Ischaemic stroke caused by Group B Streptococcus associated meningoencephalitis in young, immunocompetent adults - a case series and systematic review of literature.

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.

Cardiovascular risk prevalence in South Africans with drug-resistant tuberculosis: a cross-sectional study.

In South Africa, the risk factors for cardiovascular disease (CVD) are increasing, thereby impacting patients with drug-resistant tuberculosis (DR-TB). To determine the prevalence of traditional CVD risk factors (diabetes mellitus [DM], smoking, hypertension, increased body mass index [BMI]) and a total risk score for CVD among patients with DR-TB. This cross-sectional study was nested within an ongoing cluster-randomized trial in 10 DR-TB hospitals in South Africa. The data for the present study were collected between November 2014 and July 2016. Of 900 participants aged 18 years, 75.1% were co-infected with the human immunodeficiency virus (HIV), and 52.3% had one or more CVD risk factors. The prevalence of CVD risk factors was hypertension (16.7%), increased BMI (16.6%), DM (5.2%), and smoking (31.4%). Among patients with DM or hypertension, 58.8-95.5% had additional comorbid CVD risk factors. Of 398 participants eligible for the CVD risk score (age 35 years), 23.4% had a moderate or high CVD risk score. Patients with multiple diseases, including DR-TB and HIV, with traditional CVD risk factors, may have higher risks for negative outcomes during treatment for DR-TB. TB providers should identify people at risk to initiate primary and secondary prevention to improve outcomes. .

A systematic review of the effectiveness of smoking cessation interventions among patients with tuberculosis.

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.

Le tabac constitue un facteur de risque significatif en termes de morbidité et de mortalité, particulièrement pour les patients atteints de tuberculose (TB). L'arrêt du tabac a été recommandé par l'Organisation Mondiale de la Santé et l'Union Internationale contre la Tuberculose et les Maladies Respiratoires ; aucune évaluation n'a cependant été publiée à propos des interventions de sevrage du tabac parmi les personnes atteintes de TB. Le but de cette revue a été de synthétiser les données probantes relatives à ces interventions et de suggérer les implications en matière de pratique, de recherche et de politique. Une revue systématique de la littérature a identifié 14 études revues par des pairs, décrivant 13 interventions d'arrêt du tabac entre 2007 et 2017 : 5 essais randomisés contrôlés, 3 interventions non randomisées et 5 études prospectives de cohorte. Les types principaux d'intervention ont consisté en brefs conseils (n = 9), en conseil comportemental (n = 4), en médicaments (n = 3) et en prise en charge communautaire (n = 3). Les interventions ont été mises en œuvre par toute une gamme de personnel de santé­médecins, infirmiers, personnel des dispensaires, travailleurs de santé communautaire­et par des membres de la famille. Ces interventions ont été significativement hétérogènes en matière de schéma, de définition du tabagisme et de l'abstinence et de mise en œuvre, ce qui a rendu difficiles les comparaisons entres les études. Dans l'ensemble, toutes les interventions ont accru le taux d'arrêt du tabac de 15% à 82%, mais de nombreuses études sont très sujettes aux biais, notamment les six études dépourvues de groupe témoin. Le type de personnel de mise en œuvre n'a pas entrainé de modifications majeures en termes de résultats, ce qui suggère que les programmes nationaux TB peuvent adapter la mise en œuvre de ces interventions à leurs besoins et à leurs limites. Les membres de la famille semblent jouer un rôle important en matière de soutien et de plaidoyer. Des recherches ultérieures devraient standardiser les définitions de la consommation et de l'arrêt du tabac afin de permettre des comparaisons entre les études. Les décideurs politiques devraient encourager la collaboration entre les initiatives liées au tabac et celles liées à la TB et élaborer des mesures d'arrêt du tabac pour maximiser les résultats dans les contextes de faibles ressources.

El tabaquismo representa un importante factor de riesgo de morbilidad y mortalidad, sobre todo para los pacientes con tuberculosis (TB). La Organización Mundial de la Salud y la Unión Internacional contra la Tuberculosis y las Enfermedades Respiratorias han recomendado que se promueva la deshabituación tabáquica, pero aún no se ha publicado una evaluación de las intervenciones que favorecen el abandono del tabaquismo en las personas con diagnóstico de TB. La finalidad de la presente revisión consistió en reunir la evidencia existente sobre estas intervenciones y proponer los corolarios que se podrían aplicar en la práctica, la investigación y la formulación de políticas. En una revisión sistemática de artículos científicos se encontraron 14 estudios publicados del 2007 al 2017 en revistas con comité de lectura que describían 13 intervenciones de deshabituación tabáquica. Los artículos abordaban 5 ensayos aleatorizados, 3 intervenciones no aleatorizadas y 5 estudios de cohortes prospectivos. Los principales tipos de intervenciones consistieron en asesoramiento breve (n = 9), orientación conductual (n = 4), tratamiento médico (n = 3) y atención al nivel comunitario (n = 3). Diversos profesionales de salud participaron en la ejecución de las intervenciones como miembros del personal médico, de enfermería, auxiliares clínicos, agentes de salud comunitarios y miembros de la familia. Se observó una gran heterogeneidad con respecto al diseño de los estudios, la definición de tabaquismo y de la abstinencia de tabaco y a la ejecución, que dificultó las comparaciones entre los estudios. En general, todas las intervenciones de deshabituación tabáquica aumentaron el abandono del tabaco de 15% a 82%, pero en muchos de los artículos existía la probabilidad de sesgo como en seis estudios que no contaban con un grupo testigo. El tipo de personal que ejecutaba la intervención no tuvo un efecto notorio en los resultados de abandono, lo cual indica que los programas nacionales contra la TB pueden adaptar las iniciativas a sus necesidades y limitaciones. Los miembros de la familia pueden cumplir una función importante de apoyo o promoción del abandono del tabaco. En las investigaciones futuras es preciso normalizar las definiciones de tabaquismo y de abandono del tabaco con el fin de facilitar las comparaciones entre los estudios. Las instancias normativas deben fomentar la colaboración entre las iniciativas contra el tabaquismo y contra la TB y formular medidas encaminadas a la deshabituación tabáquica que optimicen sus resultados en los entornos con bajos recursos.

Trophic effects of essential fatty acids on pig skin.

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.

The radiation response of the cervical spinal cord of the pig: effects of changing the irradiated volume.

PURPOSE: An investigation of the field size effect for the cervical spinal cord of the pig after single doses of gamma-rays. In this study, clinically relevant volumes of the spinal cord were irradiated. METHODS AND MATERIALS: The effects of the local irradiation of different lengths of the spinal cord (2.5 cm, 5.0 cm, and 10.0 cm) have been evaluated in mature pigs (37-43 weeks). Single doses of 25-31 Gy were given using a 60Co gamma-source, at a dose rate of 0.21-0.30 Gy/min. The incidence of radiation-induced paralysis was used as the endpoint. The data were analyzed using probit analysis and a normal tissue complication probability (NTCP)-model. RESULTS: Twenty-five animals out of a total of 53 developed paralysis, with histological evidence of parenchymal and vascular changes in their white matter. The slope of the dose-response curves decreased with the decrease in field size; however, there was no significant difference at the radiation dose associated with a 50% incidence of paralysis (ED50) irrespective of the method of analysis. The ED50 values +/- standard errors (+/- SE) were 27.02 +/- 0.36 Gy, 27.68 +/- 0.57 Gy, and 28.28 +/- 0.78 Gy for field lengths of 10, 5, and 2.5 cm, respectively. Analysis of the data with a normal tissue complication probability (NCTP) model gave similar results. The latent period for paralysis was 7.5-16.5 weeks with no significant differences between dose and field size. CONCLUSION: No significant field size-related differences in response were detectable in the cervical spinal cord of mature pigs after single dose irradiations, specifically at a clinically relevant level of effect (< ED10).

A new model of radiation-induced myelopathy: a comparison of the response of mature and immature pigs.

PURPOSE: The development of an experimental model of radiation-induced myelopathy in the pig which would facilitate the study of the effects of clinically relevant treatment volumes. METHODS AND MATERIALS: The effects of local spinal cord irradiation, to a standard 10 x 5 cm field, have been evaluated in mature (37-42.5 weeks) and immature (15.5-23 weeks) pigs. Irradiation was with single doses of 60Co gamma-rays at a dose-rate of 0.21-0.65 Gy/min. The incidence of paralysis was used as an endpoint. RESULTS: Irradiation of mature animals resulted in the development of frank paralysis with animals showing combined parenchymal and vascular pathologic changes in their white matter. These lesions, in common with those seen in patients, had a clear evidence of an inflammatory component. The latency for paralysis was short, 7.5-16.5 weeks, but within the wide range reported for patients. However, it was shorter than that reported in other large animal models. The ED50 value (+/- SE) for paralysis was 27.02 +/- 0.36 Gy, similar to that in rats taking into account dose-rate factors. The irradiation of immature pigs only resulted in transient neurological changes after doses comparable to those used in the mature animals, ED50 value (+/- SE) 26.09 +/- 0.37 Gy. The reasons for these transient neurological symptoms are uncertain. CONCLUSION: A reliable experimental model of radiation-induced myelopathy has been developed for mature pigs. This model is suitable for the study of clinically relevant volume effects.

Boron neutron capture therapy: a guide to the understanding of the pathogenesis of late radiation damage to the rat spinal cord.

PURPOSE: Before the commencement of new boron neutron capture therapy (BNCT) clinical trials in Europe and North America, detailed information on normal tissue tolerance is required. In this study, the pathologic effects of BNCT on the central nervous system (CNS) have been investigated using a rat spinal cord model. METHODS AND MATERIALS: The neutron capture agent used was 10B enriched sodium mercaptoundecahydro-closododecaborate (BSH), at a dosage of 100 mg/kg body weight. Rats were irradiated on the thermal beam at the Brookhaven Medical Research Reactor. The large spine of vertebra T2 was used as the lower marker of the irradiation field. Rats were irradiated with thermal neutrons alone to a maximum physical absorbed dose of 11.4 Gy, or with thermal neutrons in combination with BSH, to maximum absorbed physical doses of 5.7 Gy to the CNS parenchyma and 33.7 Gy to the blood in the vasculature of the spinal cord. An additional group of rats was irradiated with 250 kVp X rays to a single dose of 35 Gy. Spinal cord pathology was examined between 5 and 12 months after irradiation. RESULTS: The physical dose of radiation delivered to the CNS parenchyma, using thermal neutron irradiation in the presence of BSH, was a factor of two to three lower than that delivered to the vascular endothelium, and could not account for the level of damage observed in the parenchyma. CONCLUSION: The histopathological observations of the present study support the hypothesis that the blood vessels, and the endothelial cells in particular, are the critical target population responsible for the lesions seen in the spinal cord after BNCT type irradiation and by inference, after more conventional irradiation modalities such as photons or fast neutrons.

Radiation-induced changes in glomerular and tubular cell kinetics and morphology following irradiation of a single kidney in the pig.

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.

Amelioration of both early and late radiation-induced damage to pig skin by essential fatty acids.

PURPOSE: To evaluate the possible role of essential fatty acids, specifically gamma-linolenic and eicosapentaenoic acid, in the amelioration of early and late radiation damage to the skin. METHODS AND MATERIALS: Skin sites on the flank of 22-25 kg female large white pigs were irradiated with either single or fractionated doses (20 F/28 days) of beta-rays from 22.5 mm diameter 90Sr/90Y plaques at a dose rate of approximately 3 Gy/min. Essential fatty acids were administered orally in the form of two 'active' oils, So-1100 and So-5407, which contained gamma-linolenic acid and a mixture of that oil with eicosapentaenoic acid, respectively. Oils (1.5-6.0 ml) were given daily for 4 weeks prior, both 4 weeks prior and 10-16 weeks after, or in the case of one single dose study, just for 10 weeks after irradiation. Control animals received a 'placebo' oil, So-1129, containing no gamma linolenic acid or eicosapentaenoic acid over similar time scales before and after irradiation. Acute and late skin reactions were assessed visually and the dose-related incidence of a specific reaction used to compare the effects of different treatment schedules. RESULTS: A reduction in the severity of both the early and late radiation reactions in the skin was only observed when 'active' oils were given over the time course of the expression of radiation damage. Prior treatment with oils did not modify the radiation reaction. A 3.0 ml daily dose of either So-1100 or So-5407 given prior to, but also after irradiation with single and fractionated doses of beta-rays produced the most significant modification to the radiation reactions, effects consistent with dose modification factors between 1.06-1.24 for the acute reactions of bright red erythema and/or moist desquamation, and of 1.14-1.35 for the late reactions of dusky/mauve erythema and dermal necrosis. There was the strong suggestion of an effect produced by the 'placebo' oil, So-1129, after higher daily doses of oil. CONCLUSIONS: Essential fatty acids can modulate normal tissue reactions when given over the time when radiation damage is normally expressed. Dose modification factors suggest that a > or = 10% higher dose is required to produce the same level of normal tissue injury. Clinical application of selected essential fatty acids at appropriate doses may lead to a significant increase in the therapeutic gain in patients treated for cancer by radiotherapy.

Repair, repopulation and cell cycle redistribution in rat foot skin.

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.

Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis.

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.

Sequential evaluation of radiation-induced glomerular ultrastructural changes in the pig kidney.

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.

A morphological study of radiation nephropathy in the pig.

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.

Radiation-induced changes in the kinetics of glomerular and tubular cells in the pig kidney.

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.

Cisplatin-induced reductions in renal functional reserve uncovered by unilateral nephrectomy: an experimental study in the pig.

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.

Long-term studies of cisplatin-induced reductions in porcine renal functional reserve.

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.

Radiation response of mouse lip mucosal epithelium: a cell kinetic study.

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.

Influence of a low protein diet on radiation nephropathy in the pig.

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.

Modification of late dermal necrosis in the pig by treatment with multi-wavelength light.

Low-level light from a multi-wavelength light source has been used to prevent late X-ray-induced dermal necrosis in the pig. Skin fields, measuring 4 cm x 4 cm on the flank, were irradiated with graded doses of X rays and the incidence of late dermal necrosis at 10-16 weeks after irradiation was scored. The control skin sites were irradiated only with 250 kV X rays but the test skin sites were subsequently exposed to low-level light. Local light exposure was from an array of gallium aluminium arsenide diodes, which produced wavelengths of 660, 820, 880 and 950 nm, pulsating at 5 kHz. Light treatment was given three times a week, from 6-16 weeks after X irradiation. Each treatment session was 1 min, which was equivalent to energy density of 1.08 Jcm-2. Light treatment increased the ED50, the dose which causes dermal necrosis in 50% of the irradiated skin fields, from 20.10 +/- 0.12 Gy to 21.94 +/- 0.30 Gy. This difference, although small, was highly significant (p < 0.001) and was equivalent to a dose modification factor (DMF) of 1.09. The effect of light treatment was minimal at incidence levels of less than the 50% but greater at higher levels of effect. These findings suggest that low-level light, when applied appropriately, may be useful in the prevention of late X-ray-induced damage to the dermis.

Effects of Lipochromin and Levosinum in the modulation of radiation-induced injury to pig skin.

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.