Fumonisin B1 protects against long-chained polyunsaturated fatty acid-induced cell death in HepG2 cells - implications for cancer promotion.

Fumonisin B1 (FB1), a food-borne mycotoxin, is a cancer promoter in rodent liver and augments proliferation of initiated cells while inhibiting the growth of normal hepatocytes by disrupting lipid biosynthesis at various levels. HepG2 cancer cells exhibited resistance to FB1-induced toxic effects presumably due to their low content of polyunsaturated fatty acids (PUFA) even though FB1-typical lipid changes were observed, e.g. significantly increased phosphatidylethanolamine (PE), decreased sphingomyelin and cholesterol content, increased sphinganine (Sa) and sphinganine/sphingosine ratio, increased C18:1ω-9, decreased C20:4ω-6 content in PE and decreased C20:4ω-6_PC/PE ratio. Increasing PUFA content of HepG2 cells with phosphatidylcholine (PC) vesicles containing C20:4ω-6 (SAPC) or C22:6ω-3 (SDPC) disrupted cell survival, cellular redox status and induced oxidative stress and apoptosis. A partially protective effect of FB1 was evident in PUFA-enriched HepG2 cells which may be related to the FB1-induced reduction in oxidative stress and the disruption of key cell membrane constituents indicative of a resistant lipid phenotype. Interactions between different ω-6 and ω-3 PUFA, membrane constituents including cholesterol, and the glycerophospho- and sphingolipids and FB1 in this cell model provide further support for the resistant lipid phenotype and its role in the complex cellular effects underlying the cancer promoting potential of the fumonisins.

Risk factors for not finishing an ultramarathon: 4-year study in 23,996 race starters, SAFER XXI.

BACKGROUND: Limited data support prerace medical screening to identify risk factors for not finishing an endurance running race. The aim of the study was to determine risk factors associated with not finishing an ultramarathon. METHODS: A prospective, cross-sectional study of Two Oceans ultramarathon (56 km) race starters who completed a prerace medical screening questionnaire. Race day environmental conditions were recorded on race day. Univariate analyses of risk factors associated with the did-not-finish (DNF) included race day factors and prerace medical screening history. RESULTS: Risk factors for DNF amongst 23,996 starters during the 56 km race included older age and females (P<0.0001). After adjusting for age and sex, the following were significant univariate risk factors: fewer years of running (P<0.0001), less previous race experience (P<0.0001), less training/racing per week (P=0.0002), lower average weekly training distance (P=0.0016), slower race vs. training speed (P<0.0001), lack of allergies (P=0.0100) and average wet-bulb globe temperature (P<0.0001). CONCLUSIONS: Females, older age, training-related factors (less training/racing, average weekly training distance, race vs. training speed) and average wet-bulb temperature, were risk factors for not finishing an ultramarathon. The results may not only assist runners and coaches in race preparation, but also have clinical implications for the medical planning prior to races.

Differential Cytotoxicity of Rooibos and Green Tea Extracts against Primary Rat Hepatocytes and Human Liver and Colon Cancer Cells - Causal Role of Major Flavonoids.

Differential anti-proliferative and pro-apoptotic effects of aqueous extracts of green rooibos (Rg; Aspalathus linearis) and green tea (GT; Camellia sinensis) and an aspalathin-enriched extract of green rooibos (GRE), were investigated in primary rat hepatocytes (PH) and human liver (HepG2) and colon (HT-29) cancer cells. Rooibos flavonoids, aspalathin and luteolin, and the green tea flavanol, epigallocatechin gallate (EGCG), were included to assess their contribution relative to their extract concentrations. GRE was the most effective in reducing cell growth parameters which was associated with a high total polyphenol content and high ferric reducing potential. Differential cell responses were noticed with HepG2 cells more sensitive than PH toward the induction of apoptosis by GRE. Luteolin induced apoptosis in PH and HepG2 cells while aspalathin lacked any effect. EGCG induced apoptosis in HepG2 cells while PH were resistant. HT-29 cells were resistant to apoptosis induction by the tea and pure flavonoids. Differences existed in the individual effects of the major rooibos and GT flavonoids against cell growth parameters compared to their equivalent concentrations in the extract mixtures. Diversity of the flavonoid constituents, physicochemical properties and cellular redox status governing cell survival are likely to explain the differential cell responses.

Pre-race screening and stratification predicts adverse events-A 4-year study in 29585 ultra-marathon entrants, SAFER X.

BACKGROUND: Pre-race screening and risk stratification in recreational endurance runners may predict adverse events (AEs) during a race. AIM: To determine if pre-race screening and risk stratification predict AEs during a race. METHODS: A total of 29 585 participants (Male 71.1%, average age = 42.1 years; Female 28.9%, average age = 40.2 years) at the Two Oceans ultra-marathon races (56 km) completed a pre-race medical screening questionnaire and were risk stratified into four pre-specified groups [very high risk (VHR; existing cardiovascular disease-CVD:3.2%), high risk (HR; risk factors for CVD:10.5%), intermediate risk (IR; existing other chronic disease, medication use or injury:53.3%), and low risk (LR:33.0%)]. Race starters, finishers, and medical encounters (ME) were recorded. Did-not-start (DNS) rate (per 1000 entrants that did-not-start), did-not-finish (DNF) rate (per 1000 starters that did-not-finish), AE rate [per 1000 starters that either DNF or had an ME], and ME rate (per 1000 starters with an ME) were compared across risk categories. RESULTS: Adverse events were significantly higher (per 1000 starters; 95%CI) in the VHR (68.9; 52.4-89.9:P = .0407) compared with the LR (51.3; 46.5-56.7). The DNS rate was significantly different between the IR (190.3; 184.0-196.9) and LR (207.4; 199.2-216.0: P = .0011). DNF rates were not different in the VHR (56.4; 41.9-75.9) compared to LR (44.2; 39.7-49.1: P = .1295), and ME rate was also not different between risk categories, however, VHR (12.9; 7.0-23.9) was approaching significance compared to LR (6.9; 5.2-9.1: P = .0662). CONCLUSION: Pre-race medical screening and risk stratification may identify athletes at higher risk of AEs. Further studies should be performed in larger cohorts to clarify the role of pre-race medical screening in reducing AEs in endurance runners.

Prerace medical screening and education reduce medical encounters in distance road races: SAFER VIII study in 153 208 race starters.

OBJECTIVES: To examine the efficacy and feasibility of an online prerace medical screening and educational intervention programme for reducing medical complications in long-distance races. METHODS: This was an 8-year observational study of medical encounter rates among 153 208 Two Oceans race starters (21.1 and 56 km) in South Africa. After the first 4-year control (CON) period, we introduced an online prerace medical screening (based on European pre-exercise screening guidelines) and an automated educational intervention programme. We compared the incidence of medical encounters (per 1000 starters; all and serious life threatening) in the CON versus the 4-year intervention (INT) period. RESULTS: In comparison to the CON period (2008-2011: 65 865 starters), the INT period (2012-2015: 87 343 starters) had a significantly lower incidence (adjusted for age group, sex, race distance) of all medical encounters by 29% (CON=8.6 (7.9-9.4); INT=6.1 (5.6-6.7), p<0.0001), in the 21.1 km race by 19% (CON=5.1 (4.4-5.9); INT=4.1 (3.6-4.8), p=0.0356) and in the 56 km race by 39% (CON=14.6 (13.1-16.3); INT=9.0 (7.9-10.1), p<0.0001). Serious life-threatening encounters were significantly reduced by 64% (CON=0.6 (0.5-0.9); INT=0.2 (0.1-0.4); p=0.0003) (adjusted for age group and sex). Registration numbers increased in the INT period (CON=81 345; INT=106 743) and overall % race starters were similar in the CON versus INT period. Wet-bulb globe temperature was similar in the CON and INT periods. CONCLUSION: All medical encounters and serious life-threatening encounters were significantly lower after the introduction of a prescreening and educational intervention programme, and the programme was feasible.

Novel Factors Associated With Analgesic and Anti-inflammatory Medication Use in Distance Runners: Pre-race Screening Among 76 654 Race Entrants-SAFER Study VI.

OBJECTIVE: Analgesic/anti-inflammatory medication (AAIM) increases the risk of medical complications during endurance races. We determined how many runners use AAIM before or during races, AAIM types, and factors associated with AAIM use. DESIGN: Cross-sectional study. SETTING: 21.1-km and 56-km races. PARTICIPANTS: Seventy-six thousand six hundred fifty-four race entrants. METHODS: Participants completed pre-race medical screening questions on AAIM use, running injury or exercise-associated muscle cramping (EAMC) history, and general medical history. MAIN OUTCOME MEASURES: Analgesic/anti-inflammatory medication use, types of AAIM (% runners; 95% confidence interval), and factors associated with AAIM use (sex, age, race distance, history of running injury or EAMC, and history of chronic diseases) [prevalence ratio (PR)]. RESULTS: Overall, 12.2% (12.0-12.5) runners used AAIM 1 week before and/or during races (56 km = 18.6%; 18.0-19.1, 21.1 km = 8.3%; 8.1-8.6) (P < 0.0001). During races, nonsteroidal anti-inflammatory drugs (NSAIDs) (5.3%; 5.1-5.5) and paracetamol (2.6%; 2.4-2.7) were used mostly. Independent factors (adjusted PR for sex, age, and race distance; P < 0.0001) associated with AAIM use were running injury (2.7; 2.6-2.9), EAMC (2.0; 1.9-2.1), cardiovascular disease (CVD) symptoms (2.1; 1.8-2.4), known CVD (1.7; 1.5-1.9), CVD risk factors (1.6; 1.5-1.6), allergies (1.6; 1.5-1.7), cancer (1.3; 1.1-1.5), and respiratory (1.7; 1.6-1.8), gastrointestinal (2.0; 1.9-2.2), nervous system (1.9; 1.7-2.1), kidney/bladder (1.8; 1.6-2.0), endocrine (1.5; 1.4-1.7), and hematological/immune (1.5; 1.2-1.8) diseases. CONCLUSIONS: 12.2% runners use AAIM before and/or during races, mostly NSAIDs. Factors (independent of sex, age, and race distance) associated with AAIM use were history of injuries, EAMC, and numerous chronic diseases. We suggest a pre-race screening and educational program to reduce AAIM use in endurance athletes to promote safer races.

Underlying Chronic Disease, Medication Use, History of Running Injuries and Being a More Experienced Runner Are Independent Factors Associated With Exercise-Associated Muscle Cramping: A Cross-Sectional Study in 15778 Distance Runners.

BACKGROUND: Exercise-associated muscle cramping (EAMC) is a significant medical complication in distance runners, yet factors associated with EAMC are poorly documented. OBJECTIVE: To document risk factors associated with EAMC in runners. DESIGN: Cross-sectional study. SETTING: Two ocean races (21.1 km, and 56 km). PARTICIPANTS: Fifteen thousand seven hundred seventy-eight race entrants. METHODS: Participants completed a prerace medical history screening tool including: training, cardiovascular disease (CVD), risk factors for, and symptoms of CVD, history of diseases affecting major organ systems, cancer, allergies, medication use, and running injury. Runners were grouped as having a history of EAMC (hEAMC group = 2997) and a control group (Control = 12 781). RESULTS: Independent factors associated with a higher prevalence ratio (PR) of hEAMC were any risk factor for CVD (PR = 1.16; P = 0.0002), symptoms of CVD (PR = 2.38; P < 0.0001), respiratory disease (PR = 1.33; P < 0.0001), gastrointestinal disease (PR = 1.86; P < 0.0001), nervous system or psychiatric disease (PR = 1.51; P < 0.0001), kidney or bladder disease, (PR = 1.60; P < 0.0001), haematological or immune disease (PR = 1.54; P = 0.0048), cancer (PR = 1.34; P = 0.0031), allergies (PR = 1.37; P < 0.0001), regular medication use (PR = 1.80; P < 0.0001), statin use (PR = 1.26; P = 0.0127), medication use during racing (PR = 1.88; P < 0.0001), running injury (PR = 1.66; P < 0.0001), muscle injury (PR = 1.82; P < 0.0001), tendon injury (PR = 1.62; P < 0.0001), and runners in the experienced category (PR = 1.22; P < 0.0001). CONCLUSION: Novel risk factors associated with EAMC in distance runners were underlying chronic disease, medication use, a history of running injuries, and experienced runners. These factors must be identified as possible associations, and therefore be considered in the diagnosis and treatment of EAMC.

In Vitro Chemopreventive Properties of Green Tea, Rooibos and Honeybush Extracts in Skin Cells.

The chemopreventive properties of the herbal teas rooibos (Aspalathus linearis) and honeybush (Cyclopia spp.) have been demonstrated on mouse skin in vivo but the underlying mechanisms are not clear. The aim of the current study was to determine the anti-proliferative and pro-apoptotic activity of methanol and aqueous extracts of rooibos and two Cyclopia species in different skin cells, using green tea (Camellia sinensis) as a benchmark. Extracts were also characterised for their major individual polyphenols by high performance liquid chromatography and spectroscopically for the total polyphenol (TP) groups. The methanol extract of rooibos, containing higher levels of polyphenols than its aqueous extract, displayed similar activity to green tea as it selectively targeted premalignant cells by inhibiting cell proliferation at lower concentrations whilst inducing apoptosis via membrane depolarisation at higher concentrations. Specific roles of the major rooibos dihydrochalcones and flavanol/proanthocyanidin-type (FLAVA) compounds are likely to be involved. The aqueous extracts of the Cyclopia species were more active against cell proliferation and at inducing apoptosis which was associated with a higher FLAVA content and a reduced TP/FLAVA ratio. In contrast, their methanol extracts exhibited a cytoprotective effect against apoptosis which was related to their monomeric xanthone and flavanone content. The underlying chemopreventive properties of green tea and the herbal teas appear to be associated with diverse and complex monomeric/polymeric polyphenolic cell interactions.

Anti-Inflammatory Effects of Aspalathus linearis and Cyclopia spp. Extracts in a UVB/Keratinocyte (HaCaT) Model Utilising Interleukin-1α Accumulation as Biomarker.

Ultraviolet B (UVB) radiation is one of the major predisposing risk factors of skin cancer. The anticancer and photoprotective effects of unoxidized rooibos (Aspalathus linearis) and honeybush (Cyclopia) herbal teas, containing high levels of dihydrochalones and xanthones, respectively, have been demonstrated in skin cancer models in vivo. In the current study, the anti-inflammatory effects of methanol and aqueous extracts of these herbal teas were investigated in a UVB/HaCaT keratinocyte model with intracellular interleukin-1α (icIL-1α) accumulation as a biomarker. Extracts of green tea (Camellia sinensis) served as benchmark. Both extracts of green tea and rooibos, as well as the aqueous extract of C. intermedia, enhanced UVB-induced inhibition of cell viability, proliferation and induction of apoptosis, facilitating the removal of icIL-1α. The underlying mechanisms may involve mitochondrial dysfunction exhibiting pro-oxidant responses via polyphenol-iron interactions. The methanol extracts of honeybush, however, protected against UVB-induced reduction of cell growth parameters, presumably via antioxidant mechanisms that prevented the removal of highly inflamed icIL-1α-containing keratinocytes via apoptosis. The dual antioxidant and/or pro-oxidant role of the polyphenolic herbal tea constituents should be considered in developing preventive strategies against UVB-induced skin carcinogenesis. The indirect removal of UVB damaged keratinocytes by herbal tea extracts via apoptosis may find application in the prevention of photo-induced inflammation.

The potential role of polyphenols in the modulation of skin cell viability by Aspalathus linearis and Cyclopia spp. herbal tea extracts in vitro.

OBJECTIVES: The relationship between polyphenol constituents, antioxidant properties of aqueous and methanol extracts of green tea (Camellia sinensis), the herbal teas, rooibos (Aspalathus linearis) and honeybush (Cyclopia spp.), against skin cell viability was investigated in vitro. METHODS: The effect of extracts, characterised in terms of polyphenol content and antioxidant properties, on cell viability of premalignant, normal and malignant skin cells was determined. KEY FINDINGS: Phenolic composition, particularly high levels of potent antioxidants, of rooibos and green tea methanol extracts was associated with a strong reduction in cell viability specifically targeting premalignant cells. In contrast, the aqueous extracts of Cyclopia spp. were more effective in reducing cell viability. This correlated with a relatively high flavanol/proanthocyanidin content and ABTS radical cation scavenging capacity. The major green tea flavanol (epigallocatechin gallate) and rooibos dihydrochalcone (aspalathin) exhibited differential effects against cell viability, while the major honeybush xanthone (mangiferin) and flavanone (hesperidin) lacked any effect presumably due to a cytoprotective effect. The underlying mechanisms against skin cell viability are likely to involve mitochondrial dysfunction resulting from polyphenol-iron interactions. CONCLUSIONS: The polyphenol constituents and antioxidant parameters of herbal tea extracts are useful tools to predict their activity against skin cell survival in vitro and potential chemopreventive effects in vivo.

Symmetry symptoms in obsessive-compulsive disorder: clinical and genetic correlates

Objective: In obsessive-compulsive disorder (OCD), symmetry-related symptoms may be important. Although clinical correlates of symmetry-related symptoms have been identified in OCD, few data exist on genetic associations. Animal studies indicate involvement of dopamine in symmetry-related behavior, suggesting this may be relevant to analogous symptoms in OCD. Alterations in dopamine may also reflect environmental influences. However, the association of symmetry-related symptomatology, early adversity, and polymorphisms in dopaminergic genes has not been investigated in OCD. Methods: Clinical information and polymorphisms in key dopaminergic genes were compared between OCD patients with primary symmetry symptoms and those without. Results: OCD patients with primary symmetry symptoms comprised 46.6% (n=210) of the sample (n=451), and were older (p < 0.01), had longer illness duration (p < 0.01), higher OCD severity scores (p = 0.01), and greater comorbidity (p < 0.01) than those without. In Caucasians (n=343), genotype frequency differed significantly between groups for ANKK1 rs1800497, with more OCD patients with symmetry symptoms being homozygous for the A2 (CC) genotype (χ2 = 7.296; p = 0.026). Conclusion: Symmetry symptoms have some distinct clinical features and may represent a marker of severity in OCD. However, clinical associations, in combination with the association found with the ANKK1 rs1800497 A2 variant, suggest that primary symmetry symptoms may represent a distinctive clinical and psychobiological profile.

Severe events in the first 6 months of life in a cohort of HIV-unexposed infants from South Africa: effects of low birthweight and breastfeeding status.

OBJECTIVE: To report on risk factors for severe events (hospitalisation or infant death) within the first half of infancy amongst HIV-unexposed infants in South Africa. METHODS: South African data from the multisite community-based cluster-randomised trial PROMISE EBF promoting exclusive breastfeeding in three sub-Saharan countries from 2006 to 2008 were used. The South African sites were Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal. This analysis included 964 HIV-negative mother-infant pairs. Data on severe events and infant feeding practices were collected at 3, 6, 12 and 24 weeks post-partum. We used a stratified extended Cox model to examine the association between the time to the severe event and covariates including birthweight, with breastfeeding status as a time-dependent covariate. RESULTS: Seventy infants (7%) experienced a severe event. The median age at first hospitalisation was 8 weeks, and the two main reasons for hospitalisation were cough and difficult breathing followed by diarrhoea. Stopping breastfeeding before 6 months (HR 2.4; 95% CI 1.2-5.1) and low birthweight (HR 2.4; 95% CI 1.3-4.3) were found to increase the risk of a severe event, whilst maternal completion of high school education was protective (HR 0.3; 95% CI 0.1-0.7). CONCLUSIONS: A strengthened primary healthcare system incorporating promotion of breastfeeding and appropriate caring practices for low birthweight infants (such as kangaroo mother care) are critical. Given the leading reasons for hospitalisation, early administration of oral rehydration therapy and treatment of suspected pneumonia are key interventions needed to prevent hospitalisation in young infants.

Modulating effects of rooibos and honeybush herbal teas on the development of esophageal papillomas in rats.

Widespread consumption of herbal teas has stimulated interest in their role as cancer preventive agents. The present investigation monitored the modulation of methylbenzylnitrosamine (MBN)-induced esophageal squamous cell carcinogenesis by rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) herbal and Camellia sinensis teas in male F344 rats. The tumor multiplicity was significantly (P < 0.05) inhibited by unfermented honeybush (45.5%), green (50%), and black (36%) teas, while the other teas exhibited weaker effects (<30% inhibition). The mean total papilloma size was reduced by unfermented rooibos (87%), unfermented honeybush (94%), and fermented honeybush (74%) due to the absence of large papillomas (>10 mm(3)). Reduction of the mean total papilloma number correlated with the total polyphenol (TPP) (r = 0.79; P < 0.02) and flavanol/proanthocyanidin (FLAVA) (r = 0.89; P < 0.008) intake (mg/100 g body weight) of the teas and the FLAVA (r = 0.89; P < 0.04) and flavonol/flavones/xanthones (r = 0.99; P < 0.002) intake when considering only the herbal teas. A daily TPP intake threshold of 7 mg/100 g body weight existed below where no inhibition of papilloma development was observed. Fermentation of herbal teas reduced the inhibitory effects on papilloma development associated with a reduction in the polyphenolic constituents. The inhibitory effect of herbal teas on papilloma development is associated with different flavonoid subgroups and/or combination thereof.

Chemoprotective properties of rooibos (Aspalathus linearis), honeybush (Cyclopia intermedia) herbal and green and black (Camellia sinensis) teas against cancer promotion induced by fumonisin B1 in rat liver.

The chemoprotective properties of unfermented and fermented rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) herbal teas, and green and black teas (Camellia sinensis) were investigated against fumonisin B1 (FB1) promotion in rat liver utilizing diethylnitrosamine (DEN) as cancer initiator. The various teas differently affected the clinical chemical parameters associated with liver and kidney damage associated with FB1 suggesting specific FB1/iron/polyphenolic interactions. Green tea enhanced (P<0.05) the FB1-induced reduction of the oxygen radical absorbance capacity, while fermented herbal teas and unfermented honeybush significantly (P<0.05) decreased FB1-induced lipid peroxidation in the liver. The teas exhibited varying effects on FB1-induced changes in the activities of catalase, glutathione peroxidase (GPx) glutathione reductase (GR) as well as the glutathione (GSH) status. Unfermented rooibos and honeybush significantly (P<0.05) to marginally (P<0.1) reduced the total number of foci (>10microm), respectively, while all the teas reduced the relative amount of the larger foci. Fermentation seems to reduce the protective effect of the herbal teas. Differences in the major polyphenolic components and certain FB1/polyphenolic/tissue interactions may explain the varying effects of the different teas on the oxidative parameters, hepatotoxic effects and cancer promotion in rat liver.

Inhibition of tumour promotion in mouse skin by extracts of rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia), unique South African herbal teas.

The modulating effect of ethanol/acetone (E/A) soluble fractions, prepared from methanolic extracts of processed and unprocessed rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) as well as green (Camellia sinensis) teas was established in a two-stage mouse skin carcinogenesis assay. Topical application of the tea fractions prior to the tumour promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), on ICR mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) suppressed skin tumorigenesis significantly (P<0.001) with the green tea E/A fraction exhibiting a 100% inhibition, unprocessed honeybush 90%, processed honeybush 84.2%, processed rooibos 75% and unprocessed rooibos 60%. The green tea fraction, with the highest flavanol/proanthocyanidin content, also exhibited the highest protective activity (99%) against hepatic microsomal lipid peroxidation, and completely inhibited skin tumour formation. Differences in the flavanol/proanthocyanidin and flavonol/flavone composition and/or non polyphenolic constituents are likely to be important determinants in the inhibition of tumour promotion by the herbal tea E/A fractions in mouse skin.

Disruption of sphingolipid biosynthesis in hepatocyte nodules: selective proliferative stimulus induced by fumonisin B1.

In order to investigate the role of sphingolipid disruption in the cancer promoting potential of fumonisin B(1) (FB(1)) in the development of hepatocyte nodules, male Fischer 344 rats were subjected to cancer initiation (FB(1) containing diet or diethylnitrosamine (DEN) by i.p. injection) and promotion (2-acetylaminofluorene with partial hepatectomy, 2-AAF/PH) treatments followed by a secondary FB(1) dietary regimen. Sphinganine (Sa) and sphingosine (So) levels were measured by high performance liquid chromatography in control, surrounding and nodular liver tissues of the rats. The disruption of sphingolipid biosynthesis by the secondary FB(1) treatment in the control rats was significantly (P < 0.05) enhanced by the 2-AAF/PH cancer promotion treatment. The nodular and surrounding Sa levels returned to baseline following FB(1) initiation and 2-AAF/PH promotion. When comparing the groups subjected to the secondary FB(1) treatment, the initiation effected by FB(1) was less (P < 0.01) sensitive to the accumulation of Sa in the nodular and surrounding tissues than DEN initiation and the 2-AAF/PH control treatment. In contrast, the So level of FB(1) initiation was marginally increased in the nodules compared to the surrounding liver after 2-AAF/PH promotion and significantly (P < 0.05) higher with the secondary FB(1) treatment. Although, the FB(1)-induced hepatocyte nodules were not resistant to the disruption of sphingolipid biosynthesis, the nodular So levels were increased and might provide a selective growth stimulus possibly induced by bio-active sphingoid intermediates such as sphingosine 1-phosphate (S1P).

Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study.

Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor alpha inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study. The purpose of the present study was to assess the effect of adjunctive thalidomide in addition to standard antituberculosis and corticosteroid therapy on the outcome of tuberculous meningitis. Thalidomide (24 mg/kg/day orally) or placebo was administered in a double-blind randomized fashion for 1 month to patients with stage 2 or 3 tuberculous meningitis. The study was terminated early because all adverse events and deaths occurred in one arm of the study (thalidomide group). Thirty of the 47 children enrolled received adjunctive thalidomide, of whom 6 (20%) developed a skin rash, 8 (26%) hepatitis, and 2 (6%) neutropenia or thrombocytopenia. Four deaths (13%) occurred in patients with very severe neurologic compromise at baseline; two deaths were associated with a rash. Motor outcome after 6 months of antituberculosis therapy was similar in the two groups, even though the thalidomide group showed greater neurologic compromise on admission. In addition, the mean IQ of the two treatment groups did not differ significantly (mean IQ thalidomide group 57.8 versus mean IQ control group 67.5; P = .16). These results do not support the use of adjunctive high-dose thalidomide therapy in the treatment of tuberculous meningitis.

Cancer patterns in four districts of the Transkei region--1991-1995.

BACKGROUND: Oesophageal cancer (OC) is an important public health problem among the Xhosa-speaking people of the Transkei region in the Eastern Cape Province, South Africa, with incidence rates for males among the highest in the world. OBJECTIVES: To record the occurrence of cancer among men and women of all ages in four districts in the Transkei during the period 1991-1995, to identify common cancers and to compare the variations in cancer incidences in this region with incidences in Africa and the rest of the world. DESIGN: Cancer registration of cases reported from all clinics and hospitals was conducted in the four selected districts. SETTING: The districts included Centane (Kentani), Butterworth, Bizana and Lusikisiki in the Transkei region. METHODS: Active and passive methods were used to collect data, which were analysed using the Statistical Analyses Systems (SAS) package. RESULTS: The mean annual number of all cancer cases reported was 310, with age-standardised incidence rates (ASIRs, world standard) of 98.2/100,000 and 74.3/100,000 for males and females, respectively. The most frequently reported cancer was OC, with mean annual ASIRs of 76.6/100,000 and 36.5/100,000 for males and females, respectively, with a male/female ratio of 2:1. CONCLUSION: The present data confirm previous reports that OC rates in Centane have consistently remained very high, whereas time-dependent changes in the incidence of OC have occurred in Butterworth, Bizana and Lusikisiki suggesting changes in the risk determinants in these districts.

Oesophageal and other cancer patterns in four selected districts of Transkei, Southern Africa: 1985-1990.

New data regarding the incidence of oesophageal and other cancers during the period 1985-1990 are reported for all clinics and hospitals in four selected districts of Transkei, Southern Africa i.e Kentani, Butterworth, Lusikisiki and Bizana. Active and passive methods were used to obtain the hospital-based cancer registry data. The mean annual number of cancer cases recorded for the period 1985-1990 was 292. Age-standardized incidence rates (ASIIR, African Standard) for all recorded cancers were 81.4 and 52.6/100,000 for males and females, respectively. Histopathogical examination of 52.6% of recorded tumours revealed that 67.3% were squamous carcinomas, 21.7% adenocarcinomas and the remainder non-epithelial neoplasms. Cancer of the oesophagus (EC) was the most frequently recorded cancer and accounted for 46.5% of the cases with mean ASIR of 46.7 and 19.2/100,000 for males and females, respectively. The male/female ratio was 2:4:1. The highest mean ASIR per annum for OC in males (55.6/100,000) occurred in Kentani and in females (22.3/100,000) in Lusikisiki, whereas the lowest rates in both sexes (37.0 and 11.7/100,000 respectively) occurred in Bizana. Comparison of the OC rates in the four districts of Transkei during 1985-1990 with previously reported trends, confirms a consistently high rate in the south-western district of Kentani during the past 35 years and progressively increasing rates in the north-eastern districts of Bizana and Lusikisiki. These results have profound implications for further epidemiological and aetiological studies on OC in Transkei, but need to be corroborated by data from other sources such as statistics on histologically diagnosed cancer in Transkei by district in the South African National Cancer Registry. The second most frequently recorded cancer among males was liver cancer with a mean annual ASIR of 6.0/100,0000 and a male: female ratio of 3:1. The most frequently recorded cancer with a mean annual AISR of 20.9/100,000 followed by OC (19.2/100,000) and breast cancer (5.8/100,000).