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High-grade gliomas are rapidly progressing and generally fatal neoplasms of the brain. Chemotherapy has continued to provide only limited benefit for patients harboring these tumors. The recurrence of common mutations, combined with the similarities of many of the acquired capabilities and characteristics of solid tumors, suggest many common therapeutic targets. During the past few decades, an increased understanding of many of the cellular regulatory mechanisms associated with carcinogenesis has provided an opportunity for the development of pathway-specific small molecule targeted inhibitors (SMIs). This article reviews the use of SMIs in the treatment of high-grade glioma., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Dynamic nuclear polarization can be used to increase the sensitivity of solution state (13)C magnetic resonance spectroscopy by four orders of magnitude. We show here that [1-(13)C]glutamate can be polarized to 28%, representing a 35,000-fold increase in its sensitivity to detection at 9.4 T and 37°C. The metabolism of hyperpolarized glutamate to α-ketoglutarate, catalyzed by the enzyme alanine transaminase, was detected in vitro in human hepatoma cells (HepG2). Incubation of the cells with sodium pyruvate increased the level of the hyperpolarized label in the α-ketoglutarate pool, with an associated increase in the apparent rate constant describing flux of hyperpolarized (13)C label between glutamate and α-ketoglutarate. The metabolism of hyperpolarized glutamate was observed in vivo following coadministration of pyruvate in a murine lymphoma model. This represents a new method to probe glutamate metabolism and citric acid cycle activity in vivo; as glutamate is an endogenous molecule, it has the potential to be used in the clinic., (Copyright © 2011 Wiley-Liss, Inc.)

We show here that hyperpolarized [1-(13) C]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with (18) fluoro-2-deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. (13) C chemical shift images acquired following intravenous injection of hyperpolarized [1-(13) C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized (13) C label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 ± 0.16 to 0.23 ± 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy., (Copyright © 2010 Wiley-Liss, Inc.)

Participation of extended family members, particularly custodial grandparents, has generally resulted in better outcomes for abused children and relief for an overburdened child welfare system. This research explores the risk of adolescent perpetrated violence in custodial grandparent households with data from the Florida Department of Juvenile Justice. Findings suggest that living arrangements with custodial grandparents have a significant and differential impact on rates of violent offending for chronic and serious offenders by race and gender.

Measurements of the conversion of hyperpolarized [1-(13)C]pyruvate into lactate, in the reaction catalyzed by lactate dehydrogenase, have shown promise as a metabolic marker for the presence of disease and response to treatment. However, it is unclear whether this represents net flux of label from pyruvate to lactate or exchange of isotope between metabolites that are close to chemical equilibrium. Using saturation and inversion transfer experiments, we show that there is significant exchange of label between lactate and pyruvate in a murine lymphoma in vivo. The rate constants estimated from the magnetization transfer experiments, at specific points during the time course of label exchange, were similar to those obtained by fitting the changes in peak intensities during the entire exchange time course to a kinetic model for two-site exchange. These magnetization transfer experiments may therefore provide an alternative and more rapid way of estimating flux between pyruvate and lactate to serial measurements of pyruvate and lactate (13)C peak intensities following injection of hyperpolarized [1-(13)C]pyruvate.

Detection of early tumor responses to treatment can give an indication of clinical outcome. Positron emission tomography measurements of the uptake of the glucose analog, [(18)F] 2-fluoro-2-deoxy-D-glucose (FDG), have demonstrated their potential for detecting early treatment response in the clinic. We have shown recently that (13)C magnetic resonance spectroscopy and spectroscopic imaging measurements of the uptake and conversion of hyperpolarized [1-(13)C]pyruvate into [1-(13)C]lactate can be used to detect treatment response in a murine lymphoma model. The present study compares these magnetic resonance measurements with changes in FDG uptake after chemotherapy. A decrease in FDG uptake was found to precede the decrease in flux of hyperpolarized (13)C label between pyruvate and lactate, both in tumor cells in vitro and in tumors in vivo. However, the magnitude of the decrease in FDG uptake and the decrease in pyruvate to lactate flux was comparable at 24 hours after drug treatment. In cells, the decrease in FDG uptake was shown to correlate with changes in plasma membrane expression of the facilitative glucose transporters, whereas the decrease in pyruvate to lactate flux could be explained by an increase in poly(ADP-ribose) polymerase activity and subsequent depletion of the NAD(H) pool. These results show that measurement of flux between pyruvate and lactate may be an alternative to FDG-positron emission tomography for imaging tumor treatment response in the clinic.

Dynamic nuclear polarization (DNP) is an emerging technique for increasing the sensitivity of (13)C MR spectroscopy (MRS). [5-(13)C(1)]Glutamine was hyperpolarized using this technique by up to 5%, representing a 6000-fold increase in sensitivity. The conversion of hyperpolarized glutamine to glutamate by mitochondrial glutaminase was demonstrated using (13)C-MRS measurements in cultured human hepatoma cells (HepG2). These results represent the first step in developing an imaging technique for detecting glutamine metabolism in vivo. Furthermore, since glutamine utilization has been correlated with cell proliferation, the study suggests a new technique for detecting changes in tumor cell proliferation., ((c) 2008 Wiley-Liss, Inc.)

As alterations in tissue pH underlie many pathological processes, the capability to image tissue pH in the clinic could offer new ways of detecting disease and response to treatment. Dynamic nuclear polarization is an emerging technique for substantially increasing the sensitivity of magnetic resonance imaging experiments. Here we show that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized bicarbonate (H(13)CO(3)(-)) and (13)CO(2) following intravenous injection of hyperpolarized H(13)CO(3)(-). The technique was demonstrated in a mouse tumour model, which showed that the average tumour interstitial pH was significantly lower than the surrounding tissue. Given that bicarbonate is an endogenous molecule that can be infused in relatively high concentrations into patients, we propose that this technique could be used clinically to image pathological processes that are associated with alterations in tissue pH, such as cancer, ischaemia and inflammation.

Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.

Background: The Australian government sponsored trials aimed at addressing problems in after hours primary medical care service use in five different parts of the country with different after hours care problems. The study's objective was to determine in four of the five trials where telephone triage was the sole innovation, if there was a reduction in emergency GP after hours service utilization (GP first call-out) as measured in Medicare Benefits Schedule claim data. Monthly MBS claim data in both the pre-trial and trial periods was monitored over a 3-year period in each trial area as well as in a national sample outside the trial areas (National comparator). Poisson regression analysis was used in analysis., Results: There was significant reduction in first call out MBS claims in three of the four study areas where stand-alone call centre services existed. These were the Statewide Call Centre in both its Metropolitan and Non-metropolitan areas in which it operated - Relative Risk (RR) = 0.87 (95% Confidence interval: 0.86 - 0.88) and 0.60 (95% CI: 0.54 - 0.68) respectively. There was also a reduction in the Regional Call Centre in the non-Metropolitan area in which it operated (RR = 0.46 (95% CI: 0.35 - 0.61) though a small increase in its Metropolitan area (RR = 1.11 (95% CI: 1.06 - 1.17). For the two telephone triage services embedded in existing organisations, there was also a significant reduction for the Deputising Service - RR = 0.62 (95% CI: 0.61 - 0.64) but no change in the Local Triage centre area., Conclusion: The four telephone triage services were associated with reduced GP MBS claims for first callout after hours care in most study areas. It is possible that other factors could be responsible for some of this reduction, for example, MBS submitted claims for after hours GP services being reclassified from 'after hours' to 'in hours'. The goals of stand-alone call centres which are aimed principally at meeting population needs rather than managing demand may be being met only in part.

A nematic liquid crystal spatial light modulator used as a phase-modulating device and operating in the reflective mode is analyzed using three-dimensional modeling. Two configurations, which differ in their electrode placement relative to a fixed quarter-wave plate, are considered across a range of steering directions, with the grating conformal and in some cases oblique to the pixel grid. For each steering direction the sensitivity of the diffraction orders to the polarization state of the incident wavefront is studied. Optimal alignment of the liquid crystal is suggested to reduce this sensitivity.

Background: The After Hours Primary Medical Trials were initiated by the Australian government to redress difficulties in after hours (AH) GP care in areas of high need. The study's objective is to study the impact of two standalone call centres and one GP cooperative offering comprehensive services, in improving consumer access to services for residents of a defined geographic area., Methods: A pre-post design was used to evaluate their impact after adjusting for secular trend at a national level. Access was considered in terms of availability, accessibility, affordability, acceptability and responsiveness of care. Unmet need and ease of obtaining AH telephone professional medical advice were also considered. Pre-trial and post-trial telephone surveys of two separate random samples of approximately 350 households using AH services in each trial area as well as in a national sample outside the trial areas., Results: Consumer acceptability and affordability increased in residents in the area served by the GP cooperative. Access, however measured, did not improve in either of the standalone call centre areas. Reduction in unmet need approached but did not achieve statistical significance in most but not all trial areas., Conclusions: Improvements in access in the GP cooperative conformed to expectations based on current and pre-existing AH care arrangements put in place. Absence of improvements in access in the standalone call centres did not conform to expectations but may be partly explained by the reductions in consumer acceptability, following introduction of telephone triage systems reported elsewhere.

Background: The Australian government sponsored five local trials aimed at addressing problems in after hours (AH) primary medical care (PMC). The study's objective was to determine if the four trials, where telephone triage was the sole innovation, led to a reduction in AH service utilisation and change in service mix towards AH GP clinics. Changes in utilisation and mix of AH GP clinic and home visits, ED and ambulance use were monitored in the trial areas, and in a national sample to adjust for the effects of secular trend. Pre- and post-trial telephone surveys of two separate random samples of approximately 350 AH PMC user households in each area were conducted., Results: Some types of AH PMC use became more frequent in both of the standalone services using nurse-administered proprietary call centre software, which were aimed at better addressing population need (Statewide call centre; Regional call centre). Service use overall (95%CI: 1.03-1.83) and GP clinic use (95%CI: 1.07-2.00) increased in the metro area of the Statewide call centre and in GP clinic (95%CI: 1.04-2.14) and home visits (95%CI: 1.03-3.91) in the non-metro area of the Regional call centre. Service mix only changed in the non-metro area of the Regional call centre with increased contact in GP home visits (95%CI: 1.02-4.38). Levels of use remained unchanged in both embedded services using other than proprietary software, which were established to support the GP workforce (Deputising service; Local triage centre). Service mix only changed in the Deputising service with a change away from AH GP clinics in both contact (95%CI: 0.39-0.97) and frequency (95% CI: -2.12 - -0.7)., Conclusion: Bearing in mind limitations in estimating AH PMC utilisation levels and mix, it is concluded that the impacts of telephone triage were generally smaller in Australia than reported elsewhere. There were different impacts on levels of service utilisation and service mix in standalone call centres and embedded services. Impacts of telephone triage on service utilisation and mix are influenced by the type of telephone triage offered, the goals of the agency providing the service, as well as local factors.

Background: Recent increases in the bulk-billing rate have been taken as an indication that the Federal government's Strengthening Medicare initiative, and particularly the bulk-billing incentives, are 'working'. Given the enduring geographic differences in the supply of general practitioners (GPs) it is timely to reconsider the impact that this increase in the provision of 'free care' will have on access to Medicare-funded GP services in rural and urban areas of Australia. Utilisation has been modelled as two different stochastic processes: the decision to consult and the frequency of consultation., Results: In the decision to consult model the supply of FFS GPs is a more important predictor of utilisation than the bulk-billing rate. Paradoxically the modelling predicts that ceteris paribus increases in either GP supply or the bulk-billing rate appear to have perverse effects in some areas by decreasing utilisation. In the frequency of consultation model, GP density is not a predictor and increasing the bulk-billing rate will unambiguously increase the frequency of consultation across all areas. In both models, the positive impacts associated with changes in supply and cost are constrained outside the inner metropolitan area by reduced geographic accessibility to Medicare-funded GP services. The modelling also shows that people are more likely to consult a GP in areas of high socioeconomic disadvantage, although socioeconomic status is not a predictor of frequency of consultation., Conclusion: Bulk-billing rates and the supply of FFS GPs are important features of the Australian health care system that are, potentially, amenable to policy manipulation. The implications of this research are that government policies designed to achieve similarity in these characteristics across geographic areas will not result in equity of access because they fail to address problems caused by geographic inaccessibility in rural and remote areas. Attempting to increase bulk-billing rates in some of these areas may, in fact, reduce access to FFS GP services.

A program of care co-ordination (CC) in Melbourne for individuals with a history of high use of in-patient services was evaluated. The intervention involved care planning by a general practitioner (GP) and graduated case management depending on client health status. Services were purchased from pooled funds of participating health care agencies. A randomised control trial of 2,742 participants demonstrated no significant differences between the intervention and usual care group for two quality of life measures, the SF-36 and the AQoL (assessment of quality of life), and no difference in mortality rates. Total resource usage in the CC group was substantially higher, principally due to the extra costs for care planning and case management and for administering the CC model. Results conform to the higher costs typically found in other CC trials, although the failure to demonstrate improved client outcomes is less often reported. The reasons for this failure, whether in trial design, implementation, or theoretical underpinnings are explored in a companion paper.

The study investigated why the goals of the Australian Coordinated Care trials for clients with complex care needs were not achieved. Significantly higher health service use and costs were incurred in the absence of clear evidence of improved client health outcomes. The validity of assumptions underpinning trial design and the success of implementation at each step in application of the model were examined. There were failures in both design and implementation. Many clients did not require care coordination. The funds pooling arrangements contributed to limited possibilities for service substitution and training of GP care coordinators was inadequate. Trial design did not focus on either clinical guidelines or consumer empowerment. Furthermore, the expectations of the overall national trial were unrealistic both in trial design and expected outcomes given the rigidities and realities of the Australian health care system. Broader system reform in the form of funds pooling and health services planning at the regional level, based on large populations, may be a more effective means to address problems of care coordination and an inflexible supply system.

The comparison of disparate interventions for the prevention and management of osteoarthritis (OA) is limited by the quality and quantity of published efficacy studies and the use of disparate measures for reporting clinical trial outcomes. The "transfer to utility" technique was used to translate published trial outcomes into a health-related quality-of-life (utility) scale, creating a common metric which supported comparisons between disparate interventions. Total hip replacement (THR) and total knee replacement (TKR) surgery were the most effective treatments and also highly cost-effective, at estimated cost per quality-adjusted life-year (QALY) of 7500 dollars for THR and 10000 dollars for TKR (best estimate). Other apparently highly cost-effective interventions were exercise and strength training for knee OA (< 5000 dollars/QALY), knee bracing, and use of capsaicin or glucosamine sulfate (< 10000 dollars/QALY). The cost per QALY estimates of non-specific and COX-2 inhibitor non-steroidal anti-inflammatory drugs were affected by treatment-related deaths and highly sensitive to the discounting of life-years lost. OA interventions that have been shown to be ineffective (eg, arthroscopy) are targets for redistribution of healthcare resources. OA interventions which lack efficacy studies (eg, prevention programs) require further research to assist priority setting. The application of the Health-sector Wide model to OA demonstrates its role as an evidence-based model that can be successfully applied to identify marginal interventions - those to be expanded and contracted to reduce the expected burden of disease, within current healthcare resources.

For decades, the fluid-filled lung has been a valuable research model for understanding normal and abnormal pulmonary physiology. It has lagged behind, however, as a useful therapeutic tool. Recently, the potential applications of perflubron's physicochemical and biologic properties have been realized. In animal models of several types of hypoxic respiratory failure, perflubron's efficacy in improving gas exchange and compliance has been demonstrated. Preliminary clinical studies of PLV in neonates who have RDS and CDH, and in children and adults who have ARDS have shown promise. Pivotal prospective, controlled studies have yet to be completed.

Objective: To determine if the use of inhaled nitric oxide therapy reduces the need for extracorporeal membrane oxygenation (ECMO) in persistent pulmonary hypertension of the newborn., Design: A matched cohort study with retrospective data extraction., Setting: Pediatric and neonatal intensive care units at a medical school-affiliated children's hospital serving as a regional referral center for respiratory failure., Patients: Records of all neonates transferred for rescue therapy for persistent pulmonary hypertension during the study period were analyzed, with inclusion in the study based on defined gas exchange parameters, and with exclusion from the study based on the presence of congenital heart disease, diaphragmatic hernia, or lethal chromosomal abnormality. Assignment to cohorts was based on availability of inhaled nitric oxide therapy: group 1 patients were admitted when inhaled nitric oxide was unavailable; group 2 patients were admitted when inhaled nitric oxide was available., Interventions: Standard criteria (alveolar-arterial oxygen tension gradient of > 600 torr [> 80 kPa], or oxygenation index of > 40) were used to trigger initial evaluation for ECMO when these criteria were met for 2 hrs, and ECMO was initiated if these criteria continued to be met for 12 hrs, or if cardiovascular instability occurred. Ventilator management in all patients was directed to improve arterial oxygenation, such that ECMO criteria were no longer met. Patients in group 2 only were treated with inhaled nitric oxide after meeting ECMO evaluation criteria, and they continued to receive inhaled nitric oxide if a quantifiable improvement in gas exchange occurred., Measurements and Main Results: Fifty patients qualified for inclusion in the analysis (29 patients in group 1, and 21 patients in group 2). In group 1, 21 (72%) patients met ECMO criteria, and 16 (76%) patients required ECMO therapy. In group 2, 16 (76%) patients met ECMO criteria, 15 patients received inhaled nitric oxide therapy, and only four (25%) patients required ECMO therapy (p = .003 compared with group 1). Treatment with inhaled nitric oxide resulted in an initial increase in PaO2, without adverse effects, in all of the treated patients. The reduction in ECMO utilization in group 2 was achieved with a higher rate of complication-free survival (survival without oxygen, requirement at 28 days, p = .018; survival without intracranial hemorrhage, p = .048), and a lower hospital cost per survivor (p = .021), compared with group 1 patients., Conclusion: In neonates with persistent pulmonary hypertension, therapy with inhaled nitric oxide reliably and safely improves oxygenation, thereby resulting in a decreased need for ECMO therapy, improved patient outcome, and lower hospital costs.

Background: Studies in developing countries have shown that children with measles have low serum retinol concentrations and that lower retinol levels are associated with measles-related mortality. Vitamin A therapy has been shown to reduce mortality among African children with acute measles., Objectives: To determine whether serum retinol concentration is low among children with measles in the United States and to determine whether retinol concentration is associated with illness severity., Setting: Pediatric referral hospital and clinic in Milwaukee, WI, during the measles outbreak of 1989-1990., Patients: One hundred fourteen patients < or = 5 years of age evaluated for serologically confirmed measles with serum obtained within 5 days following rash onset., Methods: Serum retinol concentration was determined by high-performance liquid chromatography. Clinical data were collected by hospital record review. A modified Pediatric Risk of Mortality (PRISM) score was used to assess physiologic instability as a measure of illness severity., Results: Retinol concentrations ranged from 0.25 to 1.18 mumol/L (median 0.58 mumol/L); 82 (72%) patients had low retinol concentration (< or = 0.70 mumol/L). Median retinol concentrations were lower among hospitalized patients (0.56 vs 0.70, P = .006) and patients with pneumonia (0.52 vs 0.64, P = .02) but higher among children with otitis media (0.63 vs 0.54, P = .01). Higher modified PRISM scores, reflecting greater physiologic instability, were associated with lower retinol concentration (beta coefficient -.0147, P = .025). In multivariate analysis, higher modified PRISM scores were associated with lower retinol concentration (beta coefficient -.0144, P = .025) even after controlling for hospitalization, presence of complications, race, age, receipt of Aid to Families With Dependent Children, gender, and interval from rash onset until serum was collected., Conclusions: Among these children with measles in an urban United States community, retinol concentrations were depressed, and the degree of depression was associated with illness severity. Vitamin A therapy should be considered for children with measles in the United States who require hospitalization.

During the period of interhospital transfer, a critically ill child is at risk from the disease, the therapy, and the transfer itself. This risk can be minimized by good communication between the referring and receiving caretakers, careful evaluation and management, anticipation of complications, and a well-equipped and well-trained transport team providing a level of care as close as possible to that available at the receiving critical care unit.

Objective: A large number of children with measles were hospitalized at a children's hospital during a metropolitan measles outbreak. In this study we addressed the appropriateness of those admissions., Methods: Charts of all 634 patients with a diagnosis of measles who were treated between August 1989 and April 1990 were reviewed. Determination of the appropriateness of hospital admission was based on severity of illness and presence of severe complications of measles., Results: Of 564 patients with clinical measles or serologic evidence of recent infection, 252 were inpatients (median age 1.5 years) and 312 were outpatients (median age 2.1 years). Fifty-nine (23.4%) of the inpatients had been inappropriately admitted. Inpatients were significantly more likely than outpatients to have physiologic instability or a clinical complication. Children 15 months of age or younger were more likely to be hospitalized, as were children evaluated in the first 3 months of the outbreak period, even if admission was not appropriate on the basis of physiologic instability or complications., Conclusions: Younger patients with measles and patients evaluated earlier in the epidemic were more likely to be admitted to the hospital even when admission was inappropriate as assessed by degree of physiologic instability or presence of complications.

In the past 10 years, we have seen tremendous growth in the use of ECMO for neonatal cardiopulmonary failure, and new indications are being recognized for the use of ECMO and other forms of ECLS in older children and adults. The number of medical centers providing ECLS is and will always be limited, so services are needed to transport critically ill patients to ECLS centers. Transport teams should be thoroughly familiar with the pathophysiology of cardiac and respiratory failure. They should be equipped to continue the monitoring and treatment initiated at the referring center, to maintain that level of care during transfer, and to treat complications of the diseases or of the therapy itself. The responsibilities of the referring centers are to acquaint themselves with ECLS programs in their geographic areas and with transport services available. Early communication with complete and accurate information is essential. Developing a program for ECLS during transport is a huge undertaking that should be considered seriously. Not every ECLS center has the resources to embark on such a program. Timely referral should make such complex transfers unnecessary for most patients.

An immunogold labelling technique was used to label the pili of the bacterium Bacteroides nodosus. The labelling was distinct and highly specific, and individual pili could be recognised beneath the gold probe. The labelling of somatic antigens could be distinguished from that of pilus antigens. Furthermore, labelling of fragments of cytoplasm released by cell lysis and trapped in the pili could be distinguished from pilus labelling. An antiserum that had been raised against strain 80200 (serotype N) labelled pili of strain 215 (serotype B). Double labelling experiments with this antiserum and the antiserum against strain 215 (serotype B) showed that both antisera label the same pili bundles. The ease of detection of the immunocytochemical reaction should enable this technique to be used as a routine screen for pilus antigens. It also possesses the potential for much wider applications for immunolabelling other antigens, such as viruses, that can be obtained in suspension.

Circadian rhythmicity has been reported in various small intestinal digestive-absorptive functions and in the mitotic activity of intestinal crypt cells. These functional activity rhythms and perhaps the mitotic rhythms are cued by the feeding schedule. We now report that circadian rhythms also occurred in both the villus height and cell number in rats maintained on morning or afternoon feeding schedules for 7 days. Villus width was constant. In afternoon-fed rats both villus height and cell number were 50% greater just before feeding than 12 h later. The amplitudes of the two rhythms in the morning fed rats were decreased, the general shape of the cycles were changed and the average number of cells was increased. These changes between morning and afternoon feeding are attributed to incomplete phase shifting due to an insufficient adaptation span for the morning fed rats. We conclude that circadian rhythms occurring in villus height and cell number are affected by the feeding schedule. Similarities to some previously reported functional rhythms suggest that fluctuations in cell number and/or villus length might be related to the functional changes.