Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.

"Smoking during pregnancy - Perinatal outcomes, financial implications, and tobacco treatment services".

Objective: Smoking in pregnancy is the leading modifiable risk factor for poor pregnancy outcomes. A sample population from United Lincolnshire Hospital NHS Trust (ULHT), with the highest prevalence of smoking at the time of delivery (SATOD) in England from April 2020 to March 2021 was studied. The project mapped the journey of women who smoked during pregnancy until birth and compared with a non-smoking cohort. In addition, it explored the options for possible changes to the current tobacco treatment service and importance of catering to the population demographics. Methods: Data was analysed using Chi-squared or Mann Whitney and student T-test for categorical and continuous variables respectively. A p-value of < 0.05 was considered statistically significant. Results: All women who smoked during pregnancy were referred to the stop smoking service. However, only 34.9 % accessed the service. Smoking mothers were younger (P = 0.001), had more complex obstetric history (P = 0.044), required increased fetal surveillance (P=<0.001), delivered at an earlier gestation (P = 0.033), and had babies with lower birth-weight (P=<0.001) compared to non-smokers. In addition, women who smoked demonstrated a downward trend in breast feeding their babies at birth and on discharge (P=<0.001 and P=<0.001 respectively). Conclusions: Findings from the study informed a successful business case for improvements to the current tobacco treatment service and the development of in-house maternity model for pregnant smokers at ULHT.

Sonographically guided intratendinous injections of hyperosmolar dextrose/lidocaine: a pilot study for the treatment of chronic plantar fasciitis.

OBJECTIVE: To report on the effectiveness of sonographically guided injections of hyperosmolar dextrose at reducing the pain associated with chronic plantar fasciitis. DESIGN: Case series. SETTING: Ultrasound division of St Paul's Hospital. PATIENTS: 20 referrals (3 men, 17 women; age 51 (SD 13) years) from local sports medicine primary care practitioners who had failed previous conservative treatments. INTERVENTIONS: A 27-gauge needle administered a 25% dextrose/lidocaine solution under sonographic guidance at 6 week intervals returning for a median of three consultations. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) items for pain levels at rest (VAS1), activities of daily living (VAS2), and during or after physical activity (VAS3) were recorded at baseline and at the final treatment consultation (post-test). A telephone interview conducted an average of 11.8 months after the post-test consultation provided a measure of long-term follow-up. RESULTS: 16 patients reported a good to excellent outcome, while the symptoms in 4 patients were unchanged. There was a significant decrease (p<0.001) in all mean VAS items from pre-test to post-test: VAS1 (36.8 (SD 25.6) to 10.3 (10.9)), VAS2 (74.7 (20.8) to 25.0 (27.7)) and VAS3 (91.6 (9.2) to 38.7 (35.1)) and there were no apparent changes after the follow-up interview. CONCLUSIONS: Sonographically guided dextrose injections showed a good clinical response in patients with chronic plantar fasciitis insofar as pain was reduced during rest and activity. Further studies including a control group are needed to validate these outcomes.

Analysis of metal radioisotope impurities generated in [(18)O]H(2)O during the cyclotron production of fluorine-18.

We show the separation of metal radioisotope impurities using capillary electrophoresis (CE). The methodology used is an improvement of existent protocols for separation of stable metal ions. Production of fluorine-18 using [(18)O]H(2)O-enriched water encased in a titanium target body results in the production of several metal radioisotope impurities. Optimisation of the conditions for CE separation of the metal radioisotope impurities incorporated the use of 6 mM 18-Crown-6 in combination with 12 mM glycolic acid as complexing agents within the running buffer (10 mM pyridine, pH 4.0). Using this optimised procedure, we were able to separate and detect a number of metal radioisotopes, including chromium, cobalt, manganese, vanadium and berillium, within the fM concentration range.

Microfluidic technology for PET radiochemistry.

This paper describes the first application of a microfabricated reaction system to positron emission tomography (PET) radiochemistry. We have applied microfluidic technology to synthesise PET radiopharmaceuticals using (18)F and (124)I as labels for fluorodeoxyglucose (FDG) and Annexin-V, respectively. These reactions involved established methods of nucleophilic substitution on a mannose triflate precursor and direct iodination of the protein using iodogen as an oxidant. This has demonstrated a proof of principle of using microfluidic technology to radiochemical reactions involving low and high molecular weight compounds. Using microfluidic reactions, [(18)F]FDG was synthesised with a 50% incorporation of the available F-18 radioactivity in a very short time of 4s. The radiolabelling efficiency of (124)I Annexin-V was 40% after 1 min reaction time. Chromatographic analysis showed that such reaction yields are comparable to conventional methods, but in a much shorter time. The yields can be further improved with more optimisation of the microfluidic device itself and its fluid mixing profiles. This demonstrates the potential for this technology to have an impact on rapid and simpler radiopharmaceutical synthesis using short and medium half-life radionuclides.

Microfluidic reactor for the radiosynthesis of PET radiotracers.

Here we show the first application of a microfabricated reaction system to PET radiochemistry, we term "microfluidic PET". The short half-life of the positron emitting isotopes and the trace chemical quantities used in radiolabelling make PET radiochemistry amenable to miniaturisation. Microfluidic technologies are capable of controlling and transferring tiny quantities of liquids which allow chemical and biochemical assays to be integrated and carried out on a small scale. Such technologies provide distinct advantages over current methods of PET radiochemical synthesis. To demonstrate "proof of principle" we have investigated the radiohalogenation of small and large molecular weight molecules using the microfluidic device. These reactions involved the direct radioiodination of the apoptosis marker Annexin V using iodine-124, the indirect radioiodination of the anti-cancer drug doxorubicin from a tin-butyl precursor and the radiosynthesis of 2-[(18)F]FDG from a mannose triflate precursor and fluorine-18 and hence provide a test bed for microfluidic reactions. We demonstrate the rapid radioiodination of the protein Annexin V (40% radiochemical yield within 1 min) and the rapid radiofluorination of 2-[(18)F]FDG (60% radiochemical yield within 4s) using a polymer microreactor chip. Chromatographic analysis showed that the labelling efficiency of the unoptimised microfluidic chip is comparable to conventional PET radiolabelling reactions.

Combined modality therapy of Hodgkin's disease: 10-year results of National Cancer Institute of Canada Clinical Trials Group multicenter clinical trial.

The purpose of this study was to compare four methods of treatment for stage III-IV Hodgkin's disease. Between January 1972 and September 1976, 266 patients with stage IIIB, IVA, and IVB Hodgkin's disease from 21 cancer treatment centers across Canada were registered as eligible; 40 were found to be ineligible. Of the 226 remaining patients, only seven were followed for less than 10 years. All patients received three courses of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy, which induced a complete response (CR) in 36%; an additional 42% obtained adequate disease control. Patients were randomly assigned to (1) treatment with radiation to the abdomen and mantle (group AX3, 62 patients) or (2) continue their treatment with an additional three courses of MOPP (group A, 105 patients). For the A group, a second randomization took place 3 months later (regardless of status at that time) to (1) no further treatment (AC6, 23 patients), (2) radiotherapy to the abdomen and mantle (AX6, 48 patients), or (3) maintenance chemotherapy at 3-month intervals for 1 year (AC10, 26 patients). The survival of AX3 patients was somewhat better than for the A group, but the difference was not significant (P = .0565). However, there was a significant interaction (P = .0029) between age and treatment, so that among patients less than 30 years of age, the survival of the A group was better, whereas for older patients, treatment with AX3 resulted in improved survival. Age itself remained a significant prognostic factor for survival after controlling for the amount of radiotherapy delivered to the abdomen and the dose intensity of vincristine for the first three courses of chemotherapy. The addition of radiation therapy to MOPP significantly reduced the frequency of nodal relapses. These results suggest that combined modality therapy may be beneficial for some patients with Hodgkin's disease and that age must be carefully considered in interpreting the results of clinical trials in Hodgkin's disease.

Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophageal cancer.

AIMS: Patients with oesophageal cancer undergoing chemoradiation with curative intent are at high risk of malnutrition and its complications, including increased side effects of treatment. We have developed a nutrition pathway (NP), involving the early then periodic nutrition assessment of all patients presenting to the multidisciplinary oesophageal clinic who were planned to receive definitive chemoradiation. MATERIALS AND METHODS: Patients were assessed as at 'low', 'moderate' or 'severe' nutrition risk, and were provided with appropriate nutrition intervention ranging from preventative advice (low risk), oral nutrition support (moderate risk) to enteral feeding (severe risk). Outcomes for 24 patients treated before implementation of the NP were compared with those of 24 patients treated using the NP. RESULTS: Patients managed using the NP experienced less weight loss (mean weight change -4.2 kg +/-6.4 cf. -8.9 kg +/- 5.9, P = 0.03), greater radiotherapy completion rates (92% cf. 50%, P = 0.001), fewer patients had an unplanned hospital admission (46% cf. 75%, P = 0.04), and those that did had a shorter length of stay (3.2 days +/- 5.4 cf. 13.5 days +/- 14.1, P = 0.002). CONCLUSION: Early and regular nutrition assessment/intervention and a multidisciplinary approach to nutrition care results in improved treatment tolerance for patients with oesophageal cancer receiving chemoradiation.

The epidemiology of iodine-deficiency disorders in relation to goitrogenic factors and thyroid-stimulating-hormone regulation.

In children aged 5-7 y from goiter-endemic areas in Ubangi, Zaire, and Ntcheu, Malawi, mean serum thyroxin (T4) concentrations were 53 +/- 49 vs 81 +/- 33 nmol/L (P < 0.05), and thyroid-stimulating hormone (TSH) values were 24.3 +/- 9.6 vs 4.5 +/- 3.3 mU/L respectively (P < 0.01); mean urinary iodine concentrations were 0.14 +/- 0.02 vs 0.09 +/- 0.02 mumol/L, and mean thiocyanate concentrations were 0.33 +/- 0.05 vs 0.17 +/- 0.05 nmol/L, respectively (P < 0.05). Mean serum selenium concentrations were 0.343 +/- 0.176 mumol/L in Ubangi and 0.437 +/- 0.178 mumol/L in Ntcheu (P < 0.05). In two groups of 11 adolescent girls from Ubangi, the mean values for excretion of urinary iodine were 1.31 +/- 0.14 and 0.58 +/- 0.17 mumol/L (P < 0.05) after a meal of cassava or a control meal of rice, respectively. In euthyroid subjects from Ubangi, mean serum TSH for a given serum T4 was approximately twice as high for children aged < 15 y than for those aged 16-25 y. The high frequency of myxedematous cretins observed in Ubangi very probably result from both severe iodine and selenium deficiency together with thiocyanate overload.

Hypofractionated radiotherapy for the palliation of advanced pelvic malignancy.

Forty-two patients, with a variety of advanced pelvic malignancies, have been treated with a hypofractionated radiotherapy regimen. The most common schedule was 30 Gy in three fractions at monthly intervals. This has provided effective palliation with acceptable morbidity in the select patient group treated. The results in advanced rectal and ovarian tumors were particularly encouraging. The most effective dose/fraction and interfraction interval is, at present, under active investigation within our institution.

Effect of body posture and time on grip strength in patients with cervical spondylosis.

Ninety-eight patients with cervical spondylosis were tested for grip strength in different spinal postures (standing and sitting), but with standard upper arm position. Unilateral symptoms of cervical spondylosis significantly affected grip strength in that arm whether or not it was the dominant upper limb, in contrast to normals. Grip strength is stronger in the standing position than in a sitting posture with the neck flexed (P < 0.01; at 10 min), and this effect is increased by duration in the posture.

Comparison and evaluation of chemically speciated mobile source PM2.5 particulate matter profiles.

Mobile sources are significant contributors to ambient PM2.5, accounting for 50% or more of the total observed levels in some locations. One of the important methods for resolving the mobile source contribution is through chemical mass balance (CMB) receptor modeling. CMB requires chemically speciated source profiles with known uncertainty to ensure accurate source contribution estimates. Mobile source PM profiles are available from various sources and are generally in the form of weight fraction by chemical species. The weight fraction format is commonly used, since it is required for input into the CMB receptor model. This paper examines the similarities and differences in mobile source PM2.5 profiles that contain data for elements, ions, elemental carbon (EC) and organic carbon (OC), and in some cases speciated organics (e.g., polycyclic aromatic hydrocarbons [PAHs]), drawn from four different sources. Notable characteristics of the mass fraction data include variability (relative contributions of elements and ions) among supposedly similar sources and a wide range of average EC:OC ratios (0.60 +/- 0.53 to 1.42 +/- 2.99) for light-duty gasoline vehicles (LDGVs), indicating significant EC emissions from LDGVs in some cases. For diesel vehicles, average EC:OC ratios range from 1.09 +/- 2.66 to 3.54 +/- 3.07. That different populations of the same class of emitters can show considerable variability suggests caution should be exercised when selecting and using profiles in source apportionment studies.

Particulate emission rates for unpaved shoulders along a paved road.

This paper reports the first empirical estimate of particle emissions from unpaved shoulders along paved roads. Its objectives are to develop and demonstrate an emission rate measurement methodology that can be applied in different areas; identify the mechanisms that suspend dust from unpaved shoulders and the observables related to this suspension process; and quantify PM10 mass emissions in the form of an emission rate. To achieve these objectives, fast-response observations from nephelometers and a sonic anemometer were used to characterize short-lived dust plumes generated by passing vehicles. In addition, detailed soil surface measurements determined the mechanical properties of the shoulder surfaces. Large traffic-induced turbulence events that led to significant dust entrainment were almost exclusively caused by "large" vehicles such as trucks, semis, and vehicles pulling trailers, all traveling 50-65 mph. PM10 emission rates for these large, fast-traveling vehicles were determined to be 8 +/- 4 grams per vehicle kilometer traveled under dry conditions. Emissions due to smaller vehicles such as cars, vans, and sport utility vehicles were negligible for normal on-road driving. These results indicate that the majority of PM10 emissions from unpaved shoulders is caused by relatively few vehicles.

Middle- and Neighborhood-Scale Variations of PM10 Source Contributions in Las Vegas, Nevada.

The Las Vegas Valley PM10 Study was conducted during 1995 to determine the contributions to PM10 aerosol from fugitive dust, motor vehicle exhaust, residential wood combustion, and secondary aerosol sources. Twenty-four-hr PM10 samples were collected at two neighborhood-scale sites every sixth day for 13 months. Five week-long intensive studies were conducted over a middle-scale sub-region at 29 locations that contained many construction projects emitting fugitive dust. The study found that the zone of influence around individual emitters was less than 1 km. Most of the sampling sites in residential and commercial areas yielded equivalent PM10 concentrations in the neighborhood region, even though they were more distant from each other than they were from the nearby construction sources. Based on chemical mass balance (CMB) receptor modeling, fugitive dust accounted for 80-90% of the PM10, and motor vehicle exhaust accounted for 3-9% of the PM10 in the Las Vegas Valley.

Overview of delivery system issues in pediatric asthma.

The range of drugs now available to treat asthma should guarantee that almost all patients are treated effectively, and yet asthma still causes significant morbidity. The delivery system is a vital part of treatment, and its selection requires close attention to ensure optimal drug delivery to each individual patient. Children's physical capabilities change as they mature, and so the more convenient and portable systems, which may be impossible for initial consideration, become available for use as they grow. Treatment devices must be selected to ensure effective use, especially when the child is not well. Device technique should be reassessed at every clinic visit. Non-compliance is a major cause of apparent treatment failure. Most non-compliance is because the patient or caregiver feels uncertain about some aspects of the treatment process. The clinician must explain to the patient and caregiver the goals of therapy, the effects of the medications involved, and how the devices and drugs should be used to treat asthma. For educational material to be at its most effective, it must be individualized. Knowledge of how children and adults learn during different stages of their life will assist the education process. Selection of the delivery system and optimal device technique are essential in the management of asthma. The patient and caregiver are vital parts of this process and must know what to do.

Paediatric attendance at Waikato Hospital accident and emergency department 1980-86.

All attendances at Waikato Hospital accident and emergency department since 1980 have been coded and stored in computer files. Fifty thousand children under age 15 years attended A&E between 1980 and 1986. Age-specific attendance rates were determined and major reasons for consultation examined. The attendance rate for illness was very high in infants with levels above 1200/10,000 for every year. This rate declined as children became older. Attendance rates for injury events were highest for infants (1601/10,000), with the 10-14 year olds second (1100/10,000). Age and ethnic group specific rates were determined and show a very high rate of attendance for Maori infants with 60% attending A&E in 1986. Respiratory illnesses form the major reason for consultation for illness, with the highest rate in children under five years. Thirty-two percent in the under one year group and 43% in the 1-4 year group came to A&E with respiratory illnesses. Injury involving falls or hitting an object are the major reasons for consultation in all age groups under 10 years. This involved 41% of all accidents in the under 1 year age group, 46% in 1-4 and 47% in the 5-9 age group. Sporting injuries dominated the 10-14 age group with 28% of all accidents being sports related. Road traffic injuries reflect the mobility of each age group with 7% of accidents in the under 1 group, rising to 14% for all children over 4 years. The implications of these patterns are discussed.

Occupational asthma cases notified to OSH from 1996 to 1999.

AIMS: To update notifications to the Occupational Safety and Health Service of the Department of Labour (OSH) Notifiable Occupational Disease System (NODS) from June 1996 to the beginning of 1999. METHODS: All notifications received for non-asbestos related occupational respiratory disease were reviewed to confirm the clinical diagnosis, occupational causation, and to identify the causative agent where possible. RESULTS: 54 cases of asthma were notified, of which 21 (39%) were accepted as being occupationally caused. These cases arose from 'predictable' industries. CONCLUSIONS: NODS offers sentinel data from interested practitioners and workplaces. Occupational asthma and other occupational respiratory diseases remain poorly notified to this system. NODS confirms the presence of occupational asthma in New Zealand from predictable and preventable causes not dissimilar to other countries. This data collection system needs supplementation by other mechanisms.

Occupational asthma and other nonasbestos occupational respiratory diseases notified between 1993 and 1996.

AIM: To review notifications to the Occupational Safety and Health Service of the Department of Labour Notifiable Occupational Disease System since its inception until June 1996. METHODS: All notifications received for non asbestos related occupational respiratory disease were reviewed to evaluate the outcome of the notification and to identify the causative agent where possible. RESULTS: There were 277 cases notified and investigated including worksite investigations. Of these 73 cases were confirmed as having occupational asthma, 35 by the asthma validation panel. Nineteen cases of other occupational respiratory disease were notified of which 11 were reviewed by the panel. Extrinsic allergic alveolitis secondary to organic dusts was the most common such notification. CONCLUSIONS: Isocyanates are well recognised as a cause of occupational asthma in New Zealand. It is suspected that occupational asthma and other occupational respiratory diseases are poorly notified to this system. Better mechanisms are needed to identify occupational causes of respiratory (and other) disease.

A community trial of a written self management plan for children with asthma. Asthma Foundation of NZ Children's Action.

AIMS: To determine the effect of introducing an action plan to children with mild to moderate asthma, who have never used a plan before. METHODS: Children were recruited from general practitioner records with a diagnosis of asthma, and who agreed to participate, having identified that they had not used an action plan before and that they had mild or moderate asthma based upon symptoms, acute episodes and the need for preventative medication. The families were given a plan, and its use was explained to them by their general practitioner. A symptom diary was kept, and, where appropriate, peak flow measurements were recorded. A number of outcomes were measured to determine changes that could be attributed to the introduction of the plan. RESULTS: Following the introduction of the plan, the percentage of nights woken for asthma fell from 18.2% to 12.2% (P<0.001) and the number of days out of action fell from 6.4 to 4.1 (P<0.001). The requirement for acute medical treatment also fell during the intervention period with general practitioner visits falling from 129 to 42 (p<0.001). Most participants commented favourably about the usefulness of the plan in giving them a better idea of the state of their asthma at any time, and in knowing what to do about it. CONCLUSIONS: The children's action plan, when introduced into a group of asthmatic children was effective and acceptable in the self management of asthma.

Rapid screening of 2-[18F]-fluoro-2-deoxy-D-glucose infusions for volatile organic compound contaminants by solid phase microextraction with gas chromatography-selective ion monitoring mass spectrometry (SPME-GC-SIMMS).

A method compatible with radioactive samples, capable of detecting trace volatile components in a sample volume of ca. 1cm(3) of 2-[18F]-fluoro-2-deoxy-D-glucose solution is described. The approach, based on solid phase micro-extraction gas chromatography-mass spectrometry with a carboxen/polydimethylsiloxane based fibre, was optimised with respect to extraction time (10 min), extraction temperature (60 degrees C) and phase volume ratio (1). The analysis time, including extraction, was less than 20 min with linear responses for acetonitrile and ethanol over the ranges: 0.09-80 microg cm(-3) (22 degrees C, acetonitrile) and 0.78-79 microg cm(-3) (22 degrees C, ethanol). The detection limits were estimated to be ca. 0.78 microg cm(-3) for ethanol and 0.09 microg cm(-3) for acetonitrile. Stability studies indicated analyte losses of up to 75% over 24h and analysis of aged 2-[18F]FDG samples showed that levels of ethanol and acetonitrile were not less than 100 microg cm(-3), indicative of levels substantially greater than this in the original infusions given to human subjects.