that rs2228145 (scaled to a 2-fold increase in s-IL6R) was associated with reduced risk of CD (odds ratio 0.876; 95% confidence interval 0.822-0.933; P [ .00003) or UC (odds ratio 0.932; 95% confidence interval 0.875-0.996; P [ .036). These findings indicate that therapeutics designed to block IL6R signaling might be effective in treatment of IBD.
Journal of Hepatology, Dec 1, 2020
Institute of Health Informatics, Faculty of Population Health Sciences, University College London... more Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK; Perspectum Diagnostics Ltd., Oxford, UK; Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK; Health Data Research UK London, Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK; Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK; Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
Epidemiology, 2021
Background: Cross-sectional measures of body mass index (BMI) are associated with cardiovascular ... more Background: Cross-sectional measures of body mass index (BMI) are associated with cardiovascular disease (CVD) incidence, but less is known about whether weight change affects the risk of CVD. Methods: We estimated the effect of 2-y weight change interventions on 7-y risk of CVD (CVD death, myocardial infarction, stroke, hospitalization from coronary heart disease, and heart failure) by emulating hypothetical interventions using electronic health records. We identified 138,567 individuals with 45–69 years of age without chronic disease in England from 1998 to 2016. We performed pooled logistic regression, using inverse-probability weighting to adjust for baseline and time-varying confounders. We categorized each individual into a weight loss, maintenance, or gain group. Results: Among those of normal weight, both weight loss [risk difference (RD) vs. weight maintenance = 1.5% (0.3% to 3.0%)] and gain [RD = 1.3% (0.5% to 2.2%)] were associated with increased risk for CVD compared wit...
Alimentary Pharmacology & Therapeutics, Jul 14, 2017
Journal of Crohn's and Colitis, Jan 16, 2018
Smoking is associated with a decreased requirement for thiopurines however it does not impact on ... more Smoking is associated with a decreased requirement for thiopurines however it does not impact on the risk of corticosteroid dependency or colectomy. The risks associated with smoking outweigh any benefits and smoking cessation should be encouraged.
British Journal of Cancer
Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 p... more Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). Methods The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic (‘COVID’ cohort, 16/03/2020-10/05/2020), with 12-month follow-up. Results Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, ...
European Heart Journal, 2017
Background: There are increasing opportunities for junior doctors to deliver teaching as well as ... more Background: There are increasing opportunities for junior doctors to deliver teaching as well as formally develop teaching skills. Near-peer teaching (NPT) programmes, like that established in South-East Scotland, not only provide additional learning opportunities for students but also have potential benefits for the teachers. Context: Achieving the multiple competencies required of both the medical school and the foundation programme poses significant challenges. Medical students have reduced exposure to bedside teaching, which may be contributing to the concerns raised regarding the clinical skills of recently graduated junior doctors. NPT increases the pool of tutors available to students, helps facilitate both practical and small group teaching and has other advantages, such as peer tutors being more approachable than senior staff. Innovation: The NPT programme in South-East Scotland was devised by a group of junior doctors keen to improve, expand and formalise NPT. It started i...
Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 Brit... more Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription- or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9-dependent hotspots, demonstrating PRDM9 redundancy in humans.
BMJ case reports, Jan 19, 2012
BMJ case reports, Jan 30, 2012
A 39-year-old woman presented to the gastroenterology clinic with recurrent right-upper-quadrant ... more A 39-year-old woman presented to the gastroenterology clinic with recurrent right-upper-quadrant pain and elevated liver enzymes. Endoscopy revealed a small submucosal mass at the edge of the major duodenal papilla, which was not amenable to endoscopic resection. The mass was successfully resected by laparoscopy. The papilla was subsequently reconstructed and a cannula inserted in the common bile duct. The postoperative period was uneventful and the patient was discharged on the third postoperative day. Subsequent pathological examination of the excised mass revealed a gangliocytic paraganglioma. Six weeks later, the patient was free of symptoms and the cannula was removed by duodenoscopy.
International Journal of Paediatric Dentistry, 2011
Midazolam sedation poses a significant dilemma in paediatric dentistry, which is to find out the ... more Midazolam sedation poses a significant dilemma in paediatric dentistry, which is to find out the optimal dosing with minimal undesirable adverse events. In this study, we aimed to compare the effect of three doses of oral midazolam (0.5, 0.75, and 1 mg/kg) on the sedative state and cooperative behaviour of children during dental treatment. We further compared completion rates, parent satisfaction, and all adverse events. Ninety children aged 3-10 years were randomised to three equal groups. Groups A, B, and C received 0.5, 0.75, and 1 mg/kg of oral midazolam, respectively. Levels of sedation, cooperative behaviour, procedures completion rates, parent satisfaction, and adverse events were prospectively recorded. Sedation scores in B and C were higher (P < 0.001) than in A. Cooperation scores (CS) in B and C were higher (P < 0.001) than in A. Significant increase in completion rates was observed between A and C (P = 0.025). Parent satisfaction was greater in B and C (P < 0.001) compared to A. Adverse events were higher in C (P < 0.05) than in A or B. Amount of 0.75 mg/kg oral midazolam appears to be the optimal oral dose in terms of effectiveness, acceptability, and safety for dental treatments in paediatric patients, when administered by an experienced, paediatric anaesthetist.
The Clinical Teacher, 2013
Background: There are increasing opportunities for junior doctors to deliver teaching as well as ... more Background: There are increasing opportunities for junior doctors to deliver teaching as well as formally develop teaching skills. Near-peer teaching (NPT) programmes, like that established in SouthEast Scotland, not only provide additional learning opportunities for students but also have potential benefits for the teachers. Context: Achieving the multiple competencies required of both the medical school and the foundation programme poses significant challenges. Medical students have reduced exposure to bedside teaching, which may be contrib
Pediatric Surgery International, 2012
Purpose To discuss developments in paediatric anaesthesia and explore the factors which have cont... more Purpose To discuss developments in paediatric anaesthesia and explore the factors which have contributed to improved anaesthetic-related patient outcomes. Methods Narrative review of findings in the literature retrieved from MEDLINE/Pubmed and manual search. Results Adverse perioperative outcomes related to anaesthesia have been extensively debated over the past few decades, with studies implicating factors such as major human error and equipment failure. Case series and event registries have enlightened physicians on sources of error and patient risk factors such as extremes of age, comorbidity and emergent circumstances. Anaesthetic-related deaths in children fell from 6.4 per 10,000 anaesthetics in the early 1950s to as low as 0.1 per 10,000 anaesthetics by the end of the century. Advances in anaesthetic agents, techniques, monitoring technologies and training programmes in paediatric anaesthesia play a vital role in driving this downward trend. Conclusion Despite substantial progress, there is still much room for improvement in areas such as adverse-event reporting, anaesthetic-related risk and late neurocognitive outcomes. Systematic reviews comparing paediatric patient outcomes after neuroaxial block versus general anaesthesia are currently unavailable. The future of paediatric anaesthesia will most likely be influenced by much-needed large prospective studies, which can provide further insight into patient safety and service delivery.
Journal of Clinical Anesthesia, 2012
To assess the rate of restoration of gastrointestinal (GI) function following combined spinal-epi... more To assess the rate of restoration of gastrointestinal (GI) function following combined spinal-epidural (CSE) anesthesia compared with general anesthesia in young infants undergoing elective intestinal surgery. Prospective, randomized, controlled study. Operating room and neonatal intensive care unit of a university hospital. 50 young infants undergoing elective intestinal surgery. 50 young infants were randomly allocated to two groups of 25 patients each, a general anesthesia group and a CSE anesthesia group. The two groups were further divided into two subgroups according to whether the surgical procedure was performed on the small or large intestine. The main outcome of this study was to measure the recovery times of GI function by determining the time to the first postoperative stool, duration of nasogastric feeding, and onset time of full enteral nutrition. The secondary outcome was to detect adverse events postoperatively. Recovery of intestinal function was faster (P < 0.0001) and the frequencies of postoperative abdominal distension and pneumonia were less (P < 0.04) in infants who were anesthetized with CSE anesthesia than general anesthesia. Combined spinal-epidural anesthesia leads to faster restoration of GI function while reducing adverse events in infants who require elective intestinal surgery.
Journal of Cellular Physiology, 2007
Bone elongation is predominantly driven by the volume expansion of growth plate chondrocytes. Thi... more Bone elongation is predominantly driven by the volume expansion of growth plate chondrocytes. This mechanism was initially believed to be ''hypertrophy'', describing a proportional increase of cell water and organelles. However, morphometrical analysis subsequently assumed the increase to be ''swelling'', resulting in a disproportionate increase of cell water (osmotically active fraction). Histological approaches were performed on fixed tissue, and for the ''swelling'' assumption to be valid, the osmotic sensitivity of living cells before and during volume increase should differ. To test this, analysis of images acquired by 2-photon laser scanning microscopy (2PLSM) were used to determine the osmotic sensitivity, and osmotically active/inactive proportions of in situ chondrocytes from 15 living rat growth plates exposed to varying media osmolarities ($0-580 mOsm). The dimensions of cell volume swelling in hypotonic media were different to the preferential lengthening seen in vivo, confirming the complexity of directional cell volume increase. Boyle-van't Hoff analysis of cell volume over the range of media osmolarity indicated no significant difference (Student's t-test) in the osmotically inactive fraction, 39.5 AE 2.9% and 47.0 AE 4.3% (n ¼ 13) for proliferative and hypertrophic zones, respectively, or the sensitivity of volume to changes in media osmolarity (proliferative 15.5 AE 0.8 and hypertrophic zone 15.5 AE 1.2%volume Á Osm). The osmotic fractions did not change as chondrocytes progress from proliferative to hypertrophic regions of the growth plate. Our data suggest cell volume increase by hypertrophy may play a greater role in cell enlargement than swelling, and should be re-evaluated as a mechanism responsible for growth plate chondrocyte volume increase and hence bone elongation.
Diagnostic and prognostic research, May 23, 2019
European Journal of Human Genetics, 2019
Gastroenterology, Aug 1, 2018
Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to... more Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to contribute to development of inflammatory bowel diseases (IBD). The single nucleotide polymorphism rs2228145 in IL6R associates with increased levels of soluble IL6R (s-IL6R), as well as reduced IL6R signaling and risk of inflammatory disorders; its effects are similar to those of a therapeutic monoclonal antibody that blocks IL6R signaling. We used the effect of rs2228145 on s-IL6R level as an indirect marker to investigate whether reduced IL6R signaling associates with risk of ulcerative colitis (UC) or Crohn's disease (CD). In a genome-wide meta-analysis of 20,550 patients with CD, 17,647 patients with UC, and more than 40,000 individuals without IBD (controls), we found that rs2228145 (scaled to a 2-fold increase in s-IL6R) was associated with reduced risk of CD (odds ratio 0.876; 95% confidence interval 0.822-0.933; P [ .00003) or UC (odds ratio 0.932; 95% confidence interval 0.875-0.996; P [ .036). These findings indicate that therapeutics designed to block IL6R signaling might be effective in treatment of IBD.
Journal of Hepatology, Dec 1, 2020
Institute of Health Informatics, Faculty of Population Health Sciences, University College London... more Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK; Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK; Perspectum Diagnostics Ltd., Oxford, UK; Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK; Health Data Research UK London, Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK; Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK; Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
Epidemiology, 2021
Background: Cross-sectional measures of body mass index (BMI) are associated with cardiovascular ... more Background: Cross-sectional measures of body mass index (BMI) are associated with cardiovascular disease (CVD) incidence, but less is known about whether weight change affects the risk of CVD. Methods: We estimated the effect of 2-y weight change interventions on 7-y risk of CVD (CVD death, myocardial infarction, stroke, hospitalization from coronary heart disease, and heart failure) by emulating hypothetical interventions using electronic health records. We identified 138,567 individuals with 45–69 years of age without chronic disease in England from 1998 to 2016. We performed pooled logistic regression, using inverse-probability weighting to adjust for baseline and time-varying confounders. We categorized each individual into a weight loss, maintenance, or gain group. Results: Among those of normal weight, both weight loss [risk difference (RD) vs. weight maintenance = 1.5% (0.3% to 3.0%)] and gain [RD = 1.3% (0.5% to 2.2%)] were associated with increased risk for CVD compared wit...
Alimentary Pharmacology & Therapeutics, Jul 14, 2017
Journal of Crohn's and Colitis, Jan 16, 2018
Smoking is associated with a decreased requirement for thiopurines however it does not impact on ... more Smoking is associated with a decreased requirement for thiopurines however it does not impact on the risk of corticosteroid dependency or colectomy. The risks associated with smoking outweigh any benefits and smoking cessation should be encouraged.
British Journal of Cancer
Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 p... more Introduction CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). Methods The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic (‘COVID’ cohort, 16/03/2020-10/05/2020), with 12-month follow-up. Results Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, ...
European Heart Journal, 2017
Background: There are increasing opportunities for junior doctors to deliver teaching as well as ... more Background: There are increasing opportunities for junior doctors to deliver teaching as well as formally develop teaching skills. Near-peer teaching (NPT) programmes, like that established in South-East Scotland, not only provide additional learning opportunities for students but also have potential benefits for the teachers. Context: Achieving the multiple competencies required of both the medical school and the foundation programme poses significant challenges. Medical students have reduced exposure to bedside teaching, which may be contributing to the concerns raised regarding the clinical skills of recently graduated junior doctors. NPT increases the pool of tutors available to students, helps facilitate both practical and small group teaching and has other advantages, such as peer tutors being more approachable than senior staff. Innovation: The NPT programme in South-East Scotland was devised by a group of junior doctors keen to improve, expand and formalise NPT. It started i...
Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 Brit... more Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription- or doctor-consultation rate, and no disease-related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9-dependent hotspots, demonstrating PRDM9 redundancy in humans.
BMJ case reports, Jan 19, 2012
BMJ case reports, Jan 30, 2012
A 39-year-old woman presented to the gastroenterology clinic with recurrent right-upper-quadrant ... more A 39-year-old woman presented to the gastroenterology clinic with recurrent right-upper-quadrant pain and elevated liver enzymes. Endoscopy revealed a small submucosal mass at the edge of the major duodenal papilla, which was not amenable to endoscopic resection. The mass was successfully resected by laparoscopy. The papilla was subsequently reconstructed and a cannula inserted in the common bile duct. The postoperative period was uneventful and the patient was discharged on the third postoperative day. Subsequent pathological examination of the excised mass revealed a gangliocytic paraganglioma. Six weeks later, the patient was free of symptoms and the cannula was removed by duodenoscopy.
International Journal of Paediatric Dentistry, 2011
Midazolam sedation poses a significant dilemma in paediatric dentistry, which is to find out the ... more Midazolam sedation poses a significant dilemma in paediatric dentistry, which is to find out the optimal dosing with minimal undesirable adverse events. In this study, we aimed to compare the effect of three doses of oral midazolam (0.5, 0.75, and 1 mg/kg) on the sedative state and cooperative behaviour of children during dental treatment. We further compared completion rates, parent satisfaction, and all adverse events. Ninety children aged 3-10 years were randomised to three equal groups. Groups A, B, and C received 0.5, 0.75, and 1 mg/kg of oral midazolam, respectively. Levels of sedation, cooperative behaviour, procedures completion rates, parent satisfaction, and adverse events were prospectively recorded. Sedation scores in B and C were higher (P < 0.001) than in A. Cooperation scores (CS) in B and C were higher (P < 0.001) than in A. Significant increase in completion rates was observed between A and C (P = 0.025). Parent satisfaction was greater in B and C (P < 0.001) compared to A. Adverse events were higher in C (P < 0.05) than in A or B. Amount of 0.75 mg/kg oral midazolam appears to be the optimal oral dose in terms of effectiveness, acceptability, and safety for dental treatments in paediatric patients, when administered by an experienced, paediatric anaesthetist.
The Clinical Teacher, 2013
Background: There are increasing opportunities for junior doctors to deliver teaching as well as ... more Background: There are increasing opportunities for junior doctors to deliver teaching as well as formally develop teaching skills. Near-peer teaching (NPT) programmes, like that established in SouthEast Scotland, not only provide additional learning opportunities for students but also have potential benefits for the teachers. Context: Achieving the multiple competencies required of both the medical school and the foundation programme poses significant challenges. Medical students have reduced exposure to bedside teaching, which may be contrib
Pediatric Surgery International, 2012
Purpose To discuss developments in paediatric anaesthesia and explore the factors which have cont... more Purpose To discuss developments in paediatric anaesthesia and explore the factors which have contributed to improved anaesthetic-related patient outcomes. Methods Narrative review of findings in the literature retrieved from MEDLINE/Pubmed and manual search. Results Adverse perioperative outcomes related to anaesthesia have been extensively debated over the past few decades, with studies implicating factors such as major human error and equipment failure. Case series and event registries have enlightened physicians on sources of error and patient risk factors such as extremes of age, comorbidity and emergent circumstances. Anaesthetic-related deaths in children fell from 6.4 per 10,000 anaesthetics in the early 1950s to as low as 0.1 per 10,000 anaesthetics by the end of the century. Advances in anaesthetic agents, techniques, monitoring technologies and training programmes in paediatric anaesthesia play a vital role in driving this downward trend. Conclusion Despite substantial progress, there is still much room for improvement in areas such as adverse-event reporting, anaesthetic-related risk and late neurocognitive outcomes. Systematic reviews comparing paediatric patient outcomes after neuroaxial block versus general anaesthesia are currently unavailable. The future of paediatric anaesthesia will most likely be influenced by much-needed large prospective studies, which can provide further insight into patient safety and service delivery.
Journal of Clinical Anesthesia, 2012
To assess the rate of restoration of gastrointestinal (GI) function following combined spinal-epi... more To assess the rate of restoration of gastrointestinal (GI) function following combined spinal-epidural (CSE) anesthesia compared with general anesthesia in young infants undergoing elective intestinal surgery. Prospective, randomized, controlled study. Operating room and neonatal intensive care unit of a university hospital. 50 young infants undergoing elective intestinal surgery. 50 young infants were randomly allocated to two groups of 25 patients each, a general anesthesia group and a CSE anesthesia group. The two groups were further divided into two subgroups according to whether the surgical procedure was performed on the small or large intestine. The main outcome of this study was to measure the recovery times of GI function by determining the time to the first postoperative stool, duration of nasogastric feeding, and onset time of full enteral nutrition. The secondary outcome was to detect adverse events postoperatively. Recovery of intestinal function was faster (P < 0.0001) and the frequencies of postoperative abdominal distension and pneumonia were less (P < 0.04) in infants who were anesthetized with CSE anesthesia than general anesthesia. Combined spinal-epidural anesthesia leads to faster restoration of GI function while reducing adverse events in infants who require elective intestinal surgery.
Journal of Cellular Physiology, 2007
Bone elongation is predominantly driven by the volume expansion of growth plate chondrocytes. Thi... more Bone elongation is predominantly driven by the volume expansion of growth plate chondrocytes. This mechanism was initially believed to be ''hypertrophy'', describing a proportional increase of cell water and organelles. However, morphometrical analysis subsequently assumed the increase to be ''swelling'', resulting in a disproportionate increase of cell water (osmotically active fraction). Histological approaches were performed on fixed tissue, and for the ''swelling'' assumption to be valid, the osmotic sensitivity of living cells before and during volume increase should differ. To test this, analysis of images acquired by 2-photon laser scanning microscopy (2PLSM) were used to determine the osmotic sensitivity, and osmotically active/inactive proportions of in situ chondrocytes from 15 living rat growth plates exposed to varying media osmolarities ($0-580 mOsm). The dimensions of cell volume swelling in hypotonic media were different to the preferential lengthening seen in vivo, confirming the complexity of directional cell volume increase. Boyle-van't Hoff analysis of cell volume over the range of media osmolarity indicated no significant difference (Student's t-test) in the osmotically inactive fraction, 39.5 AE 2.9% and 47.0 AE 4.3% (n ¼ 13) for proliferative and hypertrophic zones, respectively, or the sensitivity of volume to changes in media osmolarity (proliferative 15.5 AE 0.8 and hypertrophic zone 15.5 AE 1.2%volume Á Osm). The osmotic fractions did not change as chondrocytes progress from proliferative to hypertrophic regions of the growth plate. Our data suggest cell volume increase by hypertrophy may play a greater role in cell enlargement than swelling, and should be re-evaluated as a mechanism responsible for growth plate chondrocyte volume increase and hence bone elongation.