Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by anthrones

The present study was designed to compare the skin tumor promotingand epidermal ornithine decarboxylase (ODC) inducing activitiesof various structural analogs of anthralin (1, 8-dihydroxy-9-anthrone)and chrysarobin (1, 8-dihydroxy-3- methyl-9-anthrone). Groupsof 30 SENCAR mice each were initiated with 7, 12-dimethylbenz[a]anthraceneand 2 weeks later promoted with once- or twice-weekly applicationsof various doses of these anthrone derivatives. Carbon-10 (C₁₀)-acylderivatives of anthralin were active skin tumor promoters inthe range of 25–440 nmol per mouse. 10-Acetylanthralinwas significantly more active than 10-myristoyl-anthralin atlow doses (e.g. 25 and 50 nmol per mouse) and nearly as potentas the unsubstituted compound. Higher doses ( 100 nmol per mouse)of this derivative were toxic, hence, reducing the final papillomaresponse. On a relative activity scale where anthralin is 1.0,these derivatives had activities that were 0.7 and 0.2, respectively.10, 10-Dipropylanthralin was totally inactive at the doses tested.C⁶-Substituted derivatives of chrysarobin demonstrated diversetumor promoting activities when tested in the range of 25–440nmol per mouse. On a relative activity scale where chrysarobinis 1.0, 6-methoxychrysarobin (physcion anthrone) was 0.9, whereas6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanicacid (1, 8-dihydroxy-3-methyl-9, 10-anthraquinone) was alsoinactive as a tumor promoter at the doses tested. In general,the tumor promoting activities of these anthrone derivativescorrelated very well with their ability to induce epidermalODC after a single topical application indicating an importantrole for this enzyme in skin tumor promotion by anthones. Theability of C₁₀-substituted derivatives of anthralin to undergobase catalyzed oxidation in vitro correlated with both ODC inducingand tumor promoting activities. In addition, copper(II) bis(diisopropylsalicylate)was found to inhibit both ODC induction and skin tumor promotionby chrysarobin. These latter data, when taken together, suggesta role for oxidation at C₁₀ in skin tumor promotion by anthronederivatives.     

Seasonal prevalence of major congenital malformations in the Fylde of Lancashire 1957-1981.

The seasonal prevalence of major congenital malformations was studied in a prospective survey of 88,449 children born in the circumscribed Fylde of Lancashire to residents there over 25 years. Ascertainment was thought to be as complete as was practically possible because cases were recorded daily by one, and for 17 years the only, paediatrician and a very high rate of necropsies was maintained. The number of malformations were classified by month of maternal last menstrual period and seasonal variation was assessed by three statistical models. Neural tube defects showed a significant seasonal variation in month of last menstrual period but not in month of birth. From May 1956 to April 1968, when the prevalence of neural tube defects was high (5.5 per 1000 total births), conceptions were significantly more common in December to May. For anencephaly alone the figures were not significant, but spina bifida and cranium bifidum were more common in March to May. From May 1968 to April 1981, when the prevalence of neural tube defects fell below the national average, the significant variations disappeared. Seasonality for spina bifida and cranium bifidum was seen only in "singles" (cases with no other major lesion), but for anencephaly it was seen only in "multiples" (cases with other lesions). The three types of cardiac septal defect and persistent ductus each showed a higher prevalence of conceptions at some time during May to October. In contrast the commonest group of cyanotic cases showed no such pattern but with greater numbers in winter. There was evidence of a seasonal variation for bilateral renal agenesis and for vesicoureteric reflux as ascertained. Seasonal prevalence in an aetiological factor for certain malformations of the central nervous system, cardiac and urinary systems.     

Novel mutations in type 2 Gaucher disease in Chinese and their functional characterization by heterologous expression

We investigated 10 unrelated Chinese patients with type 2 Gaucher disease and performed ex vivo expression for the novel mutations to characterize their functional defects. These patients were diagnosed by enzymatic assays and clinicopathologic features over the past five years in a national centre in China. Genomic DNA was sequenced by a two-stage PCR approach for mutations in the functional GBA gene. Novel mutations were expressed with baculovirus-transfected Sf21 cells. Six novel mutations were found (in traditional nomenclature): P122L, Y363C, N382K, L383R, L385P, and M416V. Review of reported mutations indicated clustering of type 2 mutations in three regions of the GBA gene. Expression of novel mutations revealed that the enzyme defect could arise from one of two mechanisms: loss of catalytic activity (Y363C and M416V) or enzyme instability (P122L and N382K).     

Effects of long working hours and the night shift on severe sleepiness among workers with 12‐hour shift systems for 5 to 7 consecutive days in the automobile factories of Korea

We investigated the effects of 12‐hour shift work for five to seven consecutive days and overtime on the prevalence of severe sleepiness in the automobile industry in Korea. [Correction added after online publication 28 Nov: Opening sentence of the summary has been rephrased for better clarity.] A total of 288 randomly selected male workers from two automobile factories were selected and investigated using questionnaires and sleep‐wake diaries in South Korea. The prevalence of severe sleepiness at work [i.e. Karolinska Sleepiness Scale (KSS) score of 7 or higher] was modeled using marginal logistic regression and included theoretical risk factors related to working hours and potential confounding factors related to socio‐economic status, work demands, and health behaviors. Factors related to working hours increased the risk for severe sleepiness at the end of the shift in the following order: the night shift [odds ratio (OR): 4.7; 95% confidence interval (CI): 3.6–6.0)], daily overtime (OR: 2.2; 95% CI: 1.7–2.9), weekly overtime (OR: 1.6; 95% CI: 1.0–2.6), and night overtime (OR: 1.6; 95% CI: 0.8–3.0). Long working hours and shift work had a significant interactive effect for severe sleepiness at work. Night shift workers who worked for 12 h or more a day were exposed to a risk of severe sleepiness that was 7.5 times greater than day shift workers who worked less than 11 h. Night shifts and long working hours were the main risk factors for severe sleepiness among automobile factory workers in Korea. Night shifts and long working hours have a high degree of interactive effects resulting in severe sleepiness at work, which highlight the need for immediate measures to address these characteristics among South Korean labor force patterns.     

The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity

Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE(-/-)/RAG-2(-/-) with bone marrow from immunocompetent ApoE(-/-)/RAG-2(+/+) mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE(-/-) mice deficient in selective T-lymphocyte subsets (either TCRalphabeta+, CD4+, CD8+, or TCRgammadelta+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE(-/-) mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.     

Pathogenesis of fever in delayed hypersensitivity: factors influencing release of pyrogen-inducing lymphokines.

In continuing studies on the pathogenesis of fever in states of delayed hypersensitivity, we have investigated the conditions for the release of an endogenous pyrogen (EP)-inducing lymphokine from draining-lymph-node lymphocytes of rabbits with delayed hypersensitivity to bovine gamma globulin. Using doses of 4 X 10(7) to 5 X 10(7) blood leukocytes (BL) as a source of EP, we found that ratios of about 5:1 of viable lymphocytes to BL were required to stimulate the BL to produce detectable amounts of EP in vitro. Both irradiated lymphocytes (1,700 R) as well as those from steroid-treated donors retained their ability to activate BL when incubated with antigen, properties consistent with activated "T" lymphocytes. In experiments to determine effects of temperature and duration of incubation on lymphokine release, the maximum EP-releasing activity was found to be present in supernatants of sensitized lymphocytes incubated with antigen for 18 h at 37 degrees C. These studies have confirmed that sensitized lymphocytes release a soluble, pyrogen-inducing lymphokine when incubated with antigen and further demonstrate that tissue macrophages (Kupffer cells) as well as BL can be activated to produce EP in vitro by this agent.     

Neuromuscular adaptations in rats trained by muscle stretch-shortening

The aim of this study was the analysis of neurophysiological, mechanical and histochemical parameters to demonstrate muscle adaptation with training. If the parameters studied were to show correlated changes, it would be possible to propose that the neural and the muscle components of motor units are both affected by the training programme used. The training consisted of repeated stretch-shortening cycles known to use extensively fast fibres. After the training period electromyographical reflex activities of the ankle plantar-flexors were recorded in awake rats and then mechanical and histochemical measurements were made on isolated soleus muscles of the control and trained rats. The reflexes studied were the H-response to electrical stimulation of the sciatic nerve and the T-response to an Achilles tendon tap. The H-response analysis indicated a decrease in reflex excitability of the trained muscles. The trained soleus muscle also presented a higher contractility as demonstrated by significantly smaller twitch contraction times and higher maximal velocities of shortening measured during tetanic contractions. The reflex and contractile muscle changes were accompanied by relative increases in the number of type II fibres. The T-response was not significantly modified by training despite the decrease in motoneuron excitability demonstrated by the decrease in H-response. This would suggest that the peripheral components of the reflex pathway such as tendon stiffness and/or spindle sensitivity might be modified by training. This would imply that both the motor and the sensory parts of a muscle are affected by training.     

In vivo seasonal assessment of Plasmodium falciparum sensitivity to chloroquine in two different malaria endemic communities in Southern Ghana

A two year (1992 to 1993) in vivo assessment of Plasmodium falciparum sensitivity to chloroquine was conducted in two communities at Dodowa (hyperendemic) and Prampram (mesoendemic) in Southern Ghana. A slightly modified World Helath Organization standard field test (7 day test) for response of Plasmodium falciparum asexual parasites to chloroquine was used for the survey. In 1992, 16.2% (12/74) responses were classified as exhibiting chloroquine resistance at RI (14.8% ) and RII (1.4%) in the dry season and 8.2% (10/122) responses at RI in the wet season in the hyperendemic community. Only a single response (1/144; 0.7%) at RI showed resistance in the mesoendemic community. The rest of the responses in both communities were classified as sensitive to chloroquine. In the hyperendemic community, 8.4% (13/154) of responses in the dry season showed resistance at RI and 1.3% (82/150) at RI (0.7%) and RII (0.7%) in the wet season in 1993. In the mesoendemic community 1 (1.0%) response was resistant at RI in the wet season. The rest of the responses were classified as sensitive responses to chloroquine. No RIII response was encountered in any of the communities. The pattern of RI and RII responses did not show any seasonal variations in the mesoendemic community. However, they were generally higher in the dry season than in the wet season in the hyperendemic community.