Synthesis and Antiviral Properties of Arabino and Ribonucleosides of 1,3‐Dideazaadenine, 4‐Nitro‐1, 3‐dideazaadenine and Diketopiperazine

Different arabinosides and ribosides, viz. Ara‐DDA or 9(1‐β‐d‐arabinofuranosyl) 1,3‐dideazaadenine (6), Ara‐NDDP or 9(1‐β‐d‐arabinofuranosyl) 4‐nitro‐1,3‐dideazapurine (7), Ara‐DKP or 1(1‐β‐d‐arabinofuranosyl) diketopiperazine (8), Ribo‐DDA or 9(1‐β‐d‐ribofuranosyl) 1,3‐dideazaadenine (9) and Ribo‐NDDP or 9(1‐β‐d‐ribofuranosyl) 4‐nitro‐1,3‐dideazapurine (10) have been synthesized as probable antiviral agents. The arabinosides have been synthesized using the catalyst TDA‐1 that causes stereospecific formation of β‐nucleosides while a one‐pot synthesis procedure was adopted for the synthesis of the ribonucleosides where β‐anomers were obtained in higher yields. All the five nucleoside analogs have been screened for antiviral property against HIV‐1 (III_B), HSV‐1 and 2, parainfluenza‐3, reovirus‐1 and many others. It was observed that arabinosides had greater inhibitory action than ribosides. The compound 7 or Ara‐NDDP has shown maximum inhibition of HIV‐1 replication than the rest of the molecules with an IC₅₀ of 79.4 µg/mL.     

Design,Efficient Synthesis,and Anti‐HIV Activity of 4′‐C‐Cyano‐ and 4′‐C‐Ethynyl‐2′‐deoxy Purine Nucleosides

Some 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides showed the most potent anti‐HIV activity among the series of 4′‐C‐substituted 2′‐deoxynucleosides whose 4′‐C‐substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show. Thus, 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′‐C‐cyano‐2′‐deoxy purine nucleosides (4′‐CNdNs) and 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides (4′‐EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′‐deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C‐4′ position of the sugar moiety from 2′‐deoxyadenosine and 2,6‐diaminopurine 2′‐deoxyriboside. Unfortunately, 4′‐C‐cyano derivatives showed lower activity against HIV‐1, and two 4′‐C‐ethynyl derivatives suggested high toxicity in vivo.     

24‐Hour,Weekly, and Annual Patterns in Traumatic and Non‐Traumatic Surgical Pediatric Emergencies

24 h patterns with high frequency components in the incidence of pediatric trauma were validated and quantified in one of our earlier studies. Herein, we further explored the temporal—high frequency, 24 h, weekly (7 d), hemi‐weekly (3.5 d), and annual – patterns in traumatic (1990–1997; n=15,110 events) and non‐traumatic pediatric surgical emergencies (PSE) (1992–2001; n=5,593 events) as well as automobile accidents (AA) (1990–1997; n=67,712) in the County of Vaud, Switzerland. The latter served as a reference system of human adult activity and risk. Two‐way ANOVA, χ2, correlation, and cosinor analyses were used as statistical tools. A 24 h pattern, reproducible from year to year, was validated in traumatic and non‐traumatic PSE and AA. The 24 h patterns were not correlated and differed from one another in terms of their acrophase (peak time) and amplitude. A gender‐related difference was found only in the non‐traumatic time series for weekly (7 d) and hemi‐weekly (3.5 d) patterns. The latter were detected in boys but not girls. No statistically significant difference was found in the acrophase and amplitude between boys and girls in the temporal patterns of other periods. An annual pattern was validated in automobile accidents (acrophase: 4th of September ±37 d (SD)) and pediatric trauma (acrophase: 14th of June ±10 d), but not in non‐traumatic PSE. These results suggest that environmental modulations differ between the incidence of traumatic and non‐traumatic PSE. Presumably, the two phenomena involve different aspects of the temporal organization and/or different levels of susceptibility of a set of biological rhythms to environmental factors.     

Thiosugar Nucleosides. Synthesis and Biological Activity of 1,3,4‐Thiadiazole,Thiazoline and Thiourea Derivatives of 5‐Thio‐d‐Glucose

New acylated 5‐thio‐β‐d‐glucopyranosylimino‐disusbstituted 1,3,4‐thiadiazols 8, and 11 were prepared, via spontaneous rearrangements, by cycloaddition of the glycosyl isothiocyanate 2 with the reactive intermediates 1‐aza‐2‐azoniaallene hexachloroantimonates 4 and 6, respectively. Reaction of 2 with aminoacetone or chloroethylamine afforded the acylated 5‐thio‐β‐d‐glucopyranosyl‐4‐imidazoline‐2‐thione nucleoside 16 and glucopyranosylamino‐2‐thiazoline derivative 18, respectively. Deblocking of 8, 11, 17 and 19 furnished the free nucleoside analogues 9, 12, 18 and 20, respectively. Analogously, treatment of 2 with chloroethylamine in the 1:2 ratio afforded the thioureylendisaccharide 21. No in vitro antiviral activity against HIV‐1, HIV‐2, human cytomegallovirus (HMCV), has been found for the new synthesized compounds.     

Sex Difference in Sleep‐Time Preference and Sleep Need: A Cross‐Sectional Survey among Italian Pre‐Adolescents,Adolescents, and Adults

The aim of this study was to examine sex differences in sleep‐time preference by age among Italian pre‐adolescents, adolescents, and adults. The final sample consisted of 8,972 participants (5,367 females and 3,605 males) from 10 to 87 yrs of age. To assess preferred sleep habits, we considered the answers to the open‐ended questions of the Morningness‐Eveningness Questionnaire (MEQ). In agreement with previous studies, we found that sleep‐time preference started to shift toward eveningness from the age of 13 yrs. Females reached their peak in eveningness earlier (about 17 yrs of age) than males (about 21 yrs of age). Thereafter, the ideal sleep‐time preference advanced in men and women with increasing age. Females presented a more significant advanced sleep phase than males only during the years when sexual hormones are typically active. Moreover, females reported a longer ideal sleep duration than males across all age groups examined, except in over 55 yrs one. (Author correspondence: vincenzo.natale@unibo.it)     

Building‐Site Camps and Extended Work Hours: A Two‐Week Monitoring of Self‐Reported Physical Exertion,Fatigue, and Daytime Sleepiness

Large‐scale construction work often requires people to work longer daily hours and more than the ordinary five days in a row. In order to minimize transportation times and optimize the use of personnel, workers are sometimes asked to live in temporary building‐site camps in the proximity of the work site. However, little is known about the biological and psychological effects of this experience. The objective of the present study was to investigate whether exposure to long work hours and extended workweeks while living in building‐site camps in between work shifts was associated with a build‐up of increased complaints of poor sleep, daytime sleepiness, physical exertion, and fatigue across a two‐week work cycle. Two groups of construction workers were examined. The camp group of 13 participants (mean age: 42±11 S.D. yrs) lived in building‐site camps and worked extended hours (between 07:00 and 18:00 h) and extended workweeks (six days in a row, one day off, five days in a row, nine days off). The home group of 16 participants (mean age 40±9 yrs) worked ordinary hours between 07:00 and 15:00 h and returned home after each workday. Self‐ratings of daytime sleepiness (Karolinska Sleepiness Scale), physical exertion (Borg CR‐10), and mood were obtained six or seven times daily during two workweeks. Fatigue ratings were obtained once daily in the evening, and ratings of sleep disturbances were obtained once daily in the morning with the Karolinska Sleep Diary. Data were evaluated in a repeated measures design. The results showed that both groups reported a similar level of daytime sleepiness, physical exertion, and mood across workdays and time points within a workday (all three‐way interactions had p>0.898). Although the home group reported earlier wake‐up times, the pattern of sleep disturbance ratings across the workdays did not differ between the groups. Both groups reported few sleep disturbances and good mood. However, the camp group reported higher physical exertion already at the start of work and showed a more gentle increase in ratings during the work shift and a smaller decline between the end of work and bedtime. The camp group also reported higher fatigue scores than the home group. However, none of the groups showed signs of increasing ratings in the progress of the two workweeks. For both groups, the ratings of daytime sleepiness formed a U‐shaped pattern, with the highest scores at awakening and at bedtime. Yet, the camp group reported higher daytime sleepiness than the home group at lunch break and at the second break in the afternoon. In conclusion, there were no signs of fatigue build‐up or accumulation of daytime sleepiness, physical exertion, or sleep disturbances in either group. Despite the fact that the camp group showed some signs of having trouble in recuperating in between work shifts, as indicated by the higher physical exertion ratings at the start of work, higher fatigue scores, and higher daytime sleepiness, the results constitute no real foundation for altering the camp group's current work schedule and living arrangements.     

Ethnography,Orientalism and the avant‐garde film

Drawing on the work of Edward Said and James Clifford, this article discusses the theoretical and practical possibilities for producing images of “otherness” which do not participate in an Orientalist discourse. Works by two avant‐garde filmmakers, Leslie Thornton and Trinh T. Minh‐ha, are examined in the light of these theoretical discussions. While avant‐garde film practice is no guarantee of escaping the pitfalls of Orientalism or cultural relativism, selective viewing of avant‐garde work may provide useful models for visual production.     

Individualism,self‐control,and the Finnish temperance movement*

This article analyzes the role of self‐control, moral and ethical doctrines in the rise of individualist world‐view in Finland. In the Finnish case, the formation of the modern individual was closely linked with the temperance movement, the ideology of which is therefore used as an illustrative example. The guiding line in the article is not to treat self‐control as a theoretical concept used in analyzing individual behavior, but as a legitimation of an increasing use of a utilitarian framework. The author discusses the developments in Finnish individualist world‐view by analyzing the main turning points in Finnish notions about drinking. First he discusses the end of the 19th century and the beginning of the 20th century, the era of the strength of Finnish temperance movement. Secondly he analyzes the way in which conceptions about drinking changed when the temperance movement lost its appeal to the masses.     

Synthesis and Biological Evaluation of Novel Apio Nucleosides with Thiazole‐4‐carboxamide and 1,2,4‐Triazole‐3‐carboxamide

In view of biological activities of azole nucleosides and apio‐dideoxynucleoside, novel apio nucleoside analogues (1 and 2) with thiazole and triazole base moiety were synthesized using 2,3‐O‐isopropylidene‐apio‐β‐d‐furanose (3), which was prepared from d‐mannose.     

Density‐dependent parasitism in biological control of soil‐borne insects,nematodes, fungi and bacteria

Temporal density‐dependent parasitism appears to explain the development of some pest‐ and pathogen‐suppressive soils. In many examples, an enrichment of hosts (soil‐borne pests or pathogens) precedes and supports a build up of beneficial parasites in perennial crops or in monocultures, and the population dynamics of hosts and parasites may be described in epidemiological terms. Although the examples support the concept of a balance of nature based on density‐dependent regulation, we lack detailed understanding of the processes that drive these beneficial epidemics. In addition, the epidemics develop slowly and often do not provide the control expected by farmers. Current research, therefore, emphasizes inundative release of beneficial agents. Nevertheless, we should study epidemics in soil in order to learn how they might be enhanced; to learn how better to utilize inoculum that is inundatively added to soil; and to contribute to the general discussion of population biology and regulation.     

Intra‐ethnic and inter‐ethnic marriage and divorce in Hawaii

Abstract

A comparison of intra‐ and inter‐ethnic divorce rates in Hawaii showed that inter‐ethnic marriages resulted in a higher proportion of divorces than did intra‐ethnic marriages when the marriage data used had to do with all marriages occurring in Hawaii. However, a sizeable portion of marriages in Hawaii are of nonresidents who, if they divorce, probably divorce elsewhere. Nonresident marriages are chiefly intra‐ethnic marriages of Caucasians. When examining the proportions of divorces to resident marriages, within‐group marriages are more at risk than inter‐ethnic marriages. As in prior research, persons who marry members of other racial/ethnic groups tend to marry persons from groups with income levels similar to their own. As in previous reports, some cross‐ethnic combinations appeared more at risk for divorce than did others. Group income appeared to be a predictor of risk. When considering only resident marriages as related to divorces, those marriages in which the bride was from a higher income group than the groom were at a significantly greater risk for divorce than marriage in which the bride came from an income group lower than that of the groom.     

Age‐Related Differences in the Lifestyle Regularity of Seniors Experiencing Bereavement,Care‐Giving,Insomnia, and Advancement Into Old‐Old Age

Compared to younger adults, seniors (≥60 yrs) often adopt a highly regular lifestyle, perhaps as an adaptive response to age‐related changes in their sleep and circadian rhythms. At baseline, diary measures of lifestyle regularity (SRM‐5) were obtained from 104 seniors of three separate groups. Thirty‐three subjects were challenged by spousal bereavement or the need to care for a spouse at home with dementia (Challenged); 33 were suffering from formally diagnosed (DSM‐IV) insomnia (Insomnia); and 38 were healthy, well‐functioning older seniors in the second half of their eighth decade of life or later (Healthy Older). The objective of this study was to determine whether lifestyle regularity increased as a function of age within each of these three senior groups. Overall, age was significantly correlated with SRM‐5 (r=0.41, p<0.001), with the SRM score increasing by 0.67 units/decade. The same was true for the Challenged and Insomnia groups, which also showed a significant correlation between SRM and age (Challenged: r=0.48, p<0.01; Insomnia: r=0.36, p<0.05), though with a slightly faster rate of SRM increase in the Challenged (0.95 units/decade) than Insomnia (0.55 units/decade) group. Perhaps there was no correlation between age and SRM (r=0.07, n.s.) in the Healthy Older group due to the small age range, although this group did have a higher overall SRM score than the other two groups (p<0.01). The study thus confirmed that the previously observed increase in lifestyle regularity over the adult lifespan persists into later life. This may represent an adaptive behavioral response that might be used in future therapeutic approaches.     

Complement activation,regulation, and molecular basis for complement‐related diseases

The complement system is an essential element of the innate immune response that becomes activated upon recognition of molecular patterns associated with microorganisms, abnormal host cells, and modified molecules in the extracellular environment. The resulting proteolytic cascade tags the complement activator for elimination and elicits a pro‐inflammatory response leading to recruitment and activation of immune cells from both the innate and adaptive branches of the immune system. Through these activities, complement functions in the first line of defense against pathogens but also contributes significantly to the maintenance of homeostasis and prevention of autoimmunity. Activation of complement and the subsequent biological responses occur primarily in the extracellular environment. However, recent studies have demonstrated autocrine signaling by complement activation in intracellular vesicles, while the presence of a cytoplasmic receptor serves to detect complement‐opsonized intracellular pathogens. Furthermore, breakthroughs in both functional and structural studies now make it possible to describe many of the intricate molecular mechanisms underlying complement activation and the subsequent downstream events, as well as its cross talk with, for example, signaling pathways, the coagulation system, and adaptive immunity. We present an integrated and updated view of complement based on structural and functional data and describe the new roles attributed to complement. Finally, we discuss how the structural and mechanistic understanding of the complement system rationalizes the genetic defects conferring uncontrolled activation or other undesirable effects of complement.     

Origin, functions and chemistry of H‐2 regulated odorants

Genes located within the major histocompatibility complex (MHC) of mice are responsible for individual differences in body odor (odortypes). In this review we suggest that the MHC genes themselves are responsible for odor differences among MHC‐congenic mice. Recent studies indicating that volatile carboxylic acids are at least in part responsible for the individual odors and what this finding implies about the pathway from gene to odorant are also reviewed. We suggest that odorants or their precursors are bound directly by MHC products and are released into serum and concentrated in urine. Finally, possible functions of MHC odortypes in mice are enumerated and important future research questions are raised. This revised version was published online in July 2006 with corrections to the Cover Date.     

Reproductive and socioeconomic determinants of child survival: Confounded,interactive, and age‐dependent effects

Abstract

Studies of infant and child mortality have evolved to distinguish between two sets of explanatory variables—factors related to reproductive or maternal characteristics and socioeconomic factors, generally described as characteristics of the family or household. Almost all multivariate analyses include variables from each of these two sets, but there has been little consideration of the relationship between them. We examine how these two sets of variables jointly affect mortality. We test first for confounded effects by examining socioeconomic effects while excluding and then including reproductive variables in nested multivariate models. Next, we look for age‐dependent effects among the explanatory variables and find that reproductive and socioeconomic factors affect mortality at differing ages of children. Finally, we examine interactive effects of the two sets of variables. We conclude that the higher mortality observed among the low status groups is not a result of greater concentration of poor reproductive patterns in those groups. Instead, higher status groups probably have more resources available for combating the negative effects of the same high‐risk reproductive patterns.     

Citizenship,ethnicity and multiculturalism: Post‐national membership between Utopia and reality

Neil Bissondath, SELLING ILLUSIONS: THE CULT OF MULTI‐CULTURALISM IN CANADA, Toronto: Penguin Books Canada, 1994, 234 pp., $16.99 (paper).

David A. Hollinger, POSTETHNIC AMERICA: BEYOND MULTI‐CULTURALISM, New York: Basic Books, 1995, 210 pp., $22.00

Will Kymlicka, MULTICULTURAL CITIZENSHIP, Oxford: Oxford University Press, 1995, 280 pp., npl.

Yasemin Nuhoglu Soysal, LIMITS OF CITIZENSHIP: MIGRANTS AND POSTNATIONAL MEMBERSHIP IN EUROPE, Chicago: Chicago University Press, 1994 (paper), npl.     

Synthesis, 18F‐Radiolabelling and Biological Evaluations of C‐6 Alkylated Pyrimidine Nucleoside Analogues

Synthesis of pyrimidine derivatives with a side‐chain attached to the C‐6 of pyrimidine ring (6–14) is reported. Target compounds 8 and 12 were subjected to in vitro phosphorylation tests, determination of their binding affinities to herpes simplex virus (HSV‐1) thymidine kinase (TK) and catalytic turnover constants. Fluorinated pyrimidine derivative 12 (40 µM) exhibited better binding affinity for HSV‐1 TK than acyclovir (ACV, 170 µM) and ganciclovir (GCV, 48 µM). Catalytic turnover constant (k _cat) of 12 (0.08 s^? 1) was close to the k _cat values of ACV (0.10 s^? 1) and GCV (0.10 s^? 1). Furthermore, compounds 8 and 12 showed no cytotoxic effects in HSV‐1 TK‐transduced and non‐transduced cell lines. Besides, compounds 8 and 12 did not exhibit antiviral or cytostatic activities against several viruses and malignant tumor cell lines that were evaluated. The new fluorinated pyrimidine derivative 16 that is phosphorylated by HSV‐1 TK could be developed as non‐toxic PET‐tracer molecule. Thus, ¹⁸F labelling of the precursor 14 was performed by nucleophilic substitution using [¹⁸F] tetrabutylammonium fluoride as the fluorinating reagent.     

Relationships between pregnancy spacing,sex of infants,maternal age,and birth order,and neonatal and post‐neonatal mortality in Bangladesh

Abstract

The relationships between length of the interpregnancy interval, outcome of the pregnancy preceding the interval, sex of the infants, pregnancy order, maternal age, and maternal history of previous child deaths and neonatal and postneonatal mortality were explored in a rural Bangladeshi population using a multiple regression analysis. Specific interactions between the interpregnancy interval, outcome of the pregnancy preceding the interval, sex of the infants, and history of previous child deaths were examined. An inverse relationship was observed between postneonatal mortality and the length of the interpregnancy interval when the pregnancy preceding the interval was a surviving infant. No such trend was observed for neonatal mortality. Post‐neonatal mortality rates among children whose mothers had experienced two or more previous child deaths were essentially the same as that for infants whose mothers had experienced 0–1 child deaths when the interpregnancy intervals were more than 24 months. Although female infants have a lower neonatal mortality than male infants, the neonatal mortality rate for female infants conceived less than twelve months following a male infant birth was higher than for a male infant conceived less than twelve months following another male infant birth. Post‐neonatal mortality is consistently higher for female compared to male infants in all interval categories.     

Farm background,socioeconomic status,and fertility: The two‐generation hypothesis

Abstract

This paper reports on an examination of whether the effects of farm background on socioeconomic differentials in fertility are diminished among nonfarm couples. The data are for a sample of white ever‐married women belonging to the 1901–1910 birth cohorts. The research provides another test of the two‐generation‐urbanite hypothesis first advanced by Goldberg. Unlike a number of other studies, the findings do not support the hypothesis. Reasons for the lack of support are discussed, and methodological weaknesses of previous studies are identified.