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Objectives: Chronic diarrhoea and severe wasting associated with HIV infection were first described in East African patients as slim disease (SD) in 1985. The main histological features are flattening of the villi (villous atrophy) and crypt hyperplasia (elongated crypts), i.e., HIV enteropathy (HIVE). Selective loss of mucosal clusters of differentiation 4 (CD4)+ T helper (Th)17+ lymphocytes is the immunological hallmark of HIVE. This review explores (i) the historical background of HIVE and SD, (ii) the relationship between gut mucosal CD4+ Th17+ and intestinal-resident intra-epithelial gamma delta (IRIE) T lymphocytes in pathogenesis of HIVE, (iii) the role of cytokines in regulation of intestinal epithelial proliferation, and (iv) the role of antiretroviral therapy in HIVE., Methods: Recent studies have highlighted the role of IRIE T lymphocytes, mostly CD8+, in regulating gut epithelial regeneration. CD4+Th17+ and IRIE T cells are necessary to maintain intestinal barrier integrity and mucosal antimicrobial immune defence. However, the immunological cross-talk between such lymphocyte sub-sets culminating in HIVE is uncertain. We undertook a narrative literature review under the headings 'HIVE', 'SD', and 'Highly active antiretroviral therapy (HAART). Relevant studies were located using the electronic search engines Google Scholar and PubMed from 1984 to 2022., Results: Depletion of Th17+ cells in the lamina propria, attributed to low-level viraemia, is accompanied by concomitant increase in the density of gut mucosal IRIE T lymphocytes in AIDS. The latter express a broad range of cytokines (interferon-gamma, tumor necrosis factor-alpha, interleukin-17) and chemokines e.g., keratinocyte growth factor, post exposure to HIV-infected cells. Keratinocyte growth factor induces epithelial proliferation mainly in the crypts, leading to functional immaturity of enterocytes, reduced gut absorptive surface area and malabsorption in animal experiments. Of note, the absence of IRIE T cells is associated with a reduction in epithelial cell turnover. Patients with HIVE receiving early HAART show enhanced expression of mucosal repair genes and improvement of gut symptoms., Conclusion: Multiple lines of enquiry suggest HIVE is directly related to HIV infection and is a consequence of perturbations in mucosal CD4+Th17+ and IRIE T lymphocytes. The pathological result is enterocyte immaturity and dysfunction. SD whose main features are malabsorption, diarrhoea and weight loss, is a severe clinical expression of HIVE. A better understanding of immuno-pathogenesis of HIVE opens a window of opportunity for the potential use of immunotherapy in HIV disease and other T cell-mediated enteropathies., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Exertional-heat stress adversely distrupts (GI) barrier integrity and, through subsequent microbial translocation (MT), can result in potentially fatal exertional-heat stroke. Acute glutamine (GLN) supplementation is a potential nutritional countermeasure, although the practical value of current supplementation regimens is questionable. Method: Ten males completed two high-intensity exertional-heat stress tests (EHST) involving running in the heat (40°C and 40% relative humidity) at lactate threshold to volitional exhaustion. Participants ingested GLN (0.3 g kg FFM -1 ) or a non-calorific placebo (PLA) one hour prior to the EHST. Venous blood was drawn pre-, post- and one-hour post-EHST. GI permeability was assessed using a serum dual-sugar absorption test (DSAT) and small intestinal epithelial injury using plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using the Bacteroides /total 16S DNA ratio. Results: Volitional exhaustion occurred after 22:19 ± 2:22 (minutes: seconds) in both conditions, during which whole-body physiological responses and GI symptoms were not different ( p > 0.05). GI permeability (serum DSAT) was greater following GLN (0.043 ± 0.020) than PLA (0.034 ± 0.019) ( p  = 0.02; d  = 0.47), but small intestine epithelial injury (I-FABP) increased comparably ( p  = 0.22; η p 2  = 0.16 ) following the EHST in both trials (GLN Δ = 1.25 ± 0.63 ng ml -1 ; PLA Δ = 0.92 ± 0.44 ng ml -1 ). GI MT ( Bacteroides /total 16S DNA ratio) was unchanged in either condition following the EHST ( p  = 0.43). Conclusion: Acute low-dose (0.3 g kg -1 fat free mass) GLN supplementation ingested one hour before high-intesity exertional-heat stress worsened GI permeability, but did not influence either small intestinal epithilial injury or microbial translocation. Abbreviations: ANOVA: Analysis of variance; CV: Coefficient of Variation; DSAT: Dual Sugar Absorption Test; EDTA: Ethylenediaminetetraacetic acid; EHST: Exertional Heat Stress Test; ELISA: Enzyme Linked Immunosorbent Assay; FFM: Fat Free Mass; GI: Gastrointestinal; GFR: Glomerular Filtration Rate; GLN: Glutamine; HPLC: High Performance Liquid Chromatography; HR: Heart Rate; I-FABP: Intestinal Fatty-Acid Binding Protein; ISAK: International Society for the Advancement of Anthropometric Kinanthropometry; L/R: Lactulose-to-Rhamnose; LT: Lactate Threshold; MT: Microbial Translocation; mVAS: Modified Visual Analogue Scale; PBS: Phosphate-Buffered Saline; PLA: Placebo; qPCR: Quantitative Polymerase Chain Reaction; RH: Relative Humidity; RPE: Rate of Perceived Exertion; SD: Standard Deviation; SEM: Sensor Electronics Module; T core : Core Body Temperature; T body : Mean Body Temperature; T skin : Mean Skin Temperature; TS: Thermal Sensation; V̇O 2max : Maximal Oxygen Uptake. Highlights The pathophysiology of exertional-heat stroke is widely hypothesised to be at least in part attributable to a systemic inflammatory response caused by the leak of gastrointestinal microbes into the circulating blood.Acute high-dose (0.9 g kg FFM -1 ) L -glutamine supplementation is widely promoted as a practical strategy to protect gastrointestinal barrier integrity during exertional-heat stress. However, previously validated doses are often poorly tolerated and cannot be recommended for widespread implementation.This study examined the efficacy of low-dose (0.30 g kg FFM -1 ; ∼20 grams) acute L -glutamine supplementation on small intestinal injury, permeability, and microbial translocation in response a high-intensity exertional-heat stress test to exhaustion (20-30 min). This type of exercise accounts for the majority of exertional-heat stroke cases in the military.Despite being universally well-tolerated across all participants, acute low-dose L -glutamine supplementation worsened gastrointestinal permeability, without influencing either small intestinal injury or microbial translocation. These findings do not support the application of low-dose L -glutamine supplementation to help prevent exertional-heat stroke.

Exertional heat stress disrupts gastrointestinal permeability and, through subsequent bacterial translocation, can result in potentially fatal exertional heat stroke. Glutamine supplementation is a potential countermeasure although previously validated doses are not universally well tolerated. Ten males completed two 80-minute subclinical exertional heat stress tests (EHSTs) following either glutamine (0.3 g kg FFM -1 ) or placebo supplementation. Small intestinal permeability was assessed using the lactulose/rhamnose dual sugar absorption test and small intestinal epithelial injury using Intestinal Fatty-Acid Binding Protein (I-FABP). Bacterial translocation was assessed using the total 16S bacterial DNA and Bacteroides /total 16S DNA ratio. The glutamine bolus was well tolerated, with no participants reporting symptoms of gastrointestinal intolerance. Small intestinal permeability was not influenced by glutamine supplementation ( p = 0.06) although a medium effect size favoring the placebo trial was observed ( d = 0.73). Both small intestinal epithelial injury ( p < 0.01) and Bacteroides /total 16S DNA ( p = 0.04) increased following exertional heat stress, but were uninfluenced by glutamine supplementation. Low-dose acute oral glutamine supplementation does not protect gastrointestinal injury, permeability, or bacterial translocation in response to subclinical exertional heat stress., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 Informa UK Limited, trading as Taylor & Francis Group.)

Significance: Current methods for analyzing pathological muscle tissue are time consuming and rarely quantitative, and they involve invasive biopsies. Faster and less invasive diagnosis of muscle disease may be achievable using marker-free in vivo optical sensing methods., Aim: It was speculated that changes in the biochemical composition and structure of muscle associated with pathology could be measured quantitatively using visible wavelength optical spectroscopy techniques enabling automated classification., Approach: A fiber-optic autofluorescence (AF) and diffuse reflectance (DR) spectroscopy device was manufactured. The device and data processing techniques based on principal component analysis were validated using in situ measurements on healthy skeletal and cardiac muscle. These methods were then applied to two mouse models of genetic muscle disease: a type 1 neurofibromatosis (NF1) limb-mesenchyme knockout (Nf1Prx1  -  /  -  ) and a muscular dystrophy mouse (mdx)., Results: Healthy skeletal and cardiac muscle specimens were separable using AF and DR with receiver operator curve areas (ROC-AUC) of >0.79. AF and DR analyses showed optically separable changes in Nf1Prx1  -  /  -   quadriceps muscle (ROC-AUC >0.97) with no differences detected in the heart (ROC-AUC <0.67), which does not undergo gene deletion in this model. Changes in AF spectra in mdx muscle were seen between the 3 week and 10 week time points (ROC-AUC = 0.96) and were not seen in the wild-type controls (ROC-AUC = 0.58)., Conclusion: These findings support the utility of in vivo fiber-optic AF and DR spectroscopy for the assessment of muscle tissue. This report highlights that there is considerable scope to develop this marker-free optical technology for preclinical muscle research and for diagnostic assessment of clinical myopathies and dystrophies.

Purpose: Exertional-heat stress adversely disrupts gastrointestinal (GI) barrier integrity, whereby subsequent microbial translocation (MT) can result in potentially serious health consequences. To date, the influence of aerobic fitness on GI barrier integrity and MT following exertional-heat stress is poorly characterised., Method: Ten untrained (UT; VO 2max  = 45 ± 3 ml·kg -1 ·min -1 ) and ten highly trained (HT; VO 2max  = 64 ± 4 ml·kg -1 ·min -1 ) males completed an ecologically valid (military) 80-min fixed-intensity exertional-heat stress test (EHST). Venous blood was drawn immediately pre- and post-EHST. GI barrier integrity was assessed using the serum dual-sugar absorption test (DSAT) and plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using plasma Bacteroides/total 16S DNA., Results: UT experienced greater thermoregulatory, cardiovascular and perceptual strain (p < 0.05) than HT during the EHST. Serum DSAT responses were similar between the two groups (p = 0.59), although Δ I-FABP was greater (p = 0.04) in the UT (1.14 ± 1.36 ng·ml -1 ) versus HT (0.20 ± 0.29 ng·ml -1 ) group. Bacteroides/Total 16S DNA ratio was unchanged (Δ; -0.04 ± 0.18) following the EHST in the HT group, but increased (Δ; 0.19 ± 0.25) in the UT group (p = 0.05). Weekly aerobic training hours had a weak, negative correlation with Δ I-FABP and Bacteroides/total 16S DNA responses., Conclusion: When exercising at the same absolute workload, UT individuals are more susceptible to small intestinal epithelial injury and MT than HT individuals. These responses appear partially attributable to greater thermoregulatory, cardiovascular, and perceptual strain.

We hypothesized that probiotic supplementation (PRO) increases the absorption and oxidation of orally ingested maltodextrin during 2 h endurance cycling, thereby sparing muscle glycogen for a subsequent time trial (simulating a road race). Measurements were made of lipid and carbohydrate oxidation, plasma metabolites and insulin, gastrointestinal (GI) permeability, and subjective symptoms of discomfort. Seven male cyclists were randomized to PRO (bacterial composition given in methods) or placebo for 4 wk, separated by a 14-day washout period. After each period, cyclists consumed a 10% maltodextrin solution (initial 8 mL/kg bolus and 2 mL/kg every 15 min) while exercising for 2 h at 55% maximal aerobic power output, followed by a 100-kJ time trial. PRO resulted in small increases in peak oxidation rates of the ingested maltodextrin (0.84 ± 0.10 vs. 0.77 ± 0.09 g/min; P = 0.016) and mean total carbohydrate oxidation (2.20 ± 0.25 vs. 1.87 ± 0.39 g/min; P = 0.038), whereas fat oxidation was reduced (0.40 ± 0.11 vs. 0.55 ± 0.10 g/min; P = 0.021). During PRO, small but significant increases were seen in glucose absorption, plasma glucose, and insulin concentration and decreases in nonesterified fatty acid and glycerol. Differences between markers of GI damage and permeability and time-trial performance were not significant ( P > 0.05). In contrast to the hypothesis, PRO led to minimal increases in absorption and oxidation of the ingested maltodextrin and small reductions in fat oxidation, whereas having no effect on subsequent time-trial performance.

Purpose: Exertional heat stress adversely distrupts (GI) barrier integrity and, through subsequent microbial translocation (MT), negativly impacts health. Despite widespread application, the temporal reliability of popular GI barrier integity and MT biomarkers is poorly characterised., Method: Fourteen males completed two 80-min exertional heat stress tests (EHST) separated by 7-14 days. Venous blood was drawn pre, immediately- and 1-hr post both EHSTs. GI barrier integrity was assessed using the serum Dual-Sugar Absorption Test (DSAT), Intestinal Fatty-Acid-Binding Protein (I-FABP) and Claudin-3 (CLDN-3). MT was assessed using plasma Lipopolysaccharide Binding Protein (LBP), total 16S bacterial DNA and Bacteroides DNA., Results: No GI barrier integrity or MT biomarker, except absolute Bacteroides DNA, displayed systematic trial order bias (p ≥ .05). I-FABP (trial 1 = Δ 0.834 ± 0.445 ng ml -1 ; trial 2 = Δ 0.776 ± 0.489 ng ml -1 ) and CLDN-3 (trial 1 = Δ 0.317 ± 0.586 ng ml -1 ; trial 2 = Δ 0.371 ± 0.508 ng ml -1 ) were increased post-EHST (p ≤ .01). All MT biomarkers were unchanged post-EHST. Coefficient of variation and typical error of measurement post-EHST were: 11.5% and 0.004 (ratio) for the DSAT 90-min postprobe ingestion; 12.2% and 0.004 (ratio) at 150-min postprobe ingestion; 12.1% and 0.376 ng ml -1 for I-FABP; 4.9% and 0.342 ng ml -1 for CLDN-3; 9.2% and 0.420 µg ml -1 for LBP; 9.5% and 0.15 pg µl -1 for total 16S DNA; and 54.7% and 0.032 for Bacteroides/total 16S DNA ratio., Conclusion: Each GI barrier integrity and MT translocation biomarker, except Bacteroides/total 16S ratio, had acceptable reliability at rest and postexertional heat stress., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Purpose: To evaluate the effects of probiotic supplementation on gastrointestinal (GI) symptoms, circulatory markers of GI permeability, damage, and markers of immune response during a marathon race., Methods: Twenty-four recreational runners were randomly assigned to either supplement with a probiotic (PRO) capsule [25 billion CFU Lactobacillus acidophilus (CUL60 and CUL21), Bifidobacterium bifidum (CUL20), and Bifidobacterium animalis subs p. Lactis (CUL34)] or placebo (PLC) for 28 days prior to a marathon race. GI symptoms were recorded during the supplement period and during the race. Serum lactulose:rhamnose ratio, and plasma intestinal-fatty acid binding protein, sCD14, and cytokines were measured pre- and post-races., Results: Prevalence of moderate GI symptoms reported were lower during the third and fourth weeks of the supplement period compared to the first and second weeks in PRO (p < 0.05) but not PLC (p > 0.05). During the marathon, GI symptom severity during the final third was significantly lower in PRO compared to PLC (p = 0.010). The lower symptom severity was associated with a significant difference in reduction of average speed from the first to the last third of the race between PLC (- 14.2 ± 5.8%) and PRO (- 7.9 ± 7.5%) (p = 0.04), although there was no difference in finish times between groups (p > 0.05). Circulatory measures increased to a similar extent between PRO and PLC (p > 0.05)., Conclusion: Probiotics supplementation was associated with a lower incidence and severity of GI symptoms in marathon runners, although the exact mechanisms are yet to be elucidated. Reducing GI symptoms during marathon running may help maintain running pace during the latter stages of racing.

Purpose: To examine the dose-response effects of acute glutamine supplementation on markers of gastrointestinal (GI) permeability, damage and, secondary, subjective symptoms of GI discomfort in response to running in the heat., Methods: Ten recreationally active males completed a total of four exercise trials; a placebo trial and three glutamine trials at 0.25, 0.5 and 0.9 g kg -1 of fat-free mass (FFM) consumed 2 h before exercise. Each exercise trial consisted of a 60-min treadmill run at 70% of [Formula: see text] in an environmental chamber set at 30 °C. GI permeability was measured using ratio of lactulose to rhamnose (L:R) in serum. Plasma glutamine and intestinal fatty acid binding protein (I-FABP) concentrations were determined pre and post exercise. Subjective GI symptoms were assessed 45 min and 24 h post-exercise., Results: Relative to placebo, L:R was likely lower following 0.25 g kg -1 (mean difference: - 0.023; ± 0.021) and 0.5 g kg -1 (- 0.019; ± 0.019) and very likely following 0.9 g kg - 1 (- 0.034; ± 0.024). GI symptoms were typically low and there was no effect of supplementation., Discussion: Acute oral glutamine consumption attenuates GI permeability relative to placebo even at lower doses of 0.25 g kg -1 , although larger doses may be more effective. It remains unclear if this will lead to reductions in GI symptoms. Athletes competing in the heat may, therefore, benefit from acute glutamine supplementation prior to exercise in order to maintain gastrointestinal integrity.

The purpose of this study was to investigate the effects of high-intensity interval running on markers of gastrointestinal (GI) damage and permeability alongside subjective symptoms of GI discomfort. Eleven male runners completed an acute bout of high-intensity interval training (HIIT) (eighteen 400-m runs at 120% maximal oxygen uptake) where markers of GI permeability, intestinal damage, and GI discomfort symptoms were assessed and compared with resting conditions. Compared with rest, HIIT significantly increased serum lactulose/rhamnose ratio (0.051 ± 0.016 vs. 0.031 ± 0.021, p = 0.0047; 95% confidence interval (CI) = 0.006 to 0.036) and sucrose concentrations (0.388 ± 0.217 vs. 0.137 ± 0.148 mg·L -1 ; p < 0.001; 95% CI = 0.152 to 0.350). In contrast, urinary lactulose/rhamnose (0.032 ± 0.005 vs. 0.030 ± 0.005; p = 0.3; 95% CI = -0.012 to 0.009) or sucrose concentrations (0.169% ± 0.168% vs. 0.123% ± 0.120%; p = 0.54; 95% CI = -0.199 to 0.108) did not differ between HIIT and resting conditions. Plasma intestinal-fatty acid binding protein (I-FABP) was significantly increased (p < 0.001) during and in the recovery period from HIIT whereas no changes were observed during rest. Mild symptoms of GI discomfort were reported immediately and at 24 h post-HIIT, although these symptoms did not correlate to GI permeability or I-FABP. In conclusion, acute HIIT increased GI permeability and intestinal I-FABP release, although these do not correlate with symptoms of GI discomfort. Furthermore, by using serum sampling, we provide data showing that it is possible to detect changes in intestinal permeability that is not observed using urinary sampling over a shorter time-period.

Hyperlenses and hyperbolic media endoscopes can overcome the diffraction limit by supporting propagating high spatial frequency extraordinary waves. While hyperlenses can resolve subwavelength details far below the diffraction limit, images obtained from them are not perfect: resonant high spatial frequency slab modes as well as diffracting ordinary waves cause image distortion and artefacts. In order to use hyperlenses as broad-band subwavelength imaging devices, it is thus necessary to avoid or correct such unwanted artefacts. Here we introduce three methods, namely convolution, field averaging, and power averaging, to remove imaging artefacts over wide frequency bands, and numerically demonstrate their effectiveness based on simulations of a wire medium endoscope. We also define a projection in spatial Fourier space to effectively filter out all ordinary waves, leading to considerable reduction in image distortion. These methods are outlined and demonstrated for simple and complex apertures.

We present a novel approach to the design and manufacture of optrodes for use in the biomedical research field of optogenetic neural interfacing. Using recently developed optical fiber drawing techniques that involve co-drawing metal/polymer composite fiber, we have assembled and characterized a novel optrode with promising optical and electrical functionality. The fabrication technique is flexible, scalable, and amenable to extension to implantable optrodes with high-density arrays of multiple electrodes, waveguides, and drug delivery channels.

Using conventional materials, the resolution of focusing and imaging devices is limited by diffraction to about half the wavelength of light, as high spatial frequencies do not propagate in isotropic materials. Wire array metamaterials, because of their extreme anisotropy, can beat this limit; however, focusing with these has only been demonstrated up to microwave frequencies and using propagation over a few wavelengths only. Here we show that the principle can be scaled to frequencies orders of magnitudes higher and to considerably longer propagation lengths. We demonstrate imaging through straight and tapered wire arrays operating in the terahertz spectrum, with unprecedented propagation of near field information over hundreds of wavelengths and focusing down to 1/28 of the wavelength with a net increase in power density. Applications could include in vivo terahertz-endoscopes with resolution compatible with imaging individual cells.

Metamaterials are man-made composite materials, fabricated by assembling components much smaller than the wavelength at which they operate (1). They owe their electromagnetic properties to the structure of their constituents, instead of the atoms that compose them. For example, sub-wavelength metal wires can be arranged to possess an effective electric permittivity that is either positive or negative at a given frequency, in contrast to the metals themselves (2). This unprecedented control over the behaviour of light can potentially lead to a number of novel devices, such as invisibility cloaks (3), negative refractive index materials (4), and lenses that resolve objects below the diffraction limit (5). However, metamaterials operating at optical, mid-infrared and terahertz frequencies are conventionally made using nano- and micro-fabrication techniques that are expensive and produce samples that are at most a few centimetres in size (6-7). Here we present a fabrication method to produce hundreds of meters of metal wire metamaterials in fiber form, which exhibit a terahertz plasmonic response (8). We combine the stack-and-draw technique used to produce microstructured polymer optical fiber (9) with the Taylor-wire process (10), using indium wires inside polymethylmethacrylate (PMMA) tubes. PMMA is chosen because it is an easy to handle, drawable dielectric with suitable optical properties in the terahertz region; indium because it has a melting temperature of 156.6 °C which is appropriate for codrawing with PMMA. We include an indium wire of 1 mm diameter and 99.99% purity in a PMMA tube with 1 mm inner diameter (ID) and 12 mm outside diameter (OD) which is sealed at one end. The tube is evacuated and drawn down to an outer diameter of 1.2 mm. The resulting fiber is then cut into smaller pieces, and stacked into a larger PMMA tube. This stack is sealed at one end and fed into a furnace while being rapidly drawn, reducing the diameter of the structure by a factor of 10, and increasing the length by a factor of 100. Such fibers possess features on the micro- and nano- scale, are inherently flexible, mass-producible, and can be woven to exhibit electromagnetic properties that are not found in nature. They represent a promising platform for a number of novel devices from terahertz to optical frequencies, such as invisible fibers, woven negative refractive index cloths, and super-resolving lenses.

We characterize spatial dispersion in longitudinally invariant drawn metamaterials with a magnetic response at terahertz frequencies, whereby a change in the angle of the incident field produces a shift in the resonant frequency. We present a simple analytical model to predict this shift. We also demonstrate that the spatial dispersion is eliminated by breaking the longitudinal invariance using laser ablation. The experimental results are in agreement with numerical simulations.

We present a novel method for producing drawn metamaterials containing slotted metallic cylinder resonators, possessing strong magnetic resonances in the terahertz range. The resulting structures are either spooled to produce a 2-dimensional metamaterial monolayer, or stacked to produce three-dimensional multi-layered metamaterials. We experimentally investigate the effects of the resonator size and number of metamaterial layers on transmittance, observing magnetic resonances between 0.1 and 0.4 THz, in good agreement with simulations. Such fibers promise future applications in mass-produced stacked or woven metamaterials., (© 2011 Optical Society of America)

We present the design of an invisible metamaterial fibre operating at optical frequencies, which could be fabricated by adapting existing fibre drawing techniques. The invisibility is realised by matching the refractive index of the metamaterial fibre with the surroundings. We present a general recipe for the fabrication of such fibres, and numerically characterise a specific example using hexagonally arranged silver nanowires in a silica background. We find that invisibility is highly sensitive to details of the metamaterial boundary, a problem that is likely to affect most invisibility and cloaking schemes.

Cerenkov radiation is generated as an unwanted background when optical fibers carrying signals pass through radiation fields. The angular dependence of the intensity of ? Cerenkov radiation transmitted in silica-core fibers was measured using 6 and 12 MeV electron beams from a Varian Clinic accelerator. These confirmed theoretical predictions that the angular variation of ? Cerenkov radiation transmitted along optical fibers depends only on the refractive index difference Dn between the core and the cladding, and that the peak intensity is proportional to the cube of the fiber core radius.

Radiation dose measurements based on scintillator detection are conveniently made by coupling the light from the scintillator into an optical fiber. The low light levels involved typically require sensitive photodetectors, so it is advantageous to increase the available signal by optimizing the optical coupling efficiency between the scintillator and optical fiber. We model this process using geometric optics and finite-element ray tracing to determine the features that maximize the amount of light coupled to an optical fiber from a cylindrical scintillator. We also address whether the coupling can be improved by using an intermediate optical element such as a lens, and we provide a means for calculating its required optical properties for a given geometry.

Cerenkov radiation is generated in optical fibers immersed in radiation fields and can interfere with signal transmission. We develop a theory for predicting the intensity of Cerenkov radiation generated within the core of a multimode optical fiber by using a ray optic approach and use it to make predictions of the intensity of radiation transmitted down the fiber in propagating modes. The intensity transmitted down the fiber is found to be dominated by bound rays with a contribution from tunneling rays. It is confirmed that for relativistic particles the intensity of the radiation that is transmitted along the fiber is a function of the angle between the particle beam and the fiber axis. The angle of peak intensity is found to be a function of the fiber refractive index difference as well as the core refractive index, with larger refractive index differences shifting the peak significantly toward lower angles. The angular range of the distribution is also significantly increased in both directions by increasing the fiber refractive index difference. The intensity of the radiation is found to be proportional to the cube of the fiber core radius in addition to its dependence on refractive index difference. As the particle energy is reduced into the nonrelativistic range the entire distribution is shifted toward lower angles. Recommendations on minimizing the quantity of Cerenkov light transmitted in the fiber optic system in a radiation field are given.

Background: Occult hypovolaemia is a key factor in the aetiology of postoperative morbidity and may not be detected by routine heart rate and arterial pressure measurements. Intraoperative gut hypoperfusion during major surgery is associated with increased morbidity and postoperative hospital stay. We assessed whether using intraoperative oesophageal Doppler guided fluid management to minimize hypovolaemia would reduce postoperative hospital stay and the time before return of gut function after colorectal surgery., Methods: This single centre, blinded, prospective controlled trial randomized 128 consecutive consenting patients undergoing colorectal resection to oesophageal Doppler guided or central venous pressure (CVP)-based (conventional) intraoperative fluid management. The intervention group patients followed a dynamic oesophageal Doppler guided fluid protocol whereas control patients were managed using routine cardiovascular monitoring aiming for a CVP between 12 and 15 mm Hg., Results: The median postoperative stay in the Doppler guided fluid group was 10 vs 11.5 days in the control group P<0.05. The median time to resuming full diet in the Doppler guided fluid group was 6 vs 7 for controls P<0.001. Doppler patients achieved significantly higher cardiac output, stroke volume, and oxygen delivery. Twenty-nine (45.3%) control patients suffered gastrointestinal morbidity compared with nine (14.1%) in the Doppler guided fluid group P<0.001, overall morbidity was also significantly higher in the control group P=0.05., Conclusions: Intraoperative oesophageal Doppler guided fluid management was associated with a 1.5-day median reduction in postoperative hospital stay. Patients recovered gut function significantly faster and suffered significantly less gastrointestinal and overall morbidity.

Aims: To investigate whether changes in carbohydrate structure of IgG are related to malignancy and stage of disease in myeloma and monoclonal gammopathy of uncertain significance (MGUS)., Methods: 61 patients were studied at diagnosis: 14 with MGUS, nine with stage I multiple myeloma, 11 with stage II, 21 with stage III, and five with solitary plasmacytoma. IgG was extracted from serum by protein G affinity chromatography. Oligosaccharides were cleaved from the protein backbone enzymatically by N-glycosidase F. Oligosaccharide analysis was performed by high pressure anion exchange chromatography with pulsed electrochemical detection (HPAE-PED)., Results: Up to 15 oligosaccharide peaks were identified in three major fractions: neutral, monosialylated, and disialylated. Patients with myeloma showed an increase in the proportion of sialylated oligosaccharides in comparison with patients with MGUS. The ratio of neutral to sialylated oligosaccharides (N:S) was reduced at all stages of myeloma compared with MGUS: MGUS, 11.35; myeloma stage I, 7.6 (p = 0.047); stage II, 5.20 (p = 0.035); stage III, 3.60 (p = 0.0002); plasmacytoma, 7.5 (p = 0.046). The N:S ratio was independent of paraprotein concentration (r = 0.05)., Conclusions: The ratio of neutral to sialylated oligosaccharides may act as a new marker of malignancy in IgG paraproteinaemia and warrants further investigation.

Objectives: To investigate the effect of small intestinal disease (SID) on the absorption of zidovudine (ZDV) in patients with AIDS., Methods: Fourteen fasted homosexual men with AIDS received a single oral dose of ZDV (5 mg/kg). Nine subjects had clinical evidence of intestinal disease (chronic diarrhoea with wasting) confirmed by reduced fat absorption measured indirectly using the 14C-triolein test. Five subjects had AIDS-related symptoms other than those affecting the gastrointestinal tract with normal fat absorption. Sequential measurements of plasma ZDV including its glucuronide metabolite (GZDV) were obtained using radio-immunoassay and ZDV/GZDV concentrations-time profiles of both groups of subjects were compared. Comparisons were also made for each of the following computed variables: the maximum plasma concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-6 h), the elimination half-life (t 1/2), and apparent oral clearance (CL0)., Results: In patients with SID, Cmax ZDV was reduced (6.39 +/- 3.39 versus 11.51 +/- 5.01 mumol/l; P < 0.05) and Tmax ZDV prolonged (0.81 +/- 0.51 versus 0.40 +/- 0.14 h; P < 0.05) but AUC0-6 h ZDV was no different from the non-SID group (8.03 +/- 2.73 versus 14.56 +/- 9.0 mumol/l-1xh; P = 0.06). There were no differences in t 1/2 ZDV (1.22 +/- 0.20 versus 1.13 +/- 0.30 h) or CL0 ZDV (3017 +/- 1158 versus 1700 +/- 889 ml/min; P > 0.05) between SID and non-SID groups, respectively, and GZDV values were comparable between the two groups., Conclusions: These data suggest delayed absorption rather than altered metabolism of ZDV in AIDS-related SID and raise the possibility of drug malabsorption. The clinical efficacy of orally administered low-dose ZDV regimens may require further evaluation in patients with chronic diarrhoea and AIDS.

The percentage dose of lactulose and mannitol excreted in urine after oral ingestion is used as a noninvasive method of assessing small intestinal permeability. The collection of incomplete or inaccurately timed urine samples can lead to errors in estimation of sugar probe molecules. We describe an HPLC method for the simultaneous determination of lactulose and mannitol in serum after oral ingestion of test sugars. We applied the test to healthy volunteers and to subjects undergoing jejunal biopsy for suspected gluten-sensitive enteropathy. The ratio of concentrations of lactulose and mannitol in serum discriminated well between subjects with a normal biopsy and those with villous atrophy, discrimination being best at 90 min postdose. The results agree well with lactulose:mannitol ratios determined in urine (r= 0.88), and the two methods can be used interchangeably. The determination of mannitol and lactulose in serum provides an acceptable alternative to urine collection and may be particularly useful in young children. It also reduces the time spent on the investigation from 5 h to 90 min.

Objectives: To investigate both small and large intestinal permeability in HIV-positive subjects, and correlate variation in intestinal mucosal abnormality with immunological and nutritional markers of HIV disease., Methods: Small and large intestinal permeability studies were performed in 14 HIV-seropositive patients and eight healthy men. Eight out of the 14 patients had diarrhoea and all subjects were negative for enteropathogens. Small intestinal permeability was determined using the lactulose-mannitol test and large intestinal permeability using the colonic absorption of 51Cr-EDTA. In addition, CD4 cell count, beta 2-microglobulin, C-reactive protein estimation and anthropometry were carried out in all subjects., Results: HIV-seropositive subjects had higher lactulose-mannitol ratios (LMR; 0.084 +/- 0.007 versus 0.013 +/- 0.0008) and lower 51Cr activity (1.986 +/- 0.066 versus 3.115 +/- 0.560) than controls (P < 0.0004 and P < 0.05, respectively). Colonic uptake of 51Cr-EDTA was no different between subjects with and those without diarrhoea (2.04 +/- 0.124 versus 1.92 +/- 0.143, P > 0.05). A negative correlation was found between LMR and 51Cr-EDTA, but only for patients with diarrhoea (r = -0.81; P = 0.015)., Conclusion: Regional variation affecting intestinal absorptive function occurs in patients with HIV-related diarrhoea and is characterized by increased LMR and reduced colonic uptake of 51Cr-EDTA. The pathogenesis and clinical significance of such changes are unknown.

Objective: The concept that HIV infection per se alters small intestinal mucosal structure and function (HIV enteropathy) remains controversial and in this study we report in vitro experiments designed to elucidate the matter., Methods: Twenty pairs of human fetal intestinal tissue explants were maintained in vitro for up to 14 days; one explant of each pair was incubated and infected with HIV, and the other served as a matched uninfected control. At various times after infection, explant culture fluid and tissue were removed, p24 concentration was measured and tissue formalin fixed. Explant tissue was embedded in paraffin wax and sections stained by an immunoperoxidase method directed against proliferating cell nuclear antigen (PCNA). The percentage of proliferating crypt and villous epithelial cells, stained by PCNA, was calculated in paired samples. The difference between the percentage for paired samples was designated delta crypt proliferation (delta CP) and delta villous proliferation (delta VP), respectively. Epithelial cell proliferation was deemed to be enhanced if the percentage of PCNA-stained cells was greater in the HIV-infected than in the control tissue., Results: Explant culture fluid from tissue exposed to HIV showed a progressive rise in p24 antigen (Ag) level, indicating HIV infection of these explants. Fifteen pairs of explants showed progressively positive delta CP with time (P < 0.01) indicating crypt hyperplasia and all 20 pairs of explants showed positive delta VP, indicating hyperplasia of villous epithelial cells., Conclusions: This study provides direct evidence that HIV stimulates epithelial cell proliferation in intestinal mucosa. HIV-infected human intestinal explants provide a model of crypt hyperplastic villous atrophy previously described as HIV enteropathy and detected in clinical biopsy specimens from HIV-infected patients.

Mannitol, 3-O-methylglucose and lactulose administered orally are used to investigate small intestinal absorption pathways and mucosal integrity. Current methods of analysis include thin-layer chromatography, gas chromatography (GC) and enzymatic analysis, which require separate estimation of mono- and disaccharides and for GC, prior derivatization. We describe a high-pressure anion-exchange chromatographic method coupled with pulsed electrochemical detection allowing simultaneous measurement of all three sugars and its clinical application in monitoring intestinal damage in human immunodeficiency virus (HIV) infection. Sample preparation is simple and fast. All sugars are resolved within 10 min. Mean recovery is 93.3% for all sugars and the overall relative standard deviation is 4.2%. Intestinal permeability (lactulose/mannitol ratio) rises with disease progression to AIDS, indicating mucosal damage. The greatest increase in permeability is associated with chronic diarrhoea. The method is an ideal non-invasive test to assess gut mucosal damage in HIV infection.

The percentage of an oral dose of mannitol, 3-O-methyl glucose, and lactulose excreted in urine is used in noninvasive investigation of active and passive intestinal mucosal transport. We developed a high-pressure liquid-chromatographic method involving anion exchange and pulsed electrochemical detection that allows the simultaneous determination of all three sugar probes in urine. Sample preparation is simple: diluting, mixing with internal standard (melibiose), and desalting. With use of a Dionex 250 x 40 mm Carbopac PA-1 column and elution with an isocratic mixture of 120 mmol/L NaOH and 0.5 mmol/L zinc acetate, all sugars were resolved within 10 min. The standard curve of the method is linear to the following concentrations: mannitol 125 mg/L, 3-O-methyl glucose 300 mg/L, and lactulose 40 mg/L. The minimal detectable concentration of lactulose is 0.4 mg/L. Analytical recovery of the sugars is between 89.0% and 99.5%. The precision of estimation (CV) ranges from 1.76% to 5.6% overall. Reference intervals were established from results for 28 healthy children. The method is adaptable for the study of carbohydrates at low concentrations in other biological fluids.

Objective: To directly infect human fetal intestine with HIV in vitro., Design: Human fetal intestinal explant cultures were exposed to HIV-1 and monitored for evidence of infection by biochemical assay, immunohistochemistry and in situ hybridization., Methods: Human fetal intestinal explants (14-21 weeks) were established in culture and exposed to HIV-1. Tissue culture fluid was assayed for p24 antigen and reverse transcriptase activity over a 14-day period. Explants were removed from culture on days 4, 7, 10 and 14 postinoculation and subjected (1) to immunohistochemistry to detect p24 and gp160/41 antigens, and (2) to in situ hybridization to detect HIV-1 RNA. Explant tissue culture fluid was cocultured with Jurkat T-cells to detect infectious viral particles., Results: Reverse transcriptase activity and p24 antigen levels in fetal explant culture fluid rose between 7 and 14 days after viral inoculation. Jurkat T-cell cocultures confirmed the presence of infectious virus. Cells in the lamina propria resembling lymphocytes and macrophages of both small intestine and colon stained positively for the viral proteins p24 and gp41. The same type of cells also stained positively for HIV-1 RNA using in situ hybridization. Dual-label immunohistochemistry, combined immunohistochemistry and in situ hybridization confirmed the presence of viral protein and RNA in cells bearing the CD3, CD4 (lymphocyte) or CD68 (macrophage) surface markers. There was no evidence at any time of HIV-1 infection of epithelial cells., Conclusions: Cells of the lamina propria of the small intestine and colon, bearing lymphocyte or macrophage markers, can be directly infected by and support the replication of HIV-1. Such infection may be implicated in the pathogenesis of HIV enteropathy.

Normal human bone marrow, cultured in vitro with interleukin 5 to promote eosinophil production and maturation, was inoculated with cell-free isolates of human immunodeficiency virus type 1 (HIV-1). CD4 expression by eosinophil precursors, determined by immunocytochemistry, was found to be greatest early in their maturation with a rapid decline after 28 d in culture. Productive HIV infection of eosinophil precursors was detected 14 d after inoculation, by a combination of immunostaining for HIV-1 p24 and gp41/160 and in situ hybridization for viral RNA, together with assay of culture supernatants for p24 antigen and reverse transcriptase activity. Thus, eosinophils are susceptible to productive HIV-1 infection in vitro and may be an important reservoir for the virus in vivo.

1. Small-intestine integrity in Caucasian and African patients infected with human immunodeficiency virus was determined by measuring the permeation across the mucosa of two sugars, lactulose and mannitol. 2. The sugars were assayed by h.p.l.c. and pulsed amperometric detection in 6 h urine samples. Stool microscopy for enteropathogens was performed in all patients. 3. The ratio of lactulose to mannitol recovered in urine was increased in Caucasian and African patients with advanced human immunodeficiency virus infection. Asymptomatic human-immunodeficiency-virus-infected subjects had a normal lactulose/mannitol ratio. African patients with diarrhoea showed a twofold reduction in mannitol excretion. Such a change in mannitol absorption was not detected in Caucasian patients and occurred regardless of the presence of enteropathogens. 4. Altered small-intestinal permeability is associated with symptomatic diarrhoea in human immunodeficiency virus infection in both Caucasian and African patients.

Small intestinal absorptive function was investigated in six patients with the acquired immunodeficiency syndrome (AIDS) who had diarrhoea and weight loss. Proximal function was assessed by [14C]Triolein test of fat absorption. Distal function was determined by a test of bile acid absorption in which the loss of radio-labelled synthetic bile acid, 75seleno-23-homocholic acid-taurine ([75Se]HCAT), from the enterohepatic circulation was quantified by abdominal gamma-scanning and by a vitamin B12-intrinsic factor absorption test. Concurrently indirect tests of small intestinal bacterial overgrowth ([14C]glycocholate and breath hydrogen) were carried out. In addition, jejunal histological examination and stool microscopy and culture for enteropathogens were performed. Fat absorption was reduced in all six patients, four of whom had jejunal villous atrophy. Bile acid and vitamin B12 absorption were normal in four subjects. Enteropathogens were not detected in any of the four subjects with normal terminal ileal absorptive function. In contrast, reduced bile acid and vitamin B12 absorption were detected in two of six subjects. Both patients had an enteropathogen (Cryptosporidium spp. and Isospora belli) present on stool and jejunal histological examination. Neither subject had evidence of small-intestinal bacterial overgrowth. AIDS patients therefore may have normal ileal absorptive function in the presence of jejunal disease. Infection with Cryptosporidium spp. or I. belli may however, be associated with severe ileal dysfunction.

The lactulose/mannitol dual sugar absorption test is a non-invasive test of intestinal permeability. Its widespread use has been limited by the difficulties of analysis for carbohydrates in urine at low concentrations. We describe a "high-pressure" liquid-chromatographic method for determining lactulose and mannitol in urine, in which anion-exchange chromatography and pulsed amperometric detection are used. Sample preparation is simple and fast, and lactulose and mannitol and the internal standards arabinose and cellobiose are well resolved within 15 min. Analytical response of the method is linear with concentrations to 3 g/L, and one can detect as little as 0.3 mg of lactulose per liter of urine. Analytical recovery was between 90% and 107% for all sugars analyzed, and there was good agreement with results by a gas-chromatographic method (r = 0.993 lactulose, 0.984 mannitol). The method may potentially be applied to the study of other carbohydrates present in biological fluids at low concentrations.

Exocrine pancreatic function and fat absorption were determined using a 'tubeless' test in 25 human immunodeficiency virus (HIV) antibody positive subjects (23 males, two females), CDC criteria groups II (four), III (one), and IV (20). In 12 fat absorption was poor but in only three of these were the results indicative of pancreatic insufficiency and in all three this was mild. In nine of the cases the results were compatible with small intestinal malabsorption. Mild, but not severe, exocrine pancreatic insufficiency may occur in acquired immune deficiency syndrome; however fat malabsorption is more commonly associated with a small intestinal cause.