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ABSTRACTElucidating factors that drive microhabitat selection in a species is important for informing the conservation management of the species. For species that use microhabitats as long-term refuge sites, selection pressures are likely to be strong because the microhabitat must fulfil their eco-physiological and life history requirements. Smaug giganteus(Sungazer) is a threatened (Vulnerable) cordylid lizard species in the highveld grasslands of South Africa – a key agricultural area in the country. Individuals dig burrows as refuges, which increases their sensitivity to habitat transformation. In addition, previous attempts to translocate populations have failed due to a lack of knowledge about their specific microhabitat requirements. We assessed microhabitat characteristics that may influence burrow site selection by measuring vegetation characteristics surrounding Sungazer burrows and comparing these to vegetation at randomly selected sites. We also recorded orientation, aspect, soil composition, and the presence of other animal dung. Sungazers selected sites with sparse vegetation cover, and where grass height was short, but had no preference for soil composition. There was no relationship between the presence of ungulate dung and the placement of Sungazer burrows. Most Sungazer burrows were orientated in a northerly direction on north-facing slopes, suggesting that burrow placement has thermoregulatory advantages. We recommend that to identify suitable sites for Sungazer translocations, landscapes are thoroughly surveyed with cognisance to the findings in this study, and that a soft-release translocation protocol follows to maximise translocation success.

Alzheimer disease (AD) is the most common contributor to dementia in the world, but strategies that slow or prevent its clinical progression have largely remained elusive, until recently. This Review highlights the latest advances in biomarker technologies and therapeutic development to improve AD diagnosis and treatment. We review recent results that enable pathological staging of AD with neuroimaging and fluid-based biomarkers, with a particular emphasis on the role of amyloid, tau and neuroinflammation in disease pathogenesis. We discuss the lessons learned from randomized controlled trials, including some supporting the proposal that certain anti-amyloid antibodies slow cognitive decline during the mildly symptomatic phase of AD. In addition, we highlight evidence for newly identified therapeutic targets that may be able to modify AD pathogenesis and progression. Collectively, these recent discoveries—and the research directions that they open—have the potential to move AD clinical care toward disease-modifying treatment strategies with maximal benefits for patients.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3rhad delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3ris enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

The article focuses on the decision of the Supreme Court of Canada in the Quebec (Attorney General) v. Canada (Attorney General) related to federal gun registry and the facilitating of the cooperative federalism and judicial review.

Background:Tubular retractors are FDA approved and in the Neurosurgical marketplace, but adaptation has been hampered by lack of evidence showing superiority over traditional retractors when performing subcortical surgery. This study examines brain injury associated with traditional brain retractors versus tubular retractors. Methods:Nine porcine models underwent a simulated neurosurgical operation. Retractors were inserted for four hours after which the porcine model was euthanized. The en-bloc extracted porcine brain was fixed in 10% formalin, paraffin embedded, sectioned at 4 um and stained with hematoxylin and eosin (H&E) using standard laboratory protocols. Computer algorithms were generated to calculate areas of cerebral edema and hemorrhage adjacent to retractor surfaces. Results:Using a two-tailed t-test with a significance level of 0.05, traditional brain retractors were associated with statistically significant greater areas of cerebral edema when compared to tubular retractors (17.36 um2vs. 12.42 um2; p = 0.0038). There was no statistically significant difference in mean areas of hemorrhage between traditional brain retractors and tubular retractors (3.43 um2vs 3.60 um2; p = 0.8297). Conclusions:Tubular retractors are associated with significantly less edema in surrounding brain than traditional retractors. On histopathological merits, this study supports the application of tubular retractors over traditional retractors.

The article reports the decision of the Canadian Supreme Court in the case 'Bank of Montreal v. Marcotte' in which the court held that that the credit card activities of banks are also subject to provincial consumer protection requirements.

Background: Tubular retractors are FDA approved and in the Neurosurgical marketplace, but adaptation has been hampered by lack of evidence showing superiority over traditional retractors when performing subcortical surgery. This study examines brain injury associated with traditional brain retractors versus tubular retractors. Methods: Nine porcine models underwent a simulated neurosurgical operation. Retractors were inserted for four hours after which the porcine model was euthanized. The en-bloc extracted porcine brain was fixed in 10% formalin, paraffin embedded, sectioned at 4 um and stained with hematoxylin and eosin (H&E) using standard laboratory protocols. Computer algorithms were generated to calculate areas of cerebral edema and hemorrhage adjacent to retractor surfaces. Results: Using a two-tailed t-test with a significance level of 0.05, traditional brain retractors were associated with statistically significantly greater cerebral edema when compared to tubular retractors (17.36 um2vs. 12.42 um2; p = 0.0038). There was no statistically significant difference in mean areas of hemorrhage between traditional brain retractors and tubular retractors noted (3.43 um2vs 3.60 um2; p = 0.8297). Conclusions: Tubular retractors are associated with significantly less edema in surrounding brain than traditional retractors. On histopathological merits, this study supports the application of tubular retractors over traditional retractors.

The prevalence of vasomotor symptoms (VMS) among women aged 45 years or older who report regular menses has not been described well. Variability by raceethnicity is expected.

Objective.To determine whether multidrug-resistant (MDR) gram-negative organisms are present in Afghanistan or Iraq soil samples, contaminate standard deployed hospital or modular operating rooms (ORs), or aerosolize during surgical procedures.Design.Active surveillance.Setting.US military hospitals in the United States, Afghanistan, and Iraq.Methods.Soil samples were collected from sites throughout Afghanistan and Iraq and analyzed for presence of MDR bacteria. Environmental sampling of selected newly established modular and deployed OR high-touch surfaces and equipment was performed to determine the presence of bacterial contamination. Gram-negative bacteria aerosolization during OR surgical procedures was determined by microbiological analysis of settle plate growth.Results.Subsurface soil sample isolates recovered in Afghanistan and Iraq included various pansusceptible members of Enterobacteriaceae, Vibriospecies, Pseudomonasspecies, Acinetobacter Iwojfii, and coagulase-negative Staphylococcus(CNS). OR contamination studies in Afghanistan revealed 1 surface with a Micrococcus luteus. Newly established US-based modular ORs and the colocated fixed-facility ORs revealed no gram-negative bacterial contamination prior to the opening of the modular OR and 5 weeks later. Bacterial aerosolization during surgery in a deployed fixed hospital revealed a mean gram-negative bacteria colony count of 12.8 colony-forming units (CFU)/dm2/h (standard deviation [SD], 17.0) during surgeries and 6.5 CFU/dm2/h (SD, 7.5; P= .14) when the OR was not in use.Conclusion.This study demonstrates no significant gram-negative bacilli colonization of modular and fixed-facility ORs or dirt and no significant aerosolization of these bacilli during surgical procedures. These results lend additional support to the role of nosocomial transmission of MDR pathogens or the colonization of the patient themselves prior to injury.

The increased incidence of sexually transmitted infections has historically been associated with military personnel at war. The incidence of gonorrhea and Chlamydia in personnel deployed in the current wars in Iraq and Afghanistan has not been reported. An electronic records' review of testing done from January 2004 to September 2009 revealed higher rates of Chlamydia than gonorrhea, especially among females who deploy to Iraq. Additionally, increasing Chlamydia rates were noted over the study. Overall, the rates of gonorrhea and Chlamydia were the same or lower than age- and year-matched U.S. rates reported by the Center for Disease Control and Prevention. Ongoing education with emphasis on prevention and treatment are needed, as are development of specific projects to define the risk factors and timing of acquisition of sexually transmitted infections in combat zones.

Methicillin-resistant Staphylococcus aureus (MRSA) in health-care settings results in life-threatening infections. We examined the incidence of MRSA at the combat support hospital located at the Ibn Sina Hospital in Baghdad, Iraq. We compiled isolate data from 2005 to 2009 characterizing antibiotic susceptibilities, annual trends, patient populations, infection sites, and hospital locations. Approximately 46.1% of S. aureus were MRSA, with increase in numbers of yearly isolates. MRSA was isolated in higher numbers from U.S. military personnel. Non-U.S. patient isolates displayed higher antibiotic susceptibility compared to U.S. military personnel isolates. Outpatient clinic, forward operating bases, and intermediate care ward 1 isolated the most MRSA. Common isolation sites were wound and skin cultures. Community-acquired MRSA was likely present in 291 out of 303 isolates based on antibiotic susceptibility. Our data suggests that most MRSA were community-acquired with limited nosocomial spread. We recommend increases in combat support hospital molecular lab capability to rapidly identify both MRSA categories.

Background.Multidrug-resistant (MDR) Acinetobacter baumanniiand Pseudomonas aeruginosahave emerged as the causes of nosocomial infections in critically ill patients.Objective.To characterize the incidence of these MDR bacteria over time in the military healthcare system, comparing isolates recovered from overseas combat casualties with isolates recovered from local military and civilian patients.Methods.Retrospective electronic records review of culture and/or susceptibility testing results of patients admitted to a military level I trauma center in San Antonio, Texas, during the period from January 2001 through December 2008. Multidrug resistance was defined as the first isolated organism resistant to 3 or more classes of antimicrobial agents.Results.Over time, the percentage of MDR A. baumanniiisolates increased from 4% to 55%, whereas the percentage of MDR P. aeruginosaisolates increased from 2% to 8%. Respiratory tract specimens had a higher percentage of MDR A. baumanniiisolates (49%), compared with specimens obtained from blood (30%), wound sites (24%), or urine (19%). No difference in the percentages of MDR P. aeruginosaisolates was observed with regard to source of specimen. The percentage of MDR A. baumanniiisolates recovered was higher among patients who had been deployed overseas (52%) than among local patients (20%). When isolates recovered from patients in the burn intensive care unit (53% of MDR A. baumanniiisolates) were removed from analysis, the percentage of MDR A. baumanniiisolates decreased from 38% to 30% while the percentage of MDR P. aeruginosaisolates remained unaffected.Conclusion.The percentage of MDR A. baumanniiisolates increased in this facility among combat casualties and among local patients, which indicates nosocomial transmission; however, there was no significant increase in the percentage of MDR P. aeruginosaisolates. Isolated changes in the MDR pathogens within a facility can occur. Possible interventions to limit the spread of these organisms could include implementing aggressive infection control practices, controlling antibiotic use, and using active culture surveillance.

Background.Multidrug-resistant (MDR) Acinetobacter baumanniiand Pseudomonas aeruginosahave emerged as the causes of nosocomial infections in critically ill patients.Objective.To characterize the incidence of these MDR bacteria over time in the military healthcare system, comparing isolates recovered from overseas combat casualties with isolates recovered from local military and civilian patients.Methods.Retrospective electronic records review of culture and/or susceptibility testing results of patients admitted to a military level I trauma center in San Antonio, Texas, during the period from January 2001 through December 2008. Multidrug resistance was defined as the first isolated organism resistant to 3 or more classes of antimicrobial agents.Results.Over time, the percentage of MDR A. baumanniiisolates increased from 4% to 55%, whereas the percentage of MDR P. aeruginosaisolates increased from 2% to 8%. Respiratory tract specimens had a higher percentage of MDR A. baumanniiisolates (49%), compared with specimens obtained from blood (30%), wound sites (24%), or urine (19%). No difference in the percentages of MDR P. aeruginosaisolates was observed with regard to source of specimen. The percentage of MDR A. baumanniiisolates recovered was higher among patients who had been deployed overseas (52%) than among local patients (20%). When isolates recovered from patients in the burn intensive care unit (53% of MDR A. baumanniiisolates) were removed from analysis, the percentage of MDR A. baumanniiisolates decreased from 38% to 30% while the percentage of MDR P. aeruginosaisolates remained unaffected.Conclusion.The percentage of MDR A. baumanniiisolates increased in this facility among combat casualties and among local patients, which indicates nosocomial transmission; however, there was no significant increase in the percentage of MDR P. aeruginosaisolates. Isolated changes in the MDR pathogens within a facility can occur. Possible interventions to limit the spread of these organisms could include implementing aggressive infection control practices, controlling antibiotic use, and using active culture surveillance.

Retrospective cohort.

U.S. combat casualties from Iraq and Afghanistan continue to develop infections with multidrug-resistant (MDR) bacteria. This study assesses the infection control database and clinical microbiology antibiograms at a single site from 2005 to 2007, a period when all Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) casualties admitted to the facility underwent initial isolation and screening for MDR pathogens. During this 3-year period, there were 2,242 OIF/OEF admissions: 560 in 2005, 724 in 2006, and 958 in 2007. The most commonly recovered pathogens from OIF/OEF admission screening cultures were methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae and Acinetobacter. The yearly nosocomial infection rate of these three pathogens among OIF/OEF admissions ranged between 2 and 4%. There were remarkable changes in resistance profiles for Acinetobacter, K. pneumoniae, and S. aureus over time. Despite aggressive infection control procedures, there is continued nosocomial transmission within the facility and increasing antimicrobial resistance in some pathogens. Novel techniques are needed to control the impact of MDR bacteria in medical facilities.

ABSTRACTFluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75· (BGA/26)1.739· (PNA/2)0.237· serum creatinine (SCRT)−4.896(when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75· (BGA/26)1.739· (PNA/2)0.237· serum creatinine (SCRT)–4.896(when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Synthetic routes to new C-B-N-containing mesophase materials from borazarene-type precursors have been explored. Such mesophases have the potential for forming C/BN alloys which could be processed in analogous ways to carbonaceous mesophases, e.g. into cokes, fibres and composites. Carbon-boron-nitrogen-based mesophase pitches have been generated at ambient pressure by pyrolysis of borazarenes in the presence of AlCl 3 . The AlCl 3 is essential for mesophase formation in these systems. Pyrolyses of 10-chloro-9-aza-10-boraphenanthrene and 2,2′-bis(dichloroborylamino)biphenyl have both yielded black, optically anisotropic pitches. These precursors form C/BN ceramic alloys which are turbostratic following heat treatment to 1000 °C. The alloys show a clear advantage in terms of their oxidation resistance, compared with that of carbon derived from naphthalene mesophase pitch, despite contamination with AlCl 3 , which probably catalyses their oxidation.

The authors tested the effects of the antiestrogenic agent tamoxifen on telomerase activity and cell proliferation in MCF-7 and MDA-MB-231 breast carcinoma cell lines. MCF-7 cells belong to a known estrogen receptor positive cell line, whereas MDA-MB-231 cells, previously thought to be estrogen receptor negative, are now shown to contain estrogen receptor-β. Both cell lines were grown in the presence of tamoxifen 10⁻⁶, 10⁻⁷, 10⁻⁸, and 10⁻⁹ M for 10 days. Cells in separate flasks were harvested daily for determination of total cell number, protein was extracted for determination of telomerase activity, and RNA was extracted for reverse transcriptase–polymerase chain reaction analysis to measure expression levels of the telomerase components (the RNA component and the catalytic subunit) and estrogen receptors. Total cell counts and telomerase activity levels of both cell lines with 10⁻⁸ M tamoxifen treatment were lower than control cells and other tamoxifen treatments. Changes in the expression of individual telomerase components correlated with telomerase activity. Estrogen receptor status did not correlate with telomerase activity. Tamoxifen strongly affected both cell count and telomerase activity within the 10⁻⁸ M concentration of both cell lines. Cells were able to overcome drug inhibition at all other doses after 4 days. Telomerase activity and cell proliferation were correlated in both cell lines and depended on drug concentration. Tamoxifen showed long term effects on cell proliferation of the MCF-7 cells. Cancer 1999;85:1523–9. © 1999 American Cancer Society.

Quantitative tools to assess vascular macromolecular distributions have been limited by low signal‐to‐noise ratios, reduced spatial resolution, postexperimental motion artifact, and the inability to provide multidimensional drug distribution profiles. Fluorescence microscopy offers the potential of identifying exogenous compounds within intact tissue by reducing autofluorescence, the process by which endogenous compounds emit energy at the same wavelength as fluorescent labels. A new technique combining fluorescence microscopy with digital postprocessing has been developed to address these limitations and is now described in detail. As a demonstration, histologic cross‐sections of calf carotid arteries that had been loaded endovas‐cularly with FITC‐Dextran (20 kD) ex vivo were imaged at two different locations of the electromagnetic spectrum, one exciting only autofluorescent structures and the other exciting both autofluorescent elements and exogenous fluorescent labels. The former image was used to estimate the autofluorescence in the latter. Subtraction of the estimated autofluorescence resulted in an autofluorescence‐corrected image. A standard curve, constructed from arteries that were incubated until equilibrium in different bulk phase concentrations of FITC‐Dextran, was used to convert fluorescent intensities to tissue concentrations. This resulted in a concentration map with spatial resolution superior to many of the previous methods used to quantify macromolecular distributions. The transvascular concentration profiles measured by quantitative fluorescence microscopy compared favorably with those generated from the proven en faceserial sectioning technique, validating the former. In addition, the fluorescence method demonstrated markedly increased spatial resolution. This new technique may well prove to be a valuable tool for elucidating the mechanisms of macromolecular transport, and for the rational design of drug delivery systems.

Quantitative tools to assess vascular macromolecular distributions have been limited by low signal-to-noise ratios, reduced spatial resolution, postexperimental motion artifact, and the inability to provide multidimensional drug distribution profiles. Fluorescence microscopy offers the potential of identifying exogenous compounds within intact tissue by reducing autofluorescence, the process by which endogenous compounds emit energy at the same wavelength as fluorescent labels. A new technique combining fluorescence microscopy with digital postprocessing has been developed to address these limitations and is now described in detail. As a demonstration, histologic cross-sections of calf carotid arteries that had been loaded endovas-cularly with FITC-Dextran (20 kD) ex vivo were imaged at two different locations of the electromagnetic spectrum, one exciting only autofluorescent structures and the other exciting both autofluorescent elements and exogenous fluorescent labels. The former image was used to estimate the autofluorescence in the latter. Subtraction of the estimated autofluorescence resulted in an autofluorescence-corrected image. A standard curve, constructed from arteries that were incubated until equilibrium in different bulk phase concentrations of FITC-Dextran, was used to convert fluorescent intensities to tissue concentrations. This resulted in a concentration map with spatial resolution superior to many of the previous methods used to quantify macromolecular distributions. The transvascular concentration profiles measured by quantitative fluorescence microscopy compared favorably with those generated from the proven en face serial sectioning technique, validating the former. In addition, the fluorescence method demonstrated markedly increased spatial resolution. This new technique may well prove to be a valuable tool for elucidating the mechanisms of macromolecular transport, and for the rational design of drug delivery systems.

It is well accepted that breasteeding contributes significantly to child survival and child nutrition. Healthful child spacing is associated with improved birth outcomes and maternal recovery. On a population basis, breastfeeding may contribute more to birth spacing than all family planning use combined in many countries. However, while breastfeeding does provide a period of infertility, until recently, there was no reliable way for an individual woman to capitalize on this lactational infertility for her own efficatious child spacing. The Lactational Amenorrhea Method (LAM) is a new introductory family planning method that simultaneously promotes child spacing and breastfeeding, with its optimal nutrition and disease preventive benefits for the infant. LAM, as it is called, is based on the utilization of lactational infertility for protection from pregnancy and indicates the time for the introduction of a complementary family planning method. LAM is recommended for up to six months postpartum for women who are fully or nearly fully breastfeeding and amenorrheic, and relies on the maintenance of appropriate brastfeeding practices to prolong lactational infertility, with the concomitant delay in menses return. A recent clinical trial confirmed the theoretical 98% or higher effectiveness of the method and field trials are demonstrating its aceptability. Nonetheless, some demographers and family planning organizations continue to debate its value. The development, efficacy, and sequelae of the method are presented using data from several studies by the authors.

Origin of the right pulmonary artery from the ascending aorta is a rare congenital malformation resulting in a large left-to-right shunt through the right lung at systemic pressure. We report the CT findings in an adult with this anomaly. Computed tomography was diagnostic. The patient is the sixth adult with this condition reported in the literature.

In three experiments we used control-system theory (CST) to predict the results of tracking tasks on which people held a handle to keep a cursor even with a target on a computer screen. 10 people completed a total of 104 replications of the task. In each experiment, there were two conditions: in one, only the handle affected the position of the cursor; in the other, a random disturbance also affected the cursor. From a person's performance during Condition 1, we derived constants used in the CST model to predict the results of Condition 2. In two experiments, predictions occurred a few minutes before Condition 2; in one experiment, the delay was 1 yr. During a 1-min. experimental run, the positions of handle and cursor, produced by the person, were each sampled 1800 times, once every 1/30 sec. During a modeling run, the model predicted the positions of the handle and target for each of the 1800 intervals sampled in the experimental run. In 104 replications, the mean correlation between predicted and actual positions of the handle was .996; SD= .002.

The telomere repeat amplification protocol (TRAP) was recently developed to detect telomerase activity in cellular protein extracts. Teleomerase synthesizes a specific repeating nucleotide sequence onto the ends of telomeres, which stabilize eukaryotic chromosomes. Telomeric repeats are identified in the TRAP method by polymerase chain reaction amplification and incorporation of radionucleotides detected by autoradiography. Several drawbacks to this method have been recognized, including the time required to complete the assay, the resolution of the results, and the hazards of radioactive material. We have developed a new fluorescent method of detecting telomerase to alleviate these problems. Telomeric repeats are identified in the fluorescent TRAP (F-TRAP) assay by incorporation of fluorescein-labeled primers during amplification and subsequent detection with an automated DNA sequencer. This new method appears to be as sensitive as the standard TRAP assay and offers advantages in speed, resolution, cost, and safety.

Macroinvertebrates were collected from riffles at 104 sites in upland Wales during April and July 1984. Species assemblages were ordinated by DECORANA, classified by TWINSPAN and related to stream chemistry and other environmental factors using correlation and multiple discriminant analysis. DECORANA axis 1 was most strongly correlated with pH and aluminium concentration whilst axis 2 correlated with stream gradient and flow. Four TWINSPAN site groups established in each season were also principally related to pH and aluminium concentration, and reflected overall taxon-richness; differences between groups were most apparent during spring, when catchment forest cover and taxon-richness were also related. A dichotomous key based on indicator species was established for each season with the coleopteran Hydraena gracilis Germar and the Ephemeroptera, including Baetis rhodani Pictet, important indicators at Level 1. We propose that these indicator systems may be used for the rapid detection and assessment of acid waters throughout Wales, and that the methodology is applicable generally.

Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.