Divergent Effects of Ocean Warming On Byssal Attachment in Two Congener Mussel Species.

Organisms rely on the integrity of the structural materials they produce to maintain a broad range of processes, such as acquiring food, resisting predators or withstanding extreme environmental forces. The production and maintenance of these biomaterials, which are often modulated by environmental conditions, can therefore have important consequences for fitness in changing climates. One well-known example of such a biomaterial is mussel byssus, an array of collagen-like fibers (byssal threads) that tethers a bivalve mollusk securely to benthic marine substrates. Byssus strength directly influences mortality from dislodgement, predation or competition and depends on the quantity and quality of byssal threads produced. We compared the temperature sensitivity of byssal attachment strength of two mussel species common to the west coast of North America, Mytilus trossulus and M. galloprovincialis, when exposed to seawater temperatures ranging from 10 to 24˚C in the laboratory. We found the two species attached equally strong in seawater ≤ 18˚C, but higher temperatures caused byssal thread production rate and quality (break force and extensibility) to be greatly reduced in M. trossulus and increased in M. galloprovincialis, leading to a 2 to 10-fold difference in overall byssus strength between the two species. Using this threshold value (18˚C), we mapped habitat for each species along the west coast of North America based on annual patterns in sea surface temperature. Estimated ranges are consistent with the current distribution of the two species and suggest a potential mechanism by which ocean warming could facilitate the northern expansion of M. galloprovincialis and displacement of native M. trossulus populations.

A diagnosis of prostate cancer and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment.

BACKGROUND: Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss. METHODS: Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation. RESULTS: After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ2 test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight. CONCLUSIONS: Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC.

Prognostic value of Ki67 in localized prostate carcinoma: a multi-institutional study of >1000 prostatectomies.

BACKGROUND: Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes. METHODS: After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up). RESULTS: In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03). CONCLUSIONS: In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.

Relationship between intra-abdominal pressure and vaginal wall movements during Valsalva in women with and without pelvic organ prolapse: technique development and early observations.

OBJECTIVES: To develop and test a method for measuring the relationship between the rise in intra-abdominal pressure and sagittal plane movements of the anterior and posterior vaginal walls during Valsalva in a pilot sample of women with and without prolapse. METHODS: Mid-sagittal MRI images were obtained during Valsalva while changes in intra-abdominal pressure were measured via a bladder catheter in 5 women with cystocele, 5 women with rectocele, and 5 controls. The regional compliance of the anterior and posterior vagina wall support systems were estimated from the ratio of displacement (mm) of equidistant points along the anterior and posterior vaginal walls to intra-abdominal pressure rise (mmHg). RESULTS: The compliance of both anterior and posterior vaginal wall support systems varied along different regions of vaginal wall for all three groups, with the highest compliance found near the vaginal apex and the lowest near the introitus. Women with cystocele had more compliant anterior and posterior vaginal wall support systems than women with rectocele. The movement direction differs between cystocele and rectocele. In cystocele, the anterior vaginal wall moves mostly toward the vaginal orifice in the upper vagina, but in a ventral direction in the lower vagina. In rectocele, the direction of the posterior vaginal wall movement is generally toward the vaginal orifice. CONCLUSIONS: Movement of the vaginal wall and compliance of its support is quantifiable and was found to vary along the length of the vagina. Compliance was greatest in the upper vagina of all groups. Women with cystocele demonstrated the most compliant vaginal wall support.

Caveolin-1 and a 29-kDa caveolin-associated protein are phosphorylated on tyrosine in cells expressing a temperature-sensitive v-Abl kinase.

Caveolin-1 was originally identified as a tyrosine-phosphorylated protein in v-Src-transformed cells and it was suggested that phosphorylation of this protein could mediate transformation by the tyrosine kinase class of oncogenes (J. R. Glenney, 1989, J. Biol. Chem. 264, 20163--20166). We found that caveolin-1 is also phosphorylated on tyrosine in v-Abl-transformed cells. In fact, caveolin-1 and a caveolin-associated protein of 29 kDa are among the strongest phosphotyrosine signals detected in the Abl-expressing cells. In addition, v-Abl shows a preferential phosphorylation of caveolin-1 and the 29-kDa caveolin-associated protein over other proteins in the caveolin-enriched Triton-resistant cell fraction. These data indicate that caveolin-1 and the 29-kDa caveolin-associated protein may be preferred substrates of the Abl kinase. Caveolin-1 is phosphorylated at tyrosine 14 in v-Abl-expressing cells as has been observed previously in v-Src-expressing cells. However, using a temperature-sensitive allele of v-Abl (ts120 v-Abl) we provide evidence that caveolin-1 phosphorylation is not sufficient to mediate the loss of caveolin expression or loss of cell adhesion induced by v-Abl.

Regulation of gene expression by glucose in Saccharomyces cerevisiae: a role for ADA2 and ADA3/NGG1.

When Saccharomyces cerevisiae cells are transferred from poor medium to fresh medium containing glucose, they rapidly increase the transcription of a large group of genes as they resume rapid growth and accelerate progress through the cell cycle. Among those genes induced by glucose is CLN3, encoding a G(1) cyclin that is thought to play a pivotal role in progression through Start. Deletion of CLN3 delays the increase in proliferation normally observed in response to glucose medium. ADA2 and ADA3/NGG1 are necessary for the rapid induction of CLN3 message levels in response to glucose. Loss of either ADA2 or ADA3/NGG1 also affects a large number of genes and inhibits the rapid global increase in transcription that occurs in response to glucose. Surprisingly, these effects are transitory, and expression of CLN3 and total poly(A)(+) RNA appear normal when ADA2 or ADA3/NGG1 deletion mutants are examined in log-phase growth. These results indicate a role for ADA2 and ADA3/NGG1 in allowing rapid transcriptional responses to environmental signals. Consistent with the role of the Ada proteins in positive regulation of CLN3, deletion of RPD3, encoding a histone deacetylase, prevented the down regulation of CLN3 mRNA in the absence of glucose.

Patient-centered measurement at an academic medical center.

BACKGROUND: Harborview Medical Center (Seattle, Wash) has collected patient data on operations since 1988 and has participated in the University HealthSystem Consortium's (UHC; Oak Brook, III) patient satisfaction measurement program since 1996. The patient feedback program is intended to provide data suitable for the quality improvement process and benchmark Harborview's performance against that of other academic medical centers (AMCs). USE OF PATIENT FEEDBACK AT HARBORVIEW: The Picker Institute Adult Inpatient survey's seven dimensions of care are used to disseminate the patient data and focus the action plans. The areas with the largest problem scores and the highest correlation with overall satisfaction are identified, and then specific actions are devised to address those areas. For example, patient satisfaction data collected in May 1997 led the quality council to highlight information and education as an area for improvement for both inpatients and outpatients. Patients reported that they often got answers they could not understand. Also, they did not always get enough information at discharge to feel comfortable about going home. A Discharge/Transition Center CQI (continuous quality improvement) team was charged with developing a discharge/transition process that ensures continuity of care for patients as they move throughout the system. In addition, a hospitalwide Patient and Family Information team has been working on improving information delivery by developing both patient-friendly processes and useful educational materials. FUTURE DIRECTIONS: Harborview will continue to gather feedback through not only more targeted, specific surveys but also focus groups, which have been conducted around specific issues such as diabetes care, clinical pathways, pain management, and teen health.

Directed hydroxyl radical probing of 16S rRNA in the ribosome: spatial proximity of RNA elements of the 3' and 5' domains.

We have shown previously that directed hydroxyl radical probing of 16S rRNA from Fe(II) tethered to specific sites within the RNA gives valuable information about RNA-RNA proximities in 70S ribosomes. Here, we extend that study and present probing data from nt 424 in 16S rRNA. To tether an Fe(II) to position 424 in the rRNA we created a specific discontinuity in the RNA by in vitro transcription of the RNA as two separate fragments corresponding to nt 1-423 and 424-1542. An Fe(II)-BABE was covalently attached to a 5'-guanosine-alpha-phosphorothioate at position 424 and 30S subunits were reconstituted from the two pieces of rRNA and the small subunit proteins. Reconstituted 30S subunits capable of associating with 50S subunits were selected by isolation of 70S ribosomes. Hydroxyl radicals, generated in situ from the tethered Fe(II), cleaved positions in the RNA backbone that were close in three-dimensional space to the Fe(II), and the sites of cleavage were identified using primer extension. Fe(II) tethered to position 424 induces cleavage around nt 424, 513, and 531 in the 5'-domain of 16S rRNA and around nt 1008, 1029, 1044, and 1208 in the 3'-domain of 16S ribosomal RNA. These data constrain the positions of the 420, 1015, 1030 and 1000/1040 helices, for which there is little structural information. Since the 5'- and 3'-domains of 16S rRNA constitute the body and head, respectively, of 30S subunits, these findings provide direct evidence for proximity of RNA elements in the body and head of 30S.

Directed hydroxyl radical probing of 16S ribosomal RNA in 70S ribosomes from internal positions of the RNA.

Directed hydroxyl radical probing of 16S ribosomal RNA from Fe(II) tethered to specific sites within the RNA was used to determine RNA-RNA proximities in 70S ribosomes. We have transcribed 16S ribosomal RNA in vitro as two separate fragments, covalently attached an Fe(II) probe to a 5'-guanosine-alpha-phosphorothioate at the junction between the two fragments, and reconstituted 30S subunits with the two separate pieces of RNA and the small subunit proteins. Reconstituted 30S subunits capable of association with 50S subunits were selected by isolation of 70S ribosomes. Hydroxyl radicals, generated in situ from the tethered Fe(II), cleaved sites in the 16S rRNA backbone that were close in three-dimensional space to the Fe(II), and a primer extension was used to identify these sites of cleavage. Two sets of 16S ribosomal RNA fragments, 1-360/361-1542 and 1-448/449-1542, were reconstituted into active 30S subunits. Fe(II) tethered to position 361 results in cleavage of 16S rRNA around nucleotides 34, 160, 497, 512, 520, 537, 552, and 615, as well as around positions 1410, 1422, 1480, and 1490. Fe(II) tethered to position 449 induces cleavage around nucleotide 488 and around positions 42 and 617. Fe(II) tethered to the 5' end of 16S rRNA induces cleavage of the rRNA around nucleotides 5, 601, 615, and 642. These results provide constraints for the positioning of these regions of 16S rRNA, for which there has previously been only limited structural information, within the 30S subunit.

Synthesis, structure-activity relationships, and pharmacological evaluation of a series of fluorinated 3-benzyl-5-indolecarboxamides: identification of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyl indol- 3-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide, a potent, orally active antagonist of leukotrienes D4 and E4.

The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), which has been chosen for clinical evaluation. This compound exhibited a Ki of 0.42 nM for displacement of [3H]LTD4 on guinea pig lung membranes, a pKB of 10.13 +/- 0.14 versus LTE4 on guinea pig trachea, and an oral ED50 of 1.14 mumol/kg opposite LTD4-induced bronchoconstriction in guinea pigs. The R enantiomer was found to be modestly more potent than the S enantiomer 38o. Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity. Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist. The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.

The Islamic Republic of Pakistan: country profile.

PIP: This discussion of Pakistan covers the following: regions and cities; the dominant Islamic sect; ethnicity and language; population growth; housing; households and families; the labor force; and information sources. Currently, Pakistan is in a period of transition. In 1985 Pakistan was ruled under martial law. On December 30, 1985, martial law was lifted, and a modified version of the 1973 constitution was adopted, restoring fundamental rights of Pakistanis and powers of the judiciary. Pakistan is divided into 4 provinces. The last census recorded the 1981 population at 84.3 million, nearly double the 1961 figure of 42.9 million. By 1983, the population had tripled to nearly 93 million, making Pakistan the world's 9th most populous country, although in area it ranked 34th. Its 3% annual growth rate placed it among the world's fastest growing countries. Although created as a sanctuary for followers of Islam, Pakistan suffers from periodic disputes between the members of Islam's various sects. Generally, ethnic groups and the use of their native languages divide along provincial boundaries. Punjabi, the native tongue of Pakistan's predominant group, is spoken in 48% of all Pakistani households and in about 80% of Punjab and Islamabad Federal Territory households. Pakistan's sixth 5-year plan recognizes the need for an additional 1.4 million dwellings to adequately house the current population. In 1980, Pakistan's 12.6 million housing units averaged nearly 7 people per unit. The ideal Pakistani household is an extended family consisting of a married couple, their sons, and their sons' wives and children. At the death of the patriarch, each son establishes a separate household. Marriage solidifes all social relationships. Single adults have little place in society. Women, although protected by law, often are deprived of their legal rights where marriage is concerned. Only 23% of the population aged 10 or older has completed primary school. Fewer than 1% hold university degree. Little hard data are available about Pakistan's labor force. In 1985, the economically active population was estimated at 28.6 million compared with 10.4 million in 1951. Unemployment rose from an estimated 3.1% in 1981 to 3.5% in 1983. The Pakistani economy is currently on the upswing.^ieng

Republic of Tunisia.

PIP: The north African country of Tunisia (632,387 square miles) consists largely of desert, with some rich farmlands and a rocky transitional zone. Despite the government's family planning efforts, the population grew from 5.6 million in 1975, to 7.2 million in 1985, and, with its 2.4% annual growth rate, is projected to reach 8.1 million by 1990. Tunisia's rural population decreased to 46% in 1985 as workers and their families moved into urban areas. 98% of the population is Arab-Berber; Arabic and French are the offical languages. The age-sex distribution is typical of developing countries; the median age has increased from 16.8 years in 1966 to 19.5 in 1950 and persons over age 60 have increased from 5.1% in 1956 to 6.7% in 1980. Tunisian families average 5.7 persons in rural areas, and 5.4 persons in urban one. Marriages are declining, polygamy is outlawed, and divorce, once easy, is more difficult and declining. At independence in 1956, only 15% of Tunisians were literate, now 85-90% of primary school age children are enrolled and literacy had risen to 53% in 1980. Women, once heavily veiled, now have full rights and access to education. More than 60 thousand new workers compete for the 40,000 new job openings each year. An estimated 7000 laborers found work in Europe in 1984. Women composed only 11% of the 1975 work force, but by 1980, held 20% of jobs, although they were mainly low paying positions. In 1980, 35% of the laborers worked in agriculture, 19% in industry, 17% in service industries, and 10% in construction. Agriculture and tourism have declined in recent years, contributing to social unrest, currency decline, and inflated wages and consumer prices.^ieng

Republic of Austria. Country profile.

PIP: A summary description of Austria's demographic situation, economic conditions, labor force characteristics, housing conditions, household characteristics, and marriage patterns is provided. Austria, the former center of the Hapsburg Empire, covers 32,375 square miles and is divided into 9 provinces, including Vienna, the federal capital. Austria's population increased from 6.9 million in 1950 to 7.6 million in 1980. Since 1980 it declined slightly and in 1985 it was estimated to be 7,487,000. Between 1961-81, the industrial, western region of the country grew more rapidly than the predominantly rural eastern section of the country. Vienna, the largest city in the country, experienced a decline in population size from 1.9 million to 1.5 million since 1923. Part of the decline was due to the annihilation of the city's Jewish population in 1938. Austria has a lower urban population (56%) than most other industrialized countries. This low rate reflects the availability of tourist related jobs in the rural areas. 98% of the population is Austrian, the official language is German, and most of the inhabitants are Roman Catholic. Due to the homogeneity of the population, the country has few religious and racial problems; however, a recent study indicated that about 1/2 of the population has anti-Semetic attitudes. Life expectancy is 69 years for men and 76 years for women. Austria's population is aging. Currently, 18% of the population is under 15 years of age, and 14% is 65 years of age or older. Births are expected to increase slightly until the end of the 1900s and then decline slightly. Austrians place a high value on children and family life. Between 1978-82 the marriage rate increased from 4.5/1000 to 4.8/1000, and the median age at marriage increased from 22.4-23.0 years for women and from 25.6-25.8 years for men. The number of divorces/year increased from 11,168-14.298 between 1976-82. Currently, there are 2,767,000 households, and the average household size is 2.6 persons. The proportion of single family member households increased in recent years. Most urban dwellers live in apartments, and 20% of the dwelling in Vienna are owned by the government. Education is stressed and students take their education seriously. 41% of all students in higher education in 1980 were female. Austria's labor force is well educated, and 30% are engaged in manufacturing; 20%, in commercial, social, and personal services, 175, in commerce and hotel services; and 10%, in the primary sector. Labor disputes are generally resolved by an unofficial coalition of representatives from industry, labor unions, and the government. Strikes rarely occur. Average earning are US$850/month. Imported labor was used to supplement a deficiency in the supply of labor in the 1960s and 1970s. Currently, few imported laborers are used, and the country has some unemployment. Austria was not seriously affected by the recent economic recession. In 1985 the gross domestic product is expected to increase by 3.0%, the country has a favorable trade balance, and the economic outlook for the country is good.^ieng

Federation of Malaysia. Country profile.

PIP: The 1984 population of Malaysia has been estimated at 14.7 million and the population growth rate averaged 2.3% in 1970-80. Population growth is officially encouraged to form a substantial home market for economic development. Toward this end, the 1985 budget has increased tax deductions for families with 5 children. The capital city of Kuala Lumpur is the largest metropolitan area (1 million population) and the Federal Territory is the most densely populated region. Immigration is strictly controlled by the government, and the percentage of foreign-born citizens was 5% in 1980. China, India, and Pakistan are decreasing in importance as countries of origin. Internal mobility, however, is increasing. Rural-rural migration accounted for 45% of internal migration in 1970-80 and was largely motivated by family reasons. Only 7% of Malaysians are estimated to move in search of work. Racial tensions led the government to grant special economic privileges to native-born Islamic Malays. The greatest proportion of the population is centered in the lowest age groups. The percentage of females 15-29 years of age rose from 26% in 1970 to 30% in 1980 and is expected to continue to rise. Fertility is on the decline. The majority of households in the country involve nuclear families. There has been an increase in the number of men and women who delay marriage or remain single. Education is widely available for children aged 6-15 years and those who meet certain academic standards receive free education up to age 19 years. The current labor force is estimated at 5.4 million, with an annual growth rate of 3.1%. Malaysia's per capita income (US $1860 in 1982) is among the highest in Southeast Asia and the gross national product increased by an average annual rate of 8% in 1970-81. The government plans to move toward the development of heavier industries and more manufacturing concerns.^ieng

Spain [is growing market, but family life is still conservative]. Country profile.

PIP: This discussion of Spain focuses on regions and cities, ethnicity and religion, age distribution, households and families, literacy and education labor force the economy, women, and sources of information. Spain, at one time a mainly agrarian society, is shifting towards a more industrialized civilization. Concurrent with industrialization is a migration of workers from rural to urban areas. Spain has an estimated 1984 population of 38,717,000 of which 77% reside in urban areas. Approximately 28% live in the 3 metropolitan cities of Madrid, Bilbao, and Barcelona. 10 years ago only 70% of the population lived in any urban area. Spain's annual population growth rate currently stands at 0.5%, a marked decrease from the 1.05% average annual growth rate between 1960-80. Compared with other major Western European countries, Spain is sparsely populated with an average of only 196 people per square mile. There are 4 major ethnic groups in Spain. The largest is Spanish, which accounts for 72.8% of the population. The gypsy population numbers approximately 200,000 and is a minority group that is not fully integrated into Spanish society. Open practice of all religions is now permitted in Spain, and Roman Catholicism is no longer sanctioned as the official religion of the country. Over 90% of the population report themselves as Roman Catholic. Spain has 1 of the youngest population in Europe with 41% of the population under age 24. 11% are age 65 years or older. The birth and death rates, 19.4 and 8.2/1000 respectively in 1974, declined to 13.0 and 7.0 in 1983. Life expectancy is 73 years. Families in Spain tend to be extended families. The average household often consists of 3 generations. Single person households are a rarity. The literacy rate, defined by the number of adults age 15 or older who can read and write, has risen sharply from 87% in 1974 to 97% in 1981. Spain has the highest jobless rate in Western Europe. At the end of May 1984 the unemployment rate was 20% in a work force of 13.2 million. From 1965-74 the Spanish economy achieved an unprecedented average annual growth rate of 7%, making it the 2nd fastest growing industrialized country in the world. Occupational barriers exist that restrict most women from meaningful employment in the Spanish work place.^ieng