bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-systemic metamorphosis in male millipede appendages: long delayed, reversible effect of an early localized positional marker?
Authors: Drago Leandro , Fusco Giuseppe , Minelli Alessandro
Published: April 2008

Background

The development of specialized appendages involved in sperm transfer in the males of julid millipedes is an extreme case of specialized, complex structures differentiating in a very advanced phase of post-embryonic development. Here, a non-systemic metamorphosis affects the external morphology and the internal anatomy of a trunk double segment only.

Presentation of the hypothesis

We hypothesize that during early (possibly embryonic) development a segmental marker is produced that remains unexploited throughout late embryonic and early post-embryonic development, until, activated by a systemic signal, it finally determines the release of a segmentally localized but anatomically major change.

Testing the hypothesis

Key to testing the hypothesis are (1) the identification of both the putative segmental marker involved in the localization of the legs to be eventually metamorphosed into gonopods and the systemic signal activating it, (2) the identification of the cell population from which the gonopods are built, and (3) a longitudinal study of the marker's expression throughout late embryonic and, possibly, post-embryonic development.

Implications of the hypothesis

Proving the validity of this hypothesis would demonstrate the existence of a cryptic developmental module that will be activated only months, or years, after it has been first laid down during early development. This study also opens a window onto the very poorly explored domain of late expression of developmental genes and molecular control of late developmental events.
A Computational Model for Sex-Specific Genetic Architecture of Complex Traits in Humans: Implications for Mapping Pain Sensitivity
Authors: Wang Chenguang , Cheng Yun , Liu Tian , Li Qin , Fillingim Roger B , Wallace Margaret R , Staud Roland , Kaplan Lee , Wu Rongling
Published: April 2008

Understanding differences in the genetic architecture of complex traits between the two sexes has significant implications for evolutionary studies and clinical diagnosis. However, our knowledge about sex-specific genetic architecture is limited largely because of a lack of analytical models that can detect and quantify the effects of sex on the complexity of quantitative genetic variation. Here, we derived a statistical model for mapping DNA sequence variants that contribute to sex-specific differences in allele frequencies, linkage disequilibria, and additive and dominance genetic effects due to haplotype diversity. This model allows a genome-wide search for functional haplotypes and the estimation and test of haplotype by sex interactions and sex-specific heritability. The model, validated by simulation studies, was used to detect sex-specific functional haplotypes that encode a pain sensitivity trait in humans. The model could have important implications for mapping complex trait genes and studying the detailed genetic architecture of sex-specific differences.
Low Circulating Insulin-Like Growth Factor I Bioactivity in Elderly Men Is Associated with Increased Mortality
Authors: Brugts M. P. , van den Beld A. W. , Hofland L. J. , van der Wansem K. , van Koetsveld P. M. , Frystyk J. , Lamberts S. W. J. , Janssen J. A. M. J. L.
Published: April 2008

Context: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I.

Objective: Our objective was to study IGF-I bioactivity in relation to human survival.

Design, Setting, and Study Participants: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73–94 yr).

Main Outcome Measures: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months).

Results: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group [hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2–2.8; P = 0.01] as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3–4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2–4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I.

Conclusion: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.
Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement
Authors: Biller B. M. K. , Grossman A. B. , Stewart P. M. , Melmed S. , Bertagna X. , Bertherat J. , Buchfelder M. , Colao A. , Hermus A. R. , Hofland L. J. , Klibanski A. , Lacroix A. , Lindsay J. R. , Newell-Price J. , Nieman L. K. , Petersenn S. , Sonino N. , Stalla G. K. , Swearingen B. , Vance M. L. , Wass J. A. H. , Boscaro M.
Published: April 2008

Objective: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing’s syndrome, because there is no recent consensus on the management of this rare disorder.

Participants: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing’s syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing’s disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing’s disease, and 5) management of ectopic ACTH syndrome, Nelson’s syndrome, and special patient populations.

Evidence: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.

Consensus Process: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.

Conclusions: ACTH-dependent Cushing’s syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing’s syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing’s disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing’s syndrome, early diagnosis and prompt therapy are warranted.
The Effect of Sports Injury on Insulin-Like Growth Factor-I and Type 3 Procollagen: Implications for Detection of Growth Hormone Abuse in Athletes
Authors: Erotokritou-Mulligan Ioulietta , Bassett E. Eryl , Bartlett Christiaan , Cowan David , McHugh Cathy , Seah Rick , Curtis Benjamin , Wells Victoria , Harrison Kate , Sönksen Peter H. , Holt Richard I. G. ,   The GH-2004 Group
Published: April 2008

Context: A method to detect exogenously administered growth hormone (GH) based on the measurement of two GH-dependent markers, IGF-I and type 3 procollagen (P-III-P) has been proposed. Skeletal or soft tissue injury may alter these markers. Elevations in either of these proteins after injury might lead to a false accusation of doping with GH.

Objective: The objective of the study was to assess the effect of musculoskeletal or soft tissue injury on IGF-I and P-III-P concentrations in amateur and elite athletes and assess the effect of injury on the proposed GH detection method.

Design: This was a longitudinal observational study after sporting injury.

Setting: The study was conducted at Southampton General Hospital and British Olympic Medical Centre.

Subjects: Subjects included elite and amateur athletes after an injury.

Intervention: Interventions included measurement of IGF-I and P-III-P and application of the GH-2000 discriminant function score up to 84 d after an injury as well as classification of injury by type and severity.

Outcome Measures: IGF-I and P-III-P concentration and ability to detect GH abuse in athletes without the risk of false accusation because of an injury were measured.

Results: There was no change in IGF-I concentration after an injury. By contrast, P-III-P concentrations rose by 41.1 ± 16.6%, reaching a peak around 14 d after an injury. The rise in P-III-P varied according to injury type and severity. This rise had a trivial effect on the GH-2000 discriminant function score, and no subject reached the threshold needed for a doping offense.

Conclusions: Although there was a rise in P-III-P after injury, this was insufficient to invalidate the GH-2000 detection method based on IGF-I and P-III-P concentrations.
Iodine Prophylaxis Using Iodized Salt and Risk of Maternal Thyroid Failure in Conditions of Mild Iodine Deficiency
Authors: Moleti Mariacarla , Lo Presti Vincenzo Pio , Campolo Maria Cristina , Mattina Filiberto , Galletti Marina , Mandolfino Mattia , Violi Maria Antonia , Giorgianni Grazia , De Domenico Demetrio , Trimarchi Francesco , Vermiglio Francesco
Published: April 2008

Context: Mild to moderate iodine deficiency during pregnancy can cause transient maternal hypothyroidism and impaired mental development of the progeny. These unfavorable effects are preventable by iodine supplementation. In Europe, however, less than 50% pregnant women receive iodine-containing supplements, thus representing dietary iodized salt the only carrier of iodine for most women in this life stage.

Objective/Design: This longitudinal study is aimed to investigate the effects of long-term iodized salt consumption on maternal thyroid function during gestation.

Participants/Outcome Measures: We prospectively evaluated thyroid function in 100 consecutive thyroperoxidase antibody-negative pregnant women from a mildly iodine-deficient area. Sixty-two women who had regularly used iodized salt for at least 2 yr prior to becoming pregnant and 38 who commenced iodized salt consumption upon becoming pregnant were classified as long-term (LT) and short-term (ST) iodine supplemented, respectively.

Results: Long-term iodized salt consumption resulted in a very low prevalence of maternal thyroid failure (MTF) in LT women. Conversely, short-term iodine prophylaxis does not seem to protect against the risk of MTF, the prevalence of which was almost 6-fold higher in ST than LT women (36.8% vs. 6.4%; χ2 14.7, P < 0.0005; relative risk 5.7, 95% confidence interval 2.03–16.08, P < 0.001). The relative risk reduction amounted to 82.5%, this measure indicating the extent to which long-term iodine prophylaxis using iodized salt would reduce the risk of MTF in ST women.

Conclusions: Prolonged iodized salt significantly improves maternal thyroid economy and reduces the risk of maternal thyroid insufficiency during gestation, probably because of a nearly restoring intrathyroidal iodine stores.
Aerobic Capacity and Growth Hormone Deficiency after Traumatic Brain Injury
Authors: Mossberg Kurt A. , Masel Brent E. , Gilkison Charles R. , Urban Randall J.
Published: April 2008

Context: GH deficiency occurs in approximately 20% of all individuals who suffer from a moderate to severe traumatic brain injury.

Objective: This study determined whether GH deficiency secondary to traumatic brain injury had an effect on aerobic capacity.

Design: Subjects were screened for GH deficiency by the glucagon stimulation test and performed a maximal treadmill exercise test.

Setting: Patients were studied in the postacute recovery phase after traumatic brain injury.

Participants: Thirty-five individuals were studied. Groups were formed as follows: normal GH axis, greater than 8 ng/ml response (n = 12); insufficient, GH 3–8 ng/ml response (n = 11); and deficient, less than 3 ng/ml response (n = 12).

Intervention: There was no intervention.

Main Outcome Measure: Aerobic capacity was assessed by measuring expired gases during a graded treadmill exercise test. One-way and two-way ANOVAs were carried out on all peak and submaximal cardiorespiratory variables, respectively. Appropriate post hoc comparisons followed as necessary.

Results: Significantly higher peak oxygen consumption was found in traumatic brain injury subjects with GH normal vs. GH insufficient and deficient [26.4 ± 6.9, 20.8 ± 4.6, and 19.7 ± 5.0, respectively (P < 0.05)]. Submaximal oxygen consumption was significantly higher in the GH normal group. All other variables were statistically similar.

Conclusions: This study shows that individuals with traumatic brain injury with normal GH secretion have below normal aerobic capacity and those patients who have GH insufficiency/deficiency are further deconditioned. Studies of GH replacement in these subjects should be conducted to assess whether GH therapy can improve cardiorespiratory fitness and prevent secondary disability.
The influence of dependence on data network models
Authors: D'Auria Bernardo , Resnick Sidney I.
Published: April 2008

Consider an infinite-source marked Poisson process to model end user inputs to a data network. At Poisson times, connections are initated. The connection is characterized by a triple (F,L,R) denoting the total quantity of transmitted data in a connection, the length or duration of the connection, and the transmission rate; the three quantities are related byF=LR. How critical is the dependence structure of the mark for network characteristics such as burstiness, distribution tails of cumulative input, and long-range dependence properties of traffic measured in consecutive time slots? In a previous publication (D'Auria and Resnick (2006)) we assumed thatFandRwere independent. Here we assume thatLandRare independent. The change in dependence assumptions means that the model properties change dramatically: tails of cumulative input per time slot are dramatically heavier, traffic cannot be approximated by a Gaussian distribution, and the decay of dependence cannot be measured in the traditional way using correlation functions. Different network applications are likely to have different mark dependence structure. We argue that the present independence assumption onLandRis likely to be appropriate for network applications such as streaming media or peer-to-peer networks. Our conclusion is that it is desirable to separate network traffic by application and to model each application with its own appropriate dependence structure.
On the number of jumps of random walks with a barrier
Authors: Iksanov Alex , Möhle Martin
Published: April 2008

LetS0:= 0 andSk:=ξ1+ ··· +ξkfork∈ ℕ := {1, 2, …}, where {ξk:k∈ ℕ} are independent copies of a random variableξwith values in ℕ and distributionpk:= P{ξ=k},k∈ ℕ. We interpret the random walk {Sk:k= 0, 1, 2, …} as a particle jumping to the right through integer positions. Fixn∈ ℕ and modify the process by requiring that the particle is bumped back to its current state each time a jump would bring the particle to a state larger than or equal ton. This constraint defines an increasing Markov chain {Rk(n):k= 0, 1, 2, …} which never reaches the staten. We call this process a random walk with barriern. LetMndenote the number of jumps of the random walk with barriern. This paper focuses on the asymptotics ofMnasntends to ∞. A key observation is that, underp1> 0, {Mn:n∈ ℕ} satisfies the distributional recursionM1= 0 andforn= 2, 3, …, whereInis independent ofM2, …,Mn−1with distribution P{In=k} =pk/ (p1+ ··· +pn−1),k∈ {1, …,n− 1}. Depending on the tail behavior of the distribution ofξ, several scalings forMnand corresponding limiting distributions come into play, including stable distributions and distributions of exponential integrals of subordinators. The methods used in this paper are mainly probabilistic. The key tool is to compare (couple) the number of jumps,Mn, with the first time,Nn, when the unrestricted random walk {Sk:k= 0, 1, …} reaches a state larger than or equal ton. The results are applied to derive the asymptotics of the number of collision events (that take place until there is just a single block) forβ(a,b)-coalescent processes with parameters 0 <a< 2 andb= 1.
Probabilistic Investigations on the Explosion of Solutions of the KAC Equation with Infinite Energy Initial Distribution
Authors: Carlen Eric , Gabetta Ester , Regazzini Eugenio
Published: April 2008

Gabetta and Regazzini (2006b) have shown that finiteness of the initial energy (second moment) is necessary and sufficient for the solution of the Kac's model Boltzmann equation to converge weakly (Cb-convergence) to a probability measure on R. Here, we complement this result by providing a detailed analysis of what does actually happen when the initial energy is infinite. In particular, we prove that such a solution converges vaguely (C0-convergence) to the zero measure (which is identically 0 on the Borel sets of R). More precisely, we prove that the total mass of the limiting distribution splits into two equal masses (of value ½ each), and we provide quantitative estimates on the rate at which such a phenomenon takes place. The methods employed in the proofs also apply in the context of sums of weighted independent and identically distributed random variables x̃1, x̃2, …, where these random variables have an infinite second moment and zero mean. Then, with Tn := ∑j=1ηnλj,nx̃j, with max1 ≤ j ≤ ηnλj,n → 0 (as n → +∞), and ∑j=1ηnλj,n2 = 1, n = 1, 2, …, the classical central limit theorem suggests that T should in some sense converge to a ‘normal random variable of infinite variance’. Again, in this setting we prove quantitative estimates on the rate at which the mass splits into adherent masses to -∞ and +∞, or to ∞, that are analogous to those we have obtained for the Kac equation. Although the setting in this case is quite classical, we have not uncovered any previous results of a similar type.
Pattern Markov Chains: Optimal Markov Chain Embedding Through Deterministic Finite Automata
Authors: Nuel Grégory
Published: April 2008

In the framework of patterns in random texts, the Markov chain embedding techniques consist of turning the occurrences of a pattern over an order-m Markov sequence into those of a subset of states into an order-1 Markov chain. In this paper we use the theory of language and automata to provide space-optimal Markov chain embedding using the new notion of pattern Markov chains (PMCs), and we give explicit constructive algorithms to build the PMC associated to any given pattern problem. The interest of PMCs is then illustrated through the exact computation of P-values whose complexity is discussed and compared to other classical asymptotic approximations. Finally, we consider two illustrative examples of highly degenerated pattern problems (structured motifs and PROSITE signatures), which further illustrate the usefulness of our approach.
Feasibility of a telemedicine ‘booth’ for supporting remote care in Scotland
Authors: Mair Fiona , Peterkin Gordon , Laing Angus , Ferguson James , Fraser Susan
Published: April 2008

Summary

Access to health care in remote settings is becoming increasingly difficult in Scotland. We have investigated the feasibility of a telemedicine ‘booth’. Two telemedicine booths were constructed for display at the Royal Highland Show in Edinburgh. One was equipped for patient use and one for the doctor. The booths contained videoconferencing and physiological monitoring equipment connected via an IP link at a bandwidth of 1.1 Mbit/s. The picture resolution was 4CIF (704 x 576 pixels). A total of 238 members of the public used the booth for a teleconsultation with a doctor. Ninety-three percent completed questionnaires. Of the 221 respondents, 75% saw the booth as an opportunity to access specialist advice; 84% felt that the booth would save them attending a hospital or clinic; 60% felt that it would improve the way they looked after their own health. The concept of a telemedicine booth appears both feasible and acceptable to the public.
Telemedicine via satellite to support offshore oil platforms
Authors: Mair Fiona , Fraser Susan , Ferguson James , Webster Karyn
Published: April 2008

Summary

On any one day, approximately 15,000–28,000 oil industry personnel are employed in the North Sea oil and gas industry. First aid in this remote environment is provided by non-medical staff on the rigs. Remote specialist advice via videoconferencing should improve the quality of offshore health care and reduce avoidable medical evacuations. Satellite communications and videoconferencing equipment was installed on the ‘Alwyn North’ oil platform, with medical advice provided via a call centre in Milan. Over a nine-month period, trial telemedicine links were conducted approximately twice per week. The three onshore physicians were very satisfied on each occasion with communications and diagnostic data image quality, including the ultrasound screening carried out by the rig provider. Remote specialist advice via videoconferencing should reduce unnecessary and/or untimely patient evacuation to hospital or onshore for medical assessment.
A five-year review of ground-to-air emergency medical advice
Authors: Urwin Alastair , Ferguson James , McDonald Roderick , Fraser Susan
Published: April 2008

Summary

We reviewed five years' experience of providing ground-to-air medical advice for commercial passenger aircraft. A total of 273 events occurred in-flight where further advice was sought. The most common age group resulting in calls were from those aged 21–30 years, who generated 38 calls (16%). The 273 cases included gastrointestinal conditions (26%), neurological (22%) and cardiovascular events (14%). Most incidents were managed conservatively in-flight with oxygen and/or other medications. Aircraft diversion occurred on 9% of occasions; cardiovascular and neurological emergencies were the major cause of this. Collaboration between aviation providers should be considered to develop a common database of in-flight emergencies so that contents of medical kits can be standardized in order to improve the quality of care in the air.
Valid Treatment Options for Osteoporosis and Osteopenia in HIV-Infected Persons
Authors: Clay Patrick G , Voss Laura E , Williams Charlott , Daume Eric C
Published: April 2008

Objective:

To review clinical data on bone ossification agents that may be considered for use in the treatment of osteoporosis and osteopenia in HIV-infected patients.

Data Sources:

A literature search was performed using MEDLINE (1950-January 2008), EMBASE, PubMed, and abstracts from major HIV conferences (February 2001-October 2007). These searches were limited to human data published in English and used the key words bisphosphonates, calcitonin, raloxifene. teriparatide, HAART, osteopenia, osteoporosis, and HIV/AIDS. Additional articles were retrieved from citations of selected references.

Study Selection and Data Extraction:

Relevant information on the pharmacology, pharmacokinetics, safety, and efficacy of available treatment with hormonal and nonhormonal agents was selected. Greater emphasis was placed on randomized clinical trials than on retrospective studies.

Data Synthesis:

Osteoporosis in HIV-infected persons is at least as prevalent as in postmenopausal women, yet this population is not listed in primary care guidelines as one that should be considered for screening. In addition to bisphosphonates, calcitonin, raloxifene, and teriparatide are used to treat bone disorders. Three clinical trials to date have evaluated the use of a bisphosphonate in HIV-infected persons. The trials showed a marked increase in bone mineral density in patients taking alendronate versus those in the control groups (with/without calcium, exercise, and/or vitamin D in 1 or both arms). Dosing restrictions complicate the use of these agents; diet, exercise, and calcium supplementation remain the foremost recommended strategies to prevent bone loss. The use of estrogen, testosterone, calcitonin, and teriparatide is less studied in HIV-positive patients, but may be considered in select cases. There are some investigational drugs and agents not available in the US; however, there are not enough data to support their use.

Conclusions:

Alendronate appears to be a promising treatment option for HIV-infected patients with osteoporosis and osteopenia. Further research is required to determine the safety and efficacy of other available drugs. Until additional information is provided, and with available knowledge on the metabolism profiles of antiretroviral and bone ossification agents, alendronate appears to be the preferred agent to use in this population.
Hyperventilation and Cerebrospinal Fluid Acidosis Caused by Topiramate
Authors: Montcriol Ambroise , Meaudre Eric , Kenane Nadia , Asencio Yves , Bordes Julien , Palmier Bruno
Published: April 2008

OBJECTIVE:

To report a case of hyperventilation caused by topiramate therapy and propose a pathophysiologic mechanism for this disorder.

CASE SUMMARY:

A 52-year-old woman with refractory seizure disorder was admitted to the burn care unit with burns over 10% of her body. Her seizure medications, unchanged and well tolerated for several months, included carbamazepine 1200 mg, lamotrigine 500 mg, phenobarbital 80 mg, and topiramate 150 mg per day. During hospitalization, despite a relatively normal arterial pH, the woman developed persistent hyperventilation, with respiratory rates up to 50 breaths/min. Alkalinization did not reduce the hyperventilation. Thoracic contrast-enhanced computed tomographic scan ruled out pulmonary embolism and persistent pneumonia. Salicylate and biguanide screening were negative; results of repeated thyroid and liver function tests were normal. Cerebral magnetic resonance imaging excluded a cerebral pathology. After cerebrospinal fluid (CSF) analysis showed acidosis (pH 7.14), topiramate was withdrawn and the patient's general condition rapidly improved. Forty-eight hours later, the CSF pH had increased to 7.26. The woman was discharged from the burn care unit on the 42nd hospital day.

DISCUSSION:

Hyperchloremic normal anion gap metabolic acidosis, which can lead to hyperventilation, has been reported as an adverse effect of topiramate treatment. However, our patient had respiratory alkalosis. Concurrent etiologies of peripheral hyperventilation were excluded, leaving central neurogenic hyperventilation as the remaining etiology. Such central neurogenic hyperventilation associated with topiramate has previously been reported in intensive care. Our case report demonstrates CSF acidosis. Withdrawing topiramate reduced both CSF acidosis and hyperventilation. The mechanism of topiramate-induced CSF acidosis remains unclear. According to the Naranjo probability scale, the relationship of hyperventilation to administration of topiramate in our patient was probable.

CONCLUSIONS:

Normal doses of topiramate may provoke central neurogenic hyperventilation, as a result of CSF acidosis. The acid–base status of critically ill patients receiving topiramate should be monitored carefully.
Comparison of Simvastatin Tablets from the US and International Markets Obtained via the Internet
Authors: Veronin Michael A , Nguyen Nga T
Published: April 2008

Background:

Convenient access to prescription drugs produced outside the US has been facilitated by the Internet. Of greatest concern to clinicians and policy-makers is product quality and patient safety. The Food and Drug Administration has issued warnings to potential buyers that the safety of drugs purchased through the Internet cannot be guaranteed and may present consumers with a health risk from substandard products.

Objective:

To determine whether generic simvastatin tablets and capsules obtained via the Internet from international markets are equivalent to the US innovator product regarding major aspects of pharmaceutical quality.

Methods:

Twenty simvastatin tablets and capsules were obtained for pharmaceutical analysis: 19 generic samples from international Internet pharmacy Web sites and the US innovator product. Tablet samples were tested according to US Pbarmacopeial (USP) guidelines where applicable, using high-performance liquid chromatography, disintegration, dissolution, weight variation, hardness, and assessment of physical characteristics. These tests are often used to detect formulation defects of drug products during the manufacturing process.

Results:

Several international samples analyzed were not comparable to the US product in one or more aspects of quality assurance testing, and significant variability was found among foreign-made tablets themselves. Five samples failed to meet USP standards for dissolution and 2 for content uniformity. Among all samples, variability was observed in hardness, weight, and physical characterization.

Conclusions:

Results suggest that manufacturing standards for the international generic drug products compared with the US innovator product are not equivalent with regard to quality attributes. These findings have implications for safety and effectiveness that should be considered by clinicians to potentially safeguard patients who choose to purchase foreign-manufactured drugs via the Internet.
The assignment of moral status: Age‐related differences in the use of three mental capacity criteria
Authors: Olthof Tjeert , Rieffe Carolien , Terwogt Mark Meerum , Lalay‐Cederburg Cindy , Reijntjes Albert , Hagenaar Janneke
Published: April 2008

This study examined children's and young adults' use of three mental capacity criteria for treating an entity as one to which moral subjects have moral obligations, that is, as having moral status. In line with philosophical theorizing, these criteria were the capacity to (1) perceive; (2) suffer; and (3) think. In this study, 116 respondents aged 9 to 18 years old gave moral judgments and guilt and shame attributions in response to stories about perpetrators whose behaviour negatively affected entities with different mental capacities. The moral judgments revealed that 9‐year‐old children assigned moral status primarily on the basis of the victimized entity's ability to suffer. Eleven‐year‐old children also used the ability to suffer, but they assigned additional moral status when the victimized entity was able to perceive. Young adults also used perception as a criterion, but they assigned additional moral status when the victimized entity was simultaneously able to suffer and able to think. When compared to their moral judgments, the moral emotion attributions of respondents of all age groups were more strongly affected by the victimized entity's ability to think.
Differential Expression of Decorin by Human Malignant and Benign Vascular Tumors
Authors: Salomäki Henriikka H. , Sainio Annele O. , Söderström Mirva , Pakkanen Sari , Laine Jukka , Järveläinen Hannu T.
Published: April 2008

An increasing amount of evidence indicates that a small extracellular chondroitin/dermatan sulfate proteoglycan, decorin, is indirectly involved in angiogenesis. Given that angiogenesis is a sine qua non for tumor growth and progression, we attempted to examine whether human malignant vascular tumors differ from human benign vascular tumors in terms of their decorin expression and synthesis. CD31 immunostaining demonstrated that the human malignant vascular tumors Kaposi's sarcoma and angiosarcoma were filled with capillary-like structures, whereas in benign cavernous and capillary hemangiomas, blood vessels were not as abundantly present. By utilizing in situ hybridization and immunocytochemical assays for decorin, we showed that there was no detectable decorin mRNA expression or immunoreactivity within the tumor mass in the Kaposi's sarcoma or angiosarcoma group. Instead, decorin was expressed in the connective tissue stroma lining the sarcoma tissue. In contrast to sarcomas, in hemangiomas, decorin mRNA expression and immunoreactivity were observed also within the tumor mass, particularly in the connective tissue stroma surrounding the clusters of intratumoral blood vessels. Finally, distribution of type I collagen was found to be similar to that of decorin in these tumor tissues. Our findings can be explained with different states of angiogenesis in dissimilar growths. In sarcomas, angiogenesis is extremely powerful, whereas in hemangiomas, angiogenesis has ceased. Thus, decorin is likely to possess a suppressive effect on human tumor angiogenesis in vivo, as previously described by studies using different experimental models. Decorin certainly provides a usable biomarker for distinguishing between benign and malignant vascular tumors in patients.
Keratinocyte Migration, Proliferation, and Differentiation in Chronic Ulcers From Patients With Diabetes and Normal Wounds
Authors: Usui Marcia L. , Mansbridge Jonathan N. , Carter William G. , Fujita Mayumi , Olerud John E.
Published: April 2008

Epithelialization of normal acute wounds occurs by an orderly series of events whereby keratinocytes migrate, proliferate, and differentiate to restore barrier function. The keratinocytes in the epidermis of chronic ulcers fail to execute this series of events. To better understand the epithelial dynamics of chronic ulcers, we used immunohistochemistry to evaluate proliferation, differentiation, adhesion, and migration in keratinocytes along the margin of chronic ulcers from patients with diabetes mellitus. We compared these features with keratinocytes from the migrating epithelial tongues of acute incisional and excisional wounds from normal volunteers. Keratinocytes at the chronic ulcer edge are highly proliferative (Ki67 proliferation marker), have an activated phenotype (K16), do not stain for keratins involved in epidermal differentiation (K10 and K2), and show a reduced expression of LM-3A32 (uncleaved, precursor of the α3 chain of laminin 5), a key molecule present on migrating epithelium. In contrast, keratinocytes in normal acute wound migrating epithelium do not express the proliferation marker Ki67 but do express K10, K2, and LM-3A32. A better understanding of molecular mechanisms involved in keratinocyte migration may lead to molecular targets for therapies for impaired wound healing.
Neural Measures of Individual Differences in Selecting and Tracking Multiple Moving Objects
Authors: Drew Trafton , Vogel Edward K.
Published: April 2008

Attention can be divided so that multiple objects can be tracked simultaneously as they move among distractors. Although attentional tracking is known to be highly limited, such that most individuals can track only approximately four objects simultaneously, the neurophysiological mechanisms that underlie this capacity limitation have not been established. Here, we provide electrophysiological measures in humans of the initial selection and sustained attention processes that facilitate attentional tracking. Each measure was modulated by the number of objects the subject was tracking and was highly sensitive to each individual's specific tracking capacity. Consequently, these measures provide strong neurophysiological predictors of an individual's attentional tracking capacity. Moreover, by manipulating the difficulty of these two phases of the task, we observe that the limiting factor underlying tracking capacity can flexibly shift between these two attentional mechanisms depending on the requirements of the task.
Intelligence and Variability in a Simple Timing Task Share Neural Substrates in the Prefrontal White Matter
Authors: Ullén Fredrik , Forsman Lea , Blom Örjan , Karabanov Anke , Madison Guy
Published: April 2008

General intelligence is correlated with the mean and variability of reaction time in elementary cognitive tasks, as well as with performance on temporal judgment and discrimination tasks. This suggests a link between the temporal accuracy of neural activity and intelligence. However, it has remained unclear whether this link reflects top-down mechanisms such as attentional control and cognitive strategies or basic neural properties that influence both abilities. Here, we investigated whether millisecond variability in a simple, automatic timing task, isochronous tapping, correlates with intellectual performance and, using voxel-based morphometry, whether these two tasks share neuroanatomical substrates. Stability of tapping and intelligence were correlated and related to regional volume in overlapping right prefrontal white matter regions. These results suggest a bottom-up explanation of the link between temporal stability and intellectual performance, in which more extensive prefrontal connectivity underlies individual differences in both variables.
Conical Electron Tomography of a Chemical Synapse: Polyhedral Cages Dock Vesicles to the Active Zone
Authors: Zampighi Guido A. , Fain Nick , Zampighi Lorenzo M. , Cantele Francesca , Lanzavecchia Salvatore , Wright Ernest M.
Published: April 2008

In this study, we tested the hypothesis that the structure of the active zone of chemical synapses has remained uncertain because of limitations of conventional electron microscopy. To resolve these limitations, we reconstructed chemical synapses of rat neocortex, the archetypical “average” synapse, by conical electron tomography, a method that exhibits an isotropic in plane resolution of ∼3 nm and eliminates the need to impose symmetry or use averaging methods to increase signal-to-noise ratios. Analysis of 17 reconstructions by semiautomatic density segmentation indicated that the active zone was constructed of a variable number of distinct “synaptic units” comprising a polyhedral cage and a corona of approximately seven vesicles. The polyhedral cages measured ∼60 nm in diameter, with a density of ∼44/μm2and were associated with vesicles at the active zone (“first tier”). Vesicles in this first-tier position represented ∼7.5% of the total number of vesicles in the terminal and were contiguous, hemifused (∼4% of total), or fully fused (∼0.5% of total) to the plasma membrane. Our study supports the hypothesis that rat neocortical synapses are constructed of variable numbers of distinct synaptic units that facilitate the docking of vesicles to the active zone and determine the number of vesicles available for immediate release.
Amyloid β Protein Dimer-Containing Human CSF Disrupts Synaptic Plasticity: Prevention by Systemic Passive Immunization
Authors: Klyubin Igor , Betts Vicki , Welzel Alfred T. , Blennow Kaj , Zetterberg Henrik , Wallin Anders , Lemere Cynthia A. , Cullen William K. , Peng Ying , Wisniewski Thomas , Selkoe Dennis J. , Anwyl Roger , Walsh Dominic M. , Rowan Michael J.
Published: April 2008

The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid β protein (Aβ) can be targeted in a similar manner to animal cell-derived or synthetic Aβ. Because the structure of Aβ depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Aβ species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreatedex vivohuman CSF that contains Aβ dimers rapidly inhibits hippocampal long-term potentiationin vivoand that acute systemic infusion of an anti-Aβ monoclonal antibody can prevent this disruption of synaptic plasticity. Aβ monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Aβ oligomers in early Alzheimer's disease.
Mitochondrial Dysfunction in SOD1G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants
Authors: Cassina Patricia , Cassina Adriana , Pehar Mariana , Castellanos Raquel , Gandelman Mandi , de León Andrés , Robinson Kristine M. , Mason Ronald P. , Beckman Joseph S. , Barbeito Luis , Radi Rafael
Published: April 2008

Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase-1 (SOD1) may contribute to motor neuron injury in ALS. Here, we provide evidence that mitochondrial dysfunction in SOD1G93Arat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from SOD1G93Arat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from SOD1G93Aastrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in SOD1G93Aastrocytes. Similar defects were found in mitochondria isolated from the spinal cord of SOD1G93Arats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrrolineN-oxide restored mitochondrial function, forming adducts with mitochondrial proteinsin vivo. As shown previously, SOD1G93Aastrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of SOD1G93Aastrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (∼10 nm) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in SOD1G93Aastrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.
Phosphatidylinositol 3-Kinase Is a Key Mediator of Central Sensitization in Painful Inflammatory Conditions
Authors: Pezet Sophie , Marchand Fabien , D'Mello Richard , Grist John , Clark Anna K. , Malcangio Marzia , Dickenson Anthony H. , Williams Robert J. , McMahon Stephen B.
Published: April 2008

Here, we show that phosphatidylinositol 3-kinase (PI3K) is a key player in the establishment of central sensitization, the spinal cord phenomenon associated with persistent afferent inputs and contributing to chronic pain states. We demonstrated electrophysiologically that PI3K is required for the full expression of spinal neuronal wind-up. In an inflammatory pain model, intrathecal administration of LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a potent PI3K inhibitor, dose-dependently inhibited pain-related behavior. This effect was correlated with a reduction of the phosphorylation of ERK (extracellular signal-regulated kinase) and CaMKII (calcium/calmodulin-dependent protein kinase II). In addition, we observed a significant decrease in the phosphorylation of the NMDA receptor subunit NR2B, decreased translocation to the plasma membrane of the GluR1 (glutamate receptor 1) AMPA receptor subunit in the spinal cord, and a reduction of evoked neuronal activity as measured using c-Fos immunohistochemistry. Our study suggests that PI3K is a major factor in the expression of central sensitization after noxious inflammatory stimuli.
Robos and Slits Control the Pathfinding and Targeting of Mouse Olfactory Sensory Axons
Authors: Nguyen-Ba-Charvet Kim T. , Di Meglio Thomas , Fouquet Coralie , Chédotal Alain
Published: April 2008

Odorants are detected by olfactory receptor neurons (ORNs) located in the olfactory epithelium. In mice, ORNs expressing the same odorant receptor (OR) project to a single glomerulus out of 1800 in the olfactory bulb (OB). It has been proposed that OR-derived cAMP signals guide ORN axons to their glomeruli rather than OR themselves. Recently, it has also been shown that the axon guidance molecule Slit1 and its receptor Robo2 control the dorsoventral segregation of ORN axons as they are projecting to the OB. We have analyzed the development of olfactory projections inSlit1/Slit2andRobo1/Robo2single and double mutants. We show that inRobo1−/−;Robo2−/−mice, most ORN axons fail to enter the OB and instead project caudally into the diencephalon. Moreover, in these mice, ORN axons expressing the same OR project to several glomeruli at ectopic positions. Thus, Slit1, Slit2, Robo1, and Robo2 cooperate to control the convergence of ORN axons to the OB and the precise targeting of ORN axons to specific glomeruli.
Kinetics and Mechanism of Oxidation of Benzoic Acid Hydrazide by Bromate Catalyzed by Anderson Type Hexamolybdochromate(III) in Aqueous Acidic Medium
Authors: Kadam S. D. , Supale A. R. , Gokavi G. S.
Published: April 2008

The reaction between benzoic acid hydrazide and potassium bromate catalyzed by Anderson type hexamolybdochromate(III) was carried out under pseudo-first-order condition keeping large excess of hydrazide concentration over that of the oxidant. The reaction is accelerated by the hydrogen ion concentration due to the involvement of the prior protonation equilibria of both catalyst and the hydrazide. The protonated forms of the catalyst and the substrate are the active species in the reaction. The initiation of the reaction occurs through oxidation of the catalyst H[CrMo6O24H6]2− to [O = CrVMo6O24H6]3− which then reacts with the hydrazide to give product without any intervention of free radical. The oxidized form of the catalyst [O = CrVMo6O24H6]3−was isolated and characterized by its FTIR spectra. The rate of the reaction also increases with increase in ionic strength and the decrease in the relative permittivity of the medium. Along with the effect of ionic strength and relative permittivity the activation parameters determined also support the mechanism. The detailed mechanism and the rate equation are proposed for the reaction.
Surface Analysis of Nanoscale Aluminium and Silicon Films Made by Electrodeposition in Ionic Liquids
Authors: Bebensee Fabian , Borissenko Natalia , Frerichs Martin , Höfft Oliver , Maus-Friedrichs Wolfgang , Abedin Sherif Zein El , Endres Frank
Published: April 2008

We present a spectroscopic and microscopic study of nanoscale Al and Si films electrodeposited in water- and air-stable ionic liquids. The choice of cations for such ionic liquids has previously been shown to have a significant effect on the crystallite size of electrodeposited Al or Si films. We found that the deposits are generally uniform, dense, metallic bright, and adherent with crystallite sizes in the nanometer range. The nanocrystalline films were characterized using X-ray Photoelectron Spectroscopy (XPS) and High-Resolution Scanning Electron Microscopy (HRSEM). The XPS results show that the surface of both films is oxidized although the deposition was done in an inert gas glove box. Furthermore our results suggest that as a consequence of oxygen attack the nanoparticles are composed of a metallic core surrounded by a thin oxidic shell. Our XPS study also shows that neither the cation nor the anion of the ionic liquid is entrapped in the deposit. Thus, electrodeposition in ionic liquids delivers pure materials.
Berlin Urban Spaces as Social Surfaces: Machine Aesthetics and Surface Texture
Authors: Wagner Monika
Published: April 2008

In the Berlin of the Weimar Republic, conflict raged not only over a new architecture corresponding to the optical culture but also over new forms of urban space. This essay, through a broad overview of the social spaces of Berlin, explores the tension between "artisanal" and "industrial" production and between collective and individual labor. It shows how different sociopolitical environments mobilized artisanal and industrial tropes and analyzes the ways in which they were construed iconographically.