Search

Background: Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsychological tests requires the use of normative data. Traditionally, normative data have been reported for discrete categories such as age. More recently continuous norms have been developed using multivariable regression equations that account for multiple demographic factors. Regression-based norms have been developed for use in the Canadian population for tests included in the MACFIMS and BICAMS test batteries. Establishing the generalizability of these norms is essential for application in clinical and research settings.Objectives: We aimed to (i) test the performance of previously published Canadian regression-based norms in an independently collected sample of Canadian healthy controls; (ii) compare the ability of Canadian and non-Canadian regression-based norms to discriminate between healthy controls and persons with MS; and (iii) develop regression-based norms for several cognitive tests drawn from batteries commonly used in MS that incorporated race/ethnicity in addition to age, education, and sex.Methods: We included 93 adults with MS and 96 healthy adults in this study, with a replication sample of 104 (MS) and 39 (healthy adults). Participants reported their sociodemographic characteristics, and each was administered the oral Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). From the healthy control data, we developed regression-based norms incorporating race, age, education and sex. We then applied existing discrete norms and regression-based norms for the cognitive tests to the healthy controls, and generated z-scores which were compared using Spearman rank and concordance coefficients. We also used receiver operating characteristic (ROC) curves to compare the ability of each set of norms to discriminate between participants with and without MS. Within the MS samples we compared the ability of each set of norms to discriminate between differing levels of disability and employment status using relative efficiency.Results: When we applied the published regression norms to our healthy sample, impairment classification rates often differed substantially from expectations (7%), even when the norms were derived from a Canadian (Ontario) population. Most, but not all of the Spearman correlations between z-scores based on different existing published norms for the same cognitive test exceeded 0.90. However, concordance coefficients were often lower. All of the norms for the SDMT reliably discriminated between the MS and healthy control groups. In contrast, none of the norms for the CVLT-II or BVMT-R discriminated between the MS and healthy control groups. Within the MS population, the norms varied in their ability to discriminate between disability levels or employment status; locally developed norms for the SDMT and CVLT-II had the highest relative efficiency.Conclusion: Our findings emphasize the value of local norms when interpreting the results of cognitive tests and demonstrate the need to consider and assess the performance of regression-based norms developed in other populations when applying them to local populations, even when they are from the same country. Our findings also strongly suggest that the development of regression-based norms should involve larger, more diverse samples to ensure broad generalizability.

Explicit mechanisms describing the complex degradation pathways of atmospheric volatile organic compounds (VOCs) are important, since they allow the study of the contribution of individual VOCS to secondary pollutant formation. They are computationally expensive to solve however, since they contain large numbers of species and a wide range of time-scales causing stiffness in the resulting equation systems. This paper and the following companion paper describe the application of systematic and automated methods for reducing such complex mechanisms, whilst maintaining the accuracy of the model with respect to important species and features. The methods are demonstrated via application to version 2 of the Leeds Master Chemical Mechanism. The methods of Jacobian analysis and overall rate sensitivity analysis proved to be efficient and capable of removing the majority of redundant reactions and species in the scheme across a wide range of conditions relevant to the polluted troposphere. The application of principal component analysis of the rate sensitivity matrix was computationally expensive due to its use of the decomposition of very large matrices, and did not produce significant reduction over and above the other sensitivity methods. The use of the quasi-steady state approximation (QSSA) proved to be an extremely successful method of removing the fast time-scales within the system, as demonstrated by a local perturbation analysis at each stage of reduction. QSSA species were automatically selected via the calculation of instantaneous QSSA errors based on user-selected tolerances. The application of the QSSA led to the removal of a large number of alkoxy radicals and excited Criegee bi-radicals via reaction lumping. The resulting reduced mechanism was shown to reproduce the concentration profiles of the important species selected from the full mechanism over a wide range of conditions, including those outside of which the reduced mechanism was generated. As a result of a reduction in the number of species in the scheme of a factor of 2, and a reduction in stiffness, the computational time required for simulations was reduced by a factor of 4 when compared to the full scheme.

This paper presents a formal method of species lumping that can be applied automatically to intermediate compounds within detailed and complex tropospheric chemical reaction schemes. The method is based on grouping species with reference to their chemical lifetimes and reactivity structures. A method for determining the forward and reverse transformations between individual and lumped compounds is developed. Preliminary application to the Leeds Master Chemical Mechanism (MCMv2.0) has led to the removal of 734 species and 1777 reactions from the scheme, with minimal degradation of accuracy across a wide range of test trajectories relevant to polluted tropospheric conditions. The lumped groups are seen to relate to groups of peroxy acyl nitrates, nitrates, carbonates, oxepins, substituted phenols, oxeacids and peracids with similar lifetimes and reaction rates with OH. In combination with other reduction techniques, such as sensitivity analysis and the application of the quasi-steady state approximation (QSSA), a reduced mechanism has been developed that contains 35% of the number of species and 40% of the number of reactions compared to the full mechanism. This has led to a speed up of a factor of 8 in terms of computer calculation time within box model simulations.

Background: Specialist forensic community teams for people with intellectual disability and/or autism have been developed, but little is known about their extent and delivery., Aims: To describe specialist forensic community teams for people with intellectual disability and/or autism across the UK., Method: An online survey was sent to representatives of each UK Trust/Health Board providing adult mental health and/or intellectual disability services. Questions covered the availability, structure and activities of specialist community forensic services. Quantitative data were summarised and associations between access to specialist forensic teams and care were tested with Chi-squared tests. Thematic analysis of free-text survey responses was used to understand the challenges of providing community forensic mental health services for this group., Results: A total of 49 out of 78 (63%) eligible Trusts/Health Boards responded, of which 25 (51%) had access to a specialist forensic community team. Teams operated either as part of a single Trust/Board ( n = 13) or over a larger regional footprint ( n = 12). The availability of specialist forensic community teams was associated with better access to offence-related interventions (χ 2 = 15.1002, P < 0.005) and co-production of patient care plans (χ 2 = 7.8726, P = 0.005). Respondents reported a wide variation in availability, expertise and perceived quality of community services. The availability of secure and generic in-patient beds, commissioning and legal barriers were also significant challenges in providing appropriate care., Conclusions: Coverage of specialist community forensic teams is not universal. There are indications that such teams are associated with improved care processes, but further work is needed to establish longer-term outcomes and the optimal model of care.

A 51-year-old man presented with mild headache followed by sudden onset of right sided weakness and dysarthria on the background of one week history of right sided sciatica and malaise. He was apparently immunocompetent with only past medical history being hypertension. There was no consumption of tobacco or excess alcohol and he previously had normal liver and renal function.

Outbreaks of Guillain-Barré syndrome (GBS) are uncommon. In May 2019, national surveillance in Peru detected an increase in GBS cases in excess of the expected incidence of 1.2 cases/100,000 population. Several clinical and epidemiologic findings call into question the suggested association between this GBS outbreak and Campylobacter.

Whole-grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. The present study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomised, two-way crossover trial, twenty-six healthy participants consumed two isoenergetic/isovolumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP), peptide YY, gastric volumes and appetite ratings were collected 2 h postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental AUC (iAUC2h) for blood glucose was not significantly different between the porridges (P > 0·05). The iAUC2h for gastric volume was larger for PMP compared with SOP (P = 0·045). The iAUC2h for GIP concentration was significantly lower for PMP compared with SOP (P = 0·001). Other hormones and appetite responses were similar between meals. In conclusion, the present study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable alternative with health-promoting characteristics comparable with oats. GIP is an incretin hormone linked to TAG absorption in adipose tissue; therefore, the lower GIP response for PMP may be an added health benefit.

Smoking is a significant risk factor for morbidity and mortality, particularly among patients with tuberculosis (TB). Although smoking cessation is recommended by the World Health Organization and the International Union Against Tuberculosis and Lung Disease, there has been no published evaluation of smoking cessation interventions among people with TB. The purpose of this review was to synthesize the evidence on interventions and suggest practice, research and policy implications. A systematic review of the literature identified 14 peer-reviewed studies describing 13 smoking cessation interventions between 2007 and 2017. There were five randomized controlled trials, three non-randomized interventions, and five prospective cohort studies. The primary types of interventions were brief advice ( n = 9), behavioral counseling ( n = 4), medication ( n = 3), and community-based care ( n = 3). A variety of health care workers (HCWs) implemented interventions, from physicians, nurses, clinic staff, community health workers (CHWs), as did family members. There was significant heterogeneity of design, definition of smoking and smoking abstinence, and implementation, making comparison across studies difficult. Although all smoking interventions increased smoking cessation between 15% and 82%, many studies had a high risk for bias, including six without a control group. The implementing personnel did not make a large difference in cessation results, suggesting that national TB programs may customize according to their needs and limitations. Family members may be important supporters/advocates for cessation. Future research should standardize definitions of smoking and cessation to allow comparisons across studies. Policy makers should encourage collaboration between tobacco and TB initiatives and develop smoking cessation measures to maximize results in low-resource settings., Competing Interests: Conflicts of interest: none declared.

Background: Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) in South Africa remain close to 50%. Lack of access to timely, decentralized care is a contributing factor. We evaluated MDR-TB treatment outcomes from a clinical cohort with task-sharing between a clinical nurse practitioner (CNP) and a medical officer (MO)., Methods: We completed a retrospective evaluation of outcomes from a prospective, programmatically-based MDR-TB cohort who were enrolled and received care between 2012 and 2015 at a peri-urban hospital in KwaZulu-Natal, South Africa. Treatment was provided by either by a CNP or MO., Findings: The cohort included 197 participants with a median age of 33 years, 51% female, and 74% co-infected with HIV. The CNP initiated 123 participants on treatment. Overall MDR-TB treatment success rate in this cohort was 57.9%, significantly higher than the South African national average of 45% in 2012 (p<0·0001) and similar to the provincal average of 60% (p = NS). There were no significant differences by provider type: treatment success was 61% for patients initiated by the CNP and 52.7% for those initiated by the MO., Interpretation: Clinics that adopted a task sharing approach for MDR-TB demonstrated greater treatment success rates than the national average. Task-sharing between the CNP and MO did not adversely impact treatment outcome with similar success rates noted. Task-sharing is a feasible option for South Africa to support decentralization without compromising patient outcomes. Models that allow sharing of responsibility for MDR-TB may optimize the use of human resources and improve access to care.

Background: Mobile phone Short Message Service (SMS) is a tool now used by the health research community, providing the capability for instant communication between patients and health professionals. Greater understanding of how to best use SMS as a means to improve healthcare delivery and outcomes will foster innovation in research and provide an opportunity to progress as a public health community., Purpose: The purposes of this systematic review are 2-fold: (1) to provide insight on the most used mobile phone SMS practices and characteristics in hypertension (HTN) outcome-focused publications and (2) to critically evaluate empirical evidence associated with SMS utilization and BP outcomes., Methods: Two independent systematic literature searches were completed. The final selected studies each then underwent data extraction and quality-rating assessment, followed by an evaluation for a meta-analysis to measure mean difference of the change in BP., Results: A total of 6 studies meeting the inclusion criteria were included in the review. Feasibility assessment for a meta-analysis was found unfavorable because of the variation among studies. Short Message Service interventions focused on BP management were most effective in studies featuring 2-way communication and individual patient-tailored content, and guided by evidence-based HTN management practices., Implications: Short Message Service interventions for HTN management were supported through evidence provided by the studies reviewed. Short Message Service holds strong potential to bring greater innovation to HTN management and care, especially in racial/ethnic minority populations that face psychosocial and structural barriers in healthcare access and utilization.

Background: Easy access to health-related information on the Internet has the potential to empower patients in making health-related decisions. However, little is known regarding the association between Internet use and decision-making preference in older adults. The aim of the study is to evaluate the association between Internet use and decision-making preference in older adults., Method: The study analyzed cross-sectional data from 1,945 participants of the National Health and Aging Trends Study., Results: Older adults who used the Internet had greater odds of active decision-making preference (OR 1.75, 95%CI 1.22-2.52, p=0.002) compared to older adults who did not use the Internet. Similarly, older adults, who searched the Internet for health-related information, had higher odds of active decision-making preference (OR 2.16, 95%CI 1.14-4.09, p=0.019) compared to their counterparts., Conclusion: Internet use was found to be associated with active decision-making preference in older adults. Similarly, health-related Internet use was positively associated with decision-making involvement in older adults.

Little is known about the effects of burdensome symptoms dur- ing chemotherapy treatment in African-American women. This study explored the symptom burden occurring during chemotherapy treatment and how these symptoms impacted functional well-being and quality of life (QOL). A sample of 30 African-American women with breast cancer (BC) completed a battery of questionnaires that were used to collect the data at baseline, midpoint, and at the completion of chemotherapy. There were significant differences in the severity of symptoms for worse pain, pain inteiference with activities of daily living (ADLs), present fatigue and history offatigue, present nausea and history of nausea and insomnia as well as lower intensity of QOL measures over the course of chemotherapy treatment. All symptoms had greater intensity at midpoint and completion than at baseline. Worst pain had a significant negative effect on functional well-being. Both pain and depression each had significant negative effects on QOL.

Pig skin was used as a model to study the effectiveness of two topically applied creams, Lipochromin and Levosinum, in modifying the development of both early and late radiation damage to pig skin. Irradiated skin sites that received daily topical application of Levosinum or Lipochromin after exposure were compared with sites on the contralateral flank of the same animal that received irradiation only. Irradiation was with graded doses of 90Sr/90Y beta-rays. Incidence of moist desquamation (acute) and ischaemic dermal necrosis (late) were used as end-points. The latency period for the development of moist desquamation and its healing time was also assessed. The latency period for the development of moist desquamation in this model ranged from 4.00-6.75 weeks. There was no significant difference between the cream treatment and control sites. Application of Levosinum shortened the healing time of moist desquamation at each dose level by 5-10 days. In three out of four dose levels used, this shortening of the healing time was statistically significant (p < 0.03). Treatment with these topical applications also reduced the incidence of late dermal necrosis and increased the ED50 values for the incidence of dermal necrosis. This increase in ED50 values was equivalent to a dose modification factor of 1.11-1.13.

Normal tissue radiation injury occurs after sufficient irradiation, thus limiting the curative potential of x-ray therapy. In the kidney, radiation injury results in fibrosis and, ultimately, renal failure. The mediators of fibrosis in radiation nephropathy have received scant attention. Therefore, we evaluated the sequential presence of alpha smooth muscle actin (alphasma), fibrin, collagen, and TGFbeta1 in a porcine model of radiation nephropathy using 9.8 Gy single-dose local kidney irradiation. During the 24-week study, there was progressive and significant collagen accumulation in glomeruli and in interstitium. In glomeruli, this was associated with significant mesangial alphasma expression by 2 weeks after irradiation, a further rise at 4 weeks, and then a gradual fall to baseline. Glomerular fibrin deposition was significant by 4 weeks after irradiation, and remained elevated thereafter. There was little or no glomerular TGFbeta1 expression at any time point. Tubular fibrin deposition was significant at 4 weeks after irradiation but declined thereafter. There was little or no tubulo-interstitial alphasma expression at any time after irradiation. At 6 weeks after irradiation, there was a significant peak of tubular epithelial TGFbeta1 expression that declined thereafter. The early glomerular injury is evident as mesangial alphasma expression but is not proceeded by TGFbeta1 expression. There is sustained glomerular fibrin deposition with deposition of fibrin in tubular lumens, suggesting that tubular fibrin derives and flows out from injured glomerular tufts. We conclude that i) alphasma expression is an early marker of glomerular radiation injury, presaging scarring; ii) fibrin deposition is involved in glomerular and tubular radiation injury; and iii) TGFbeta1 is not an early event in radiation nephropathy, and not apparent in glomeruli in this model, but may correlate with later tubulo-interstitial fibrosis. Thus, the mediators of scarring in this model differ according to time after injury and also according to the affected tissue compartment.

The influence of the phenomena of the repair of sublethal damage, repopulation and the role of the reassortment of surviving clonogenic target cells within the cell cycle have been examined in the foot skin of rats using a series of split dose experiments. The dose-related incidence of moist desquamation was used as an end-point. Initially the iso-effect dose for moist desquamation (ED50) increased with an increasing time interval (1-22 h) between two equal fractions. This effect was attributed to the well established phenomenon of the repair of sublethal damage. This appeared to be maximal with a 22 h gap between fractions. A further increase in the time interval, from 2-7 days, between two equal fractions resulted in a decrease in the ED50 value for moist desquamation. The phenomenon is most likely to be explained by a shortening of the cell cycle time in surviving epithelial target cells as repopulation first initiated. With intervals between two fractions of greater than 10 days the ED50 for moist desquamation again increased. This is likely to represent an increase in the number of epidermal target cells (repopulation). Further evidence for the effect of a reassortment of cells in the cell cycle has come from another study in which a half-tolerance priming dose of 16.8 Gy was followed by three daily fractions starting 48 or 125 h after the priming dose. The ED50 for moist desquamation based on the total fractionated dose (three fractions) was significantly lower (P < 0.05) after the longer time interval, i.e. fractions given on days 5, 6 and 7 after the primary dose. These findings were supported by the results of a cell proliferation kinetic study and jointly question the validity of a frequently made assumption of equal biological effect per fraction in a prolonged fractionated irradiation schedule.

Fibrosis in chronic renal failure is closely associated with declining function. Its role in affecting function is less well defined. The radiation model of chronic renal failure was used to examine the tissue distribution of fibrosis and scarring and its role in influencing the loss of function in chronic renal disease. A striking and progressive pattern of fibrosis and narrowing of the glomerulotubular neck was found in irradiated pig kidneys. These narrowed necks increased in prevalence with time after irradiation. At 20 weeks after irradiation, the average neck diameter reduction was 60%, as compared with nonirradiated controls, a percentage that is consistent with a reduction in flow and pressure at this critical point of the nephron. Glomerulotubular neck narrowing may thus directly reduce the glomerular filtration rate of an individual nephron. Fibrotic neck stenoses may be a factor in progressive chronic renal failure.

A histopathological study was carried out on the spinal cord of rats after boron neutron capture (BNC) irradiation. Rats were irradiated with thermal neutrons alone or in combination with borocaptate sodium (BSH) or p-boronophenylalanine (BPA). Spinal cords were examined 1 year after irradiation, or at earlier times in rats developing myelopathy. Considered overall, the pathology of the spinal cord after BNC irradiation was comparable with that reported previously after X irradiation of the spinal cord in the identical strain of rat. When BSH was used as the neutron capture agent, the biologically effective dose of radiation delivered to the CNS parenchyma was a factor of -2.7 lower than that delivered to the vascular endothelium. In effect, the blood vessels were selectively irradiated using this BNC modality. The resultant pathology was similar to that observed after irradiation with thermal neutrons alone or in the presence of BPA, situations in which the CNS vasculature was not selectively irradiated. This points to the vascular endothelium as being the critical target cell population, damage to which results in the development of the lesions seen in the spinal cord after BNC irradiation and, by inference, after irradiation with more conventional modalities.

Purpose: Radiation-induced changes in glomerular and tubular cell kinetics and morphology following irradiation of a single pig kidney were assessed., Methods and Materials: The right kidney of 13 adult female Large White pigs was irradiated with a single dose of 9.8 Gy gamma rays. Animals were serially killed between 2 and 24 weeks postirradiation (PI); 1 h prior to postmortem each pig received 500 mg bromodeoxyuridine (BrdUrd). At postmortem, both kidneys were removed and tissue taken to prepare cell suspensions. The labeling index (LI) of these suspensions was measured using flow cytometry; in vivo BrdUrd incorporation in glomerular and tubular cells was determined immunohistochemically. The kidneys were also assessed histologically., Results: Irradiation of the right kidney alone resulted in a significant increase in renal cell LI in both the irradiated and the contralateral unirradiated kidney within 2 weeks of irradiation; peak values of 1.57 +/- 0.32% and 1.04 +/- 0.13%, respectively, were seen 4 weeks PI, significantly greater (P < 0.001) than the preirradiation value of 0.18 +/- 0.01%. The LI values then declined with time, but remained greater than those seen prior to irradiation. A similar pattern of response was determined from counts of labeled glomerular and tubular cells identified immunohistochemically. The increase in labeled glomerular cells was seen 2 weeks PI, whereas that for the tubular cells did not occur until 4 weeks PI. The irradiated kidney exhibited diffuse, progressive glomerular alterations. In contrast, tubular damage was focal; the irradiated kidney also exhibited a prominent vasculopathy, involving arteriolar and peripheral interlobular artery thickening. The contralateral unirradiated kidney appeared unchanged., Conclusion: These findings confirm the hypothesis that the morphologic and kinetic responses observed after irradiation of a single kidney are similar to those observed after irradiation of both kidneys. Renal irradiation results in significant alterations in glomerular and tubular cell proliferation and morphology within 2-4 weeks of irradiation; glomerular changes appear predominant.

The daily oral administration of 3 ml of two oils (So-5407 and So-1129) containing essential fatty acids (EFAs) for 16 weeks resulted in a transient increase in cell proliferative activity in the skin of female Large White pigs. The So-5407 oil contained 7% gamma-linolenic acid (GLA) whereas So-1129 was an oil of similar composition, but with no GLA. Hyperplasia of the epidermis was observed after the administration of both oils, and this was characterized by an increase in the size of the rete pegs. The maximum effect occurred at 4 weeks after the start of oil administration, at which time the number of viable cell layers had increased by a factor of approximately 1.5, and mean epidermal thickness (excluding the stratum corneum) was approximately 40% greater than that of the epidermis prior to oil administration. There was a marked increase in the labelling index (LI) of the basal cell layer of the epidermis in pigs receiving So-5407. Maximum LIs were quantified at 4 weeks after the start of administration and were 18.8 +/- 1.3% and 13.1 +/- 1.7% for pigs receiving So-5407 and So-1129, respectively. After this time the LI declined progressively and had returned to values within normal limits (P > 0.1) by 8 weeks after the start of administration of both oils. A similar pattern of change in the LI was seen in the follicular epithelium, although the peak values at 4 weeks after the start of oil administration of 12.2 +/- 1.8% and 10.8 +/- 0.9 for the groups receiving So-5407 and So-1129, respectively, were lower than in the epidermis. Labelled cells were also counted in the papillary dermis and maximum values were again seen at 4 weeks after the start of oil administration. Of the two oils, So-1129 had the greatest effect, with the number of labelled cells in the papillary dermis being a factor of three to four-fold higher than in skin prior to oil administration, between 2 and 12 weeks after the start of administration.

Both kidneys of 13 mature female Large White pigs were irradiated with a single dose of 9.8 Gy 60Co gamma rays. The pigs were killed serially between 2 to 24 weeks after irradiation. One hour prior to sacrifice bromodeoxyuridine (BrdU) (500 mg/pig) was injected intravenously. At postmortem the kidneys were removed and tissue was taken to prepare cell suspensions. The labeling index (LI) of these suspensions was determined using flow cytometry. In vivo BrdU incorporation in tubular and glomerular cells was determined immunohistochemically. The kinetics of glomerular and tubular cells was evaluated by counting the number of labeled cells/glomerulus and the number of labeled tubular cells/field of view. An average of 1200 glomeruli and 1500 fields of view/time were counted. Similar analyses were performed on renal tissue from unirradiated control animals. Flow cytometry revealed rapid and significant increases in the LI of kidney cells; 2 weeks after irradiation the LI increased from a control value of 0.18 +/- 0.01 to 1.23 +/- 0.22% (P < 0.001). By 4 weeks the maximal value of 2.45 +/- 0.36% was seen; the LI then declined progressively but at 24 weeks after irradiation still remained significantly above control values (P < 0.001). A similar pattern of response was determined by counting the labeled glomerular and tubular cells identified immunohistochemically. However, the increase in labeled glomerular cells occurred 2 weeks after irradiation, whereas that for the tubules occurred 4 weeks after irradiation. These findings indicate that irradiation of the kidney, classically regarded as a "late-responding" organ, is associated with rapid and significant changes in the kinetics of both tubular and glomerular cells.

Nine mature, approximately 45-week-old pigs, were fed a standard diet (SD) containing 16% protein; 10 pigs were fed an isocaloric low protein (LP) pig feed containing 4% protein 2 weeks prior to and 16 weeks after renal or sham-irradiation. The pigs then received the SD for a further 4 weeks. Both kidneys of seven pigs fed the LP diet, and six pigs fed the SD, were irradiated with a single dose of 9.8 Gy of 60Co gamma-rays. The remaining pigs received sham-irradiation. The individual kidney glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the haematocrit were serially measured before and up to 20 weeks after irradiation. The radiation-induced reduction in mean individual kidney GFR, expressed as either absolute values or as a percentage of the respective sham-irradiated controls, was significantly greater in pigs fed the SD compared with pigs fed the LP diet (p < 0.05). In contrast, the radiation-induced reduction in mean individual kidney ERPF, expressed as absolute values, observed in pigs fed the SD was not significantly different from that seen in pigs fed the LP diet. However, if these data were expressed as a percentage of the respective sham-irradiated controls, then a significantly greater reduction in ERPF was seen in pigs fed the SD compared with pigs fed the LP diet (p < 0.001). Morphological analysis of renal tissue removed 20 weeks after irradiation showed that the extent and severity of the glomerular lesions seen in pigs fed the SD were significantly reduced in pigs fed the LP diet. Thus dietary protein restriction appears to reduce some of the signs of radiation nephropathy in the pig.

Both kidneys of 12 mature female pigs received either a single dose of 9.8 Gy 60Co gamma rays or sham irradiation. At intervals of 1-4 weeks serial renal biopsies were obtained, followed by sacrifice at 24 weeks after irradiation. Individual kidney glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the hematocrit (Hct) were measured routinely. Renal irradiation resulted in a progressive decline in GFR, ERPF, and Hct, with minimal values being observed within 12 weeks of irradiation. No change in any of these parameters was noted in the sham-irradiated pigs. The initial morphological change in irradiated glomeruli was leukocyte attachment to capillary endothelial cells 3-6 weeks after irradiation followed by activation and swelling of the endothelial cells. This was followed by pronounced increases in capillary permeability with fluid and erythrocyte, leukocyte, and platelet exudation into the subendothelial/mesangial space. This resulted in compression of glomerular capillary lumina, which occurred concomitantly with the reduction in GFR. By 12 to 15 weeks after irradiation the changes in endothelial cells were less evident. However, mesangial cells exhibited evidence of activation and proliferation accompanied by progressive mesangial expansion and sclerosis. Thus the glomerular capillary endothelial and mesangial cells appear particularly important in the pathogenesis of radiation nephropathy.

The ability of essential fatty acids (EFAs) to modulate radiation-induced normal tissue injury was assessed in pig skin. Female Large White pigs (approximately 25 Kg) received 3 ml/day orally of either an 'active' oil [So-1100, containing 9% gamma-linolenic acid (GLA)] or a 'placebo' oil (So-1129) for just 4 weeks before or for 4 weeks before and for 16 weeks after irradiation; localised irradiation of skin was with single doses of beta-rays from 22.5 mm diameter 90Sr/90Y plaques. The severity of the acute reaction, assessed in terms of erythema or moist desquamation, was significantly less in those pigs that received So-1100 both before and after irradiation, as compared with those receiving that oil only prior to irradiation and the 'placebo' groups. Dose modification factors (DMFs) of between 1.13-1.24 were obtained. A similar reduction in the severity of acute skin injury was seen in pigs receiving So-1100 for only 10 weeks after irradiation. Late skin damage, assessed in terms of late erythema or dermal necrosis, was also reduced with So-1100, with DMFs of 1.14-1.51. No such modification was observed if So-1100 was only administered for 4 weeks prior to irradiation. No adverse side-effects were apparent as a result of EFA administration. So-1100 may represent a safe and valuable method of increasing the therapeutic gain in radiotherapy.

Background: Therapeutic abdominal irradiation may be accompanied by late occurring progressive renal disease associated with glomerular mesangial sclerosis and tubular degeneration. Pathogenesis of this lesion is disputed., Experimental Design: Kidneys of mature pigs were irradiated with a single dose of 9.8 Gy 60Co gamma-rays; serial individual kidney glomerular filtration rate and renal biopsies were obtained at 3-4-week intervals with death 24 weeks after irradiation., Results: Irradiated pigs displayed a progressive reduction in glomerular filtration rate with minimal values observed 12 weeks postirradiation. Morphologic changes in irradiated glomeruli were characterized by leukocytic attachment to capillary endothelial cells 3-6 weeks after irradiation followed by activation and swelling of endothelial cells and occasional microthrombi formation. Similar changes were noted focally in peritubular capillaries with accompanying tubular degeneration and atrophy. In glomeruli these endothelial cell changes were followed by increased capillary permeability and fluid, erythrocyte, platelet, and leukocytic exudation into the subendothelial/mesangial space resulting in compression of glomerular capillary lumina. By 12 weeks postirradiation mesangial cells showed evidence of activation and proliferation accompanied by progressive mesangial expansion and sclerosis with continued reduction of glomerular filtration rate., Conclusions: It is concluded that endothelial cell injury represents the primary site of radiation damage in the kidney and that the progressive glomerular mesangial sclerosis and reduced renal function of radiation nephropathy may be associated with exposure of capillary elements to various vasoactive and growth promoting factors that stimulate mesangial contraction and proliferation resulting in reduced glomerular filtration area and glomerular filtration rate.

Changes in the cell proliferation kinetics of the epithelium of mouse lip mucosa have been assessed after local irradiation with a single dose of 18 Gy of 60Co gamma-rays. By the fifth day after irradiation, two distinct sub-populations of epithelial cells could be discerned. The larger of the two populations consisted of cells exhibiting varying degrees of radiation-induced damage, and the smaller population was composed of cells of normal size and appearance, intermingled between the radiation-damaged cells. There was a progressive decline in the epithelial cell density with time after irradiation, and focal denudation was seen after 11 days. Cell colonies were evident in the remnants of the epithelium by day 7. Degenerate cells could be identified in the basal layer of the mucosal epithelium, both before and after irradiation. The proportion of degenerate cells was increased 5 days after irradiation with the maximum number, approximately 3.6% being counted on days 7 and 8. In the first 2 days after irradiation, there was a reduction in the labelling index (LI) of basal cells in the epithelium. This was followed by recovery to control values on day 3. The LIs of both the radiation-damaged cells and those with a normal appearance remained relatively constant between days 5 and 11, at approximately 10 and approximately 60%, respectively. The LI of basal cells in the cell colonies was very high (approximately 70%). The estimated turnover time (TT) for the basal cell population with a normal appearance and for those in cell colonies (groups of normal cells with a cord length > or = 10 cells), was extremely short < 1 day. There was some fluctuation in TT values for basal cells exhibiting radiation-induced damage, with the shortest value (approximately 3 days) at 7 and 8 days after irradiation. It was concluded from the cell kinetic data that repopulation of the lip mucosal epithelium started between 3 and 5 days after irradiation and the overall response of the mucosa to irradiation was consistent with that predicted by a hierarchical model of cell proliferative organization.

Mature Large White female pigs aged approx. 10 months received single intravenous doses of 1.5, 2, or 2.5 mg/kg cisplatin. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) in individual kidneys were measured prior to and at 4-week intervals for up to 24 weeks after cisplatin administration by renography using [99mTc]-diethylenetriamminepentaacetic acid (DTPA) and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated pig and that of three age-matched control pigs was then removed, and GFR and ERPF values were measured in the remaining kidney at 4-week intervals for a further 24 weeks after unilateral nephrectomy (UN). Pigs treated with cisplatin showed no significant reduction in GFR or ERPF for up to 24 weeks after drug infusion. As measured using inductively coupled plasma mass spectrometry, the mean renal platinum concentration in the left kidney removed at UN was 77.5 +/- 9.1 ng/g kidney per mg/kg cisplatin. Histological evaluation of these kidneys revealed narrow interconnecting rays of interstitial fibrosis in the deep cortex and medulla; in these areas, glomeruli exhibited thickened Bowman's capsules and occasionally shrunken sclerotic capillaries. In cisplatin-treated pigs, UN was associated with a marked reduction in the ability of the remaining kidney to increase its function in terms of GFR and, to a lesser extent, of ERPF. The increase seen in GFR following UN in the cisplatin-treated pigs was only ca. 50%-70% of that seen in age-matched UN controls. Histologically, these kidneys revealed resolution of the peritubular fibrosis observed at UN; occasional sclerotic glomeruli were also evident. Platinum remained detectable in these kidneys, the mean levels being 18.8 +/- 4.9 ng/g kidney per mg/kg cisplatin. These findings confirm previous observations and illustrate the need for caution in considering further treatment of patients who have previously received cisplatin along with a second potentially nephrotoxic agent.

Both kidneys of mature pigs received a single dose of 9.8 Gy 60Co gamma rays. Pigs were killed between 2 and 24 weeks after irradiation and the kidneys examined histologically. Glomerular and tubular changes were observed within 2 weeks of irradiation. Neutrophils and other leukocytes were seen within glomerular capillary loops; mesangial matrix and cell number increased. A progressive increase in thickening of the basement membrane and a decrease in capillary lumina were then noted. Basement membrane duplication occurred within 12 weeks. By 24 weeks these lesions had increased in severity, sclerotic endstage glomeruli, predominantly subcapsular or juxtamedullary, being evident. Tubular lesions initially consisted of focal areas of tubular atrophy in the juxtamedullary region. By 6 weeks subcapsular foci of tubular degeneration, regeneration, and necrosis were found; these appeared to resolve 12 weeks after irradiation. At later times the severity of the tubular lesions varied between pigs, with some exhibiting interstitial fibrosis involving a complete band of subcapsular tissue, while others showed relatively mild changes. There was no apparent change in the vasculature. These findings indicate that (a) there is no one target or dose-limiting cell, and (b) the vasculature does not play a primary role in the development of radiation nephropathy.

The durations of the cell cycle and its component phases have been determined for the basal layer of the epidermis of the skin from the upper surface of the hind foot of the rat using single pulse [3H]-thymidine labelling and the percent labelled mitosis (PLM) technique. Rats of three age groups were used, namely 7, 14 and 52 weeks. The duration of DNA synthesis (Ts) and the G2 plus M phase (TG2 + M) were comparable in 7-week and 52-week-old rats (P greater than 0.1). The major difference between 7-week and 52-week-old rats was in the duration of the G1 phase (TG1). In 7-week-old rats TG1 was 15.0 +/- 0.8 h and in 52-week-old rats TG1 was 31.2 +/- 3.5 h. A consequence of this variation was that the overall duration of the cell cycle was longer in 52-week-old rats (53.9 +/- 5.3 h) than in 7-week-old rats (30.1 +/- 1.3 h). Difficulties were found in fitting a simple curve to the PLM data for 14-week-old rats. This suggests that the proliferative cell population of the epidermis of rats of this age group may be heterogeneous. A satisfactory fit to the data was obtained using a computer model which assumed that the proliferative population of the epidermis of 14-week-old rats was a mixture of cells with cell cycle parameters the same as those of the 7-week and the 52-week-old rats. These two sub-populations of relatively slowly and rapidly proliferating cells were present in the ratio of 2:1.

Groups of mature Large White female pigs, approximately 10 months of age, received single intravenous infusions of 1.5, 2 or 2.5 mg/kg body weight (equivalent to approximately 90, approximately 120 and approximately 150 mg/m2) cisplatin. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured before and at 4 weeks after cisplatin infusion by renography using [99 mTc]-DTPA (diethylenetriamminepentaacetic acid and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated animal plus that of four age-matched control pigs was then removed surgically, and GFR and ERPF were measured in the remaining kidney at 4 weekly intervals for up to 24 weeks after unilateral nephrectomy (UN). The pigs treated with cisplatin exhibited no consistent change in either GFR or ERPF at 4 weeks after treatment. A histological evaluation of kidneys from animals treated with greater than or equal to 2 mg/kg cisplatin that had been removed at UN revealed both tubular and glomerular lesions. The latter consisted of cell proliferation on the parietal surface of the urinary space; damage to the S1 portion of the proximal convolution was also noted. Following UN there was a pronounced dose-dependent reduction in the functional status of the remaining kidney such that the increase in GFR and ERPF in pigs initially receiving 2.5 mg/kg cisplatin was less than 50% of that seen in age-matched UN controls. Moreover, the glomerular lesions observed at 4 weeks after cisplatin infusion had apparently progressed to glomerular hyalinisation by 24 weeks after UN. Thus, prior treatment with cisplatin may cause a permanent reduction in renal functional reserve that may be clinically "silent" until exposure to an additional nephrotoxic insult.